Inhibition of Rac1 reduces store overload-induced calcium release and protects against ventricular arrhythmia

Rac1 is a small GTPase and plays key roles in multiple cellular processes including the production of reactive oxygen species (ROS). However, whether Rac1 activation during myocardial ischaemia and reperfusion (I/R) contributes to arrhythmogenesis is not fully understood. We aimed to study the effects of Rac1 inhibition on store overload-induced Ca2+ release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1f/f and cardiac-specific Rac1 knockdown (Rac1ckd) mice were subjected to myocardial I/R and their electrocardiograms (ECGs) were monitored for ventricular arrhythmia. Myocardial Rac1 activity was increased and ventricular arrhythmia was induced during I/R in Rac1f/f mice. Remarkably, I/R-induced ventricular arrhythmia was significantly decreased in Rac1ckd compared to Rac1f/f mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R-induced ventricular arrhythmia. Ca2+ imaging analysis showed that in response to a 6 mM external Ca2+ concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca2+ waves in Rac1f/f cardiomyocytes. Notably, SOICR was diminished by pharmacological and genetic inhibition of Rac1 in adult cardiomyocytes. Moreover, I/R-induced ROS production and ryanodine receptor 2 (RyR2) oxidation were significantly inhibited in the myocardium of Rac1ckd mice. We conclude that Rac1 activation induces ventricular arrhythmia during myocardial I/R. Inhibition of Rac1 suppresses SOICR and protects against ventricular arrhythmia. Blockade of Rac1 activation may represent a new paradigm for the treatment of cardiac arrhythmia in ischaemic heart disease

Seasonal and interannual variability in wind field and commercial catch rates of austroglossus pectoralis (soleidae)

The impact of deviations in the direction and strength of the wind field on the spatial, seasonal and interannual variability in catch rates of Agulhas sole Austroglossus pectoralis was investigated. Temporal variabilityin the wind cycle on the Agulhas Bank during the period 1981–1996 was deduced mainly from trends in the pressure gradient, measured from south of Cape Agulhas (35°S) to the region of westwind drift (40°S).Because interannual deviations in the catch rates differed between seasons, catch rates were assessed by season. Coastal catch rates of Agulhas sole between Cape Agulhas and Cape Infanta were high in autumn and winter, when offshore north-westerly winds prevailed, and low in spring and late summer, when onshore south-easterly winds dominated. There was often a secondary peak in catch rates in November–December,coincident with a midsummer change in the pressure gradient. Between the period 1982 and 1996, catch rates in autumn and early winter (April–July) were highest during years when the winter north-westerly winds were strongest (r2 = 0.62, p < 0.01). Catch rates usually peaked in May–June. This pattern changed in some years, depending on the timing and rate of change to winter wind conditions. Seasonal and interannual fluctuations in catch rate are associated with deviations in the wind field, but the  mechanism whereby this  effect is mediated remains unknown

S-Nitrosylation of STIM1 by Neuronal Nitric Oxide Synthase Inhibits Store-Operated Ca\u3csup\u3e2 +\u3c/sup\u3e Entry

Store-operated Ca2 + entry (SOCE) mediated by stromal interacting molecule-1 (STIM1) and Orai1 represents a major route of Ca2 + entry in mammalian cells and is initiated by STIM1 oligomerization in the endoplasmic or sarcoplasmic reticulum. However, the effects of nitric oxide (NO) on STIM1 function are unknown. Neuronal NO synthase is located in the sarcoplasmic reticulum of cardiomyocytes. Here, we show that STIM1 is susceptible to S-nitrosylation. Neuronal NO synthase deficiency or inhibition enhanced Ca2 + release-activated Ca2 + channel current (ICRAC) and SOCE in cardiomyocytes. Consistently, NO donor S-nitrosoglutathione inhibited STIM1 puncta formation and ICRAC in HEK293 cells, but this effect was absent in cells expressing the Cys49Ser/Cys56Ser STIM1 double mutant. Furthermore, NO donors caused Cys49- and Cys56-specific structural changes associated with reduced protein backbone mobility, increased thermal stability and suppressed Ca2+ depletion-dependent oligomerization of the luminal Ca2 +-sensing region of STIM1. Collectively, our data show that S-nitrosylation of STIM1 suppresses oligomerization via enhanced luminal domain stability and rigidity and inhibits SOCE in cardiomyocytes

