Identification and functional analysis of novel phosphorylation sites in the RNA surveillance protein Upf1.

One third of inherited genetic diseases are caused by mRNAs harboring premature termination codons as a result of nonsense mutations. These aberrant mRNAs are degraded by the Nonsense-Mediated mRNA Decay (NMD) pathway. A central component of the NMD pathway is Upf1, an RNA-dependent ATPase and helicase. Upf1 is a known phosphorylated protein, but only portions of this large protein have been examined for phosphorylation sites and the functional relevance of its phosphorylation has not been elucidated in Saccharomyces cerevisiae. Using tandem mass spectrometry analyses, we report the identification of 11 putative phosphorylated sites in S. cerevisiae Upf1. Five of these phosphorylated residues are located within the ATPase and helicase domains and are conserved in higher eukaryotes, suggesting a biological significance for their phosphorylation. Indeed, functional analysis demonstrated that a small carboxy-terminal motif harboring at least three phosphorylated amino acids is important for three Upf1 functions: ATPase activity, NMD activity and the ability to promote translation termination efficiency. We provide evidence that two tyrosines within this phospho-motif (Y-738 and Y-742) act redundantly to promote ATP hydrolysis, NMD efficiency and translation termination fidelity

A Randomized Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder.

Objective: Selective serotonin reuptake inhibitors like sertraline have been shown in observational studies and anecdotal reports to improve language development in young children with fragile X syndrome (FXS). A previous controlled trial of sertraline in young children with FXS found significant improvement in expressive language development as measured by the Mullen Scales of Early Learning (MSEL) among those with comorbid autism spectrum disorder (ASD) in post hoc analysis, prompting the authors to probe whether sertraline is also indicated in nonsyndromic ASD. Methods: The authors evaluated the efficacy of 6 months of treatment with low-dose sertraline in a randomized, double-blind, placebo-controlled trial in 58 children with ASD aged 24 to 72 months. Results: 179 subjects were screened for eligibility, and 58 were randomized to sertraline (32) or placebo (26). Eight subjects from the sertraline arm and five from the placebo arm discontinued. Intent-to-treat analysis showed no significant difference from placebo on the primary outcomes (MSEL expressive language raw score and age equivalent combined score) or secondary outcomes. Sertraline was well tolerated, with no difference in side effects between sertraline and placebo groups. No serious adverse events possibly related to study treatment occurred. Conclusion: This randomized controlled trial of sertraline treatment showed no benefit with respect to primary or secondary outcome measures. For the 6-month period, treatment in young children with ASD appears safe, although the long-term side effects of low-dose sertraline in early childhood are unknown. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02385799

Lattice dynamics and spin excitations in the metal-organic framework [CH3_3NH3_3][Co(HCOO)3_3]

In metal-organic-framework (MOF) perovskites, both magnetic and ferroelectric orderings can be readily realized by compounding spin and charge degrees of freedom. The hydrogen bonds that bridge the magnetic framework and organic molecules have long been thought of as a key in generating multiferroic properties. However, the underlying physical mechanisms remain unclear. Here, we combine neutron diffraction, quasielastic and inelastic neutron scattering, and THz spectroscopy techniques to thoroughly investigate the dynamical properties of the multiferroic MOF candidate [CH$_3$NH$_3$][Co(HCOO)$_3$] through its multiple phase transitions. The wide range of energy resolutions reachable by these techniques enables us to scrutinize the coupling between the molecules and the framework throughout the phase transitions and interrogate a possible magnetoelectric coupling. Our results also reveal a structural change around 220 K which may be associated with the activation of a nodding donkey mode of the methylammonium molecule due to the ordering of the CH$_3$ groups. Upon the occurrence of the modulated phase transition around 130 K, the methylammonium molecules undergo a freezing of its reorientational motions which is concomitant with a change of the lattice parameters and anomalies of collective lattice vibrations. No significant change has been however observed in the lattice dynamics around the magnetic ordering, which therefore indicates the absence of a substantial magneto-electric coupling in zero-field

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

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Ovine Abortion by Neospora caninum: First Case Reported in Argentina

Purpose: The aim of this study was to describe for the first time a natural case of ovine abortion associated with Neospora caninum in a flock with reproductive losses in Argentina. Materials and Methods: The analyzed flock consisted of 256 Texel sheep, of which 134 had been mated. A single blood sample was obtained by jugular vein puncture from 220 ewes (116 adult ewes, 104 yearling ewes) and 93 lambs. Serum samples and fetal fluid were tested using the indirect fluorescence antibody test to detect antibodies against N. caninum and T. gondii. Fetal and placental tissues from aborted fetus were examined by standard gross pathology procedures and were tested using histopathology and immunohistochemistry. Moreover, DNA from fetal and placental tissues was isolated and a PCR assay to detect N. caninum, T. gondii and Chlamydia spp. was used. Results and Discussion: The pregnancy rate was 89% (119/134), the abortion rate was 8.4% (10/119) whereas the perinatal mortality rate was 15% (16/109). Out of 116 adult ewes sampled, 34.48% presented anti-N. caninum antibodies. Ten ewes had aborted, and one fetus was directly submitted to the diagnostic laboratory for further processing. Antibodies against N. caninum were detected in fetal fluid and in the aborted dam. Histopathological analysis in fetal tissues showed multifocal lymphohistiocytic glossitis, diffuse mild lymphohistiocytic endocarditis, pericarditis and focally extensive myocarditis. Severe multifocal necrotizing placentitis and diffuse mild lymphohistiocytic placentitis with the presence of lymphohistiocytic vasculitis were observed in placenta. N. caninum was immunolabeled in the placenta and fetal tongue. In addition, N. caninum DNA was detected in placenta, central neural system, lung and heart of the aborted fetus. There was no evidence of other infectious abortifacients in the aborted fetus. Conclusion: The present study described for the first time an ovine abortion caused by N. caninum in Argentina. Further investigations at a larger scale are required to establish the role of N. caninum as an important cause of reproductive losses in sheep flocks from the region.Facultad de Ciencias Veterinaria

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN