Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons

Tonic conductance mediated by extrasynaptic GABAA receptors has been implicated in the modulation of network oscillatory activity. Using an in vitro brain slice to produce oscillatory activity and a kinetic model of GABAA receptor dynamics, we show that changes in tonic inhibitory input to fast spiking interneurons underlie benzodiazepine-site mediated modulation of neuronal network synchrony in rat primary motor cortex. We found that low concentrations (10 nM) of the benzodiazepine site agonist, zolpidem, reduced the power of pharmacologically-induced beta-frequency (15-30 Hz) oscillatory activity. By contrast, higher doses augmented beta power. Application of the antagonist, flumazenil, also increased beta power suggesting endogenous modulation of the benzodiazepine binding site. Voltage-clamp experiments revealed that pharmacologically-induced rhythmic inhibitory postsynaptic currents were reduced by 10 nM zolpidem, suggesting an action on inhibitory interneurons. Further voltage-clamp studies of fast spiking cells showed that 10 nM zolpidem augmented a tonic inhibitory GABAA receptor mediated current in fast spiking cells whilst higher concentrations of zolpidem reduced the tonic current. A kinetic model of zolpidem-sensitive GABAA receptors suggested that incubation with 10 nM zolpidem resulted in a high proportion of GABAA receptors locked in a kinetically slow desensitized state whilst 30 nM zolpidem favoured rapid transition into and out of desensitized states. This was confirmed experimentally using a challenge with saturating concentrations of GABA. Selective modulation of an interneuron-specific tonic current may underlie the reversal of cognitive and motor deficits afforded by low-dose zolpidem in neuropathological states

On the Continuous Formation of Field Spheroidal Galaxies in Hierarchical Models of Structure Formation

We re-examine the assembly history of field spheroidals as a potentially powerful discriminant of galaxy formation models. Whereas monolithic collapse and hierarchical, merger-driven, models suggest radically different histories for these galaxies, neither the theoretical predictions nor the observational data for field galaxies have been sufficiently reliable for precise conclusions to be drawn. A major difficulty in interpreting the observations, reviewed here, concerns the taxonomic definition of spheroidals in merger-based models. Using quantitative measures of recent star formation activity drawn from the internal properties of a sample of distant field galaxies in the Hubble Deep Fields, we undertake a new analysis to assess the continuous formation of spheroidal galaxies. Whereas abundances and redshift distributions of modelled spheroidals are fairly insensitive to their formation path, we demonstrate that the distribution and amount of blue light arising from recent mergers provides a more sensitive approach. With the limited resolved data currently available, the rate of mass assembly implied by the observed colour inhomogeneities is compared to that expected in popular Lambda-dominated cold dark matter models of structure formation. These models produce as many highly inhomogeneous spheroidals as observed, but underpredict the proportion of homogeneous, passive objects. We conclude that colour inhomogeneities, particularly when combined with spectroscopic diagnostics for large, representative samples of field spheroidals, will be a more valuable test of their physical assembly history than basic source counts and redshift distributions. Securing such data should be a high priority for the Advanced Camera for Surveys on Hubble Space Telescope.Comment: 14 pages, 7 figures, submitted to MNRA

K2: A new method for the detection of galaxy clusters based on CFHTLS multicolor images

We have developed a new method, K2, optimized for the detection of galaxy clusters in multicolor images. Based on the Red Sequence approach, K2 detects clusters using simultaneous enhancements in both colors and position. The detection significance is robustly determined through extensive Monte-Carlo simulations and through comparison with available cluster catalogs based on two different optical methods, and also on X-ray data. K2 also provides quantitative estimates of the candidate clusters' richness and photometric redshifts. Initially K2 was applied to 161 sq deg of two color gri images of the CFHTLS-Wide data. Our simulations show that the false detection rate, at our selected threshold, is only ~1%, and that the cluster catalogs are ~80% complete up to a redshift of 0.6 for Fornax-like and richer clusters and to z ~0.3 for poorer clusters. Based on Terapix T05 release gri photometric catalogs, 35 clusters/sq deg are detected, with 1-2 Fornax-like or richer clusters every two square degrees. Catalogs containing data for 6144 galaxy clusters have been prepared, of which 239 are rich clusters. These clusters, especially the latter, are being searched for gravitational lenses -- one of our chief motivations for cluster detection in CFHTLS. The K2 method can be easily extended to use additional color information and thus improve overall cluster detection to higher redshifts. The complete set of K2 cluster catalogs, along with the supplementary catalogs for the member galaxies, are available on request from the authors.Comment: Accepted in ApJ. 25 pages, including 10 figures. Latex with emulateapj v03/07/0

Hubble Space Telescope Imaging of the CFRS and LDSS Redshift Surveys---III. Field elliptical galaxies at 0.2 < z < 1.0

Surface photometry has been performed on a sample of 46 field elliptical galaxies. These galaxies are described well by a deVaucouleurs R^{1/4} profile. The sample was selected from the combined Canada-France and LDSS redshift surveys and spans the range 0.20 < z < 1.00. The relationship between galaxy half-light radius and luminosity evolves such that a galaxy of a given size is more luminous by Delta M_B=-0.97 \pm 0.14 mag at z=0.92 and the mean rest-frame color shifts blueward by Delta (U-V) =-0.68 \pm 0.11 at z=0.92 relative to the local cluster relations. Approximately 1/3 of these elliptical galaxies exhibit [OII] 3727 emission lines with equivalent widths > 15 angstroms indicating ongoing star formation. Estimated star-formation rates imply that \le 5% of the stellar mass in the elliptical galaxy population has been formed since z=1. We see no evidence for a decline in the space density of early-type galaxies with look-back time. The statistics and a comparison with local luminosity functions are both consistent with the view that the population of massive early-type galaxies was largely in place by z~1. This implies that merging is not required since that time to produce the present-day space density of elliptical galaxies.Comment: 21 pages plus 8 figures plus 5 tables. Accepted by Astrophysical Journa

