The diagnostic role of T wave morphology biomarkers in congenital and acquired long QT syndrome: A systematic review

Introduction: QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear. Methods: Electronic databases were searched using the terms “LQTS,” “long QT syndrome,” “QTc prolongation,” “prolonged QT,” and “T wave,” “T wave morphology,” “T wave pattern,” “T wave biomarkers.” Whole text articles assessing TWM, independent of QTc, were included. Results: Seventeen studies met criteria. TWM measurements included T-wave amplitude, duration, magnitude, Tpeak-Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak-Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J-Tpeak; and Tpeak-Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30%) and late repolarization (LRD30%), with ERD reflecting hERG-specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5, left slope in lead V6; and COG last 25% in lead I. T wave right slope in lead I and T-roundness achieved this in aLQTS. Conclusion: Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade

Old stellar population synthesis: New age and mass estimates for Mayall II = G1

Mayall II = G1 is one of the most luminous globular clusters (GCs) in M31. Here, we determine its age and mass by comparing multicolor photometry with theoretical stellar population synthesis models. Based on far- and near-ultraviolet GALEX photometry, broad-band UBVRI, and infrared JHK_s 2MASS data, we construct the most extensive spectral energy distribution of G1 to date, spanning the wavelength range from 1538 to 20,000 A. A quantitative comparison with a variety of simple stellar population (SSP) models yields a mean age that is consistent with G1 being among the oldest building blocks of M31 and having formed within ~1.7 Gyr after the Big Bang. Irrespective of the SSP model or stellar initial mass function adopted, the resulting mass estimates (of order $10^7 M_\odot$) indicate that G1 is one of the most massive GCs in the Local Group. However, we speculate that the cluster's exceptionally high mass suggests that it may not be a genuine GC. We also derive that G1 may contain, on average, $(1.65\pm0.63)\times10^2 L_\odot$ far-ultraviolet-bright, hot, extreme horizontal-branch stars, depending on the SSP model adopted. On a generic level, we demonstrate that extensive multi-passband photometry coupled with SSP analysis enables one to obtain age estimates for old SSPs to a similar accuracy as from integrated spectroscopy or resolved stellar photometry, provided that some of the free parameters can be constrained independently.Comment: Accepted for Publication in RAA, 12 pages, 1 figure, 2 table

The N–Terminal Tail of hERG Contains an Amphipathic α–Helix That Regulates Channel Deactivation

The cytoplasmic N–terminal domain of the human ether–a–go–go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N–terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N–terminal 135 residues of hERG contains a previously described Per–Arnt–Sim (PAS) domain (residues 26–135) as well as an amphipathic α–helix (residues 13–23) and an initial unstructured segment (residues 2–9). Deletion of residues 2–25, only the unstructured segment (residues 2–9) or replacement of the α–helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α–helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N–terminal α–helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel

Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1

Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na+ ions, one H+ and the counter-transport of one K+ ion. Transport by an archaeal homologue of the human glutamate transporters, GltPh, whose three dimensional structure is known is also coupled to three Na+ ions but only two Na+ ion binding sites have been observed in the crystal structure of GltPh. In order to fully utilize the GltPh structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of GltPh and accurately determine the number and location of Na+ ions coupled to transport. Several sites have been proposed for the binding of a third Na+ ion from electrostatic calculations and molecular dynamics simulations. In this study, we have performed detailed free energy simulations for GltPh and reveal a new site for the third Na+ ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in GltPh, and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na+ compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na+ ion in GltPh and EAAT1

Proactive and politically skilled professionals: What is the relationship with affective occupational commitment?

The aim of this study is to extend research on employee affective commitment in three ways: (1) instead of organizational commitment the focus is on occupational commitment; (2) the role of proactive personality on affective occupational commitment is examined; and (3) occupational satisfaction is examined as a mediator and political skills as moderator in the relationship between proactive personality and affective occupational commitment. Two connected studies, one in a hospital located in the private sector and one in a university located in the public sector, are carried out in Pakistan, drawing on a total sample of over 400 employees. The results show that proactive personality is positively related to affective occupational commitment, and that occupational satisfaction partly mediates the relationship between proactive personality and affective occupational commitment. No effect is found for a moderator effect of political skills in the relationship between proactive personality and affective occupational commitment. Political skills however moderate the relationship between proactive personality and affective organizational commitment

Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice

Cell death by apoptosis has a critical role during embryonic development and in maintaining tissue homeostasis. In mammals, there are two converging apoptosis pathways: the ‘extrinsic’ pathway, which is triggered by engagement of cell surface ‘death receptors’ such as Fas/APO-1; and the ‘intrinsic’ pathway, which is triggered by diverse cellular stresses, and is regulated by prosurvival and pro-apoptotic members of the Bcl-2 family of proteins. Pro-survival Mcl-1, which can block activation of the proapoptotic proteins, Bax and Bak, appears critical for the survival and maintenance of multiple haemopoietic cell types. To investigate the impact on haemopoiesis of simultaneously inhibiting both apoptosis pathways, we introduced the vavP-Mcl-1 transgene, which causes overexpression of Mcl-1 protein in all haemopoietic lineages, into Faslpr/lpr mice, which lack functional Fas and are prone to autoimmunity. The combined mutations had a modest impact on myelopoiesis, primarily an increase in the macrophage/monocyte population in Mcl-1tg/lpr mice compared with lpr or Mcl-1tg mice. The impact on lymphopoiesis was striking, with a marked elevation in all major lymphoid subsets, including the non-conventional double-negative (DN) T cells (TCRβ+ CD4– CD8– B220+ ) characteristic of Faslpr/lpr mice. Of note, the onset of autoimmunity was markedly accelerated in Mcl-1tg/lpr mice compared with lpr mice, and this was preceded by an increase in immunoglobulin (Ig)-producing cells and circulating autoantibodies. This degree of impact was surprising, given the relatively mild phenotype conferred by the vavP-Mcl-1 transgene by itself: a two- to threefold elevation of peripheral B and T cells, no significant increase in the non-conventional DN T-cell population and no autoimmune disease. Comparison of the phenotype with that of other susceptible mice suggests that the development of autoimmune disease in Mcl-1tg/lpr mice may be influenced not only by Ig-producing cells but also other haemopoietic cell types

Evolution of long-lived globular cluster stars III. Effect of the initial helium spread on the position of stars in a synthetic Hertzsprung-Russell diagram

Context. Globular clusters host multiple populations of long-lived low-mass stars whose origin remains an open question. Several scenarios have been proposed to explain the associated photometric and spectroscopic peculiarities. They differ, for instance, in the maximum helium enrichment they predict for stars of the second population, which these stars can inherit at birth as the result of the internal pollution of the cluster by different types of stars of the first population. Aims. We present the distribution of helium-rich stars in present-day globular clusters as it is expected in the original framework of the fast-rotating massive stars scenario (FRMS) as first-population polluters. We focus on NGC 6752. Methods. We completed a grid of 330 stellar evolution models for globular cluster low-mass stars computed with different initial chemical compositions corresponding to the predictions of the original FRMS scenario for [Fe/H] = −1.75. Starting from the initial helium-sodium relation that allows reproducing the currently observed distribution of sodium in NGC 6752, we deduce the helium distribution expected in that cluster at ages equal to 9 and 13 Gyr. We distinguish the stars that are moderately enriched in helium from those that are very helium-rich (initial helium mass fraction below and above 0.4, respectively), and compare the predictions of the FRMS framework with other scenarios for globular cluster enrichment. Results. The effect of helium enrichment on the stellar lifetime and evolution reduces the total number of very helium-rich stars that remain in the cluster at 9 and 13 Gyr to only 12% and 10%, respectively, from an initial fraction of 21%. Within this age range, most of the stars still burn their hydrogen in their core, which widens the MS band significantly in effective temperature. The fraction of very helium-rich stars drops in the more advanced evolution phases, where the associated spread in effective temperature strongly decreases. These stars even disappear from the horizontal branch and the asymptotic giant branch at 13 Gyr. Conclusions. The helium constraint is no suitable criterion for clearly distinguishing between the scenarios for GC self-enrichment because only few very helium-rich stars are predicted in the investigated framework and because it is difficult to derive the helium content of GC stars observationally. However, the helium constraint indicates some difficulties of the original FRMS scenario that require the exploration of alternatives

81 Audit of MRSA positive cultures at a UK adult CF centre

Crystal structures provide visual models of biological macromolecules, which are widely used to interpret data from functional studies and generate new mechanistic hypotheses. Because the quality of the collected x-ray diffraction data directly affects the reliability of the structural model, it is essential that the limitations of the models are carefully taken into account when making interpretations. Here we use the available crystal structures of members of the glutamate transporter family to illustrate the importance of inspecting the data that underlie the structural models. Crystal structures of glutamate transporters in multiple different conformations have been solved, but most structures were determined at relatively low resolution, with deposited models based on crystallographic data of moderate quality. We use these examples to demonstrate the extent to which mechanistic interpretations can be made safely

The Eighth Data Release of the Sloan Digital Sky Survey: First Data from SDSS-III

The Sloan Digital Sky Survey (SDSS) started a new phase in August 2008, with new instrumentation and new surveys focused on Galactic structure and chemical evolution, measurements of the baryon oscillation feature in the clustering of galaxies and the quasar Ly alpha forest, and a radial velocity search for planets around ~8000 stars. This paper describes the first data release of SDSS-III (and the eighth counting from the beginning of the SDSS). The release includes five-band imaging of roughly 5200 deg^2 in the Southern Galactic Cap, bringing the total footprint of the SDSS imaging to 14,555 deg^2, or over a third of the Celestial Sphere. All the imaging data have been reprocessed with an improved sky-subtraction algorithm and a final, self-consistent photometric recalibration and flat-field determination. This release also includes all data from the second phase of the Sloan Extension for Galactic Understanding and Evolution (SEGUE-2), consisting of spectroscopy of approximately 118,000 stars at both high and low Galactic latitudes. All the more than half a million stellar spectra obtained with the SDSS spectrograph have been reprocessed through an improved stellar parameters pipeline, which has better determination of metallicity for high metallicity stars.Comment: Astrophysical Journal Supplements, in press (minor updates from submitted version