The role of fiscal policy in Britain's Great Inflation

We investigate whether the Fiscal Theory of the Price Level (FTPL) can explain UK inflation in the 1970s. We confront the identification problem involved by setting up the FTPL as a structural model for the episode and pitting it against an alternative Orthodox model; the models have a reduced form that is common in form but, because each model is over-identified, numerically distinct. We use indirect inference to test which model could be generating the VECM approximation to the reduced form that we estimate on the data for the episode. Neither model is rejected, though the FTPL model substantially outperforms the Orthodox. But by far the best account of the period assumes that expectations were a probability-weighted combination of the two regimes. Fiscal policy has a substantial role in this weighted model in determining inflation. A similar model accounts for the 1980s but this role of fiscal policy is much diminished

Convergent Foraging Tactics of Marine Predators with Different Feeding Strategies across Heterogeneous Ocean Environments

Advances in satellite tracking and archival technologies now allow marine animal movements and behavior to be recorded at much finer temporal scales, providing a more detailed ecological understanding that can potentially be applicable to conservation and management strategies. Pelagic sharks are commercially exploited worldwide with current concerns that populations are declining, however, how pelagic sharks use exploited environments remains enigmatic for most species. Here we analyzed high-resolution dive depth profiles of two pelagic shark species with contrasting feeding strategies to investigate movement patterns in relation to environmental heterogeneity. Seven macropredatory blue (Prionace glauca) and six plankton-feeding basking (Cetorhinus maximus) sharks were tagged with pop-off satellite-linked archival tags in the North Atlantic Ocean to examine habitat use and investigate the function of dives. We grouped dives of both species into five major categories based on the two-dimensional dive profile shape. Each dive-shape class presented similar frequency and characteristics among the two species with U- and V-shaped dives predominating. We tested the spatial occurrence of different U- and V-shape dive parameters in response to environmental field gradients and found that mean depth and mean depth range decreased with increasing levels of primary productivity (chlorophyll “a”), whereas ascent velocities displayed a positive correlation. The results suggest that a planktivore and a macropredator responded behaviourally in similar ways to environmental heterogeneity. This indicates fine-scale dive profiles of shark species with different feeding strategies can be used to identify key marine habitats, such as foraging areas where sharks aggregate and which may represent target areas for conservation

Kinetics and Dynamics of the S(^1D_2) + H_2 \to SH + H Reaction at Very Low Temperatures and Collision Energies

We report combined studies on the prototypical S(^1D_2) + H2 insertion reaction. Kinetics and crossed-beam experiments are performed in experimental conditions approaching the cold energy regime, yielding absolute rate coefficients down to 5.8 K and relative integral cross sections to collision energies as low as 0.68 meV. They are supported by quantum calculations on a potential energy surface treating long range interactions accurately. All results are consistent and the excitation function behavior is explained in terms of the cumulative contribution of various partial waves

Pandemic Influenza: Risk of Multiple Introductions and the Need to Prepare for Them

Containing an emerging influenza H5N1 pandemic in its earliest stages may be feasible, but containing multiple introductions of a pandemic-capable strain would be more difficult. Mills and colleagues argue that multiple introductions are likely, especially if risk of a pandemic is high

Implications of Oil Prices Shocks for the Major Emerging Economies: A Comparative Analysis of BRICS

This study analyses the implications of oil prices shocks for the BRICS economies. We employed a time-varying structural vector autoregressive (TV-SVA) framework in which the sources of time variation are the coefficients and variance-covariance matrix of the innovations. The quarter frequency data for the period of 1987QII – 2017QII is used for the empirical analysis. The key findings suggest that there are substantial differences and asymmetries in the response of these economies to oil shocks. These differences were profound between, and even within, oil exporters and importers. It shows that between major oil exporters i.e. Russia and Brazil the former’s economy is rather more intensively influenced by oil prices shocks. Between the two largest net oil importers i.e. India and China, comparatively, the Indian economy seems to be rather more vulnerable to oil prices shocks in terms of their adverse effects on GDP, inflation and balance of trade. The dependence of economies on oil and an increasing level of consumption continue to pose policy challenges for prices and economic stability. The analysis on South Africa also shows negative impacts of oil prices shocks, however, the effects are comparatively more time-variant than other BRICS members. While these asymmetries indicate significant differences in the structure of these economies they also indicate venues of cooperation and stronger trading relationships to overcome the adverse shocks and mutual development

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4&lt;sup&gt;+&lt;/sup&gt; T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system &lt;i&gt;in&lt;/i&gt; &lt;i&gt;vivo&lt;/i&gt;. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation