The role of inhibitory G proteins and regulators of G protein signaling in the in vivo control of heart rate and predisposition to cardiac arrhythmias

Inhibitory heterotrimeric G proteins and the control of heart rate. The activation of cell signaling pathways involving inhibitory heterotrimeric G proteins acts to slow the heart rate via modulation of ion channels. A large number of Regulators of G protein signalings (RGSs) can act as GTPase accelerating proteins to inhibitory G proteins and thus it is important to understand the network of RGS\G-protein interaction. We will review our recent findings on in vivo heart rate control in mice with global genetic deletion of various inhibitory G protein alpha subunits. We will discuss potential central and peripheral contributions to the phenotype and the controversies in the literature

The mechanisms of ventricular arrhythmia in Chagas disease

British Heart Foundation (RG/15/15/31742)Medical Research Council (MRC - MR/L016230/1 & MR/N025083/1

Do anionic phospholipids serve as cofactors or second messengers for the regulation of activity of cloned ATP-sensitive K+ channels?

The regulation of ion channels by anionic phospholipids is currently very topical. An outstanding issue is whether phosphatidylinositol 4,5-diphosphate and related species act as true second messengers in signaling or behave in a manner analogous to an enzymatic cofactor. This question is especially pertinent regarding ATP-sensitive K+ channels in smooth muscle, for which there is substantial literature supporting inhibitory regulation by hormones. In this study, we have examined regulation of the potential cloned equivalents of the smooth muscle ATP-sensitive K+ channel (SUR2B/Kir6.1 and SUR2B/Kir6.2). We find that both can be inhibited via the G(q/11)-coupled muscarinic M3 receptor but that the pathways by which this occurs are different. Our data show that SUR2B/Kir6.1 is inhibited by protein kinase C and binds anionic phospholipids with high affinity, such that potential physiological fluctuations in their levels do not influence channel activity. In contrast, Kir6.2 is not regulated by protein kinase C but binds anionic phospholipids with low affinity. In this case, phosphatidylinositol 4,5-diphosphate and related species have the potential to act as second messengers in signaling. Thus, Kir6.1 and Kir6.2 are regulated by distinct inhibitory mechanisms

Attitudes towards frailty assessment in clinical practice among psychiatrists in the UK

Purpose: Although there is substantial evidence about the association between frailty and mental illnesses in older people, there is currently little evidence about how this is integrated into psychiatric clinical practice. The purpose of this paper is to explore the attitudes of a sample of psychiatrists in the UK about the concept and assessment of frailty in their clinical practice. Design/methodology/approach: This research used a qualitative approach with semi-structured interviews. Interview schedules and transcripts were analysed using thematic analysis. NVivo software and an audit trail were used for the data analysis. Findings: There were ten respondents (all psychiatrists) in this study. From the interviews, it appeared that some respondents were not be fully familiar with existing concepts of frailty. However, from their perspectives, frailty appeared to be multidimensional, reversible and for some could be enhanced by older people’s ability. Negative stereotypes of being frail could undermine the accessibility to appropriate assessment and care. Existing multidisciplinary assessments, with some adjustments to the particular needs of psychiatric patients, can be used to establish a frailty index. Originality/value: The concept of frailty, especially those concerning its multidimensional and homeostatic nature, should be further examined to make it more applicable to psychiatric practice. Without much more effort, frailty could be assessed within current psychiatric practices. This could constitute a care plan tailored for frail people with a psychiatric illness, so as to improve the outcomes of their treatment and quality of life

A 2.5% measurement of the growth rate from small-scale redshift space clustering of SDSS-III CMASS galaxies

