FN3K expression in COPD: a potential comorbidity factor for cardiovascular disease.

INTRODUCTION: Cigarette smoking and oxidative stress are common risk factors for the multi-morbidities associated with chronic obstructive pulmonary disease (COPD). Elevated levels of advanced glycation endproducts (AGE) increase the risk of cardiovascular disease (CVD) comorbidity and mortality. The enzyme fructosamine-3-kinase (FN3K) reduces this risk by lowering AGE levels. METHODS: The distribution and expression of FN3K protein in lung tissues from stable COPD and control subjects, as well as an animal model of COPD, was assessed by immunohistochemistry. Serum FN3K protein and AGE levels were assessed by ELISA in patients with COPD exacerbations receiving metformin. Genetic variants within the FN3K and FN3K-RP genes were evaluated for associations with cardiorespiratory function in the Subpopulations and Intermediate Outcome Measures in COPD Study cohort. RESULTS: This pilot study demonstrates that FN3K expression in the blood and human lung epithelium is distributed at either high or low levels irrespective of disease status. The percentage of lung epithelial cells expressing FN3K was higher in control smokers with normal lung function, but this induction was not observed in COPD patients nor in a smoking model of COPD. The top five nominal FN3K polymorphisms with possible association to decreased cardiorespiratory function (p<0.008-0.02), all failed to reach the threshold (p<0.0028) to be considered highly significant following multi-comparison analysis. Metformin enhanced systemic levels of FN3K in COPD subjects independent of their high-expression or low-expression status. DISCUSSION: The data highlight that low and high FN3K expressors exist within our study cohort and metformin induces FN3K levels, highlighting a potential mechanism to reduce the risk of CVD comorbidity and mortality

Constraints on Nucleon Decay via "Invisible" Modes from the Sudbury Neutrino Observatory

Data from the Sudbury Neutrino Observatory have been used to constrain the lifetime for nucleon decay to ``invisible'' modes, such as n -> 3 nu. The analysis was based on a search for gamma-rays from the de-excitation of the residual nucleus that would result from the disappearance of either a proton or neutron from O16. A limit of tau_inv > 2 x 10^{29} years is obtained at 90% confidence for either neutron or proton decay modes. This is about an order of magnitude more stringent than previous constraints on invisible proton decay modes and 400 times more stringent than similar neutron modes.Comment: Update includes missing efficiency factor (limits change by factor of 2) Submitted to Physical Review Letter

The Majorana Demonstrator radioassay program

The Majorana collaboration is constructing the Majorana Demonstrator at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope 76Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are sufficiently pure is described. The resulting measurements from gamma-ray counting, neutron activation and mass spectroscopy of the radioactive-isotope contamination for the materials studied for use in the detector are reported. We interpret these numbers in the context of the expected background for the experiment

The Majorana Demonstrator radioassay program

The Majorana collaboration is constructing the Majorana Demonstrator at the Sanford Underground Research Facility at the Homestake gold mine, in Lead, SD. The apparatus will use Ge detectors, enriched in isotope Ge, to demonstrate the feasibility of a large-scale Ge detector experiment to search for neutrinoless double beta decay. The long half-life of this postulated process requires that the apparatus be extremely low in radioactive isotopes whose decays may produce backgrounds to the search. The radioassay program conducted by the collaboration to ensure that the materials comprising the apparatus are sufficiently pure is described. The resulting measurements from gamma-ray counting, neutron activation and mass spectroscopy of the radioactive-isotope contamination for the materials studied for use in the detector are reported. We interpret these numbers in the context of the expected background for the experiment. 7

Search for Neutrinoless Double-β Decay in ^{76}Ge with the Majorana Demonstrator.

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-β decay in ^{76}Ge. The Majorana Demonstrator comprises 44.1&nbsp;kg of Ge detectors (29.7&nbsp;kg enriched in ^{76}Ge) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5&nbsp;keV FWHM at Q_{ββ} and a very low background with no observed candidate events in 9.95&nbsp;kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×10^{25}  yr (90%&nbsp;C.L.). This result constrains the effective Majorana neutrino mass to below 240-520&nbsp;meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0_{-2.5}^{+3.1}  counts/(FWHM t yr)

Molecular genetic framework underlying pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of high-throughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal-dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications for lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention