Lineage tree analysis of immunoglobulin variable-region gene mutations in autoimmune diseases: chronic activation, normal selection

Autoimmune diseases show high diversity in the affected organs, clinical manifestations and disease dynamics. Yet they all share common features, such as the ectopic germinal centers found in many affected tissues. Lineage trees depict the diversification, via somatic hypermutation (SHM), of immunoglobulin variable-region (IGV) genes. We previously developed an algorithm for quantifying the graphical properties of IGV gene lineage trees, allowing evaluation of the dynamical interplay between SHM and antigen-driven selection in different lymphoid tissues, species, and disease situations. Here, we apply this method to ectopic GC B cell clones from patients with Myasthenia Gravis, Rheumatoid Arthritis, and Sjögren’s Syndrome, using data scaling to minimize the effects of the large variability due to methodological differences between groups. Autoimmune trees were found to be significantly larger relative to normal controls. In contrast, comparison of the measurements for tree branching indicated that similar selection pressure operates on autoimmune and normal control clones

D-brane Solitons in Supersymmetric Sigma-Models

Massive D=4 N=2 supersymmetric sigma models typically admit domain wall (Q-kink) solutions and string (Q-lump) solutions, both preserving 1/2 supersymmetry. We exhibit a new static 1/4 supersymmetric `kink-lump' solution in which a string ends on a wall, and show that it has an effective realization as a BIon of the D=4 super DBI-action. It is also shown to have a time-dependent Q-kink-lump generalization which reduces to the Q-lump in a limit corresponding to infinite BI magnetic field. All these 1/4 supersymmetric sigma-model solitons are shown to be realized in M-theory as calibrated, or `Q-calibrated', M5-branes in an M-monopole background.Comment: 16 pages, 3 figures, Late

Using artificial intelligence techniques for strategy generation in the Commons game

In this paper, we consider the use of artificial intelligence techniques to aid in discovery of winning strategies for the Commons Game (CG). The game represents a common scenario in which multiple parties share the use of a self-replenishing resource. The resource deteriorates quickly if used indiscriminately. If used responsibly, however, the resource thrives. We consider the scenario one player uses hill climbing or particle swarm optimization to select the course of action, while the remaining N − 1 players use a fixed probability vector. We show that hill climbing and particle swarm optimization consistently generate winning strategies

Editorial: application of cytometry in primary immunodeficiencies

Transplantation and immunomodulatio

Constraining Sources of Ultra High Energy Cosmic Rays Using High Energy Observations with the Fermi Satellite

We analyze the conditions that enable acceleration of particles to ultra-high energies, ~10^{20} eV (UHECRs). We show that broad band photon data recently provided by WMAP, ISOCAM, Swift and Fermi satellites, yield constraints on the ability of active galactic nuclei (AGN) to produce UHECRs. The high energy (MeV - GeV) photons are produced by Compton scattering of the emitted low energy photons and the cosmic microwave background or extra-galactic background light. The ratio of the luminosities at high and low photon energies can therefore be used as a probe of the physical conditions in the acceleration site. We find that existing data excludes core regions of nearby radio-loud AGN as possible acceleration sites of UHECR protons. However, we show that giant radio lobes are not excluded. We apply our method to Cen A, and show that acceleration of protons to ~10^{20} eV can only occur at distances >~ 100 kpc from the core.Comment: Extended discussion on former results; Accepted for publication in JCA

