eatris the european research infrastructure for translational medicine and a_iatris its italian node

n/

the role of molecular and imaging biomarkers in the evaluation of inflammation in oncology

n/

Mesenchymal cells recruit and regulate T regulatory cells

n/

The deep look onto the hard X-ray sky: The Swift - INTEGRAL X-ray (SIX) survey

The super-massive black-holes in the centers of Active Galactic Nuclei (AGNs) are surrounded by obscuring matter that can block the nuclear radiation. Depending on the amount of blocked radiation, the flux from the AGN can be too faint to be detected by currently flying hard X-ray (above 15 keV) missions. At these energies only ~1% of the intensity of the Cosmic X-ray Background (CXB) can be resolved into point-like sources that are AGNs. In this work we address the question of the undetected sources contributing to the CXB with a very sensitive and new hard X-ray survey: the SIX survey that is obtained with the new approach of combining the Swift/BAT and INTEGRAL/IBIS X-ray observations. We merge the observations of both missions. This enhances the exposure time and reduces systematic uncertainties. As a result we obtain a new survey over a wide sky area of 6200 deg^2 that is more sensitive than the surveys of Swift/BAT or INTEGRAL/IBIS alone. Our sample comprises 113 sources: 86 AGNs (Seyfert-like and blazars), 5 galaxies, 2 clusters of galaxies, 3 Galactic sources, 3 previously detected unidentified X-ray sources, and 14 unidentified sources. The scientific outcome from the study of the sample has been properly addressed to study the evolution of AGNs at redshift below 0.4. We do not find any evolution using the 1/V_max method. Our sample of faint sources are suitable targets for the new generation hard X-ray telescopes with focusing techniques.Comment: ApJS accepte

Faint-end Quasar Luminosity Functions from Cosmological Hydrodynamic Simulations

We investigate the predictions for the faint-end quasar luminosity function (QLF) and its evolution using fully cosmological hydrodynamic simulations which self-consistently follow star formation, black hole growth and associated feedback processes. We find remarkably good agreement between predicted and observed faint end of the optical and X-ray QLFs (the bright end is not accessible in our simulated volumes) at z < 2. At higher redshifts our simulations tend to overestimate the QLF at the faintest luminosities. We show that although the low (high) luminosity ranges of the faint-end QLF are dominated by low (high) mass black holes, a wide range of black hole masses still contributes to any given luminosity range. This is consistent with the complex lightcurves of black holes resulting from the detailed hydrodynamics followed in the simulations. Consistent with the results on the QLFs, we find good agreement for the evolution of the comoving number density (in optical, soft and hard X-ray bands) of AGN for luminosities above 10^43 erg/s. However, the luminosity density evolution from the simulation appears to imply a peak at higher redshift than constrained from hard X-ray data (but not in optical). Our predicted excess at the faintest fluxes at z >= 2 does not lead to an overestimate to the total X-ray background and its contribution is at most a factor of two larger than the unresolved fraction of the 2-8 keV background. Even though this could be explained by some yet undetected, perhaps heavily obscured faint quasar population, we show that our predictions for the faint sources at high redshifts (which are dominated by the low mass black holes) in the simulations are likely affected by resolution effects.Comment: 12 pages, 9 figures; submitted and reviewed by MNRA

Characterization of compound 584, an Abl kinase inhibitor with lasting effects

Background: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosomepositive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584). Design and Methods: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotransplanted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor. Results: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC50: 8 nM) and in cell-based assays (IC50: 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC50: 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib. Conclusions: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former. ©2008 Ferrata Storti Foundation

X-ray selected Infrared Excess AGN in the Chandra Deep Fields: a moderate fraction of Compton-thick sources

We examine the properties of the X-ray detected, Infrared Excess AGN or Dust Obscured Galaxies (DOGs) in the Chandra Deep Fields (CDF). We find 26 X-ray selected sources which obey the 24 micron to R-band flux ratio criterion f_24/f_R>1000. These are at a median redshift of 2.3 while their IR luminosities are above 10^12 solar. Their X-ray luminosities are all above a few times 10^42 erg s-1 in the 2-10 keV band unambiguously arguing that these host AGN. Nevertheless, their IR Spectral Energy Distributions are split between AGN (Mrk231) and star-forming templates (Arp220). Our primary goal is to examine their individual X-ray spectra in order to assess whether this X-ray detected DOG population contains heavily obscured or even Compton-thick sources. The X-ray spectroscopy reveals a mixed bag of objects. We find that four out of the 12 sources with adequate photon statistics and hence reliable X-ray spectra, show evidence for a hard X-ray spectral index (~1) or harder,consistent with a Compton-thick spectrum. In total 12 out of the 26 DOGs show evidence for flat spectral indices. However, owing to the limited photon statistics we cannot differentiate whether these are flat because they are reflection-dominated or because they show moderate amounts of absorption. Seven DOGs show relatively steep spectra (>1.4) indicative of small column densities. All the above suggest a fraction of Compton-thick sources that does not exceed 5%. The average X-ray spectrum of all 26 DOGs is hard (~1.1) or even harder (~0.6) when we exclude the brightest sources. These spectral indices are well in agreement with the stacked spectrum of X-ray undetected sources (~0.8 in the CDFN). This could suggest (but not necessarily prove) that X-ray undetected DOGs, in a similar fashion to the X-ray detected ones presented here, are hosting a moderate fraction of Compton-thick sources.Comment: 16 pages To appear in A&

A new method for determining the sensitivity of X-ray imaging observations and the X-ray number counts

We present a new method for determining the sensitivity of X-ray imaging observations, which correctly accounts for the observational biases that affect the probability of detecting a source of a given X-ray flux, without the need to perform a large number of time consuming simulations. We use this new technique to estimate the X-ray source counts in different spectral bands (0.5-2, 0.5-10, 2-10 and 5-10keV) by combining deep pencil-beam and shallow wide-area Chandra observations. The sample has a total of 6295 unique sources over an area of $\rm 11.8deg^2$ and is the largest used to date to determine the X-ray number counts. We determine, for the first time, the break flux in the 5-10 keV band, in the case of a double power-law source count distribution. We also find an upturn in the 0.5-2keV counts at fluxes below about 6e-17erg/s/cm2. We show that this can be explained by the emergence of normal star-forming galaxies which dominate the X-ray population at faint fluxes. The fraction of the diffuse X-ray background resolved into point sources at different spectral bands is also estimated. It is argued that a single population of Compton thick AGN cannot be responsible for the entire unresolved X-ray background in the energy range 2-10keV.Comment: Accepted for publication in MNRAS. Data products available at http://astro.imperial.ac.uk/research/xray

On the Lx-L6micron ratio as a diagnostic for Compton-thick AGN

As the mid-IR luminosity represents a good isotropic proxy of the AGN power, a low X-ray to mid-IR luminosity ratio is often claimed to be a reliable indicator for selecting Compton-thick (CT) AGN. We assess the efficiency of this diagnostic by examining the 12mu IRAS AGN sample for which high signal-to-noise XMM observations have been recently become available. We find that the vast majority (10/11) of the AGN that have been classified as CT on the basis the X-ray spectroscopy by Brightman & Nandra present a low Lx/L6 luminosity ratio, i.e. lower than a few percent of the average AGN ratio which is typical of reflection-dominated CT sources. At low Lx/L6 ratios we also find a comparable number of AGN, most of which are heavily absorbed but not CT. This implies that although most Compton-thick AGN present low Lx/L6 ratios, at least in the local, Universe, the opposite is not necessarily true. Next, we extend our analysis to higher redshifts. We perform the same analysis in the CDFS where excellent quality chandra (4 Ms) and xmm (3 Ms) X-ray spectra are available. We derive accurate X-ray luminosities for chandra sources using X-ray spectral fits, as well as 6mu luminosities from SED fits. We find 8 AGN with low Lx/L6 ratios in total, after excluding one source where the 6mu emission primarily comes from star-formation. One of these sources has been already demonstrated to host a CT nucleus, while for another one at a redshift of z=1.22 we argue it is most likely CT on the basis of its combined chandra and xmm spectrum. We find a large number of non CT contaminant with low Lx/L6 ratios. The above suggest that a low Lx/L6 ratio alone cannot ascertain the presence of a CT AGN, albeit the majority of low Lx/L6 AGN are heavily obscured. The two most reliable CT AGN in the high redshift Universe have high Lx/L6 ratios, showing that this method cannot provide complete CT AGN samples.Comment: 11 pages, to appear to A&

High precision X-ray logN-logS distributions: implications for the obscured AGN population

We have constrained the extragalactic source count distributions over a broad range of X-ray fluxes and in various energy bands to test whether the predictions from X-ray background synthesis models agree with the observational constraints provided by our measurements. We have used 1129 XMM-Newton observations at |b|>20 deg covering a sky area of 132.3 deg^2 to compile the largest complete samples of X-ray objects to date in the 0.5-1 keV, 1-2 keV, 2-4.5 keV, 4.5-10 keV, 0.5-2 keV and 2-10 keV energy bands. Our survey includes in excess of 30,000 sources down to ~10^-15 erg/cm^2/s below 2 keV and down to ~10^{-14} erg/cm^2/s above 2 keV. A break in the source count distributions was detected in all energy bands except the 4.5-10 keV band. An analytical model comprising 2 power-law components cannot adequately describe the curvature seen in the source count distributions. The shape of the logN(>S)-logS is strongly dependent on the energy band with a general steepening apparent as we move to higher energies. This is due to non-AGN populations, comprised mainly of stars and clusters of galaxies, contribute up to 30% of the source population at energies 10^{-13} erg/cm^2/s, and these populations of objects have significantly flatter source count distributions than AGN. We find a substantial increase in the relative fraction of hard X-ray sources at higher energies, from >55% below 2 keV to >77% above 2 keV. However the majority of sources detected above 4.5 keV still have significant flux below 2 keV. Comparison with predictions from the synthesis models suggest that the models might be overpredicting the number of faint absorbed AGN, which would call for fine adjustment of some model parameters such as the obscured to unobscured AGN ratio and/or the distribution of column densities at intermediate obscuration.Comment: Accepted for publication in Astronomy and Astrophysics. Abridged Abstract. 23 pages, 47 figures, 8 table