The calcilytic agent NPS 2143 rectifies hypocalcemia in a mouse model with an activating calcium-sensing-receptor (CaSR) mutation:relevance to autosomal dominant hypocalcemia type 1 (ADH1)

Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of-function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum parathyroid hormone (PTH) concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalise the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells and the effect of NPS 2143 on their intracellular calcium responses determined by flow cytometry. NPS 2143 was also administered as a single intraperitoneal bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1, and improve the hypocalcemia associated with this disorder

Correlated X-ray/Ultraviolet/Optical variability in the very low mass AGN NGC 4395

We report the results of a one year Swift X-ray/UV/optical programme monitoring the dwarf Seyfert nucleus in NGC 4395 in 2008-2009. The UV/optical flux from the nucleus was found to vary dramatically over the monitoring period, with a similar pattern of variation in each of the observed UV/optical bands (spanning 1900 - 5500 {\AA}). In particular, the luminosity of NGC 4395 in the 1900 {\AA} band changed by more than a factor of eight over the monitoring period. The fractional variability was smaller in the UV/optical bands than that seen in the X-rays, with the X-ray/optical ratio increasing with increasing flux. Pseudo-instantaneous flux measurements in the X-ray and each UV/optical band were well correlated, with cross correlation coefficients of >0.7, significant at 99.9 per cent confidence. Archival Swift observations from 2006 sample the intra-day X-ray/optical variability on NGC 4395. These archival data show a very strong correlation between the X-ray and b bands, with a cross-correlation coefficient of 0.84 (significant at >99 per cent confidence). The peak in the cross correlation function is marginally resolved and asymmetric, suggesting that X-rays lead the b band, but by 1 hour. In response to recent (August 2011) very high X-ray flux levels from NGC4395 we triggered Swift ToO observations, which sample the intra-hour X-ray/UV variability. These observations indicate, albeit with large uncertainties, a lag of the 1900 {\AA} band behind the X-ray flux of ~400 s. The tight correlation between the X-ray and UV/optical lightcurves, together with the constraints we place on lag time-scale are consistent with the UV/optical variability of NGC 4395 being primarily due to reprocessing of X-ray photons by the accretion disc.Comment: 11 pages, 9 figures, 3 tables. Accepted for publication in MNRA

Cepheid Calibration of the Peak Brightness of SNe Ia. X. SN 1991T in NGC 4527

Repeated imaging observations have been made of NGC 4527 with the Hubble Space Telescope between April and June 1999, over an interval of 69 days. Images were obtained on 12 epochs in the F555W band and on five epochs in the F814W band. The galaxy hosted the type Ia supernova SN1991T, which showed relatively unusual behavior by having both an abnormal spectrum near light maximum, and a slower declining light curve than the proto-typical Branch normal SNe Ia. A total of 86 variables that are putative Cepheids have been found, with periods ranging from 7.4 days to over 70 days. From photometry with the DoPHOT program, the de-reddened distance modulus is determined to be (m-M)_0 = 30.67 +/- 0.12 (internal uncertainty) using a subset of the Cepheid data whose reddening and error parameters are secure. A parallel analysis of the Cepheids using photometry with ROMAFOT yields (m -M)_0 =30.82 +/- 0.11. The final adopted modulus is (m -M)_0 =30.74 +/- 0.12 +/- 0.12 (d=14.1 +/- 0.8 +/- 0.8 Mpc). The photometric data for SN1991T are used in combination with the Cepheid distance to NGC 4527 to obtain the absolute magnitude for this supernova of M_V^0(max) = -19.85 +/- 0.29. The relatively large uncertainty is a result of the range in estimates of the reddening to the supernova. Thus SN1991T is seen to be only moderately brighter (by ~ 0.3 mag) than the mean for spectroscopically normal supernovae, although magnitude differences of up to 0.6 mag cannot be ruled out.Comment: 46 pages, LATEX using aaspp4.sty, including 9 embedded tables, 19 figures (gif and jpg files), a full-resolution version (ps files) is available at http://www.astro.unibas.ch/forschung/ll/cepheid.shtml, accepted for publication in the Astrophysical Journa

