Improved Measurement of Muon Antineutrino Disappearance in MINOS

We report an improved measurement of (nu) over bar (mu) disappearance over a distance of 735 km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a (nu) over bar (mu)-enhanced configuration. From a total exposure of 2.95 x 10(20) protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of Delta(m) over bar (2) = [2.62(-0.28)(+0.31)(stat) +/- 0.09(syst)] x 10(-3) eV(2) and constrain the (nu) over bar (mu) mixing angle sin(2)(2 (theta) over bar) > 0.75 (90% C.L.). These values are in agreement with Delta m(2) and sin(2)(2 theta) measured for nu(mu), removing the tension reported in [P. Adamson et al. (MINOS), Phys. Rev. Lett. 107, 021801 (2011).].

Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumor suppressor at tyrosine 240

Glioblastoma multiforme (GBM) is the most aggressive of the astrocytic malignancies and the most common intracranial tumor in adults. Although the epidermal growth factor receptor (EGFR) is overexpressed and/or mutated in at least 50% of GBM cases and is required for tumor maintenance in animal models, EGFR inhibitors have thus far failed to deliver significant responses in GBM patients. One inherent resistance mechanism in GBM is the coactivation of multiple receptor tyrosine kinases, which generates redundancy in activation of phosphoinositide-3'-kinase (PI3K) signaling. Here we demonstrate that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor is frequently phosphorylated at a conserved tyrosine residue, Y240, in GBM clinical samples. Phosphorylation of Y240 is associated with shortened overall survival and resistance to EGFR inhibitor therapy in GBM patients and plays an active role in mediating resistance to EGFR inhibition in vitro. Y240 phosphorylation can be mediated by both fibroblast growth factor receptors and SRC family kinases (SFKs) but does not affect the ability of PTEN to antagonize PI3K signaling. These findings show that, in addition to genetic loss and mutation of PTEN, its modulation by tyrosine phosphorylation has important implications for the development and treatment of GBM.

Mental Disorders in Megacities: Findings from the Sao Paulo Megacity Mental Health Survey, Brazil

Background: World population growth is projected to be concentrated in megacities, with increases in social inequality and urbanization-associated stress. Sao Paulo Metropolitan Area (SPMA) provides a forewarning of the burden of mental disorders in urban settings in developing world. The aim of this study is to estimate prevalence, severity, and treatment of recently active DSM-IV mental disorders. We examined socio-demographic correlates, aspects of urban living such as internal migration, exposure to violence, and neighborhood-level social deprivation with 12-month mental disorders. Methods and Results: A representative cross-sectional household sample of 5,037 adults was interviewed face-to-face using the WHO Composite International Diagnostic Interview (CIDI), to generate diagnoses of DSM-IV mental disorders within 12 months of interview, disorder severity, and treatment. Administrative data on neighborhood social deprivation were gathered. Multiple logistic regression was used to evaluate individual and contextual correlates of disorders, severity, and treatment. Around thirty percent of respondents reported a 12-month disorder, with an even distribution across severity levels. Anxiety disorders were the most common disorders (affecting 19.9%), followed by mood (11%), impulse-control (4.3%), and substance use (3.6%) disorders. Exposure to crime was associated with all four types of disorder. Migrants had low prevalence of all four types compared to stable residents. High urbanicity was associated with impulse-control disorders and high social deprivation with substance use disorders. Vulnerable subgroups were observed: women and migrant men living in most deprived areas. Only one-third of serious cases had received treatment in the previous year. Discussion: Adults living in Sao Paulo megacity had prevalence of mental disorders at greater levels than similar surveys conducted in other areas of the world. Integration of mental health promotion and care into the rapidly expanding Brazilian primary health system should be strengthened. This strategy might become a model for poorly resourced and highly populated developing countries.

Search for Lorentz invariance and CPT violation with muon antineutrinos in the MINOS Near Detector

We have searched for sidereal variations in the rate of antineutrino interactions in the MINOS Near Detector. Using antineutrinos produced by the NuMI beam, we find no statistically significant sidereal modulation in the rate. When this result is placed in the context of the Standard Model Extension theory we are able to place upper limits on the coefficients defining the theory. These limits are used in combination with the results from an earlier analysis of MINOS neutrino data to further constrain the coefficients.

