Modulation of TRESK background K+ channel by membrane stretch

The two-pore domain K+ channel TRESK is expressed in dorsal root ganglion and trigeminal sensory neurons where it is a major contributor to background K+ current. TRESK acts as a break to prevent excessive sensory neuron activation and decreases in its expression or function have been involved in neuronal hyperexcitability after injury/inflammation, migraine or altered sensory perception (tingling, cooling and pungent burning sensations). All these effects have implicated this channel in nociception and mechanotransduction. To determine the role of TRESK in sensory transduction, we studied its sensitivity to changes in membrane tension (stretch) in heterologous systems, F-11 cells and trigeminal neurons. Laminar shear stress increased TRESK currents by 22-30%. An increase in membrane tension induced by cell swelling (hypotonic medium) produced a reversible elevation of TRESK currents (39.9%). In contrast, cell shrinkage (hypertonic solution) produced the opposite effect. Membrane crenators or cup-formers produced equivalent effects. In trigeminal sensory neurons, TRESK channels were mechanically stimulated by negative pressure, which led to a 1.51-fold increase in channel open probability. TRESK-like currents in trigeminal neurons were additively inhibited by arachidonic acid, acidic pH and hypertonic stimulation, conditions usually found after tissue inflammation. Our results show that TRESK is modulated by changes in cell membrane tension and/or cell volume. Several key players released during inflammation or tissue injury could modulate sensory neuron activation through small changes in membrane tension

Vacancies, disorder-induced smearing of the electronic structure, and its implications for the superconductivity of anti-perovskite MgC0.93_{0.93}Ni2.85_{2.85}

The anti-perovskite superconductor MgC$_{0.93}$Ni$_{2.85}$ was studied using high-resolution x-ray Compton scattering combined with electronic structure calculations. Compton scattering measurements were used to determine experimentally a Fermi surface that showed good agreement with that of our supercell calculations, establishing the presence of the predicted hole and electron Fermi surface sheets. Our calculations indicate that the Fermi surface is smeared by the disorder due to the presence of vacancies on the C and Ni sites, but does not drastically change shape. The 20\% reduction in the Fermi level density-of-states would lead to a significant ($\sim 70\%$) suppression of the superconducting $T_c$ for pair-forming electron-phonon coupling. However, we ascribe the observed much smaller $T_c$ reduction at our composition (compared to the stoichiometric compound) to the suppression of pair-breaking spin fluctuations.Comment: 11 pages, 3 figure

Anionic Phospholipids Bind to and Modulate the Activity of Human TRESK Background K+ Channel

The background K+ channel TRESK regulates sensory neuron excitability and changes in its function/expression contribute to neuronal hyperexcitability after injury/inflammation, making it an attractive therapeutic target for pain-related disorders. Factors that change the plasma membrane bilayer composition/properties (including volatile anesthetics, chloroform, chlorpromazine, shear stress and cell swelling/shrinkage) modify TRESK current but despite the importance of anionic phospholipids (e.g. PIP2) in the regulation of many ion channels, it remains unknown if membrane lipids affect TRESK function. We describe that both human and rat TRESK contain potential anionic phospholipid binding sites (apbs) in the large cytoplasmic loop, but only the human channel is able to bind to multilamellar vesicles (MLVs), enriched with anionic phospholipids, suggesting an electrostatically-mediated interaction. We mapped the apbs to a short stretch of 14 amino acids in the loop, located at the membrane-cytosol interface. Disruption of electrostatic lipid-TRESK interactions inhibited hTRESK currents, whilst subsequent application of Folch Fraction MLVs or a PIP2 analog activated hTRESK, an effect that was absent in the rat ortholog. Strikingly, channel activation by anionic phospholipids was conferred to rTRESK by replacing the equivalent rat sequence with the human apbs. Finally, stimulation of a Gq/11-linked GPCR reduced hTRESK current when Ca2+/calcineurin is blocked, while in physiological conditions, the Ca2+-mediated stimulation is prominent. This novel regulation of hTRESK by anionic phospholipids is a characteristic of the human channel that is not present in rodent orthologs. This must be considered when extrapolating results from animal models and may open the door to the development of novel channel modulators as analgesics