Tidal Dwarf Galaxies at Intermediate Redshifts

We present the first attempt at measuring the production rate of tidal dwarf galaxies (TDGs) and estimating their contribution to the overall dwarf population. Using HST/ACS deep imaging data from GOODS and GEMS surveys in conjunction with photometric redshifts from COMBO-17 survey, we performed a morphological analysis for a sample of merging/interacting galaxies in the Extended Chandra Deep Field South and identified tidal dwarf candidates in the rest-frame optical bands. We estimated a production rate about 1.4 {\times} 10^{-5} per Gyr per comoving volume for long-lived TDGs with stellar mass 3 {\times} 10^{8-9} solar mass at 0.5<z<1.1. Together with galaxy merger rates and TDG survival rate from the literature, our results suggest that only a marginal fraction (less than 10%) of dwarf galaxies in the local universe could be tidally-originated. TDGs in our sample are on average bluer than their host galaxies in the optical. Stellar population modelling of optical to near-infrared spectral energy distributions (SEDs) for two TDGs favors a burst component with age 400/200 Myr and stellar mass 40%/26% of the total, indicating that a young stellar population newly formed in TDGs. This is consistent with the episodic star formation histories found for nearby TDGs.Comment: 9 pages, 5 figures, Accepted for publication in Astrophysics & Space Scienc

Gadobutrol-enhanced cardiac magnetic resonance imaging for detection of coronary artery disease

BACKGROUND: Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies. OBJECTIVES: The purpose of this study was to determine the sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging. METHODS: Two international, single-vendor, phase 3 clinical trials of near identical design, "GadaCAD1" and "GadaCAD2," were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant CAD. RESULTS: Because the design and results for GadaCAD1 (n = 376) and GadaCAD2 (n = 388) were very similar, results were summarized as a fixed-effect meta-analysis (n = 764). The prevalence of CAD was 27.8% defined by a ≥70% QCA stenosis. For detection of a ≥70% QCA stenosis, the sensitivity of CMR was 78.9%, specificity was 86.8%, and area under the curve was 0.871. The sensitivity and specificity for multivessel CAD was 87.4% and 73.0%. For detection of a 50% QCA stenosis, sensitivity was 64.6% and specificity was 86.6%. The optimal threshold for detecting CAD was a ≥67% QCA stenosis in GadaCAD1 and ≥63% QCA stenosis in GadaCAD2. CONCLUSIONS: Vasodilator stress and rest myocardial perfusion CMR and LGE imaging had high diagnostic accuracy for CAD in 2 phase 3 clinical trials. These findings supported the U.S. Food and Drug Administration approval of gadobutrol-enhanced CMR (0.1 mmol/kg) to assess myocardial perfusion and LGE in adult patients with known or suspected CAD

Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis

Background & Aims: Parenteral methotrexate induces clinical remission but not endoscopic improvement of mucosal inflammation in patients with ulcerative colitis (UC). We performed a randomized, placebo-controlled trial to assess the efficacy of parenteral methotrexate in maintaining steroid-free response or remission in patients with UC after induction therapy with methotrexate and steroids. Methods: We performed a 48-week trial, from February 2012 through May 2016, of 179 patients with active UC (Mayo score of 6–12 with endoscopy subscore ≥ 2) despite previous conventional or biological therapy. The study comprised a 16-week open label methotrexate induction period followed by a 32-week double-blind, placebo-controlled maintenance period. Patients were given subcutaneous methotrexate (25 mg/wk) and a 12-week steroid taper. At week 16, steroid-free responders were randomly assigned to groups that either continued methotrexate (25 mg/wk, n = 44) or were given placebo (n = 40) until week 48. We compared the efficacy of treatment by analyzing the proportion of patients who remained relapse free and were in remission at week 48 without use of steroids or other medications to control disease activity. Results: Ninety-one patients (51%) achieved response at week 16, and 84 patients were included in the maintenance period study. During this period, 60% of patients in the placebo group (24/40) and 66% in the methotrexate group (29/44) had a relapse of UC (P =.75). At week 48, 30% of patients in the placebo group (12/40) and 27% of patients in the methotrexate group (12/44) were in steroid-free clinical remission without need for additional therapies (P =.86). No new safety signals for methotrexate were detected. Conclusions: Parenteral methotrexate (25 mg/wk) was not superior to placebo in preventing relapses of UC in patients who achieved steroid-free response during induction therapy. ClinicalTrials.gov, Number: NCT01393405

Taxonomy based on science is necessary for global conservation

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