Chronotropic incompetence predicts mortality in severe obstructive pulmonary disease

We evaluated the prevalence of chronotropic incompetence (CI), a marker of autonomic dysfunction, and its prognostic value in patients with chronic obstructive pulmonary disease (COPD). We performed a retrospective analysis of 449 patients with severe COPD who underwent a cardiopulmonary exercise test, after excluding patients with lung volume reduction surgery, left ventricular dysfunction and those not in sinus rhythm. CI was defined as percent predicted heart rate reserve (%HRR). Events were defined as death or lung transplant during a median follow-up of 68 months. Median age was 61 years; median percent predicted forced expiratory volume in one second (%FEV1) of 25% and median %HRR of 33%. The hazard ratio for an event in the lowest quartile of %HRR, taking the highest quartile as reference, was of 3.2 (95% confidence interval: 2.1-4.8; p < 0.001). In a multivariate regression model, %HRR was an independent predictor of events. In conclusion, Cl was an independent and powerful outcome predictor in patients with severe COPD. (C) 2013 Elsevier B.V. All rights reserved

The Impact of Hypomania on Aerobic Capacity and Cardiopulmonary Functioning—A Case Report

Background: Hypomanic episodes are characterized by increased goal-directed behavior and psychomotor agitation. While the affective, cognitive, and behavioral manifestations of such episodes are well-documented, their physiological influence on aerobic capacity and cardiopulmonary functioning are unknown.Methods: We describe a case report of an individual with schizophrenia who experienced a hypomanic episode while serving as a control participant (wait list) in a single-blind, randomized clinical trial examining the impact of aerobic exercise (AE) on neurocognition in people schizophrenia. As part of the trial, participants completed two scheduled clinical assessments and cardiopulmonary exercise tests (VO2max) at baseline and 12 weeks later at end of study. All participants received standard psychiatric care during the trial. Following a baseline assessment in which he displayed no evidence of mood lability, the subject returned on Week-12 for his scheduled follow-up assessment displaying symptoms of hypomania. He was able to complete the follow-up assessment, as well as third assessment 2 weeks later (Week-14) when his hypomanic symptoms ebbed.Results: While not engaging in AE, the subject's aerobic capacity, as indexed by VO2max, increased by 33% from baseline to Week-12. In comparison, participants engaged in the aerobic exercise training increased their aerobic capacity on average by 18%. In contrast, participants in the control group displayed a small decline (−0.5%) in their VO2max scores. Moreover, the subject's aerobic capacity increased even further by Week-14 (49% increase from baseline), despite the ebbing of his hypomania symptoms at that time. These changes were accompanied by increases in markers of aerobic fitness including peak heart rate, respiratory exchange rate, peak minute ventilation, watts, and peak systolic blood pressure. Resting systolic and diastolic blood pressure, and peak diastolic blood pressure remained unchanged.Conclusions: Our findings suggest that hypomania produce substantial increase in aerobic capacity and that such elevations may remain sustained following the ebbing of hypomanic symptoms. Such elevations may be attributed to increased mobility and goal-directed behavior associated with hypomania, as individuals in hypomanic states may ambulate more frequently, for longer duration, and/or at higher intensity. Our results provide a first and unique view into the impact of hypomania on aerobic capacity and cardiopulmonary functioning

Broken symmetry and the variation of critical properties in the phase behaviour of supramolecular rhombus tilings

The degree of randomness, or partial order, present in two-dimensional supramolecular arrays of isophthalate tetracarboxylic acids is shown to vary due to subtle chemical changes such as the choice of solvent or small differences in molecular dimensions. This variation may be quantified using an order parameter and reveals a novel phase behaviour including random tiling with varying critical properties as well as ordered phases dominated by either parallel or non-parallel alignment of neighbouring molecules, consistent with long-standing theoretical studies. The balance between order and randomness is driven by small differences in the intermolecular interaction energies, which we show, using numerical simulations, can be related to the measured order parameter. Significant variations occur even when the energy difference is much less than the thermal energy highlighting the delicate balance between entropic and energetic effects in complex self-assembly processes

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

The S4–S5 Linker Acts as a Signal Integrator for hERG K+ Channel Activation and Deactivation Gating

Human ether-à-go-go-related gene (hERG) K+ channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4–S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4–S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4–S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4–S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4–S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4–S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel

VPS29 Is Not an Active Metallo-Phosphatase but Is a Rigid Scaffold Required for Retromer Interaction with Accessory Proteins

VPS29 is a key component of the cargo-binding core complex of retromer, a protein assembly with diverse roles in transport of receptors within the endosomal system. VPS29 has a fold related to metal-binding phosphatases and mediates interactions between retromer and other regulatory proteins. In this study we examine the functional interactions of mammalian VPS29, using X-ray crystallography and NMR spectroscopy. We find that although VPS29 can coordinate metal ions Mn2+ and Zn2+ in both the putative active site and at other locations, the affinity for metals is low, and lack of activity in phosphatase assays using a putative peptide substrate support the conclusion that VPS29 is not a functional metalloenzyme. There is evidence that structural elements of VPS29 critical for binding the retromer subunit VPS35 may undergo both metal-dependent and independent conformational changes regulating complex formation, however studies using ITC and NMR residual dipolar coupling (RDC) measurements show that this is not the case. Finally, NMR chemical shift mapping indicates that VPS29 is able to associate with SNX1 via a conserved hydrophobic surface, but with a low affinity that suggests additional interactions will be required to stabilise the complex in vivo. Our conclusion is that VPS29 is a metal ion-independent, rigid scaffolding domain, which is essential but not sufficient for incorporation of retromer into functional endosomal transport assemblies

Untangling the influence of Antarctic and Southern Ocean life on clouds

Polar environments are among the fastest changing regions on the planet. It is a crucial time to make significant improvements in our understanding of how ocean and ice biogeochemical processes are linked with the atmosphere. This is especially true over Antarctica and the Southern Ocean where observations are severely limited and the environment is far from anthropogenic influences. In this commentary, we outline major gaps in our knowledge, emerging research priorities, and upcoming opportunities and needs. We then give an overview of the large-scale measurement campaigns planned across Antarctica and the Southern Ocean in the next 5 years that will address the key issues. Until we do this, climate models will likely continue to exhibit biases in the simulated energy balance over this delicate region. Addressing these issues will require an international and interdisciplinary approach which we hope to foster and facilitate with ongoing community activities and collaborations

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types