Maurocalcine interacts with the cardiac ryanodine receptor without inducing channel modification

We have previously shown that MCa (maurocalcine), a toxin from the venom of the scorpion Maurus palmatus, binds to RyR1 (type 1 ryanodine receptor) and induces strong modifications of its gating behaviour. In the present study, we investigated the ability of MCa to bind to and modify the gating process of cardiac RyR2. By performing pull-down experiments we show that MCa interacts directly with RyR2 with an apparent affinity of 150 nM. By expressing different domains of RyR2 in vitro, we show that MCa binds to two domains of RyR2, which are homologous with those previously identified on RyR1. The effect of MCa binding to RyR2 was then evaluated by three different approaches: (i) [(3)H]ryanodine binding experiments, showing a very weak effect of MCa (up to 1 muM), (ii) Ca(2+) release measurements from cardiac sarcoplasmic reticulum vesicles, showing that MCa up to 1 muM is unable to induce Ca(2+) release, and (iii) single-channel recordings, showing that MCa has no effect on the open probability or on the RyR2 channel conductance level. Long-lasting opening events of RyR2 were observed in the presence of MCa only when the ionic current direction was opposite to the physiological direction, i.e. from the cytoplasmic face of RyR2 to its luminal face. Therefore, despite the conserved MCa binding ability of RyR1 and RyR2, functional studies show that, in contrast with what is observed with RyR1, MCa does not affect the gating properties of RyR2. These results highlight a different role of the MCa-binding domains in the gating process of RyR1 and RyR2.     

Statin therapy and stroke prevention: what was known, what is new and what is next?

PURPOSE OF REVIEW: Randomized trials have shown that statins may reduce the risk of primary stroke. There is no evidence however that statins can reduce recurrent stroke incidence. RECENT FINDINGS: In the SPARCL trial, patients with a recent stroke or transient ischemic attack randomized to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke, and a 35% reduction in major coronary events compared with placebo. This was obtained despite 25% of the placebo arm patients receiving a commercially-available statin outside of the trial. Post-hoc analysis used blinded LDL-cholesterol measurements as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-cholesterol (the group adherent to placebo or not taking a statin), the group with over 50% reduction in LDL-cholesterol had a significant 31% reduction in stroke. The next step is to define whether achieving LDL-cholesterol below 70 mg/dl is better than a standard dose of statin (LDL around 100-110 mg/dl) in the secondary prevention of stroke. SUMMARY: Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-cholesterol lowering.     

A bio-inspired flying robot sheds light on insect piloting abilities

When insects are flying forward, the image of the ground sweeps backward across their ventral viewfield and forms an "optic flow," which depends on both the groundspeed and the groundheight. To explain how these animals manage to avoid the ground by using this visual motion cue, we suggest that insect navigation hinges on a visual-feedback loop we have called the optic-flow regulator, which controls the vertical lift. To test this idea, we built a micro-helicopter equipped with an optic-flow regulator and a bio-inspired optic-flow sensor. This fly-by-sight micro-robot can perform exacting tasks such as take-off, level flight, and landing. Our control scheme accounts for many hitherto unexplained findings published during the last 70 years on insects' visually guided performances; for example, it accounts for the fact that honeybees descend in a headwind, land with a constant slope, and drown when travelling over mirror-smooth water. Our control scheme explains how insects manage to fly safely without any of the instruments used onboard aircraft to measure the groundheight, groundspeed, and descent speed. An optic-flow regulator is quite simple in terms of its neural implementation and just as appropriate for insects as it would be for aircraft.     

Cloning and molecular characterization of three arylamine N-acetyltransferase genes from Bacillus anthracis: identification of unusual enzymatic properties and their contribution to sulfamethoxazole resistance

The arylamine N-acetyltransferases (NATs) are xenobiotic-metabolizing enzymes that catalyze the N-acetylation of arylamines and their N-hydroxylated metabolites. These enzymes play a key role in detoxication of numerous drugs and xenobiotics. We report here the cloning, functional expression, and characterization of three new NAT genes (termed banatA, banatB, and banatC) from the pathogen Bacillus anthracis. The sequences of the corresponding proteins are approximately 30% identical with those of characterized eukaryotic and prokaryotic NAT enzymes, and the proteins were recognized by an anti-NAT antibody. The three genes were endogenously expressed in B. anthracis, and NAT activity was found in cell extracts. The three NAT homologues exhibited distinct structural and enzymatic properties, some of which have not previously been observed with other NAT enzymes. Recombinant BanatC displayed strong NAT activity toward several prototypic NAT substrates, including the sulfonamide antibiotic sulfamethoxazole (SMX). As opposed to BanatC, BanatB also had acetyl-CoA (AcCoA) and p-nitrophenyl acetate (PNPA) hydrolysis activity in the absence of arylamine substrates, indicating that it may act as an AcCoA hydrolase. BanatA was devoid of NAT or AcCoA/PNPA hydrolysis activities, suggesting that it may be a new bacterial NAT-like protein with unknown function. Expression of BanatC in Escherichia coli afforded higher-than-normal resistance to SMX in the recombinant bacteria, whereas an inactive mutant of the enzyme did not. These data indicate that BanatC could contribute to the resistance of B. anthracis to SMX.     

New movements in neurofilament transport, turnover and disease

Revealing the mechanisms by which neurofilament transport and turnover are regulated has proven difficult over the years but recent studies have given new insight into these processes. Mature neurofilament fibers may incorporate a fourth functional subunit, alpha-internexin, as new evidence suggests. Recent findings have made the role of phosphorylation in regulating neurofilament transport velocity controversial. Kinesin and dynein may transport neurofilaments in slow axonal transport as they have been found to associate with neurofilaments. Neurofilament transport and turnover rates may be reduced depending on the existing stationary neurofilament network. Finally, mutations in neurofilament light that have been linked to Charcot-Marie-Tooth disease as well as other neurofilament abnormalities in human disease are discussed.     

