N terminus is key to the dominant negative suppression of CaV2 calcium channels: implications for episodic ataxia type 2

Expression of the calcium channels CaV2.1 and CaV2.2 is markedly suppressed by co-expression with truncated constructs containing Domain I. This is the basis for the phenomenon of dominant negative suppression observed for many of the episodic ataxia type 2 mutations in CaV2.1 that predict truncated channels. The process of dominant negative suppression has been shown previously to stem from interaction between the full-length and truncated channels and to result in downstream consequences of the unfolded protein response and endoplasmic reticulum-associated protein degradation. We have now identified the specific domain that triggers this effect. For both CaV2.1 and CaV2.2, the minimum construct producing suppression was the cytoplasmic N terminus. Suppression was enhanced by tethering the N terminus to the membrane with a CAAX motif. The 11-amino acid motif (including Arg52 and Arg54) within the N terminus, which we have previously shown to be required for G protein modulation, is also essential for dominant negative suppression. Suppression is prevented by addition of an N-terminal tag (XFP) to the full-length and truncated constructs. We further show that suppression of CaV2.2 currents by the N terminus-CAAX construct is accompanied by a reduction in CaV2.2 protein level, and this is also prevented by mutation of Arg52 and Arg54 to Ala in the truncated construct. Taken together, our evidence indicates that both the extreme N terminus and the Arg52, Arg54 motif are involved in the processes underlying dominant negative suppression

The Productivity Puzzle in Network Industries: Evidence from the Energy Sector

What accounts for the recent widespread slowdown in the productivity in advanced economies has remained a puzzle. One plausible explanation has been attributable to regulation, particularly anti-competitive regulations and environmental regulations. Thi

A new galaxy near the Local Group in Draco

We present HST WFPC2 and ground-based images of the low surface brightness dwarf Irr/Sph galaxy KKR~25 in Draco. Its colour-magnitude diagram shows red giant branch stars with the tip at I = 22.32 mag, and the presence of some blue stars. The derived true distance modulus, 26.35 \+- 0.14 mag, corresponds to linear distances of KKR25 from the Milky Way and from the Local Group centroid of 1.86 and 1.79 Mpc, respectively. The absolute magnitude of the galaxy, M_V = -10.48, its linear diameter (0.54 Kpc) and central surface brightness (24.0 +- 0.2 mag\arcsec^2) are typical of other dIrr/dSphs in the Local Group. Being situated just beyond the radius of the zero-velocity surface of the Local Group, KKR25 moves away from the LG centroid at a velocity of V_{LG} = + 72 km/s.Comment: 9 pages, 5 figures, accepted for publication in Astronomy & Astrophysic

The Star Formation History of LGS 3

We have determined the distance and star formation history of the Local Group dwarf galaxy LGS 3 from deep Hubble Space Telescope WFPC2 observations. LGS 3 is intriguing because ground-based observations showed that, while its stellar population is dominated by old, metal-poor stars, there is a handful of young, blue stars. Also, the presence of HI gas makes this a possible ``transition object'' between dwarf spheroidal and dwarf irregular galaxies. The HST data are deep enough to detect the horizontal branch and young main sequence for the first time. A new distance of D=620+/-20 kpc has been measured from the positions of the TRGB, the red clump, and the horizontal branch. The mean metallicity of the stars older than 8 Gyr is Fe/H = -1.5 +/- 0.3. The most recent generation of stars has Fe/H ~ -1. For the first few Gyr the global star formation rate was several times higher than the historical average and has been fairly constant since then. However, we do see significant changes in stellar populations and star formation history with radial position in the galaxy. Most of the young stars are found in the central 63 pc (21''), where the star formation rate has been relatively constant, while the outer parts have had a declining star formation rate.Comment: To appear in The Astrophysical Journal, 26 pages, 14 figures, uses AASTe

FMRP regulates presynaptic localization of neuronal voltage gated calcium channels

Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism, results from the loss of fragile X mental retardation protein (FMRP). We have recently identified a direct interaction of FMRP with voltage-gated Ca2+ channels that modulates neurotransmitter release. In the present study we used a combination of optophysiological tools to investigate the impact of FMRP on the targeting of voltage-gated Ca2+ channels to the active zones in neuronal presynaptic terminals. We monitored Ca2+ transients at synaptic boutons of dorsal root ganglion (DRG) neurons using the genetically-encoded Ca2+ indicator GCaMP6f tagged to synaptophysin. We show that knock-down of FMRP induces an increase of the amplitude of the Ca2+ transient in functionally-releasing presynaptic terminals, and that this effect is due to an increase of N-type Ca2+ channel contribution to the total Ca2+ transient. Dynamic regulation of CaV2.2 channel trafficking is key to the function of these channels in neurons. Using a CaV2.2 construct with an α-bungarotoxin binding site tag, we further investigate the impact of FMRP on the trafficking of CaV2.2 channels. We show that forward trafficking of CaV2.2 channels from the endoplasmic reticulum to the plasma membrane is reduced when co-expressed with FMRP. Altogether our data reveal a critical role of FMRP on localization of CaV channels to the presynaptic terminals and how its defect in a context of FXS can profoundly affect synaptic transmission

