Blood pH is maintained in a narrow range around pH 7.4 mainly through regulation of respiration and renal acid extrusion. The molecular mechanisms involved in pH homeostasis are not completely understood. Here we show that ovarian cancer G-protein-coupled receptor 1 (OGR1), previously described as a receptor for sphingosylphosphorylcholine, acts as a proton-sensing receptor stimulating inositol phosphate formation. The receptor is inactive at pH 7.8, and fully activated at pH 6.8-site-directed mutagenesis shows that histidines at the extracellular surface are involved in pH sensing. We find that GPR4, a close relative of OGR1, also responds to pH changes, but elicits cyclic AMP formation. It is known that the skeleton participates in pH homeostasis as a buffering organ, and that osteoblasts respond to pH changes in the physiological range, but the pH-sensing mechanism operating in these cells was hitherto not known. We detect expression of OGR1 in osteosarcoma cells and primary human osteoblast precursors, and show that these cells exhibit strong pH-dependent inositol phosphate formation. Immunohistochemistry on rat tissue sections confirms the presence of OGR1 in osteoblasts and osteocytes. We propose that OGR1 and GPR4 are proton-sensing receptors involved in pH homeostasis.

Axisymmetric disturbances that preserve their form as they move through a Bose condensate are obtained numerically by the solution of the appropriate nonlinear Schrodinger equation. A continuous family is obtained that, in the momentum (p)-energy (E) plane, consists of two branches meeting at a cusp of minimum momentum around 0.140 P K~/ C ' and minimum energy about 0.145 p~~/ c , where p is density, c is the speed of sound and K is the quantum of circulation. For all larger p , there are two possible energy states. One (the lower branch) is (for large enough p) a vortex ring of circulation K ; as p + m its radius G-(~/ T K) " * becomes infinite and its forward velocity tends to zero. The other (the upper branch) lacks vorticity and is a rarefaction sound pulse that becomes increasingly one dimensional as p +a; its velocity approaches c for large p. The velocity of any member of the family is shown, both numerically and analytically, to be aE/ap, the derivative being taken along the family. At great distances, the disturbance in the condensate is pseudo-dipolar (dipolar in a stretched coordinate system); the strength of the pseudo-dipole moment is obtained numerically. Analogous calculations are presented for the corresponding two-dimensional problem. Again, a continuous sequence of solitary waves is obtained, but the momentum per unit length p and energy per unit length E have no minima. For small forward velocities, the wave consists of two widely separated parallel, oppositely directed line vortices. As the forward velocity increases the wave loses its vorticity and becomes a rarefaction pulse of ever increasing spatial extent but ever decreasing amplitude. As its velocity approaches c, both p and E tend to zero, and Elp + c.

IL-17 is a cytokine implicated in the regulation of inflammation. We investigated the role of this cytokine in neutrophil recruitment using a model of LPS-induced lung inflammation in mice. In the bronchoalveolar lavage, LPS induced a first influx of neutrophils peaking at day 1, followed by a second wave, peaking at day 2. IL-17 levels were increased during the late phase neutrophilia (day 2), and this was concomitant with an increased number of T cells and macrophages, together with an increase of KC and macrophage-inflammatory protein-2 levels in the lung tissue. Intranasal treatment with a neutralizing murine anti-IL-17 Ab inhibited the late phase neutrophilia. In the bronchoalveolar lavage cells, IL-17 mRNA was detected at days 1, 2, and 3 postchallenge, with a strong expression at day 2. This expression was associated with CD4+ and CD8+ cells, but also with neutrophils. When challenged with LPS, despite the absence of T cells, SCID mice also developed a neutrophilic response associated with IL-17 production. In BALB/c mice, IL-15 mRNA, associated mainly with neutrophils, was evidenced 1 day after LPS challenge. In vitro, IL-15 was able to induce IL-17 release from purified spleen CD4+ cells, but not spleen CD8+ or airway neutrophils. We have shown that IL-17, produced mainly by CD4+ cells, but also by neutrophils, plays a role in the mobilization of lung neutrophils following bacterial challenge. In addition, our results suggest that IL-15 could represent a physiological trigger that leads to IL-17 production following bacterial infection.

Bronchial asthma, the most prevalent cause of significant respiratory morbidity in the developed world, typically is a chronic disorder associated with long-term changes in the airways. We developed a mouse model of chronic asthma that results in markedly increased numbers of airway mast cells, enhanced airway responses to methacholine or antigen, chronic inflammation including infiltration with eosinophils and lymphocytes, airway epithelial goblet cell hyperplasia, enhanced expression of the mucin genes Muc5ac and Muc5b, and increased levels of lung collagen. Using mast cell-deficient (Kit W-sh/W-sh and/or Kit W/W-v ) mice engrafted with FcRγ +/+ or FcRγ -/-mast cells, we found that mast cells were required for the full development of each of these features of the model. However, some features also were expressed, although usually at less than wild-type levels, in mice whose mast cells lacked FcRγ and therefore could not be activated by either antigen-and IgEdependent aggregation of FcεRI or the binding of antigen-IgG1 immune complexes to FcγRIII. These findings demonstrate that mast cells can contribute to the development of multiple features of chronic asthma in mice and identify both FcRγ-dependent and FcRγ-independent pathways of mast cell activation as important for the expression of key features of this asthma model.

