Activation of TRPA1 by membrane permeable local anesthetics

<p>Abstract</p> <p>Background</p> <p>Low concentrations of local anesthetics (LAs) suppress cellular excitability by inhibiting voltage-gated Na⁺channels. In contrast, LAs at high concentrations can be excitatory and neurotoxic. We recently demonstrated that LA-evoked activation of sensory neurons is mediated by the capsaicin receptor TRPV1, and, to a lesser extent by the irritant receptor TRPA1. LA-induced activation and sensitization of TRPV1 involves a domain that is similar, but not identical to the vanilloid-binding domain. Additionally, activation of TRPV1 by LAs involves PLC and PI(4,5)P₂-signalling. In the present study we aimed to characterize essential structural determinants for LA-evoked activation of TRPA1.</p> <p>Results</p> <p>Recombinant rodent and human TRPA1 were expressed in HEK293t cells and investigated by means of whole-cell patch clamp recordings. The LA lidocaine activates TRPA1 in a concentration-dependent manner. The membrane impermeable lidocaine-derivative QX-314 is inactive when applied extracellularly. Lidocaine-activated TRPA1-currents are blocked by the TRPA1-antagonist HC-030031. Lidocaine is also an inhibitor of TRPA1, an effect that is more obvious in rodent than in human TRPA1. This species-specific difference is linked to the pore region (transmembrane domain 5 and 6) as described for activation of TRPA1 by menthol. Unlike menthol-sensitivity however, lidocaine-sensitivity is not similarly determined by serine- and threonine-residues within TM5. Instead, intracellular cysteine residues known to be covalently bound by reactive TRPA1-agonists seem to mediate activation of TRPA1 by LAs.</p> <p>Conclusions</p> <p>The structural determinants involved in activation of TRPA1 by LAs are disparate from those involved in activation by menthol or those involved in activation of TRPV1 by LAs.</p

Invasion is Contingent on Species Assemblage and Invasive Species Identity inExperimental Rehabilitation Plots

Ecological studies often suggest that diverse communities are most resistant to invasion by exotic plants, but relatively few local species may be available to a rehabilitation practitioner. We examine the ability of monocultures and diverse assemblages to resist invasion by an exotic annual grass (cheatgrass) and an exotic biennial forb (dyer’s woad) in experimental rehabilitation plots. We constructed seven assemblages that included three monocultures of grass, forb, or shrub; three four-species mixtures of grasses, forbs, or shrubs; and a three-species mixture of one species from each growth form in an experimental field setting to test resistance to invasion. Assemblages were seeded with cheatgrass and dyer’s woad for two consecutive years and quantified as biomass and density of individuals from each exotic species. Soil NO3 and leaf-area index were examined as predictors of invasive plant abundance. Cheatgrass invasion was greatest in forb and shrub assemblages, and least in mixed grass or grass monoculture; dyer’s woad invasion was greatest into mixed grass or grass monoculture, but least into monoculture or mixedspecies assemblages composed of forbs or shrubs. The community composed of grasses, forbs, and shrubs suppressed invasion by both species. Consequently, assemblages were most resistant to invasion by species of the same growth form. Moreover, these monocultures and mixtures were generally similar in conferring resistance to invasion, but a monoculture of big sagebrush was more resistant than a mixture of shrubs. Soil NO3 was correlated with invasion by cheatgrass, whereas LAI was correlated with invasion by dyer’s woad, suggesting these species were more limited by belowground and aboveground resources, respectively. Overall, increasing diversity with limited species did not necessarily enhance resistance to invasion

Snowier Winters Extend Autumn Availability of High-quality Forage for Caribou in Arctic Alaska