Early assembly of the most massive galaxies

The current consensus is that galaxies begin as small density fluctuations in the early Universe and grow by in situ star formation and hierarchical merging. Stars begin to form relatively quickly in sub-galactic sized building blocks called haloes which are subsequently assembled into galaxies. However, exactly when this assembly takes place is a matter of some debate. Here we report that the stellar masses of brightest cluster galaxies, which are the most luminous objects emitting stellar light, some 9 billion years ago are not significantly different from their stellar masses today. Brightest cluster galaxies are almost fully assembled 4-5 Gyrs after the Big Bang, having grown to more than 90% of their final stellar mass by this time. Our data conflict with the most recent galaxy formation models based on the largest simulations of dark matter halo development. These models predict protracted formation of brightest cluster galaxies over a Hubble time, with only 22% of the stellar mass assembled at the epoch probed by our sample. Our findings suggest a new picture in which brightest cluster galaxies experience an early period of rapid growth rather than prolonged hierarchical assembly.Comment: Published in Nature 2nd April 2009. This astro ph version includes main text and supplementary material combine

Enhancement of Vaccinia Virus Based Oncolysis with Histone Deacetylase Inhibitors

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells

The properties of field elliptical galaxies at intermediate redshift. III: the Fundamental Plane and the evolution of stellar populations from z~0.4 to z=0

We report on the study of a sample of 25 field early-type galaxies, in the redshift range z~0.1-0.5, selected on the basis of colours and morphology from the HST-MDS. Field early-type galaxies define a tight Fundamental Plane (FP) out to z~0.4, with scatter unchanged with respect to local samples, within the observational errors. The intermediate redshift FP is offset with respect to the FP of the Coma Cluster. The offset of the FP is found to increase with redshift. The evolution of the FP is studied quantitatively with a Bayesian-Montecarlo technique. By applying this technique, we find that the offset of the intercept of the FP (\Delta \gamma) with respect to the local FP increases as \Delta \gamma = \tau z with the following 68 per cent limits: 0.33<\tau<0.44 (for \Omega=1, \Omega_{\Lambda}=0) or 0.44<\tau<0.56 (for \Omega=0.3,\Omega_{\Lambda}=0.7). In addition, we interpret the results in terms of the evolution of the stellar populations, under the assumption of passive evolution. In a single-burst scenario, the observed properties are consistent with those of a stellar population formed at z>2 (for \Omega=1, \Omega_{\Lambda}=0, H_0=50 \kms Mpc^{-1}) or 0.8<z<1.6 (for \Omega=0.3, \Omega_{\Lambda}=0.7, H_0=65 \kms Mpc^{-1}). If a small fraction of the stellar mass is formed in a secondary burst, the primary burst may have occurred at higher z. Finally, the intercept and scatter of the FP found for field early-type galaxies and for cluster data at z~0.4 are mutually consistent, within the observational errors. If higher redshift (up to z=0.83) cluster data are considered, the ages of the stellar populations of field early-type galaxies inferred from a single-burst scenario are found to be marginally smaller than the ages derived for the cluster galaxies. [shortened]Comment: 19 pages, 23 figures, MNRAS, accepte

Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium.

BACKGROUND: Prostate cancer is a common cancer worldwide with no established modifiable lifestyle factors to guide prevention. The associations between polyunsaturated fatty acids (PUFAs) and prostate cancer risk have been inconsistent. Using Mendelian randomisation, we evaluated associations between PUFAs and prostate cancer risk. METHODS: We used individual-level data from a consortium of 22 721 cases and 23 034 controls of European ancestry. Externally-weighted PUFA-specific polygenic risk scores (wPRSs), with explanatory variation ranging from 0.65 to 33.07%, were constructed and used to evaluate associations with prostate cancer risk per one standard deviation (s.d.) increase in genetically-predicted plasma PUFA levels using multivariable-adjusted unconditional logistic regression. RESULTS: No overall association was observed between the genetically-predicted PUFAs evaluated in this study and prostate cancer risk. However, risk reductions were observed for short-chain PUFAs, linoleic (ORLA=0.95, 95%CI=0.92, 0.98) and α-linolenic acids (ORALA=0.96, 95%CI=0.93, 0.98), among men <62 years; whereas increased risk was found among men ⩾62 years for LA (ORLA=1.04, 95%CI=1.01, 1.07). For long-chain PUFAs (i.e., arachidonic, eicosapentaenoic, and docosapentaenoic acids), increased risks were observed among men <62 years (ORAA=1.05, 95%CI=1.02, 1.08; OREPA=1.04, 95%CI=1.01, 1.06; ORDPA=1.05, 95%CI=1.02, 1.08). CONCLUSION: Results from this study suggest that circulating ω-3 and ω-6 PUFAs may have a different role in the aetiology of early- and late-onset prostate cancer