The role of the CCR1 receptor in the inflammatory response to tobacco smoke in a mouse model

Objective: The aim was to create pathological changes in mice relevant to human smoke exposure that can be used to further understand the mechanisms and pathology of smoke-induced inflammatory disease. Methods: Mice were exposed to tobacco smoke or lipopolysaccharide (LPS) to generate an inflammatory infiltrate within the lungs. Results: Tobacco smoke exposure over a 4 day period led to neutrophilia in the lungs of BALB/c mice. Within the inflammatory exudates, significant changes were also seen in protein levels of IL-1B, IL-6, MIP-2, KC (IL-8) and TIMP-1 as measured by ELISA. Further protein changes, as measured via multiplex analysis revealed increased levels of MMP-9, MDC, LIF and MCP-1, amongst other mediators. Major changes in whole lung tissue gene expression patterns were observed. The neutrophilia seen after smoke exposure was steroid-insensitive, relative to doses of steroid needed to reduce LPS-driven neutrophilia in controls. This exposes pathological switches that are changed upon exposure to tobacco smoke, rendering steroids less effective under these conditions. Challenge of chemokine receptor type 1 (CCR1) KO mice in the tobacco smoke model showed that lack of this gene protected the mice from smoke-induced inflammation. Conclusions: This suggests the CCR1 receptor has a key role in the pathogenesis of smoke-induced inflammation

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

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

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

Cepheids and Long Period Variables in NGC 4395

Repeated imaging observations of NGC 4395 were made with the WIYN 3.5 m and the KPNO 2.1 m telescopes. From the photometry of the resolved brighter stars in this galaxy eleven Cepheids with periods ranging between 12 and 90 days have been identified. The true distance modulus has been derived from the apparent distance moduli in g, r and i. The distance modulus is 28.02 +/- 0.18 based on the LMC P-L relation by Sandage et al. 2003; this corresponds to a distance of 4.0 +/- 0.3 Mpc. Using the P-L relation from Madore & Freedman 1991, the distance modulus is 28.15 +/- 0.18; which corresponds to a distance of 4.3 +/- 0.4 Mpc. The reddening is calculated to be E(g-r) = 0.06 +/- 0.08 and E(r-i) = 0.10 +/- 0.08, again from the distance moduli mu_g, mu_r and mu_i. In addition, 37 other variables have been detected, the majority of which have definite periods. They are probably all red long period variables.Comment: 54 pages, 8 figures, 8 tables, accepted for publication in the Astronomical Journa

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

The very local Hubble flow: computer simulations of dynamical history

The phenomenon of the very local ($\le3$ Mpc) Hubble flow is studied on the basis of the data of recent precision observations. A set of computer simulations is performed to trace the trajectories of the flow galaxies back in time to the epoch of the formation of the Local Group. It is found that the `initial conditions' of the flow are drastically different from the linear velocity-distance relation. The simulations enable also to recognize the major trends of the flow evolution and identify the dynamical role of universal antigravity produced by cosmic vacuum.Comment: LaTeX, 10 pages, 4 figures, accepted for publication in A&