Caribou (Rangifer tarandus) rely on the short Arctic growing season to restore body condition, support the demands of lactation, and prepare for the long arctic winter, making them susceptible to even small changes in forage availability or quality. Body condition in the summer and autumn is linked to winter survival rates and fecundity in cows, critical factors in the productivity of caribou populations. Climate change predictions of warmer and wetter northern winters suggest increased snowfall over Alaska’s North Slope, which has recently been verified between 1995 and 2017. However, a comprehensive analysis of how deeper snow will affect caribou forage quality is absent across Alaska. In this study, we quantify how snow depth alters the quality and seasonality of caribou forage using a long-term (24 yr) International Tundra Experiment snow depth manipulation to evaluate how winter climate change scenarios may affect tussock tundra systems in northern Alaska. Deeper snow in prior winters leads to increases in growing season leaf N and digestible protein (DP) in deciduous shrubs (and Betula spp.) and graminoids (Carex spp. and Eriophorum spp.), but not evergreen dwarf shrubs (Rhododendron spp. and Vaccinium spp.). Dry matter digestibility varied among species with small differences (\u3c5%) associated with snow depth. Most striking was the discovery that deeper snow in the prior winter increased the duration of DP levels above the minimum threshold for protein gain in caribou by as much as 25 d in Salix pulchra and 6–9 d in Betula nana and Carex bigelowii in late summer and early autumn. Consequently, deeper winter snow may provide an extended window of opportunity for foraging and the accumulation of lean body mass and fat reserves which promote winter survival and successful calving the following spring and potentially improve the productivity of caribou in northern Alaska

Solution of generalized fractional reaction-diffusion equations

This paper deals with the investigation of a closed form solution of a generalized fractional reaction-diffusion equation. The solution of the proposed problem is developed in a compact form in terms of the H-function by the application of direct and inverse Laplace and Fourier transforms. Fractional order moments and the asymptotic expansion of the solution are also obtained.Comment: LaTeX, 18 pages, corrected typo

Fractional reaction-diffusion equations

In a series of papers, Saxena, Mathai, and Haubold (2002, 2004a, 2004b) derived solutions of a number of fractional kinetic equations in terms of generalized Mittag-Leffler functions which provide the extension of the work of Haubold and Mathai (1995, 2000). The subject of the present paper is to investigate the solution of a fractional reaction-diffusion equation. The results derived are of general nature and include the results reported earlier by many authors, notably by Jespersen, Metzler, and Fogedby (1999) for anomalous diffusion and del-Castillo-Negrete, Carreras, and Lynch (2003) for reaction-diffusion systems with L\'evy flights. The solution has been developed in terms of the H-function in a compact form with the help of Laplace and Fourier transforms. Most of the results obtained are in a form suitable for numerical computation.Comment: LaTeX, 17 pages, corrected typo

Exceptional Laguerre and Jacobi polynomials and the corresponding potentials through Darboux-Crum Transformations

Simple derivation is presented of the four families of infinitely many shape invariant Hamiltonians corresponding to the exceptional Laguerre and Jacobi polynomials. Darboux-Crum transformations are applied to connect the well-known shape invariant Hamiltonians of the radial oscillator and the Darboux-P\"oschl-Teller potential to the shape invariant potentials of Odake-Sasaki. Dutta and Roy derived the two lowest members of the exceptional Laguerre polynomials by this method. The method is expanded to its full generality and many other ramifications, including the aspects of generalised Bochner problem and the bispectral property of the exceptional orthogonal polynomials, are discussed.Comment: LaTeX2e with amsmath, amssymb, amscd 26 pages, no figure

An open-access endoscopy screen correctly and safely identifies patients for conscious sedation

