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

Optimizing internal wave drag in a forward barotropic model with semidiurnal tides

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109739/1/ocemod_buijsmanetal_2015.pd

Existence theorems in the geometrically non-linear 6-parametric theory of elastic plates

In this paper we show the existence of global minimizers for the geometrically exact, non-linear equations of elastic plates, in the framework of the general 6-parametric shell theory. A characteristic feature of this model for shells is the appearance of two independent kinematic fields: the translation vector field and the rotation tensor field (representing in total 6 independent scalar kinematic variables). For isotropic plates, we prove the existence theorem by applying the direct methods of the calculus of variations. Then, we generalize our existence result to the case of anisotropic plates. We also present a detailed comparison with a previously established Cosserat plate model.Comment: 19 pages, 1 figur

Analysis of Hamiltonian formulations of linearized General Relativity

The different forms of the Hamiltonian formulations of linearized General Relativity/spin-two theories are discussed in order to show their similarities and differences. It is demonstrated that in the linear model, non-covariant modifications to the initial covariant Lagrangian (similar to those modifications used in full gravity) are in fact unnecessary. The Hamiltonians and the constraints are different in these two formulations but the structure of the constraint algebra and the gauge invariance derived from it are the same. It is shown that these equivalent Hamiltonian formulations are related to each other by a canonical transformation which is explicitly given. The relevance of these results to the full theory of General Relativity is briefly discussed.Comment: Section Discussion is modified and references are added; 19 page

Autosis is a Na+,K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia.

A long-standing controversy is whether autophagy is a bona fide cause of mammalian cell death. We used a cell-penetrating autophagy-inducing peptide, Tat-Beclin 1, derived from the autophagy protein Beclin 1, to investigate whether high levels of autophagy result in cell death by autophagy. Here we show that Tat-Beclin 1 induces dose-dependent death that is blocked by pharmacological or genetic inhibition of autophagy, but not of apoptosis or necroptosis. This death, termed "autosis," has unique morphological features, including increased autophagosomes/autolysosomes and nuclear convolution at early stages, and focal swelling of the perinuclear space at late stages. We also observed autotic death in cells during stress conditions, including in a subpopulation of nutrient-starved cells in vitro and in hippocampal neurons of neonatal rats subjected to cerebral hypoxia-ischemia in vivo. A chemical screen of ~5,000 known bioactive compounds revealed that cardiac glycosides, antagonists of Na(+),K(+)-ATPase, inhibit autotic cell death in vitro and in vivo. Furthermore, genetic knockdown of the Na(+),K(+)-ATPase α1 subunit blocks peptide and starvation-induced autosis in vitro. Thus, we have identified a unique form of autophagy-dependent cell death, a Food and Drug Administration-approved class of compounds that inhibit such death, and a crucial role for Na(+),K(+)-ATPase in its regulation. These findings have implications for understanding how cells die during certain stress conditions and how such cell death might be prevented

Topological Defects on Fluctuating Surfaces: General Properties and the Kosterlitz-Thouless Transition

We investigate the Kosterlitz-Thouless transition for hexatic order on a free fluctuating membrane and derive both a Coulomb gas and a sine-Gordon Hamiltonian to describe it. The Coulomb-gas Hamiltonian includes charge densities arising from disclinations and from Gaussian curvature. There is an interaction coupling the difference between these two densities, whose strength is determined by the hexatic rigidity, and an interaction coupling Gaussian curvature densities arising from the Liouville Hamiltonian resulting from the imposition of a covariant cutoff. In the sine-Gordon Hamiltonian, there is a linear coupling between a scalar field and the Gaussian curvature. We discuss gauge-invariant correlation function for hexatic order and the dielectric constant of the Coulomb gas. We also derive renormalization group recursion relations that predict a transition with decreasing bending rigidity $\kappa$.Comment: REVTEX, 45 pages with 11 postscript figures compressed using uufiles. Accepted for publication in Phys. Rev.

Ghost D-branes

We define a ghost D-brane in superstring theories as an object that cancels the effects of an ordinary D-brane. The supergroups U(N|M) and OSp(N|M) arise as gauge symmetries in the supersymmetric world-volume theory of D-branes and ghost D-branes. A system with a pair of D-brane and ghost D-brane located at the same location is physically equivalent to the closed string vacuum. When they are separated, the system becomes a new brane configuration. We generalize the type I/heterotic duality by including n ghost D9-branes on the type I side and by considering the heterotic string whose gauge group is OSp(32+2n|2n). Motivated by the type IIB S-duality applied to D9- and ghost D9-branes, we also find type II-like closed superstrings with U(n|n) gauge symmetry.Comment: 49 pages, 6 figures, harvmac. v2: references and acknowledgements adde

Matter wave functions and Yukawa couplings in F-theory Grand Unification

We study the local structure of zero mode wave functions of chiral matter fields in F-theory unification. We solve the differential equations for the zero modes derived from local Higgsing in the 8-dimensional parent action of F-theory 7-branes. The solutions are found as expansions both in powers and derivatives of the magnetic fluxes. Yukawa couplings are given by an overlap integral of the three wave functions involved in the interaction and can be calculated analytically. We provide explicit expressions for these Yukawas to second order both in the flux and derivative expansions and discuss the effect of higher order terms. We explicitly describe the dependence of the couplings on the U(1) charges of the relevant fields, appropriately taking into account their normalization. A hierarchical Yukawa structure is naturally obtained. The application of our results to the understanding of the observed hierarchies of quarks and leptons is discussed.Comment: Latex, 51 pages, 4 figures, typos corrected, note adde

On the variation of the gauge couplings during inflation

It is shown that the evolution of the (Abelian) gauge coupling during an inflationary phase of de Sitter type drives the growth of the two-point function of the magnetic inhomogeneities. After examining the constraints on the variation of the gauge coupling arising in a standard model of inflationary and post-inflationary evolution, magnetohydrodynamical equations are generalized to the case of time evolving gauge coupling. It is argued that large scale magnetic fields can be copiously generated. Other possible implications of the model are outlined.Comment: 5 pages in RevTex style, one figur

Quintessence arising from exponential potentials

We demonstrate how exponential potentials that could arise in the early Universe as a result of Kaluza-Klein type compactifications of string theory, can lead to cosmological solutions which correspond to the currently observed accelerating Universe. The idea is simple, relying solely on the known scaling properties associated with exponential potentials. In particular we show that the existence of stable attractor solutions implies that the results hold for a wide range of coupling constants and initial conditions.Comment: 4 pages, 3 figures, published versio