Dark energy domination in the Virgocentric flow

The standard \LambdaCDM cosmological model implies that all celestial bodies are embedded in a perfectly uniform dark energy background, represented by Einstein's cosmological constant, and experience its repulsive antigravity action. Can dark energy have strong dynamical effects on small cosmic scales as well as globally? Continuing our efforts to clarify this question, we focus now on the Virgo Cluster and the flow of expansion around it. We interpret the Hubble diagram, from a new database of velocities and distances of galaxies in the cluster and its environment, using a nonlinear analytical model which incorporates the antigravity force in terms of Newtonian mechanics. The key parameter is the zero-gravity radius, the distance at which gravity and antigravity are in balance. Our conclusions are: 1. The interplay between the gravity of the cluster and the antigravity of the dark energy background determines the kinematical structure of the system and controls its evolution. 2. The gravity dominates the quasi-stationary bound cluster, while the antigravity controls the Virgocentric flow, bringing order and regularity to the flow, which reaches linearity and the global Hubble rate at distances \ga 15 Mpc. 3. The cluster and the flow form a system similar to the Local Group and its outflow. In the velocity-distance diagram, the cluster-flow structure reproduces the group-flow structure with a scaling factor of about 10; the zero-gravity radius for the cluster system is also 10 times larger. The phase and dynamical similarity of the systems on the scales of 1-30 Mpc suggests that a two-component pattern may be universal for groups and clusters: a quasi-stationary bound central component and an expanding outflow around it, due to the nonlinear gravity-antigravity interplay with the dark energy dominating in the flow component.Comment: 7 pages, 2 figures, Astronomy and Astrophysics (accepted

Terahertz oscillations in an In_0.53Ga_0.47As submicron planar gunn diode

The length of the transit region of a Gunn diode determines the natural frequency at which it operates in fundamental mode – the shorter the device, the higher the frequency of operation. The long-held view on Gunn diode design is that for a functioning device the minimum length of the transit region is about 1.5μm, limiting the devices to fundamental mode operation at frequencies of roughly 60 GHz. Study of these devices by more advanced Monte Carlo techniques that simulate the ballistic transport and electron-phonon interactions that govern device behaviour, offers a new lower bound of 0.5μm, which is already being approached by the experimental evidence that has shown planar and vertical devices exhibiting Gunn operation at 600nm and 700nm, respectively. The paper presents results of the first ever THz submicron planar Gunn diode fabricated in In<sub>0.53</sub>Ga<sub>0.47</sub>A on an InP substrate, operating at a fundamental frequency above 300 GHz. Experimentally measured rf power of 28 µW was obtained from a 600 nm long ×120 µm wide device. At this new length, operation in fundamental mode at much higher frequencies becomes possible – the Monte Carlo model used predicts power output at frequencies over 300 GHz

Measuring the mass of the central black hole in the bulgeless galaxy ngc 4395 from gas dynamical modeling

NGC 4395 is a bulgeless spiral galaxy, harboring one of the nearest known type 1 Seyfert nuclei. Although there is no consensus on the mass of its central engine, several estimates suggest it is one of the lightest massive black holes (MBHs) known. We present the first direct dynamical measurement of the mass of this MBH from a combination of two-dimensional gas kinematic data, obtained with the adaptive optics assisted near-infrared integral field spectrograph Gemini/NIFS and high-resolution multiband photometric data from Hubble Space Telescope's Wide Field Camera 3. We use the photometric data to model the shape and stellar mass-to-light ratio of the nuclear star cluster (NSC). From the Gemini/NIFS observations, we derive the kinematics of warm molecular hydrogen gas as traced by emission through the H2 1–0 S(1) transition. These kinematics show a clear rotational signal, with a position angle orthogonal to NGC 4395's radio jet. Our best-fitting tilted ring models of the kinematics of the molecular hydrogen gas contain a black hole with mass M={4}-3+8× {10}5 M⊙ (3σ uncertainties) embedded in an NSC of mass M=2× {10}6 M⊙. Our black hole mass measurement is in excellent agreement with the reverberation mapping mass estimate of Peterson et al. but shows some tension with other mass measurement methods based on accretion signals

The Hubble Constant

I review the current state of determinations of the Hubble constant, which gives the length scale of the Universe by relating the expansion velocity of objects to their distance. There are two broad categories of measurements. The first uses individual astrophysical objects which have some property that allows their intrinsic luminosity or size to be determined, or allows the determination of their distance by geometric means. The second category comprises the use of all-sky cosmic microwave background, or correlations between large samples of galaxies, to determine information about the geometry of the Universe and hence the Hubble constant, typically in a combination with other cosmological parameters. Many, but not all, object-based measurements give $H_0$ values of around 72-74km/s/Mpc , with typical errors of 2-3km/s/Mpc. This is in mild discrepancy with CMB-based measurements, in particular those from the Planck satellite, which give values of 67-68km/s/Mpc and typical errors of 1-2km/s/Mpc. The size of the remaining systematics indicate that accuracy rather than precision is the remaining problem in a good determination of the Hubble constant. Whether a discrepancy exists, and whether new physics is needed to resolve it, depends on details of the systematics of the object-based methods, and also on the assumptions about other cosmological parameters and which datasets are combined in the case of the all-sky methods.Comment: Extensively revised and updated since the 2007 version: accepted by Living Reviews in Relativity as a major (2014) update of LRR 10, 4, 200

