A homeostatic function of CXCR2 signalling in articular cartilage

Funding This work was funded by Arthritis Research UK (grants 17859, 17971, 19654), INNOCHEM EU FP6 (grant LSHB-CT-2005-51867), MRC (MR/K013076/1) and the William Harvey Research FoundationPeer reviewedPublisher PD

The sensory coding of warm perception

Humans detect skin temperature changes that are perceived as warm or cool. Like humans, mice report forepaw skin warming with perceptual thresholds of less than 1°C and do not confuse warm with cool. We identify two populations of polymodal C-fibers that signal warm. Warm excites one population, whereas it suppresses the ongoing cool-driven firing of the other. In the absence of the thermosensitive TRPM2 or TRPV1 ion channels, warm perception was blunted, but not abolished. In addition, trpv1:trpa1:trpm3(-/-) triple-mutant mice that cannot sense noxious heat detected skin warming, albeit with reduced sensitivity. In contrast, loss or local pharmacological silencing of the cool-driven TRPM8 channel abolished the ability to detect warm. Our data are not reconcilable with a labeled line model for warm perception, with receptors firing only in response to warm stimuli, but instead support a conserved dual sensory model to unambiguously detect skin warming in vertebrates

The Protective Effect of Ursodeoxycholic Acid in an in vitro model of the Human Fetal Heart occurs via Targeting Cardiac Fibroblasts

Bile acids are elevated in the blood of women with intrahepatic cholestasis of pregnancy (ICP) and this may lead to fetal arrhythmia, fetal hypoxia and potentially fetal death in utero. The bile acid taurocholic acid (TC) causes abnormal calcium dynamics and contraction in neonatal rat cardiomyocytes. Ursodeoxycholic acid (UDCA), a drug clinically used to treat ICP, prevents adverse effects of TC. During development, the fetus is in a state of relative hypoxia. Although this is essential for the development of the heart and vasculature, resident fibroblasts can transiently differentiate into myofibroblasts and form gap junctions with cardiomyocytes in vitro, resulting in cardiomyocyte depolarization. We expanded on previously published work using an in vitro hypoxia model to investigate the differentiation of human fetal fibroblasts into myofibroblasts.Recent evidence shows that potassium channels are involved in maintaining the membrane potential of ventricular fibroblasts and that ATP-dependent potassium (KATP) channel subunits are expressed in cultured fibroblasts. KATP channels are a valuable target as they are thought to have a cardioprotective role during ischaemic and hypoxic conditions. We investigated whether UDCA could modulate fibroblast membrane potential.We established the isolation and culture of human fetal cardiomyocytes and fibroblasts to investigate the effect of hypoxia, TC and UDCA on human fetal cardiac cells.UDCA hyperpolarized myofibroblasts and prevented TC-induced depolarisation, possibly through the activation of KATP channels that are expressed in cultured fibroblasts. Also, similar to the rat model, UDCA can counteract TC-induced calcium abnormalities in human fetal cultures of cardiomyocytes and myofibroblasts. Under normoxic conditions, we found a higher number of myofibroblasts in cultures derived from human fetal hearts compared to cells isolated from neonatal rat hearts, indicating a possible increased number of myofibroblasts in human fetal hearts. Hypoxia further increased the number of human fetal and rat neonatal myofibroblasts. However, chronically administered UDCA reduced the number of myofibroblasts and prevented hypoxia-induced depolarisation.In conclusion, our results show that the protective effect of UDCA involves both the reduction of fibroblast differentiation into myofibroblasts, and hyperpolarisation of myofibroblasts, most likely through the stimulation of potassium channels, i.e. KATP channels. This could be important in validating UDCA as an antifibrotic and antiarrhythmic drug for treatment of failing hearts and fetal arrhythmia

Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes

Aim: In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodeling in cardiac diseases is associated with down-regulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signaling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes. Methods and results: Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodeling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with Methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions: JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signaling complexes to regulate LTCC activity

Study of the ηπo\eta\pi^o system in the mass range up to 1200 MeV

The reaction $\pi^-p \to \eta\pi^o n$ has been studied with GAMS-2000 spectrometer in the secondary 38 GeV/c $\pi^-$-beam of the IHEP U-70 accelerator. Partial wave analysis of the reaction has been performed in the $\eta\pi^o$ mass range up to 1200 MeV. The $a_0(980)$-meson is seen as a sharp peak in S-wave. The $t$-dependence of $a_0(980)$ production cross section has been studied. Dominant production of the $a_0(980)$ at a small transfer momentum $t$ confirms the hypothesis of Achasov and Shestakov about significant contribution of the $\rho_2$ exchange ($I^GJ^{PC}=1^+2^{--}$) in the mechanism of $a_0(980)$ meson production in $t$-channel of the reaction.Comment: 4 pages, 3 figures, talk given at HADRON'9

