Type I interferon receptor controls B-cell expression of nucleic acid-sensing Toll-like receptors and autoantibody production in a murine model of lupus

INTRODUCTION: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of high-titer IgG autoantibodies directed against nuclear autoantigens. Type I interferon (IFN-I) has been shown to play a pathogenic role in this disease. In the current study, we characterized the role of the IFNAR2 chain of the type I IFN (IFN-I) receptor in the targeting of nucleic acid-associated autoantigens and in B-cell expression of the nucleic acid-sensing Toll-like receptors (TLRs), TLR7 and TLR9, in the pristane model of lupus. METHODS: Wild-type (WT) and IFNAR2-/- mice were treated with pristane and monitored for proteinuria on a monthly basis. Autoantibody production was determined by autoantigen microarrays and confirmed using enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation. Serum immunoglobulin isotype levels, as well as B-cell cytokine production in vitro, were quantified by ELISA. B-cell proliferation was measured by thymidine incorporation assay. RESULTS: Autoantigen microarray profiling revealed that pristane-treated IFNAR2-/- mice lacked autoantibodies directed against components of the RNA-associated autoantigen complexes Smith antigen/ribonucleoprotein (Sm/RNP) and ribosomal phosphoprotein P0 (RiboP). The level of IgG anti-single-stranded DNA and anti-histone autoantibodies in pristane-treated IFNAR2-/- mice was decreased compared to pristane-treated WT mice. TLR7 expression and activation by a TLR7 agonist were dramatically reduced in B cells from IFNAR2-/- mice. IFNAR2-/- B cells failed to upregulate TLR7 as well as TLR9 expression in response to IFN-I, and effector responses to TLR7 and TLR9 agonists were significantly decreased as compared to B cells from WT mice following treatment with IFN-alpha. CONCLUSIONS: Our studies provide a critical link between the IFN-I pathway and the regulation of TLR-specific B-cell responses in a murine model of SLE

Spatiotemporal complexity of the universe at subhorizon scales

This is a short note on the spatiotemporal complexity of the dynamical state(s) of the universe at subhorizon scales (up to 300 Mpc). There are reasons, based mainly on infrared radiative divergences, to believe that one can encounter a flicker noise in the time domain, while in the space domain, the scaling laws are reflected in the (multi)fractal distribution of galaxies and their clusters. There exist recent suggestions on a unifying treatment of these two aspects within the concept of spatiotemporal complexity of dynamical systems driven out of equilibrium. Spatiotemporal complexity of the subhorizon dynamical state(s) of the universe is a conceptually nice idea and may lead to progress in our understanding of the material structures at large scalesComment: references update

Quantum Diffusion and Localization in Disordered Electronic Systems

The diffusion of electronic wave packets in one-dimensional systems with on-site, binary disorder is numerically investigated within the framework of a single-band tight-binding model. Fractal properties are incorporated by assuming that the distribution of distances $\ell$ between consecutive impurities obeys a power law, $P(\ell) \sim \ell^{-\alpha}$. For suitable ranges of $\alpha$, one finds system-wide anomalous diffusion. Asymmetric diffusion effects are introduced through the application of an external electric field, leading to results similar to those observed in the case of photogenerated electron-hole plasmas in tilted InP/InGaAs/InP quantum wells.Comment: RevTex4, 6 pages, 6 .eps figures: published versio

Point-occurrence self-similarity in crackling-noise systems and in other complex systems

It has been recently found that a number of systems displaying crackling noise also show a remarkable behavior regarding the temporal occurrence of successive events versus their size: a scaling law for the probability distributions of waiting times as a function of a minimum size is fulfilled, signaling the existence on those systems of self-similarity in time-size. This property is also present in some non-crackling systems. Here, the uncommon character of the scaling law is illustrated with simple marked renewal processes, built by definition with no correlations. Whereas processes with a finite mean waiting time do not fulfill a scaling law in general and tend towards a Poisson process in the limit of very high sizes, processes without a finite mean tend to another class of distributions, characterized by double power-law waiting-time densities. This is somehow reminiscent of the generalized central limit theorem. A model with short-range correlations is not able to escape from the attraction of those limit distributions. A discussion on open problems in the modeling of these properties is provided.Comment: Submitted to J. Stat. Mech. for the proceedings of UPON 2008 (Lyon), topic: crackling nois

Surgical Excision Without Radiation for Ductal Carcinoma in Situ of the Breast: 12-Year Results From the ECOG-ACRIN E5194 Study