Using numerical simulations of rapidly rotating Boussinesq convection in a Cartesian box, we study the formation of long-lived, large-scale, depth-invariant coherent structures. These structures, which consist of concentrated cyclones, grow to the horizontal scale of the box, with velocities significantly larger than the convective motions. We vary the rotation rate, the thermal driving and the aspect ratio in order to determine the domain of existence of these large-scale vortices (LSV). We find that two conditions are required for their formation. First, the Rayleigh number, a measure of the thermal driving, must be several times its value at the linear onset of convection; this corresponds to Reynolds numbers, based on the convective velocity and the box depth, 100. Second, the rotational constraint on the convective structures must be strong. This requires that the local Rossby number, based on the convective velocity and the horizontal convective scale, 0.15. Simulations in which certain wavenumbers are artificially suppressed in spectral space suggest that the LSV are produced by the interactions of small-scale, depth-dependent convective motions. The presence of LSV significantly reduces the efficiency of the convective heat transport. arXiv:1403.7442v3 [physics.flu-dyn]

The linear stability of convection in a rapidly rotating sphere studied here builds on well established relationships between local and global theories appropriate to the small Ekman number limit. Soward (1977) showed that a disturbance marginal on local theory necessarily decays with time due to the process of phase mixing (where the spatial gradient of the frequency is non-zero). By implication, the local critical Rayleigh number is smaller than the true global value by an O(1) amount. The complementary view that the local marginal mode cannot be embedded in a consistent spatial WKBJ solution was expressed by Yano (1992). He explained that the criterion for the onset of global instability is found by extending the solution onto the complex s-plane, where s is the distance from the rotation axis, and locating the double turning point at which phase mixing occurs. He implemented the global criterion on a related two-parameter family of models, which includes the spherical convection problem for particular O(1) values of his parameters. Since he used one of them as the basis of a small-parameter expansion, his results are necessarily approximate for our problem.Here the asymptotic theory for the sphere is developed along lines parallel to Yano and hinges on the construction of a dispersion relation. Whereas Yano's relation is algebraic as a consequence of his approximations, ours is given by the solution of a second-order ODE, in which the axial coordinate z is the independent variable. Our main goal is the determination of the leading-order value of the critical Rayleigh number together with its first-order correction for various values of the Prandtl number.Numerical solutions of the relevant PDEs have also been found, for values of the Ekman number down to 10−6; these are in good agreement with the asymptotic theory. The results are also compared with those of Yano, which are surprisingly good in view of their approximate nature.

The correct asymptotic theory for the linear onset of instability of a Boussinesq fluid rotating rapidly in a self-gravitating sphere containing a uniform distribution of heat sources was given recently by Jones et al. (2000). Their analysis confirmed the established picture that instability at small Ekman number $E$ is characterized by quasi-geostrophic thermal Rossby waves, which vary slowly in the axial direction on the scale of the sphere radius $r_o$ and have short azimuthal length scale $O(E^{1/3}r_o)$. They also confirmed the localization of the convection about some cylinder radius $s\,{=}\,s_M$ roughly $r_o/2$. Their novel contribution concerned the implementation of global stability conditions to determine, for the first time, the correct Rayleigh number, frequency and azimuthal wavenumber. Their analysis also predicted the value of the finite tilt angle of the radially elongated convective rolls to the meridional planes. In this paper, we study small-Ekman-number convection in a spherical shell. When the inner sphere radius $r_i$ is small (certainly less than $s_M$), the Jones et al. (2000) asymptotic theory continues to apply, as we illustrate with the thick shell $r_i\,{=}\,0.35\,r_o$. For a large inner core, convection is localized adjacent to, but outside, its tangent cylinder, as proposed by Busse & Cuong (1977). We develop the asymptotic theory for the radial structure in that convective layer on its relatively long length scale $O(E^{2/9}r_o)$. The leading-order asymptotic results and first-order corrections for the case of stress-free boundaries are obtained for a relatively thin shell $r_i\,{=}\,0.65\,r_o$ and compared with numerical results for the solution of the complete PDEs that govern the full problem at Ekman numbers as small as $10^{-7}$. We undertook the corresponding asymptotic analysis and numerical simulation for the case in which there are no internal heat sources, but instead a temperature difference is maintained between the inner and outer boundaries. Since the temperature gradient increases sharply with decreasing radius, the onset of instability always occurs on the tangent cylinder irrespective of the size of the inner core radius. We investigate the case $r_i\,{=}\,0.35\,r_o$. In every case mentioned, we also apply rigid boundary conditions and determine the $O(E^{1/6})$ corrections due to Ekman suction at the outer boundary. All analytic predictions for both stress-free and rigid (no-slip) boundaries compare favourably with our full numerics (always with Prandtl number unity), despite the fact that very small Ekman numbers are needed to reach a true asymptotic regime.

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