The GALEX Ultraviolet Atlas of Nearby Galaxies

We present images, integrated photometry, surface-brightness and color profiles for a total of 1034 nearby galaxies recently observed by the GALEX satellite in its far-ultraviolet (FUV; 1516A) and near-ultraviolet (NUV; 2267A) bands. (...) This data set has been complemented with archival optical, near-infrared, and far-infrared fluxes and colors. We find that the integrated (FUV-K) color provides robust discrimination between elliptical and spiral/irregular galaxies and also among spiral galaxies of different sub-types. Elliptical galaxies with brighter K-band luminosities (i.e. more massive) are redder in (NUV-K) color but bluer in (FUV-NUV) than less massive ellipticals. In the case of the spiral/irregular galaxies our analysis shows the presence of a relatively tight correlation between the (FUV-NUV) color and the total infrared-to-UV ratio. The correlation found between (FUV-NUV) color and K-band luminosity (with lower luminosity objects being bluer than more luminous ones) can be explained as due to an increase in the dust content with galaxy luminosity. The images in this Atlas along with the profiles and integrated properties are publicly available through a dedicated web page at http://nedwww.ipac.caltech.edu/level5/GALEX_Atlas/Comment: 181 pages, 10 figures, accepted for publication in ApJS (abstract abridged

The central region of M83: Massive star formation, kinematics, and the location and origin of the nucleus

We report new near-IR integral field spectroscopy of the central starburst region of the barred spiral galaxy M83 obtained with CIRPASS on Gemini-S, which we analyse in conjunction with GHaFaS Fabry-Perot data, an AAT IRIS2 Ks-band image, and near- and mid-IR imaging from the Hubble and Spitzer space telescopes. The bulk of the current star formation activity is hidden from optical view by dust extinction, but is seen in the near- and mid-IR to the north of the nucleus. This region is being fed by inflow of gas through the bar of M83, traced by the prominent dust lane entering into the circumnuclear region from the north. An analysis of stellar ages confirms that the youngest stars are indeed in the northwest. A gradual age gradient, with older stars further to the south, characterises the well-known star-forming arc in the central region of M83. Detailed analyses of the Pa beta ionised gas kinematics and near-IR imaging confirm that the kinematic centre coincides with the photometric centre of M83, and that these are offset significantly, by about 3 arcsec or 60 pc, from the visible nucleus of the galaxy. We discuss two possible options, the first of which postulates that the kinematic and photometric centre traces a galaxy nucleus hidden by a substantial amount of dust extinction, in the range A_V=3-10 mag. By combining this information with kinematic results and using arguments from the literature, we conclude that such a scenario is, however, unlikely, as is the existence of other "hidden" nuclei in M83. We thus concur with recent authors and favour a second option, in which the nucleus of the galaxy is offset from its kinematic and photometric centre. This is presumably a result of some past interaction, possibly related to the event which lies at the origin of the disturbance of the outer disk of the galaxy. (Abridged)Comment: MNRAS, in press; 16 pages latex, 15 figure

Novel insights into the cardio-protective effects of FGF21 in lean and obese rat hearts

Aims: Fibroblast growth factor 21 (FGF21) is a hepatic metabolic regulator with pleotropic actions. Its plasma concentrations are increased in obesity and diabetes; states associated with an increased incidence of cardiovascular disease. We therefore investigated the direct effect of FGF21 on cardio-protection in obese and lean hearts in response to ischemia. Methods and Results: FGF21, FGF21-receptor 1 (FGFR1) and beta-Klotho (βKlotho) were expressed in rodent, human hearts and primary rat cardiomyocytes. Cardiac FGF21 was expressed and secreted (real time RT-PCR/western blot and ELISA) in an autocrine-paracrine manner, in response to obesity and hypoxia, involving FGFR1-βKlotho components. Cardiac-FGF21 expression and secretion were increased in response to global ischemia. In contrast βKlotho was reduced in obese hearts. In isolated adult rat cardiomyocytes, FGF21 activated PI3K/Akt (phosphatidylinositol 3-kinase/Akt), ERK1/2(extracellular signal-regulated kinase) and AMPK (AMP-activated protein kinase) pathways. In Langendorff perfused rat [adult male wild-type wistar] hearts, FGF21 administration induced significant cardio-protection and restoration of function following global ischemia. Inhibition of PI3K/Akt, AMPK, ERK1/2 and ROR-α (retinoic-acid receptor alpha) pathway led to significant decrease of FGF21 induced cardio-protection and restoration of cardiac function in response to global ischemia. More importantly, this cardio-protective response induced by FGF21 was reduced in obesity, although the cardiac expression profiles and circulating FGF21 levels were increased. Conclusion: In an ex vivo Langendorff system, we show that FGF21 induced cardiac protection and restoration of cardiac function involving autocrine-paracrine pathways, with reduced effect in obesity. Collectively, our findings provide novel insights into FGF21-induced cardiac effects in obesity and ischemia