A neuroendocrine role for chemerin in hypothalamic remodelling and photoperiodic control of energy balance

YesLong-term and reversible changes in body weight are typical of seasonal animals. Thyroid hormone (TH) and retinoic acid (RA) within the tanycytes and ependymal cells of the hypothalamus have been implicated in the photoperiodic response. We investigated signalling downstream of RA and how this links to the control of body weight and food intake in photoperiodic F344 rats. Chemerin, an inflammatory chemokine, with a known role in energy metabolism, was identified as a target of RA. Gene expression of chemerin (Rarres2) and its receptors were localised within the tanycytes and ependymal cells, with higher expression under long (LD) versus short (SD) photoperiod, pointing to a physiological role. The SD to LD transition (increased food intake) was mimicked by 2 weeks of ICV infusion of chemerin into rats. Chemerin also increased expression of the cytoskeletal protein vimentin, implicating hypothalamic remodelling in this response. By contrast, acute ICV bolus injection of chemerin on a 12h:12h photoperiod inhibited food intake and decreased body weight with associated changes in hypothalamic neuropeptides involved in growth and feeding after 24hr. We describe the hypothalamic ventricular zone as a key site of neuroendocrine regulation, where the inflammatory signal, chemerin, links TH and RA signaling to hypothalamic remodeling.BBSRC (grant number BB/K001043/1) and the Scottish Government

Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]

Background Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS). Methods The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance. Results There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype. Conclusions We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases

Testing the interaction of dark energy to dark matter through the analysis of virial relaxation of clusters Abell Clusters A586 and A1689 using realistic density profiles

Interaction between dark energy and dark matter is probed through deviation from the virial equilibrium for two relaxed clusters: A586 and A1689. The evaluation of the virial equilibrium is performed using realistic density profiles. The virial ratios found for the more realistic density profiles are consistent with the absence of interaction.Comment: 16pp 1 fig; accepted by GeR

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort

Hall-conductivity sign change and fluctuations in amorphous Nbx_{x}Ge1−x_{1-x} films

The sign change in the Hall conductivity has been studied in thin amorphous Nb$_{1-x}$Ge$_x (x\approx$0.3) films. By changing the film thickness it is shown that the field at which the sign reversal occurs shifts to lower values (from above to below the mean-field transition field $H_{c2}$) with increasing film thickness. This effect can be understood in terms of a competition between a positive normal and a negative fluctuation contribution to the Hall conductivity.Comment: 5 pages, 4 figures, to appear in Phys. Rev.

Billiards in a general domain with random reflections

We study stochastic billiards on general tables: a particle moves according to its constant velocity inside some domain ${\mathcal D} \subset {\mathbb R}^d$ until it hits the boundary and bounces randomly inside according to some reflection law. We assume that the boundary of the domain is locally Lipschitz and almost everywhere continuously differentiable. The angle of the outgoing velocity with the inner normal vector has a specified, absolutely continuous density. We construct the discrete time and the continuous time processes recording the sequence of hitting points on the boundary and the pair location/velocity. We mainly focus on the case of bounded domains. Then, we prove exponential ergodicity of these two Markov processes, we study their invariant distribution and their normal (Gaussian) fluctuations. Of particular interest is the case of the cosine reflection law: the stationary distributions for the two processes are uniform in this case, the discrete time chain is reversible though the continuous time process is quasi-reversible. Also in this case, we give a natural construction of a chord "picked at random" in ${\mathcal D}$, and we study the angle of intersection of the process with a $(d-1)$-dimensional manifold contained in ${\mathcal D}$.Comment: 50 pages, 10 figures; To appear in: Archive for Rational Mechanics and Analysis; corrected Theorem 2.8 (induced chords in nonconvex subdomains

Absence of lattice strain anomalies at the electronic topological transition in zinc at high pressure

High pressure structural distortions of the hexagonal close packed (hcp) element zinc have been a subject of controversy. Earlier experimental results and theory showed a large anomaly in lattice strain with compression in zinc at about 10 GPa which was explained theoretically by a change in Fermi surface topology. Later hydrostatic experiments showed no such anomaly, resulting in a discrepancy between theory and experiment. We have computed the compression and lattice strain of hcp zinc over a wide range of compressions using the linearized augmented plane wave (LAPW) method paying special attention to k-point convergence. We find that the behavior of the lattice strain is strongly dependent on k-point sampling, and with large k-point sets the previously computed anomaly in lattice parameters under compression disappears, in agreement with recent experiments.Comment: 9 pages, 6 figures, Phys. Rev. B (in press

Moments of isovector quark distributions from lattice QCD

We present a complete analysis of the chiral extrapolation of lattice moments of all twist-2 isovector quark distributions, including corrections from Nπ and Δπ loops. Even though the Δ resonance formally gives rise to higher order non-analytic structure, the coefficients of the higher order terms for the helicity and transversity moments are large and cancel much of the curvature generated by the wave function renormalization. The net effect is that, whereas the unpolarized moments exhibit considerable curvature, the polarized moments show little deviation from linearity as the chiral limit is approached

Electromagnetic couplings of the ChPT Lagrangian from the perturbative chiral quark model

We apply the perturbative chiral quark model to the study of the low-energy pi-N interaction. Using an effective chiral Lagrangian we reproduce the Weinberg-Tomozawa result for the S-wave pi-N scattering lengths. After inclusion of the photon field we give predictions for the electromagnetic O(p^2) low-energy couplings of the chiral perturbation theory effective Lagrangian that define the electromagnetic mass shifts of nucleons and first-order (e^2) radiative corrections to the pi-N scattering amplitude. Finally, we estimate the leading isospin-breaking correction to the strong energy shift of the pi(-)p atom in the 1s state, which is relevant for the experiment "Pionic Hydrogen" at PSI.Comment: 18 pages, 3 figure