Reducing biting rates of Aedes aegypti with metofluthrin: investigations in time and space

Background: Indoor residual spraying is key to dengue control in Cairns and other parts of northern Queensland, Australia, where Aedes aegypti is prevalent, but the strategy faces challenges with regards to slow application time and, therefore, community coverage. A faster potential improvement might be the use of polyethylene netting impregnated with the volatile pyrethroid metofluthrin (SumiOne™). This formulation was assessed in rooms in three houses in Cairns, Australia. One emanator was placed in each room and cages of 10 female Aedes aegypti were exposed at distances of 1 and 3 m. Knockdown and landings on a human hand were counted before metofluthrin exposure and at 10, 30, 60, 90 and 120 min during exposure. In addition, two trials continued over 48 h of exposure to assess the long-term sublethal effects of metofluthrin on caged mosquitoes. Results: Percentage landing rates fell to 0-2.5% in the first 10 min of exposure. Knockdown was most evident between 10 and 30 min (54% at 1 m and 33% at 3 m). Distance from the emanator strongly affected the results: mosquitoes at 3 m exhibited less knockdown and more landings than those at 1 m. As room volume increased, knockdown decreased and the number of landing increased. There is a cumulative mortality and landing inhibition and, for mosquitoes exposed to metofluthrin for > 48 h, mortality was 100% at 1 m and 90% at 3 m. Of those still alive, a small number continued to land and bite. After being removed from metofluthrin-treated rooms, exposed insect cages were found to reducing landing rates for up to 2 h. Conclusions: Despite only moderate levels of knockdown during the initial hours of exposure, metofluthrin emanators were effective in reducing mosquito landing rates, especially within 1 m, even when exposed on an open veranda. The evaluation methods and results described in this paper will help inform the optimal conditions of deployment of metofluthrin emanators. These devices have the potential to reduce contact between humans and urban disease vectors faster than indoor residual spraying so supplement our current arsenal of dengue control tools

Magnetic frustration, short-range correlations and the role of the paramagnetic Fermi surface of PdCrO₂

Frustrated interactions exist throughout nature, with examples ranging from protein folding through to frustrated magnetic interactions. Whilst magnetic frustration is observed in numerous electrically insulating systems, in metals it is a rare phenomenon. The interplay of itinerant conduction electrons mediating interactions between localised magnetic moments with strong spin-orbit coupling is likely fundamental to these systems. Therefore, knowledge of the precise shape and topology of the Fermi surface is important in any explanation of the magnetic behaviour. PdCrO2, a frustrated metallic magnet, offers the opportunity to examine the relationship between magnetic frustration, short-range magnetic order and Fermi surface topology. By mapping the short-range order in reciprocal space and experimentally determining the electronic structure, we have identified the dual role played by the Cr electrons in which the itinerant ones on the nested paramagnetic Fermi surface mediate the frustrated magnetic interactions between local moments

Pyrethroids inhibit K2P channels and activate sensory neurons: basis of insecticide-induced paraesthesias

Pyrethroid insecticides are widely used for pest control in agriculture or in human public health commonly as a topical treatment for scabies and head lice. Exposure to pyrethroids such as permethrin or tetramethrin (TM) causes sensory alterations such as transient pain, burning, stinging sensations, and paraesthesias. Despite the well-known effects of pyrethroids on sodium channels, actions on other channels that control sensory neuron excitability are less studied. Given the role of 2-pore domain potassium (K2P) channels in modulating sensory neuron excitability and firing, both in physiological and pathological conditions, we examined the effect of pyrethroids on K2P channels mainly expressed in sensory neurons. Through electrophysiological and calcium imaging experiments, we show that a high percentage of TM-responding neurons were nociceptors, which were also activated by TRPA1 and/or TRPV1 agonists. This pyrethroid also activated and enhanced the excitability of peripheral saphenous nerve fibers. Pyrethroids produced a significant inhibition of native TRESK, TRAAK, TREK-1, and TREK-2 currents. Similar effects were found in transfected HEK293 cells. At the behavioral level, intradermal TM injection in the mouse paw produced nocifensive responses and caused mechanical allodynia, demonstrating that the effects seen on nociceptors in culture lead to pain-associated behaviors in vivo. In TRESK knockout mice, pain-associated behaviors elicited by TM were enhanced, providing further evidence for a role of this channel in preventing excessive neuronal activation. Our results indicate that inhibition of K2P channels facilitates sensory neuron activation and increases their excitability. These effects contribute to the generation of paraesthesias and pain after pyrethroid exposure

