Slepton Non-Universality in the Flavor-Effective MSSM

Supersymmetric theories supplemented by an underlying flavor-symmetry $\mathcal{G}_f$ provide a rich playground for model building aimed at explaining the flavor structure of the Standard Model. In the case where supersymmetry breaking is mediated by gravity, the soft-breaking Lagrangian typically exhibits large tree-level flavor violating effects, even if it stems from an ultraviolet flavor-conserving origin. Building on previous work, we continue our phenomenological analysis of these models with a particular emphasis on leptonic flavor observables. We consider three representative models which aim to explain the flavor structure of the lepton sector, with symmetry groups $\mathcal{G}_f = \Delta(27)$, $A_4,$ and $S_3$.Comment: References added, minor typos corrected. 28 pages, 8 figure

Majorana Physics Through the Cabibbo Haze

We present a model in which the Supersymmetric Standard Model is augmented by the family symmetry \bs{\m Z_7 \rtimes \m Z_3}. Motivated by $SO(10)$, where the charge two-thirds and neutral Dirac Yukawa matrices are related, we propose, using family symmetry, a special form for the seesaw Majorana matrix; it contains a squared correlated hierarchy, allowing it to mitigate the severe hierarchy of the quark sector. It is reproduced naturally by the invariant operators of \bs{\m Z_7 \rtimes \m Z_3}, with the hierarchy carried by familon fields. In addition to relating the hierarchy of the $\Delta I_{\rm w}=1/2$ to the $\Delta I_{\rm w}=0$ sector, it contains a Gatto-Sartori-Tonin like relation, predicts a normal hierarchy for Tri-bimaximal and Golden Ratio mixings, and gives specific values for the light neutrino masses.Comment: 33 pages, 1 figure. This revised version omits a section where a particular linear combination of dimension-five operators was mistakenly claimed to produce the special form of the Majorana matrix. The main changes are to the Introduction, Sec. 5.1 of the previous version, and Summary and Conclusions. In addition to minor changes throughout, we have corrected an erroneous sign in Eq. 1

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Immunity and other defenses in pea aphids, Acyrthosiphon pisum

The genome of the pea aphid Acyrthosiphon pisum lacks genes thought to be crucial in other insects for recognition, signaling and killing of microbes

Comprehensive preclinical evaluation of human-derived anti-poly-GA antibodies in cellular and animal models of C9ORF72 disease

Hexanucleotide G4C2 repeat expansions in the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) generated by translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intracellular poly-GA and reduced aggregate formation in a poly-GA over-expressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G4C2 repeats by systemic antibody delivery for up to 16 months was well-tolerated and led to measurable brain penetration of antibodies. Long term treatment with anti-GA antibodies produced improvement in an open field movement test in aged C9ORF72450 mice. However, chronic administration of anti-GA antibodies in AAV-(G4C2)149 mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model. Significance Immunotherapy has been proposed for neurodegenerative disorders including Alzheimer’s or Parkinson’s diseases. Recent reports using antibodies against poly-GA or active immunization suggested similar immunotherapy in ALS/FTD caused by repeat expansion in the C9ORF72 gene (1, 2). Here, we systematically characterized human antibodies against multiple DPR species and tested the biological effects of antibodies targeting poly-GA in different cellular and mouse models. Target engagement was shown in three independent cellular models. Anti-GA antibodies reduced the number of intracellular poly-GA aggregates in human T98G cells but not in cultured human neurons. Whereas chronic anti-GA treatment in BAC C9ORF72450 mice did not impact poly-GA levels and modestly improved one behavioral phenotype, poly-GA levels detected by immunoassays were increased and disease progression was unaltered in AAV-(G4C2)149 mice