Local galaxy flows within 5 Mpc

We present Hubble Space Telescope/WFPC2 images of sixteen dwarf galaxies as part of our snapshot survey of nearby galaxy candidates. We derive their distances from the luminosity of the tip of the red giant branch stars with a typical accuracy of ~12%. The resulting distances are 4.26 Mpc (KKH 5), 4.74 Mpc (KK 16), 4.72 Mpc (KK 17), 4.66 Mpc (ESO 115-021), 4.43 Mpc (KKH 18), 3.98 Mpc (KK 27), 4.61 Mpc (KKH 34), 4.99 Mpc (KK 54), 4.23 Mpc (ESO 490-017), 4.90 Mpc (FG 202), 5.22 Mpc (UGC 3755), 5.18 Mpc (UGC 3974), 4.51 Mpc (KK 65), 5.49 Mpc (UGC 4115), 3.78 Mpc (NGC 2915), and 5.27 Mpc (NGC 6503). Based on distances and radial velocities of 156 nearby galaxies, we plot the local velocity-distance relation, which has a slope of H_0 = 73 km/(c * Mpc) and a radial velocity dispersion of 85 km/s. When members of the M81 and CenA groups are removed, and distance errors are taken into account, the radial velocity dispersion drops to sigma_v=41 km/s. The local Hubble flow within 5 Mpc exibits a significant anisotropy, with two infall peculiar velocity regions directed towards the Supergalactic poles. However, two observed regions of outflow peculiar velocity, situated on the Supergalactic equator, are far away (~50 degr.) from the Virgo/anti-Virgo direction, which disagrees with a spherically symmetric Virgo-centric flow. About 63% of galaxies within 5 Mpc belong to known compact and loose groups. Apart from them, we found six new probable groups, consisting entirely of dwarf galaxies.Comment: 22 pages, 7 figures. A&A Accepted. High resolution Figures 1 and 2 (9616k) are available at http://www.sao.ru/~sme/figs.tar.g

Galaxy Flow in the Canes Venatici I Cloud

We present an analysis of Hubble Space Telescope/WFPC2 images of eighteen galaxies in the Canes Venatici I cloud. We derive their distances from the luminosity of the tip of the red giant branch stars with a typical accuracy of ~12 %. The resulting distances are 3.9 Mpc (UGC 6541), 4.9 Mpc (NGC 3738), 3.0 Mpc (NGC 3741), 4.5 Mpc (KK 109), >6.3 Mpc (NGC 4150), 4.2 Mpc (UGC 7298), 4.5 Mpc (NGC 4244), 4.6 Mpc (NGC 4395), 4.9 Mpc (UGC 7559), 4.2 Mpc (NGC 4449), 4.4 Mpc (UGC 7605), 4.6 Mpc (IC 3687), 4.7 Mpc (KK 166), 4.7 Mpc (NGC 4736), 4.2 Mpc (UGC 8308), 4.3 Mpc (UGC 8320), 4.6 Mpc (NGC 5204), and 3.2 Mpc (UGC 8833). The CVn I cloud has a mean radial velocity of 286 +- 9 km/s, a mean distance of 4.1 +- 0.2 Mpc, a radial velocity dispersion of 50 km/s, a mean projected radius of 760 kpc, and a total blue luminosity of 2.2 * 10^{10} L_{\sun}. Assuming virial or closed orbital motions for the galaxies, we estimated their virial and their orbital mass-to-luminosity ratio to be 176 and 88 M_{\sun}/L_{\sun}, respectively. However, the CVn I cloud is characterized by a crossing time of 15 Gyr, and is thus far from a state of dynamical equilibrium. The large crossing time for the cloud, its low content of dSph galaxies ($< 6$ %), and the almost ``primordial'' shape of its luminosity function show that the CVn I complex is in a transient dynamical state, driven rather by the free Hubble expansion than by galaxy interactions.Comment: 23 pages, 6 figures, A&A in preparation. The version does not include Figure 2. High resolution figures 1 and 2 (11311k) are available at http://luna.sao.ru/~sme/figsCVn.tar.g