Transverse and longitudinal spin-fluctuations in INVAR Fe0.65Ni0.35

The presence of spin-fluctuations deep within the ordered state of ferromagnetic [Formula: see text] alloy [Formula: see text] has long been suspected but seldom directly observed. Inhomogeneities of one type or another have been cited as important in stabilizing [Formula: see text] behaviour-either longitudinal spin-fluctuations associated with the [Formula: see text]-state (local environment) model or transverse magnetisation arising from non-collinear spin structures. In this study we employ small-angle neutron scattering with neutron polarization analysis to distinguish between the two possibilities. Surprisingly we in fact find evidence of dominant but uncorrelated longitudinal spin-fluctuations coexisting with transverse magnetisation which exists in short-range clusters of size ~[Formula: see text]. This finding supports recent first principles calculations of [Formula: see text] in which both longitudinal spin-fluctuations and magnetic short-range order are identified as important ingredients in reproducing the equilibrium [Formula: see text] lattice

Towards Better Sharing of Cultural Heritage -- An Agenda for Copyright Reform

This paper is intended to act as a pillar and reference point for CC's advocacy work in copyright reform in the cultural heritage context, with a focus on issues arising in the digital environment. It may serve to support members of the CC community in their own advocacy efforts, guide policymakers in their legislative processes, and inform anyone interested in the policy issues gravitating around access and reuse of culture and cultural heritage. It will likely be adapted into a GLAM Guide for Policymakers and will be augmented with real-life examples, case studies and practical advice.It starts with an overview of copyright challenges to the legitimate activities of GLAMs, notably preservation (largely through digitization) and sharing of digital and digitized content images and data for access, use and reuse. It also notes copyright's chilling effects in the face of the GLAM sector's general risk aversion. The paper then offers insights towards effective copyright reform addressing those challenges, with a focus on the opportunities related to the digital environment. The proposals for reform aim to create legal certainty and international harmonization as well as to facilitate cross-border transactions.The paper encourages policymakers to recognize and support the pivotal roles of GLAMs in preserving and providing access to knowledge and culture to all members of society. It urges policymakers to engage with stakeholders to ensure there are clear, simple, and effective policies in place to support better sharing of cultural heritage in the public interest.The paper provides a high-level overview of the policy issues and, as a whole, it does not necessarily reflect the current situation in any specific jurisdiction.

Gravitational waves from asymmetric oscillon dynamics?

It has been recently suggested that oscillons produced in the early universe from certain asymmetric potentials continue to emit gravitational waves for a number of e-folds of expansion after their formation, leading to potentially detectable gravitational wave signals. We revisit this claim by conducting a convergence study using graphics processing unit (GPU)-accelerated lattice simulations and show that numerical errors accumulated with time are significant in low-resolution scenarios, or in scenarios where the run-time causes the resolution to drop below the relevant scales in the problem. Our study determines that the dominant, growing high frequency peak of the gravitational wave signals in the fiducial "hill-top model" in [arXiv:1607.01314] is a numerical artifact. This finding prompts the need for a more careful analysis of the numerical validity of other similar results related to gravitational waves from oscillon dynamics

Extreme Fermi surface smearing in a maximally disordered concentrated solid solution

We show that the Fermi surface can survive the presence of extreme compositional disorder in the equiatomic alloy Ni0.25Fe0.25Co0.25Cr0.25. Our high-resolution Compton scattering experiments reveal a Fermi surface which is smeared across a significant fraction of the Brillouin zone (up to 40% of 2π/a). The extent of this smearing and its variation on and between different sheets of the Fermi surface have been determined, and estimates of the electron mean free path and residual resistivity have been made by connecting this smearing with the coherence length of the quasiparticle states