Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

Objective: Previous studies have shown the importance of somatic mutations and arginine residues in the complementarity-determining regions (CDRs) of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies in human and murine lupus, and in studies of murine antibodies, a role of mutations at position 53 in VH CDR2 has been demonstrated. We previously demonstrated in vitro expression and mutagenesis of the human IgG1 monoclonal antibody B3. The present study was undertaken to investigate, using this expression system, the importance of the arginine residue at position 53 (R53) in B3 VH. Methods: R53 was altered, by site-directed mutagenesis, to serine, asparagine, or lysine, to create 3 expressed variants of VH. In addition, the germline sequence of the VH3-23 gene (from which B3 VH is derived) was expressed either with or without arginine at position 53. These 5 new heavy chains, as well as wild-type B3 VH, were expressed with 4 different light chains, and the resulting antibodies were assessed for their ability to bind to nucleosomes, -actinin, cardiolipin, ovalbumin, 2-glycoprotein I (2GPI), and the N-terminal domain of 2GPI (domain I), using direct binding assays. Results: The presence of R53 was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of R53 reduced binding to -actinin, ovalbumin, 2GPI, and domain I of 2GPI. The combination B3 (R53S) VH/B3 VL bound human, but not bovine, 2GPI. Conclusion: The fact that the R53S substitution significantly alters binding of B3 to different clinically relevant antigens, but that the alteration is in opposite directions depending on the antigen, implies that this arginine residue plays a critical role in the affinity maturation of antibody B3

IgG anti-apolipoprotein A-1 antibodies in patients with systemic lupus erythematosus are associated with disease activity and corticosteroid therapy: an observational study.

IgG anti-apolipoprotein A-1 (IgG anti-apoA-1) antibodies are present in patients with systemic lupus erythematosus (SLE) and may link inflammatory disease activity and the increased risk of developing atherosclerosis and cardiovascular disease (CVD) in these patients. We carried out a rigorous analysis of the associations between IgG anti-apoA-1 levels and disease activity, drug therapy, serology, damage, mortality and CVD events in a large British SLE cohort

Ricci flow for homogeneous compact models of the universe

Using quaternions, we give a concise derivation of the Ricci tensor for homogeneous spaces with topology of the 3-dimensional sphere. We derive explicit and numerical solutions for the Ricci flow PDE and discuss their properties. In the collapse (or expansion) of these models, the interplay of the various components of the Ricci tensor are studied. We dedicate this paper to honor the work of Josh Goldberg.Comment: 18 pages, 2 figure

Numerical Investigation of a Coronal Mass Ejection from an Anemone Active Region: Reconnection and Deflection of the 2005 August 22 Eruption

We present a numerical investigation of the coronal evolution of a coronal mass ejection (CME) on 2005 August 22 using a 3-D thermodynamics magnetohydrodynamic model, the SWMF. The source region of the eruption was anemone active region (AR) 10798, which emerged inside a coronal hole. We validate our modeled corona by producing synthetic extreme ultraviolet (EUV) images, which we compare to EIT images. We initiate the CME with an out-of-equilibrium flux rope with an orientation and chirality chosen in agreement with observations of a H-alpha filament. During the eruption, one footpoint of the flux rope reconnects with streamer magnetic field lines and with open field lines from the adjacent coronal hole. It yields an eruption which has a mix of closed and open twisted field lines due to interchange reconnection and only one footpoint line-tied to the source region. Even with the large-scale reconnection, we find no evidence of strong rotation of the CME as it propagates. We study the CME deflection and find that the effect of the Lorentz force is a deflection of the CME by about 3 deg/Rsun towards the East during the first 30 minutes of the propagation. We also produce coronagraphic and EUV images of the CME, which we compare with real images, identifying a dimming region associated with the reconnection process. We discuss the implication of our results for the arrival at Earth of CMEs originating from the limb and for models to explain the presence of open field lines in magnetic clouds.Comment: 14 pages, 8 Figures, accepted to Astrophysical Journa

Anti-factor Xa antibodies in patients with antiphospholipid syndrome and their effects upon coagulation assays

- Introduction: The aim of this study was to examine the prevalence and functional effects of antibodies directed against Factor (F)Xa and other serine proteases (SP) in patients with antiphospholipid syndrome (APS). - Methods: Serum from patients with APS (n = 59), systemic lupus erythematosus (SLE; n = 106), other autoimmune rheumatic disease (ARD; n = 63) and 40 healthy controls (HC) were tested for IgG activity against thrombin (Thr), FXa, FVIIa, phosphatidylserine (PS)/FXa and antithrombin (AT)-III by enzyme-linked immunosorbent assay (ELISA). Anti-FXa positive IgG were purified to measure their avidity by chaotropic ELISA and functional effects upon clotting time (FXa-ACT) and FXa enzymatic activity (± AT-III). - Results: Anti-FXa IgG were found in patients with SLE (49.1%) and APS (33.9%) (P <0.05) but not in ARD controls and HC. In contrast, anti-Thr and anti-PS/FXa IgG were identified in other ARD and anti-FVIIa IgG were low in all groups. The avidity of APS-IgG to FXa was significantly higher than SLE-IgG (P <0.05). Greatest prolongation of FXa-ACT was observed with APS-IgG and greatest inhibitory effect upon FXa enzymatic activity was found with APS-IgG followed by SLE-IgG compared to HC-IgG. ATIII inhibition of FXa was significantly reduced by APS-IgG compared with HC and SLE (P <0.05) and did not correlate with binding to AT-III. - Conclusion: APS anti-FXa IgG have higher avidity to FXa and greater effects upon the enzymatic and coagulant activity of FXa compared with SLE anti-FXa IgG. Further studies of anti-FXa antibodies in APS, SLE and other non-autoimmune thrombotic disease cohorts are now required to evaluate whether targeting FXa with selective inhibitors in patients bearing anti-FXa antibodies may be an effective treatment strategy