Anisotropic Material Properties of Wild-Type and Tectb−/− Tectorial Membranes

The tectorial membrane (TM) is an extracellular matrix that is directly coupled with the mechanoelectrical receptors responsible for sensory transduction and amplification. As such, the TM is often hypothesized to play a key role in the remarkable sensory abilities of the mammalian cochlea. Genetic studies targeting TM proteins have shown that changes in TM structure dramatically affect cochlear function in mice. Precise information about the mechanical properties of the TMs of wild-type and mutant mice at audio frequencies is required to elucidate the role of the TM and to understand how these genetic mutations affect cochlear mechanics. In this study, images of isolated TM segments are used to determine both the radial and longitudinal motions of the TM in response to a harmonic radial excitation. The resulting longitudinally propagating radial displacement and highly spatially dependent longitudinal displacement are modeled using finite-element models that take into account the anisotropy and finite dimensions of TMs. An automated, least-square fitting algorithm is used to find the anisotropic material properties of wild-type and Tectb^?/? mice at audio frequencies. Within the auditory frequency range, it is found that the TM is a highly viscoelastic and anisotropic structure with significantly higher stiffness in the direction of the collagen fibers. Although no decrease in the stiffness in the fiber direction is observed, the stiffness of the TM in shear and in the transverse direction is found to be significantly reduced in Tectb^?/? mice. As a result, TMs of the mutant mice tend to be significantly more anisotropic within the frequency range examined in this study. The effects of the Tectb^?/? mutation on the TM’s anisotropic material properties may be responsible for the changes in cochlear tuning and sensitivity that have been previously reported for these mice.     

Non‐resource effects of foundation species on meta‐ecosystem stability and function

Ecosystems such as forests and mussel beds, that are driven by foundation species can be characterized by the slow accumulation of matter that affect their structural stability. This non‐resource effect of matter on ecosystems can lead to disturbances and to pulsed release and transport of matter over regional scales. However, non‐resource effects of endogenous pulses of matter on meta‐ecosystem stability and function remain largely unknown. Using a two‐patch meta‐ecosystem model of mussel bed dynamics, we show that non‐resource effects of matter on the structural stability of mussel beds promote pulsed releases of matter and fluctuations in population abundance. These pulsed fluctuations explain the maintenance of meta‐ecosystem heterogeneity in the distribution of abundance and matter through out‐of‐phase synchrony and asynchrony over a broad range of connectivity. These regimes of spatial (a)synchrony explain a tradeoff between the regional retention of matter (ecosystem function) and metapopulation persistence. These results reveal how foundation species can cause local and catastrophic changes that can promote regional asynchrony and stability, even under strong connectivity.     

Local predation risk and matrix permeability interact to shape movement strategy

In fragmented landscapes, the reduced connectivity among patches drives the evolution of movement strategies through an increase of transience costs. Reduced movements may further alter heterogeneity in biotic and abiotic conditions experienced by individuals. The joint action of local conditions and matrix permeability may shape emigration decisions. Here, we tested the interactive effects of predation risk and matrix permeability on movement propensity, movement costs and movers’ phenotype in the common toad Bufo bufo. In a full‐crossed experimental design, we assessed the movement propensity of juveniles in three connectivity treatments (from poorly to highly permeable matrix), with or without predation risk in their living patch. We also assessed the relationships between movement propensity and morphological traits (i.e. body and leg length) and how it affected the movement cost (i.e. mass loss). Movement propensity increased in presence of predation risk, while matrix permeability had no effect. However, matrix permeability interacted with predation risk to influence movers’ phenotype and the physiological cost they endured while moving. In particular, a well‐known movement syndrome in toads (i.e. movement propensity positively related to longer legs) depended on the interaction between matrix permeability and predation risk and resulted in differences in mass loss among matrix types. Movers lost more mass on average than residents except when they also displayed longer legs or when they crossed the most permeable matrix in the presence of predation risk. Our results show that matrix permeability shapes the physiological cost of dispersal by changing the identity of individuals moving away from local conditions. As the movers’ phenotype can importantly alter (meta)population dynamics, context‐dependency of dispersal syndromes should be considered in studies predicting the functioning of human‐altered natural systems.     

The Spatial Heterogeneity of Vegetation,Hydrology and Water Chemistry in a Peatland with Open-Water Pools

Ecosystems - Ombrotrophic bogs can comprise a mosaic of vegetation patches and open-water pools, with hydrological and biogeochemical connections between pools and the surrounding peat and...     

Imbalance of peripheral follicular helper T lymphocyte subsets in active vitiligo

Vitiligo is an autoimmune disease characterized by the presence of several autoantibodies, some of which are directed against melanocyte components and have been shown to be associated with the progression of the disease. However, the mechanism involved in the production of autoantibodies remains unclear. Follicular helper CD4⁺ T cells (TFH) are specialized in B‐cell activation and antibody production, especially the TFH cell subsets type 2 and type 17. To date, TFH cell subsets have not been studied in human vitiligo. This study in 44 vitiligo patients and 19 healthy controls showed an increase in circulating TFH cells associated with disease clinical progression. A more precise analysis of TFH cell phenotype demonstrated that vitiligo is characterized by populations of peripheral TFH cells responsible for helping B‐cell function, such as TFH type 2 and type 17 which produce Th2‐ and TH17‐related cytokines, respectively. These findings suggest a new mechanism involving TFH cell subsets in the pathogenesis of human vitiligo and leading to the production of autoantibodies and disease.