Background and aims: Open-access scheduling is highly utilized for facilitating generally low-risk endoscopies. Preprocedural screening addresses sedation requirements; however, procedural safety may be compromised if screening is inaccurate. We sought to determine the reliability of our open-access scheduling system for appropriate use of conscious sedation. Methods: We prospectively and consecutively enrolled outpatient procedures booked at an academic center by open-access using screening after in-office gastroenterology (GI) consultation. We collected the cases inappropriately booked for conscious sedation and compared the characteristics for significant differences. Results: A total of 8063 outpatients were scheduled for procedures with conscious sedation, and 5959 were booked with open-access. Only 78 patients (0.97%, 78/8063) were identified as subsequently needing anesthesiologist-assisted sedation; 44 (56.4%, 44/78) were booked through open-access, of which chronic opioid (47.7%, 21/44) or benzodiazepine use (34.1%, 15/44) were the most common reasons for needing anesthesiologist-assisted sedation. Patients on chronic benzodiazepines required more midazolam than those not on chronic benzodiazepines (P = .03) of those patients who underwent conscious sedation. Similarly, patients with chronic opioid use required more fentanyl than those without chronic opioid use (P = .04). Advanced liver disease and alcohol use were common reasons for patients being booked after in-office consultation and were significantly higher than those booked with open-access (both P < .01). Conclusions: We observed that the majority of patients can be triaged for conscious sedation using a multi-tiered screening process. Importantly, few patients (<1.0%) were inappropriately booked for conscious sedation. The most common reasons for considering anesthesiologist-assisted sedation were chronic opioid, benzodiazepine and/or alcohol use and advanced liver disease. This suggests that these entities could be included in screening processes for open-access scheduling

Arctic cyclone water vapor isotopes support past sea ice retreat recorded in Greenland ice

Rapid Arctic warming is associated with important water cycle changes: sea ice loss, increasing atmospheric humidity, permafrost thaw, and water-induced ecosystem changes. Understanding these complex modern processes is critical to interpreting past hydrologic changes preserved in paleoclimate records and predicting future Arctic changes. Cyclones are a prevalent Arctic feature and water vapor isotope ratios during these events provide insights into modern hydrologic processes that help explain past changes to the Arctic water cycle. Here we present continuous measurements of water vapor isotope ratios (δ18O, δ2H, d-excess) in Arctic Alaska from a 2013 cyclone. This cyclone resulted in a sharp d-excess decrease and disproportional δ18O enrichment, indicative of a higher humidity open Arctic Ocean water vapor source. Past transitions to warmer climates inferred from Greenland ice core records also reveal sharp decreases in d-excess, hypothesized to represent reduced sea ice extent and an increase in oceanic moisture source to Greenland Ice Sheet precipitation. Thus, measurements of water vapor isotope ratios during an Arctic cyclone provide a critical processed-based explanation, and the first direct confirmation, of relationships previously assumed to govern water isotope ratios during sea ice retreat and increased input of northern ocean moisture into the Arctic water cycle.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Nature Publishing Group. The published article can be found at: http://www.nature.com/srep

Progressive increase of FcεRI expression across several PBMC subsets is associated with atopy and atopic asthma within school-aged children

Background: Antigen-specific IgE binds the Fcε receptor I (FcεRI) expressed on several types of immune cells, including dendritic cells (DCs). Activation of FcεRI on DCs in atopics has been shown to modulate immune responses that potentially contribute to asthma development. However, the extent to which DC subsets differ in FcεRI expression between atopic children with or without asthma is currently not clear. This study aimed to analyse the expression of FcεRI on peripheral blood mononuclear cells (PBMCs) from atopic children with and without asthma, and non-atopic/non-asthmatic age-matched healthy controls. Methods: We performed multiparameter flow cytometry on PBMC from 391 children across three community cohorts and one clinical cohort based in Western Australia. Results: We confirmed expression of FcεRI on basophils, monocytes, plasmacytoid and conventional DCs, with higher proportions of all cell populations expressing FcεRI in atopic compared to non-atopic children. Further, we observed that levels of FcεRI expression were elevated across plasmacytoid and conventional DC as well as basophils in atopic asthmatic compared to atopic non-asthmatic children also after adjusting for serum IgE levels. Conclusion: Our data suggest that the expression pattern of FcεRI on DC and basophils differentiates asthmatic from non-asthmatic atopic children. Given the significant immune modulatory effects observed as a consequence of FcεRI expression, this altered expression pattern is likely to contribute to asthma pathology in children