P2X receptors: epithelial ion channels and regulators of salt and water transport.

When the results from electrophysiological studies of renal epithelial cells are combined with data from in vivo tubule microperfusion experiments and immunohistochemical surveys of the nephron, the accumulated evidence suggests that ATP-gated ion channels, P2X receptors, play a specialized role in the regulation of ion and water movement across the renal tubule and are integral to electrolyte and fluid homeostasis. In this short review, we discuss the concept of P2X receptors as regulators of salt and water salvage pathways, as well as acknowledging their accepted role as ATP-gated ion channels

Active immunization with myelin-derived altered peptide ligand reduces mechanical pain hypersensitivity following peripheral nerve injury

BACKGROUND: T cells have been implicated in neuropathic pain that is caused by peripheral nerve injury. Immunogenic myelin basic protein (MBP) peptides have been shown to initiate mechanical allodynia in a T cell-dependent manner. Antagonistic altered peptide ligands (APLs) are peptides with substitutions in amino acid residues at T cell receptor contact sites and can inhibit T cell function and modulate inflammatory responses. In the present study, we studied the effects of immunization with MBP-derived APL on pain behavior and neuroinflammation in an animal model of peripheral nerve injury. METHODS: Lewis rats were immunized subcutaneously at the base of the tail with either a weakly encephalitogenic peptide of MBP (cyclo-MBP(87-99)) or APL (cyclo-(87-99)[A(91),A(96)]MBP(87-99)) in complete Freund’s adjuvant (CFA) or CFA only (control), following chronic constriction injury (CCI) of the left sciatic nerve. Pain hypersensitivity was tested by measurements of paw withdrawal threshold to mechanical stimuli, regulatory T cells in spleen and lymph nodes were analyzed by flow cytometry, and immune cell infiltration into the nervous system was assessed by immunohistochemistry (days 10 and 30 post-CCI). Cytokines were measured in serum and nervous tissue of nerve-injured rats (day 10 post-CCI). RESULTS: Rats immunized with the APL cyclo-(87-99)[A(91),A(96)]MBP(87-99) had significantly reduced mechanical pain hypersensitivity in the ipsilateral hindpaw compared to cyclo-MBP(87-99)-treated and control rats. This was associated with significantly decreased infiltration of T cells and ED1+ macrophages in the injured nerve of APL-treated animals. The percentage of anti-inflammatory (M2) macrophages was significantly upregulated in the APL-treated rats on day 30 post-CCI. Compared to the control rats, microglial activation in the ipsilateral lumbar spinal cord was significantly increased in the MBP-treated rats, but was not altered in the rats immunized with the MBP-derived APL. In addition, immunization with the APL significantly increased splenic regulatory T cells. Several cytokines were significantly altered after CCI, but no significant difference was observed between the APL-treated and control rats. CONCLUSIONS: These results suggest that immune deviation by active immunization with a non-encephalitogenic MBP-derived APL mediates an analgesic effect in animals with peripheral nerve injury. Thus, T cell immunomodulation warrants further investigation as a possible therapeutic strategy for the treatment of peripheral neuropathic pain

Colour-electric spectral function at next-to-leading order

The spectral function related to the correlator of two colour-electric fields along a Polyakov loop determines the momentum diffusion coefficient of a heavy quark near rest with respect to a heat bath. We compute this spectral function at next-to-leading order, O(alpha_s^2), in the weak-coupling expansion. The high-frequency part of our result (omega >> T), which is shown to be temperature-independent, is accurately determined thanks to asymptotic freedom; the low-frequency part of our result (omega << T), in which Hard Thermal Loop resummation is needed in order to cure infrared divergences, agrees with a previously determined expression. Our result may help to calibrate the overall normalization of a lattice-extracted spectral function in a perturbative frequency domain T << omega << 1/a, paving the way for a non-perturbative estimate of the momentum diffusion coefficient at omega -> 0. We also evaluate the colour-electric Euclidean correlator, which could be directly compared with lattice simulations. As an aside we determine the Euclidean correlator in the lattice strong-coupling expansion, showing that through a limiting procedure it can in principle be defined also in the confined phase of pure Yang-Mills theory, even if a practical measurement could be very noisy there.Comment: 38 page

Holographic Brownian Motion in Magnetic Environments

Using the gauge/gravity correspondence, we study the dynamics of a heavy quark in two strongly-coupled systems at finite temperature: Super-Yang-Mills in the presence of a magnetic field and non-commutative Super-Yang-Mills. In the former, our results agree qualitatively with the expected behavior from weakly-coupled theories. In the latter, we propose a Langevin equation that accounts for the effects of non-commutativity and we find new interesting features. The equation resembles the structure of Brownian motion in the presence of a magnetic field and implies that the fluctuations along non-commutative directions are correlated. Moreover, our results show that the viscosity is smaller than the commutative case and that the diffusion properties of the quark are unaffected by non-commutativity. Finally, we compute the random force autocorrelator and verify that the fluctuation-dissipation theorem holds in the presence of non-commutativity.Comment: 34 pages. v2: typos corrected. v3: title and abstract slightly modified in order to better reflect the contents of the paper; footnote 3 and one reference were also added; version accepted for publication in JHE

Honey bee foraging distance depends on month and forage type

To investigate the distances at which honey bee foragers collect nectar and pollen, we analysed 5,484 decoded waggle dances made to natural forage sites to determine monthly foraging distance for each forage type. Firstly, we found significantly fewer overall dances made for pollen (16.8 %) than for non-pollen, presumably nectar (83.2 %; P < 2.2 × 10−23). When we analysed distance against month and forage type, there was a significant interaction between the two factors, which demonstrates that in some months, one forage type is collected at farther distances, but this would reverse in other months. Overall, these data suggest that distance, as a proxy for forage availability, is not significantly and consistently driven by need for one type of forage over the other

Safety evaluation of substituted thiophenes used as flavoring ingredients.