Fuchsian methods and spacetime singularities

Fuchsian methods and their applications to the study of the structure of spacetime singularities are surveyed. The existence question for spacetimes with compact Cauchy horizons is discussed. After some basic facts concerning Fuchsian equations have been recalled, various ways in which these equations have been applied in general relativity are described. Possible future applications are indicated

A Higher Dimensional Stationary Rotating Black Hole Must be Axisymmetric

A key result in the proof of black hole uniqueness in 4-dimensions is that a stationary black hole that is ``rotating''--i.e., is such that the stationary Killing field is not everywhere normal to the horizon--must be axisymmetric. The proof of this result in 4-dimensions relies on the fact that the orbits of the stationary Killing field on the horizon have the property that they must return to the same null geodesic generator of the horizon after a certain period, $P$. This latter property follows, in turn, from the fact that the cross-sections of the horizon are two-dimensional spheres. However, in spacetimes of dimension greater than 4, it is no longer true that the orbits of the stationary Killing field on the horizon must return to the same null geodesic generator. In this paper, we prove that, nevertheless, a higher dimensional stationary black hole that is rotating must be axisymmetric. No assumptions are made concerning the topology of the horizon cross-sections other than that they are compact. However, we assume that the horizon is non-degenerate and, as in the 4-dimensional proof, that the spacetime is analytic.Comment: 24 pages, no figures, v2: footnotes and references added, v3: numerous minor revision

Global dynamics of the mixmaster model

The asymptotic behaviour of vacuum Bianchi models of class A near the initial singularity is studied, in an effort to confirm the standard picture arising from heuristic and numerical approaches by mathematical proofs. It is shown that for solutions of types other than VIII and IX the singularity is velocity dominated and that the Kretschmann scalar is unbounded there, except in the explicitly known cases where the spacetime can be smoothly extended through a Cauchy horizon. For types VIII and IX it is shown that there are at most two possibilities for the evolution. When the first possibility is realized, and if the spacetime is not one of the explicitly known solutions which can be smoothly extended through a Cauchy horizon, then there are infinitely many oscillations near the singularity and the Kretschmann scalar is unbounded there. The second possibility remains mysterious and it is left open whether it ever occurs. It is also shown that any finite sequence of distinct points generated by iterating the Belinskii-Khalatnikov-Lifschitz mapping can be realized approximately by a solution of the vacuum Einstein equations of Bianchi type IX.Comment: 16 page

Non-Maxwellian Proton Velocity Distributions in Nonradiative Shocks

The Balmer line profiles of nonradiative supernova remnant shocks provide the means to measure the post-shock proton velocity distribution. While most analyses assume a Maxwellian velocity distribution, this is unlikely to be correct. In particular, neutral atoms that pass through the shock and become ionized downstream form a nonthermal distribution similar to that of pickup ions in the solar wind. We predict the H alpha line profiles from the combination of pickup protons and the ordinary shocked protons, and we consider the extent to which this distribution could affect the shock parameters derived from H alpha profiles. The Maxwellian assumption could lead to an underestimate of shock speed by up to about 15%. The isotropization of the pickup ion population generates wave energy, and we find that for the most favorable parameters this energy could significantly heat the thermal particles. Sufficiently accurate profiles could constrain the strength and direction of the magnetic field in the shocked plasma, and we discuss the distortions from a Gaussian profile to be expected in Tycho's supernova remnant.Comment: 13 pages, 6 figure

Mixmaster universe in Horava-Lifshitz gravity

We consider spatially homogeneous (but generally non-isotropic) cosmologies in the recently proposed Horava-Lifshitz gravity and compare them to those of general relativity using Hamiltonian methods. In all cases, the problem is described by an effective point particle moving in a potential well with exponentially steep walls. Focusing on the closed-space cosmological model (Bianchi type IX), the mixmaster dynamics is now completely dominated by the quadratic Cotton tensor potential term for very small volume of the universe. Unlike general relativity, where the evolution towards the initial singularity always exhibits chaotic behavior with alternating Kasner epochs, the anisotropic universe in Horava-Lifshitz gravity (with parameter lambda > 1/3) is described by a particle moving in a frozen potential well with fixed (but arbitrary) energy E. Alternating Kasner epochs still provide a good description of the early universe for very large E, but the evolution appears to be non-ergodic. For very small E there are harmonic oscillations around the fully isotropic model. The question of chaos remains open for intermediate energy levels.Comment: 1+35 pages, 4 figure