A novel, <i>de novo</i> mutation in <i>PRKAG2</i> gene:infantile-onset phenotype and signaling pathway involved

PRKAG2 encodes the γ2-subunit isoform of the 5' AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload, ventricular preexcitation and hypertrophy. We identified a novel, de novo PRKAG2 mutation (K475E) in a neonate with prenatal onset of HCM. We aimed to investigate the cellular impact, signaling pathways involved and therapeutic options for K475E mutation using cells stably expressing human wild type (WT) or the K475E mutant. In HEK293 cells, the K475E mutation induced a marked increase in the basal phosphorylation of T172 and AMPK activity, reduced sensitivity to AMP in allosteric activation and a loss of response to phenformin. In H9c2 cardiomyocytes, the K475E mutation induced inhibition of AMPK and reduced response to phenformin and increases in phosphorylation of P70S6K and 4E-BP1. Primary fibroblasts from the patient with the K475E mutation also showed marked increases in phosphorylation of P70S6K and 4E-BP1, compared to those from age-matched, non-diseased controls. Moreover, overexpression of K475E induced hypertrophy in H9c2 cells which was effectively reversed by treatment with rapamycin. Taken together, we have identified a novel, de novo infantile-onset PRKAG2 mutation causing HCM. Our study suggests the K475E mutation induces alteration in basal AMPK activity and results in a hypertrophy phenotype involving the mechanistic target of rapamycin (mTOR) signaling pathway, which can be reversed with rapamycin..</p

Wall-Resolved Large Eddy Simulations of Transonic Shock-Induced Flow Separation

This paper reports the wall-resolved large eddy simulations of shock-induced boundary layer separation over an axisymmetric bump for a flow Mach number of 0.875 and a chord-based Reynolds number of 2.763 million. The incoming boundary layer has a momentum-thickness Reynolds number of 6600 at one and a half chord lengths upstream of the leading edge. The calculations simulate the experiment by Bachalo and Johnson (AIAA Journal, Vol. 24, No. 3, 1986), except that the tunnel walls are ignored and the simulations are performed assuming free air with as many as 24 billion grid points. The effects of domain span, grid resolution and time step on the predictions are examined. The results are found to show some sensitivity to the studied parameters. Owing to the outer boundary conditions, the predicted surface pressure distribution as well as the flow separation and reattachment locations tend to agree better with the experimental results from the larger (6 6 ft) tunnel than those from the smaller (2 2 ft) tunnel. The predicted Reynolds shear stress profiles in the separated region differ by as much as 31%from the experimental results that were only obtained in the smaller tunnel. The most accurate surface pressure distribution obtained in this study lies within the scatter of the measurements taken in the two facilities

Changes in heart rate variability and QT variability during the first trimester of pregnancy

The risk of new-onset arrhythmia during pregnancy is high, presumably relating to changes in both haemodynamic and cardiac autonomic function. The ability to non-invasively assess an individual's risk of developing arrhythmia during pregnancy would therefore be clinically significant. We aimed to quantify electrocardiographic temporal characteristics during the first trimester of pregnancy and to compare these with non-pregnant controls.Ninety-nine pregnant women and sixty-three non-pregnant women underwent non-invasive cardiovascular and haemodynamic assessment during a protocol consisting of various physiological states (postural manoeurvres, light exercise and metronomic breathing). Variables measured included stroke volume, cardiac output, heart rate, heart rate variability, QT and QT variability and QTVI (a measure of the variability of QT relative to that of RR).Heart rate (p &#60; 0.0005, p &#60; 0.0005, p &#60; 0.0005) and cardiac output (p = 0.043, p &#60; 0.0005, p &#60; 0.0005) were greater in pregnant women in all physiological states (respectively for the supine position, light exercise and metronomic breathing state), whilst stroke volume was lower in pregnancy only during the supine position (p &#60; 0.0005). QTe (Q wave onset to T wave end) and QTa (T wave apex) were significantly shortened (p &#60; 0.05) and QTeVI and QTaVI were increased in pregnancy in all physiological states (p &#60; 0.0005). QT variability (p &#60; 0.002) was greater in pregnant women during the supine position, whilst heart rate variability was reduced in pregnancy in all states (p &#60; 0.0005).Early pregnancy is associated with substantial changes in heart rate variability, reflecting a reduction in parasympathetic tone and an increase in sympathetic activity. QTVI shifted to a less favourable value, reflecting a greater than normal amount of QT variability. QTVI appears to be a useful method for quantifying changes in QT variability relative to RR (or heart rate) variability, being sensitive not only to physiological state but also to gestational age. We support the use of non-invasive markers of cardiac electrical variability to evaluate the risk of arrhythmic events in pregnancy, and we recommend the use of multiple physiological states during the assessment protocol

Novel insights into host-fungal pathogen interactions derived from live-cell imaging

Acknowledgments The authors acknowledge funding from the Wellcome Trust (080088, 086827, 075470 and 099215) including a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377 and FP7-2007–2013 grant agreement HEALTH-F2-2010-260338–ALLFUN to NARG.Peer reviewedPublisher PD

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE

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

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

Performance of CMS muon reconstruction in pp collision events at sqrt(s) = 7 TeV

The performance of muon reconstruction, identification, and triggering in CMS has been studied using 40 inverse picobarns of data collected in pp collisions at sqrt(s) = 7 TeV at the LHC in 2010. A few benchmark sets of selection criteria covering a wide range of physics analysis needs have been examined. For all considered selections, the efficiency to reconstruct and identify a muon with a transverse momentum pT larger than a few GeV is above 95% over the whole region of pseudorapidity covered by the CMS muon system, abs(eta) < 2.4, while the probability to misidentify a hadron as a muon is well below 1%. The efficiency to trigger on single muons with pT above a few GeV is higher than 90% over the full eta range, and typically substantially better. The overall momentum scale is measured to a precision of 0.2% with muons from Z decays. The transverse momentum resolution varies from 1% to 6% depending on pseudorapidity for muons with pT below 100 GeV and, using cosmic rays, it is shown to be better than 10% in the central region up to pT = 1 TeV. Observed distributions of all quantities are well reproduced by the Monte Carlo simulation.Comment: Replaced with published version. Added journal reference and DO