This publication is the second in a series by the Expert Panel of the Flavor and Extract Manufacturers Association summarizing the conclusions of its third systematic re-evaluation of the safety of flavorings previously considered to be generally recognized as safe (GRAS) under conditions of intended use. Re-evaluation of GRAS status for flavorings is based on updated considerations of exposure, structural analogy, metabolism, pharmacokinetics and toxicology and includes a comprehensive review of the scientific information on the flavorings and structurally related substances. Of the 12 substituted thiophenes reviewed here, 11 were reaffirmed as GRAS based on their rapid absorption, metabolism and excretion in humans and animals; the low estimated dietary exposure from flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels; and the lack of significant genotoxic and mutagenic potential. For one of the substituted thiophenes, 3-acetyl-2,5-dimethylthiophene, it was concluded that more detailed exposure information, comparative metabolism studies and comprehensive toxicity data, including an in-depth evaluation of the mechanism of action for any adverse effects observed, are required for continuation of its FEMA GRAS™ status. In the absence of these data, the compound was removed from the FEMA GRAS list

The regulatory subunit of PKA-I remains partially structured and undergoes β-aggregation upon thermal denaturation

Background: The regulatory subunit (R) of cAMP-dependent protein kinase (PKA) is a modular flexible protein that responds with large conformational changes to the binding of the effector cAMP. Considering its highly dynamic nature, the protein is rather stable. We studied the thermal denaturation of full-length RIα and a truncated RIα(92-381) that contains the tandem cyclic nucleotide binding (CNB) domains A and B. Methodology/Principal Findings: As revealed by circular dichroism (CD) and differential scanning calorimetry, both RIα proteins contain significant residual structure in the heat-denatured state. As evidenced by CD, the predominantly α-helical spectrum at 25°C with double negative peaks at 209 and 222 nm changes to a spectrum with a single negative peak at 212-216 nm, characteristic of β-structure. A similar α→β transition occurs at higher temperature in the presence of cAMP. Thioflavin T fluorescence and atomic force microscopy studies support the notion that the structural transition is associated with cross-β-intermolecular aggregation and formation of non-fibrillar oligomers. Conclusions/Significance: Thermal denaturation of RIα leads to partial loss of native packing with exposure of aggregation-prone motifs, such as the B' helices in the phosphate-binding cassettes of both CNB domains. The topology of the β-sandwiches in these domains favors inter-molecular β-aggregation, which is suppressed in the ligand-bound states of RIα under physiological conditions. Moreover, our results reveal that the CNB domains persist as structural cores through heat-denaturation. © 2011 Dao et al

Update to the study protocol, including statistical analysis plan for a randomized clinical trial comparing comprehensive cardiac rehabilitation after heart valve surgery with control: the CopenHeartVR trial

Comparative StudyRandomized Controlled TrialThis is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising because of an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post-surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesize that a comprehensive cardiac rehabilitation program can improve physical capacity and self-assessed mental health and reduce hospitalization and healthcare costs after heart valve surgery. METHODS: This randomized clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients 1:1 to an intervention or a control group, using central randomization, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise and a psycho-educational intervention comprising five consultations. The primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. The secondary outcome is self-assessed mental health measured by the standardized questionnaire Short Form-36. Long-term healthcare utilization and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design will be used to evaluate qualitative and quantitative findings, encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study. CONCLUSION: This randomized clinical trial will contribute with evidence of whether cardiac rehabilitation should be provided after heart valve surgery. The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015). TRIAL REGISTRATION: Trial registered 16 March 2012; ClinicalTrials.gov ( NCT01558765 ).This work is supported by the Strategic Research Council, The Heart Centre Research Foundation Rigshospitalet, Familien Hede Nielsens Fond, The Regional Research Council of Region Sealand (Denmark), The National Institute of Public Health, and the University of Southern Denmark

Deforming the D1D5 CFT away from the orbifold point

The D1D5 brane bound state is believed to have an `orbifold point' in its moduli space which is the analogue of the free Yang Mills theory for the D3 brane bound state. The supergravity geometry generated by D1 and D5 branes is described by a different point in moduli space, and in moving towards this point we have to deform the CFT by a marginal operator: the `twist' which links together two copies of the CFT. In this paper we find the effect of this deformation operator on the simplest physical state of the CFT -- the Ramond vacuum. The twist deformation leads to a final state that is populated by pairs of excitations like those in a squeezed state. We find the coefficients characterizing the distribution of these particle pairs (for both bosons and fermions) and thus write this final state in closed form.Comment: 30 pages, 4 figures, Late

Excitations in the deformed D1D5 CFT

We perform some simple computations for the first order deformation of the D1D5 CFT off its orbifold point. It had been shown earlier that under this deformation the vacuum state changes to a squeezed state (with the further action of a supercharge). We now start with states containing one or two initial quanta and write down the corresponding states obtained under the action of deformation operator. The result is relevant to the evolution of an initial excitation in the CFT dual to the near extremal D1D5 black hole: when a left and a right moving excitation collide in the CFT, the deformation operator spreads their energy over a larger number of quanta, thus evolving the state towards the infrared.Comment: 26 pages, Latex, 4 figure