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

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

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 Abacus Cosmos: A Suite of Cosmological N-body Simulations

We present a public data release of halo catalogs from a suite of 125 cosmological $N$-body simulations from the Abacus project. The simulations span 40 $w$CDM cosmologies centered on the Planck 2015 cosmology at two mass resolutions, $4\times 10^{10}\;h^{-1}M_\odot$ and $1\times 10^{10}\;h^{-1}M_\odot$, in $1.1\;h^{-1}\mathrm{Gpc}$ and $720\;h^{-1}\mathrm{Mpc}$ boxes, respectively. The boxes are phase-matched to suppress sample variance and isolate cosmology dependence. Additional volume is available via 16 boxes of fixed cosmology and varied phase; a few boxes of single-parameter excursions from Planck 2015 are also provided. Catalogs spanning $z=1.5$ to $0.1$ are available for friends-of-friends and Rockstar halo finders and include particle subsamples. All data products are available at https://lgarrison.github.io/AbacusCosmosComment: 13 pages, 9 figures, 3 tables. Additional figures added for mass resolution convergence tests, and additional redshifts added for existing tests. Matches ApJS accepted versio

Angular Momentum Evolution of Stars in the Orion Nebula Cluster

(Abridged) We present theoretical models of stellar angular momentum evolution from the Orion Nebula Cluster (ONC) to the Pleiades and the Hyades. We demonstrate that observations of the Pleiades and Hyades place tight constraints on the angular momentum loss rate from stellar winds. The observed periods, masses and ages of ONC stars in the range 0.2--0.5 M$_\odot$, and the loss properties inferred from the Pleiades and Hyades stars, are then used to test the initial conditions for stellar evolution models. We use these models to estimate the distribution of rotational velocities for the ONC stars at the age of the Pleiades (120 Myr). The modeled ONC and observed Pleiades distributions of rotation rates are not consistent if only stellar winds are included. In order to reconcile the observed loss of angu lar momentum between these two clusters, an extrinsic loss mechanism such as protostar-accretion disk interaction is required. Our model, which evolves the ONC stars with a mass dependent saturation threshold normalized such that $\omega_{crit} = 5.4 \omega_\odot$ at 0.5 \m, and which includes a distribution of disk lifetimes that is uniform over the range 0--6 Myr, is consistent with the Pleiades. This model for disk-locking lifetimes is also consistent with inferred disk lifetimes from the percentage of stars with infrared excesses observed in young clusters. Different models, using a variety of initial period distributions and different maximum disk lifetimes, are also compared to the Pleiades. For disk-locking models that use a uniform distribution of disk lifetimes over the range 0 to $\tau_{max}$, the acceptable range of the maximum lifetime is $3.5 < \tau_{max} < 8.5$ Myr.Comment: 21 pages, 7 figures, submitted to Ap

K-ATP channel gene expression is induced by urocortin and mediates its cardioprotective effect

Background-Urocortin is a novel cardioprotective agent that can protect cardiac myocytes from the damaging effects of ischemia/reperfusion both in culture and in the intact heart and is effective when given at reperfusion.Methods and Results-We have analyzed global changes in gone expression in cardiac myocytes after urocortin treatment using gene chip technology. We report that urocortin specifically induces enhanced expression of the Kir 6.1 cardiac potassium channel subunit. On the basis of this finding, we showed that the cardioprotective effect of urocortin both in isolated cardiac cells and in the intact heart is specifically blocked by both generalized and mitochondrial-specific K-ATP channel blockers, whereas the cardioprotective effect of cardiotrophin-1 is unaffected. Conversely, inhibiting the Kir 6.1 channel subunit greatly enhances cardiac cell death after ischemia.Conclusions-This is, to our knowledge, the first report of the altered expression of a K-ATP. channel subunit induced by a cardioprotective agent and demonstrates that K-ATP, channel opening is essential for the effect of this novel cardioprotective agent

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