Purpose To determine the 12-year risk of developing an ipsilateral breast event (IBE) for women with ductal carcinoma in situ (DCIS) of the breast treated with surgical excision (lumpectomy) without radiation. Patients and Methods A prospective clinical trial was performed for women with DCIS who were selected for low-risk clinical and pathologic characteristics. Patients were enrolled onto one of two study cohorts (not randomly assigned): cohort 1: low- or intermediate-grade DCIS, tumor size 2.5 cm or smaller (n = 561); or cohort 2: high-grade DCIS, tumor size 1 cm or smaller (n = 104). Protocol specifications included excision of the DCIS tumor with a minimum negative margin width of at least 3 mm. Tamoxifen (not randomly assigned) was given to 30% of the patients. An IBE was defined as local recurrence of DCIS or invasive carcinoma in the treated breast. Median follow-up time was 12.3 years. Results There were 99 IBEs, of which 51 (52%) were invasive. The IBE and invasive IBE rates increased over time in both cohorts. The 12-year rates of developing an IBE were 14.4% for cohort 1 and 24.6% for cohort 2 (P = .003). The 12-year rates of developing an invasive IBE were 7.5% and 13.4%, respectively (P = .08). On multivariable analysis, study cohort and tumor size were both significantly associated with developing an IBE (P = .009 and P = .03, respectively). Conclusion For patients with DCIS selected for favorable clinical and pathologic characteristics and treated with excision without radiation, the risks of developing an IBE and an invasive IBE increased through 12 years of follow-up, without plateau. These data help inform the treatment decision-making process for patients and their physicians

(Quantum) Space-Time as a Statistical Geometry of Fuzzy Lumps and the Connection with Random Metric Spaces

We develop a kind of pregeometry consisting of a web of overlapping fuzzy lumps which interact with each other. The individual lumps are understood as certain closely entangled subgraphs (cliques) in a dynamically evolving network which, in a certain approximation, can be visualized as a time-dependent random graph. This strand of ideas is merged with another one, deriving from ideas, developed some time ago by Menger et al, that is, the concept of probabilistic- or random metric spaces, representing a natural extension of the metrical continuum into a more microscopic regime. It is our general goal to find a better adapted geometric environment for the description of microphysics. In this sense one may it also view as a dynamical randomisation of the causal-set framework developed by e.g. Sorkin et al. In doing this we incorporate, as a perhaps new aspect, various concepts from fuzzy set theory.Comment: 25 pages, Latex, no figures, some references added, some minor changes added relating to previous wor

Ultrametricity and Memory in a Solvable Model of Self-Organized Criticality

Slowly driven dissipative systems may evolve to a critical state where long periods of apparent equilibrium are punctuated by intermittent avalanches of activity. We present a self-organized critical model of punctuated equilibrium behavior in the context of biological evolution, and solve it in the limit that the number of independent traits for each species diverges. We derive an exact equation of motion for the avalanche dynamics from the microscopic rules. In the continuum limit, avalanches propagate via a diffusion equation with a nonlocal, history-dependent potential representing memory. This nonlocal potential gives rise to a non-Gaussian (fat) tail for the subdiffusive spreading of activity. The probability for the activity to spread beyond a distance $r$ in time $s$ decays as $\sqrt{24\over\pi}s^{-3/2}x^{1/3} \exp{[-{3\over 4}x^{1/3}]}$ for $x={r^4\over s} \gg 1$. The potential represents a hierarchy of time scales that is dynamically generated by the ultrametric structure of avalanches, which can be quantified in terms of ``backward'' avalanches. In addition, a number of other correlation functions characterizing the punctuated equilibrium dynamics are determined exactly.Comment: 44 pages, Revtex, (12 ps-figures included

Absolute Humidity and the Seasonal Onset of Influenza in the Continental United States

Here, the authors demonstrate that variations of absolute humidity explain both the onset of wintertime influenza transmission and the overarching seasonality of this pathogen in temperate regions

Polaron and bipolaron formation in the Hubbard-Holstein model: role of next-nearest neighbor electron hopping

The influence of next-nearest neighbor electron hopping, $t^{\prime}$, on the polaron and bipolaron formation in a square Hubbard-Holstein model is investigated within a variational approach. The results for electron-phonon and electron-electron correlation functions show that a negative value of $t^{\prime}$ induces a strong anisotropy in the lattice distortions favoring the formation of nearest neighbor intersite bipolaron. The role of $t^{\prime}$, electron-phonon and electron-electron interactions is briefly discussed in view of the formation of charged striped domains.Comment: 4 figure

Avalanche Dynamics in Evolution, Growth, and Depinning Models

The dynamics of complex systems in nature often occurs in terms of punctuations, or avalanches, rather than following a smooth, gradual path. A comprehensive theory of avalanche dynamics in models of growth, interface depinning, and evolution is presented. Specifically, we include the Bak-Sneppen evolution model, the Sneppen interface depinning model, the Zaitsev flux creep model, invasion percolation, and several other depinning models into a unified treatment encompassing a large class of far from equilibrium processes. The formation of fractal structures, the appearance of $1/f$ noise, diffusion with anomalous Hurst exponents, Levy flights, and punctuated equilibria can all be related to the same underlying avalanche dynamics. This dynamics can be represented as a fractal in $d$ spatial plus one temporal dimension. We develop a scaling theory that relates many of the critical exponents in this broad category of extremal models, representing different universality classes, to two basic exponents characterizing the fractal attractor. The exact equations and the derived set of scaling relations are consistent with numerical simulations of the above mentioned models.Comment: 27 pages in revtex, no figures included. Figures or hard copy of the manuscript supplied on reques