Measurements of atmospheric neutrinos and antineutrinos in the MINOS far detector

This paper reports measurements of atmospheric neutrino and antineutrino interactions in the MINOS Far Detector, based on 2553 live-days (37.9 kton-years) of data. A total of 2072 candidate events are observed. These are separated into 905 contained-vertex muons and 466 neutrino-induced rock-muons, both produced by charged-current nu(mu) and (nu) over bar (mu) interactions, and 701 contained-vertex showers, composed mainly of charged-current nu(e) and (nu) over bar (e) interactions and neutral-current interactions. The curvature of muon tracks in the magnetic field of the MINOS Far Detector is used to select separate samples of nu(mu) and (nu) over bar (mu) events. The observed ratio of (nu) over bar (mu) to v(mu) events is compared with the Monte Carlo ( MC) simulation, giving a double ratio of R((nu) over bar/nu)data/R(nu) over bar/nu MC = 1.03 +/- 0.08(stat) +/- 0.08(syst). The v(mu) and (nu) over bar (mu) data are separated into bins of L/E resolution, based on the reconstructed energy and direction of each event, and a maximum likelihood fit to the observed L/E distributions is used to determine the atmospheric neutrino oscillation parameters. This fit returns 90% confidence limits of |Delta m(2)| = (1.9 +/- 0.4) x 10(-3) eV(2) and sin(2)2 theta > 0.86. The fit is extended to incorporate separate nu(mu) and (nu) over bar mu oscillation parameters, returning 90% confidence limits of |Delta m(2)| - |Delta(m) over bar (2)| = 0.6(-0.8)(+2.4) x 10(-3) eV(2) on the difference between the squared-mass splittings for neutrinos and antineutrinos.

Interstrain differences in the severity of liver injury induced by a choline- and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism

Nonalcoholic fatty liver disease (NAFLD) is a major health problem and a leading cause of chronic liver disease in the United States and developed countries. In humans, genetic factors greatly influence individual susceptibility to NAFLD. The goals of this study were to compare the magnitude of interindividual differences in the severity of liver injury induced by methyl-donor deficiency among individual inbred strains of mice and to investigate the underlying mechanisms associated with the variability. Feeding mice a choline-and folate-deficient diet for 12 wk caused liver injury similar to NAFLD. The magnitude of liver injury varied among the strains, with the order of sensitivity being A/J approximate to C57BL/6J approximate to C3H/HeJ < 129S1/SvImJ approximate to CAST/EiJ < PWK/PhJ < WSB/EiJ. The interstrain variability in severity of NAFLD liver damage was associated with dysregulation of genes involved in lipid metabolism, primarily with a down-regulation of the peroxisome proliferator receptor alpha (PPAR alpha)-regulated lipid catabolic pathway genes. Markers of oxidative stress and oxidative stress-induced DNA damage were also elevated in the livers but were not correlated with severity of liver damage. These findings suggest that the PPAR alpha-regulated metabolism network is one of the key mechanisms determining interstrain susceptibility and severity of NAFLD in mice.-Tryndyak, V., de Conti, A., Kobets, T., Kutanzi, K., Koturbash, I., Han, T., Fuscoe, J. C., Latendresse, J. R., Melnyk, S., Shymonyak, S., Collins, L., Ross, S. A., Rusyn, I., Beland, F. A., Pogribny, I. P. Interstrain differences in the severity of liver injury induced by a choline-and folate-deficient diet in mice are associated with dysregulation of genes involved in lipid metabolism. FASEB J. 26, 4592-4602 (2012). www.fasebj.org

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease

Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

The ArgoNeuT detector in the NuMI low-energy beam line at Fermilab

The ArgoNeuT liquid argon time projection chamber has collected thousands of neutrino and anti-neutrino events during an extended run period in the NuMI beam-line at Fermilab. This paper focuses on the main aspects of the detector layout and related technical features, including the cryogenic equipment, time projection chamber, read-out electronics, and off-line data treatment. The detector commissioning phase, physics run, and first neutrino event displays are also reported. The characterization of the main working parameters of the detector during data-taking, the ionization electron drift velocity and lifetime in liquid argon, as obtained from through-going muon data complete the present report.