Origin and Evolution of Saturn's Ring System

The origin and long-term evolution of Saturn's rings is still an unsolved problem in modern planetary science. In this chapter we review the current state of our knowledge on this long-standing question for the main rings (A, Cassini Division, B, C), the F Ring, and the diffuse rings (E and G). During the Voyager era, models of evolutionary processes affecting the rings on long time scales (erosion, viscous spreading, accretion, ballistic transport, etc.) had suggested that Saturn's rings are not older than 100 My. In addition, Saturn's large system of diffuse rings has been thought to be the result of material loss from one or more of Saturn's satellites. In the Cassini era, high spatial and spectral resolution data have allowed progress to be made on some of these questions. Discoveries such as the ''propellers'' in the A ring, the shape of ring-embedded moonlets, the clumps in the F Ring, and Enceladus' plume provide new constraints on evolutionary processes in Saturn's rings. At the same time, advances in numerical simulations over the last 20 years have opened the way to realistic models of the rings's fine scale structure, and progress in our understanding of the formation of the Solar System provides a better-defined historical context in which to understand ring formation. All these elements have important implications for the origin and long-term evolution of Saturn's rings. They strengthen the idea that Saturn's rings are very dynamical and rapidly evolving, while new arguments suggest that the rings could be older than previously believed, provided that they are regularly renewed. Key evolutionary processes, timescales and possible scenarios for the rings's origin are reviewed in the light of tComment: Chapter 17 of the book ''Saturn After Cassini-Huygens'' Saturn from Cassini-Huygens, Dougherty, M.K.; Esposito, L.W.; Krimigis, S.M. (Ed.) (2009) 537-57

Clay Bearing Units in the Region around Mawrth Vallis: Stratigraphy, Extent, and Possible Alteration Fronts

The largest exposure of phyllosilicates on Mars occurs on the highland plains around Mawrth Vallis. This exposure extends for about 300 km southward from the edge of the dichotomy boundary, covering an area greater than 200 x 300 kilometers over an elevation range of approximately 2000 meters. At least two different types of hydrated phyllosilicates (Fe/Mg-rich and Al-rich phyllosilicates) have been identified in OMEGA data based on absorption bands near 2.3 and 2.2 micrometers, respectively. These clay-bearing units are associated with layered, indurated light-toned units with complex spatial and stratigraphic relationships, and are unconfomably overlain by a darker, indurated, more heavily cratered unit. Ongoing analysis of OMEGA (approximately 1 kilometer/pixel) and CRISM multi-spectral (MSP, 200 meters/pixel) data reveal hydrated minerals with absorptions at approximately 2.2 or 2.3 micrometers in locations up to 300 kilometers away from the borders of the previously identified extent of clay-bearing units. We seek to: 1) further constrain the mineralogy of the hydrated species identified in [5], and 2) understand spatial and stratigraphic relationships between the different hydrated minerals and the cratered plains units in which they are found. In this work we perform mineralogical and stratigraphic comparisons between units to test whether these extended units may be related, in order to establish a broad zone of alteration

Identification of hydrated silicate minerals on Mars using MRO-CRISM: Geologic context near Nili Fossae and implications for aqueous alteration

The Noachian terrain west of the Isidis basin hosts a diverse collection of alteration minerals in rocks comprising varied geomorphic units within a 100,000 km2 region in and near the Nili Fossae. Prior investigations in this region by the Observatoire pour l'Minéralogie, l'Eau, les Glaces, et l'Activité (OMEGA) instrument on Mars Express revealed large exposures of both mafic minerals and iron magnesium phyllosilicates in stratigraphic context. Expanding on the discoveries of OMEGA, the Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) aboard the Mars Reconnaissance Orbiter (MRO) has found more spatially widespread and mineralogically diverse alteration minerals than previously realized, which represent multiple aqueous environments. Using CRISM near-infrared spectral data, we detail the basis for identification of iron and magnesium smectites (including both nontronite and more Mg-rich varieties), chlorite, prehnite, serpentine, kaolinite, potassium mica (illite or muscovite), hydrated (opaline) silica, the sodium zeolite analcime, and magnesium carbonate. The detection of serpentine and analcime on Mars is reported here for the first time. We detail the geomorphic context of these minerals using data from high-resolution imagers onboard MRO in conjunction with CRISM. We find that the distribution of alteration minerals is not homogeneous; rather, they occur in provinces with distinctive assemblages of alteration minerals. Key findings are (1) a distinctive stratigraphy, in and around the Nili Fossae, of kaolinite and magnesium carbonate in bedrock units always overlying Fe/Mg smectites and (2) evidence for mineral phases and assemblages indicative of low-grade metamorphic or hydrothermal aqueous alteration in cratered terrains. The alteration minerals around the Nili Fossae are more typical of those resulting from neutral to alkaline conditions rather than acidic conditions, which appear to have dominated much of Mars. Moreover, the mineralogic diversity and geologic context of alteration minerals found in the region around the Nili Fossae indicates several episodes of aqueous activity in multiple distinct environments