We perform the first fit to the anisotropic clustering of SDSS-III CMASS DR10 galaxies on scales of ~ 0.8 - 32 Mpc/h. A standard halo occupation distribution model evaluated near the best fit Planck LCDM cosmology provides a good fit to the observed anisotropic clustering, and implies a normalization for the peculiar velocity field of M ~ 2 x 10^13 Msun/h halos of f*sigma8(z=0.57) = 0.450 +/- 0.011. Since this constraint includes both quasi-linear and non-linear scales, it should severely constrain modified gravity models that enhance pairwise infall velocities on these scales. Though model dependent, our measurement represents a factor of 2.5 improvement in precision over the analysis of DR11 on large scales, f*sigma8(z=0.57) = 0.447 +/- 0.028, and is the tightest single constraint on the growth rate of cosmic structure to date. Our measurement is consistent with the Planck LCDM prediction of 0.480 +/- 0.010 at the ~1.9 sigma level. Assuming a halo mass function evaluated at the best fit Planck cosmology, we also find that 10% of CMASS galaxies are satellites in halos of mass M ~ 6 x 10^13 Msun/h. While none of our tests and model generalizations indicate systematic errors due to an insufficiently detailed model of the galaxy-halo connection, the precision of these first results warrant further investigation into the modeling uncertainties and degeneracies with cosmological parameters.Comment: 24 pages, 20 figures, submitted to MNRAS. v2 is 27 pages, 23 figures, accepted by MNRA

Cosmic Voids and Galaxy Bias in the Halo Occupation Framework

(Abridged) We investigate the power of void statistics to constrain galaxy bias and the amplitude of dark matter fluctuations. We use the halo occupation distribution (HOD) framework to describe the relation between galaxies and dark matter. After choosing HOD parameters that reproduce the mean space density n_gal and projected correlation function w_p measured for galaxy samples with M_r<-19 and M_r<-21 from the Sloan Digital Sky Survey (SDSS), we predict the void probability function (VPF) and underdensity probability function (UPF) of these samples by populating the halos of a large, high-resolution N-body simulation. If we make the conventional assumption that the HOD is independent of large scale environment at fixed halo mass, then models constrained to match n_gal and w_p predict nearly identical void statistics, independent of the scatter between halo mass and central galaxy luminosity or uncertainties in HOD parameters. Models with sigma_8=0.7 and sigma_8=0.9 also predict very similar void statistics. However, the VPF and UPF are sensitive to environmental variations of the HOD in a regime where these variations have little impact on w_p. For example, doubling the minimum host halo mass in regions with large scale (5 Mpc/h) density contrast delta<-0.65 has a readily detectable impact on void probabilities of M_r<-19 galaxies, and a similar change for delta<-0.2 alters the void probabilities of M_r<-21 galaxies at a detectable level. The VPF and UPF provide complementary information about the onset and magnitude of density- dependence in the HOD. By detecting or ruling out HOD changes in low density regions, void statistics can reduce systematic uncertainties in the cosmological constraints derived from HOD modeling, and, more importantly, reveal connections between halo formation history and galaxy properties.Comment: emulateapj, 16 pages, 13 figure

The role of the dystrophin glycoprotein complex in muscle cell mechanotransduction

Dystrophin is the central protein of the dystrophin-glycoprotein complex (DGC) in skeletal and heart muscle cells. Dystrophin connects the actin cytoskeleton to the extracellular matrix (ECM). Severing the link between the ECM and the intracellular cytoskeleton has a devastating impact on the homeostasis of skeletal muscle cells, leading to a range of muscular dystrophies. In addition, the loss of a functional DGC leads to progressive dilated cardiomyopathy and premature death. Dystrophin functions as a molecular spring and the DGC plays a critical role in maintaining the integrity of the sarcolemma. Additionally, evidence is accumulating, linking the DGC to mechanosignalling, albeit this role is still less understood. This review article aims at providing an up-to-date perspective on the DGC and its role in mechanotransduction. We first discuss the intricate relationship between muscle cell mechanics and function, before examining the recent research for a role of the dystrophin glycoprotein complex in mechanotransduction and maintaining the biomechanical integrity of muscle cells. Finally, we review the current literature to map out how DGC signalling intersects with mechanical signalling pathways to highlight potential future points of intervention, especially with a focus on cardiomyopathies