Bivalirudin versus unfractionated heparin during percutaneous coronary intervention

BACKGROUND: Whether bivalirudin is superior to unfractionated heparin in patients with stable or unstable angina who undergo percutaneous coronary intervention (PCI) after pretreatment with clopidogrel is unknown. METHODS: We enrolled 4570 patients with stable or unstable angina (with normal levels of troponin T and creatine kinase MB) who were undergoing PCI after pretreatment with a 600-mg dose of clopidogrel at least 2 hours before the procedure; 2289 patients were randomly assigned in a double-blind manner to receive bivalirudin, and 2281 to receive unfractionated heparin. The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization. RESULTS: The incidence of the primary end point was 8.3% (190 patients) in the bivalirudin group as compared with 8.7% (199 patients) in the unfractionated-heparin group (relative risk, 0.94; 95% confidence interval [CI], 0.77 to 1.15; P=0.57). The secondary end point occurred in 134 patients (5.9%) in the bivalirudin group and 115 patients (5.0%) in the unfractionated-heparin group (relative risk, 1.16; 95% CI, 0.91 to 1.49; P=0.23). The incidence of major bleeding was 3.1% (70 patients) in the bivalirudin group and 4.6% (104 patients) in the unfractionated-heparin group (relative risk, 0.66; 95% CI, 0.49 to 0.90; P=0.008). CONCLUSIONS: In patients with stable and unstable angina who underwent PCI after pretreatment with clopidogrel, bivalirudin did not provide a net clinical benefit (i.e., it did not reduce the incidence of the composite end point of death, myocardial infarction, urgent target-vessel revascularization, or major bleeding) as compared with unfractionated heparin, but it did significantly reduce the incidence of major bleeding. (ClinicalTrials.gov number, NCT00262054.)

INVESTIGATING THE IMPACTS OF STREAMBED HABITAT HETEROGENEITY ON ECOSYSTEM STRUCTURE AND PROCESSES USING BASIC AND APPLIED PERSPECTIVES

Stream restoration often focuses on increasing habitat heterogeneity to reverse ecosystem degradation. However, the connection between heterogeneity and ecosystem structure and processes is poorly understood. We looked to investigate this interaction from both applied and basic science perspectives. For the applied study, we examined two culvert replacements designed to mimic natural stream channels, to see if they were better at maintaining ecosystem processes within as well as upstream and downstream of culverts compared to non-replaced culverts. We measured three ecosystem processes (nutrient uptake, hydrologic characteristics, and coarse particulate organic matter retention) and found that stream simulation culvert restoration improved organic matter retention within culverts, and that there were no differences in processes measured upstream and downstream of both restoration designs. Our results suggest that measurements of ecosystem processes are more likely to show a response to restoration if they match the scale of the restoration activity. For the basic science study, we quantified the longitudinal spatial heterogeneity of physical and biofilm characteristics at microhabitat to segment scales on streams with different streambed variability. We found that all physical characteristics and biofilm characteristics were spatially independent at the macro-habitat scale and greater. Together, these studies demonstrate the importance of scale in ecological interactions and the value of incorporating considerations of scale into restoration activities.

Flotation of a Complex Sulphide Ore Containing Tetrahedrite

The ore investigated in this thesis is a zinc-copper-lead ore. Microscopic analysis of this complex sulphide ore showed it to contain pyrite, sphalerite, arsenopyrite, galena, chalcopyrite, tetrahedrite, and covellite, with quartz as the gangue constituent.

Controversies of fetal cardiac intervention

Remarkable advances in ultrasound imaging technology have made it possible to diagnose fetal cardiovascular lesions as early as 12-14 weeks of gestation and to assess their physiological relevance by echocardiography. Moreover, invasive techniques have been developed and refined to relieve significant congenital heart disease (CHD), such as critical aortic and pulmonary stenoses in the pediatric population including neonates. Recognition of the fact that certain CHDs can evolve in utero, and early intervention may improve the outcome by altering the natural history of such conditions has led to the evolution of a new fetal therapy, i.e. fetal cardiac intervention. Two entities, pulmonary valvar atresia and intact ventricular septum (PA/IVS) and hypoplastic left heart syndrome (HLHS), are associated with significant morbidity and mortality even with postnatal surgical therapy. These cases are believed to occur due to restricted blood flow, leading to impaired growth and function of the right or left ventricle. Therefore, several centers started the approach of antenatal intervention with the primary goal of improving the blood flow through the stenotic/atretic valve orifices to allow growth of cardiac structures. Even though centers with a reasonable number of cases seem to have improved the technique and the immediate outcome of fetal interventions, the field is challenged by ethical issues as the intervention puts both the mother and the fetus at risk. Moreover, the perceived benefits of prenatal treatment have to be weighed against steadily improving postnatal surgical and hybrid procedures, which have been shown to reduce morbidity and mortality for these complex heart defects. This review is an attempt to provide a balanced opinion and an update on fetal cardiac intervention.