The chromatin assembly factor complex 1 (CAF1) and 5-Azacytidine (5-AzaC) affect cell motility in Src-transformed human epithelial cells

Tumor invasion into surrounding stromal tissue is a hallmark of high grade, metastatic cancers. Oncogenic transformation of human epithelial cells in culture can be triggered by activation of v-Src kinase, resulting in increased cell motility, invasiveness, and tumorigenicity and provides a valuable model for studying how changes in gene expression cause cancer phenotypes. Here, we show that epithelial cells transformed by activated Src show increased levels of DNA methylation and that the methylation inhibitor 5-azacytidine (5-AzaC) potently blocks the increased cell motility and invasiveness induced by Src activation. A proteomic screen for chromatin regulators acting downstream of activated Src identified the replication-dependent histone chaperone CAF1 as an important factor for Src-mediated increased cell motility and invasion. We show that Src causes a 5-AzaC-sensitive decrease in both mRNA and protein levels of the p150 (CHAF1A) and p60 (CHAF1B), subunits of CAF1. Depletion of CAF1 in untransformed epithelial cells using siRNA was sufficient to recapitulate the increased motility and invasive phenotypes characteristic of transformed cells without activation of Src. Maintaining high levels of CAF1 by exogenous expression suppressed the increased cell motility and invasiveness phenotypes when Src was activated. These data identify a critical role of CAF1 in the dysregulation of cell invasion and motility phenotypes seen in transformed cells and also highlight an important role for epigenetic remodeling through DNA methylation for Src-mediated induction of cancer phenotypes

Components of the Extragalactic Gamma Ray Background

We present new theoretical estimates of the relative contributions of unresolved blazars and star-forming galaxies to the extragalactic gamma-ray background (EGB) and discuss constraints on the contributions from alternative mechanisms such as dark matter annihilation and truly diffuse gamma-ray production. We find that the Fermi source count data do not rule out a scenario in which the EGB is dominated by emission from unresolved blazars, though unresolved star-forming galaxies may also contribute significantly to the background, within order-of-magnitude uncertainties. In addition, we find that the spectrum of the unresolved star-forming galaxy contribution cannot explain the EGB spectrum found by EGRET at energies between 50 and 200 MeV, whereas the spectrum of unresolved FSRQs, when accounting for the energy-dependent effects of source confusion, could be consistent with the combined spectrum of the low-energy EGRET EGB measurements and the Fermi-LAT EGB measurements.Comment: version accepted for publication in the Astrophysical Journa

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Tumor surveillance by circulating microRNAs: a hypothesis

A growing body of experimental evidence supports the diagnostic relevance of circulating microRNAs in various diseases including cancer. The biological relevance of circulating microRNAs is, however, largely unknown, particularly in healthy individuals. Here, we propose a hypothesis based on the relative abundance of microRNAs with predominant tumor suppressor activity in the blood of healthy individuals. According to our hypothesis, certain sets of circulating microRNAs might function as a tumor surveillance mechanism exerting continuous inhibition on tumor formation. The microRNA-mediated tumor surveillance might complement cancer immune surveillance

Targeting the hypoxic fraction of tumours using hypoxia activated prodrugs

The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high priority target and one therapeutic strategies designed to eradicate hypoxic cells in tumours are a group of compounds known collectively as hypoxia activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (i) the ability of oxygen to either reverse or inhibit the activation process and (ii) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples

MOJAVE. X. Parsec-Scale Jet Orientation Variations and Superluminal Motion in AGN

We describe the parsec-scale kinematics of 200 AGN jets based on 15 GHz VLBA data obtained between 1994 Aug 31 and 2011 May 1. We present new VLBA 15 GHz images of these and 59 additional AGN from the MOJAVE and 2 cm Survey programs. Nearly all of the 60 most heavily observed jets show significant changes in their innermost position angle over a 12 to 16 year interval, ranging from 10º to 150º on the sky, corresponding to intrinsic variations of ∼0.5º to ∼2º. The BL Lac jets show smaller variations than quasars. Roughly half of the heavily observed jets show systematic position angle trends with time, and 20 show indications of oscillatory behavior. The time spans of the data sets are too short compared to the fitted periods (5 to 12 y), however, to reliably establish periodicity. The rapid changes and large jumps in position angle seen in many cases suggest that the superluminal AGN jet features occupy only a portion of the entire jet cross section, and may be energized portions of thin instability structures within the jet. We have derived vector proper motions for 887 moving features in 200 jets having at least five VLBA epochs. For 557 well-sampled features, there are sufficient data to additionally study possible accelerations. We find that the moving features are generally non-ballistic, with 70% of the well-sampled features showing either significant accelerations or non-radial motions. Inward motions are rare (2% of all features), are slow (<0.1 mas per y), are more prevalent in BL Lac jets, and are typically found within 1 mas of the unresolved core feature. There is a general trend of increasing apparent speed with distance down the jet for both radio galaxies and BL Lac objects. In most jets, the speeds of the features cluster around a characteristic value, yet there is a considerable dispersion in the distribution. Orientation variations within the jet cannot fully account for the dispersion, implying that the features have a range of Lorentz factor and/or pattern speed. Very slow pattern speed features are rare, comprising only 4% of the sample, and are more prevalent in radio galaxy and BL Lac jets. We confirm a previously reported upper envelope to the distribution of speed versus beamed luminosity for moving jet features. Below 10^26 W Hz−1 there is a fall-off in maximum speed with decreasing 15 GHz radio luminosity. The general shape of the envelope implies that the most intrinsically powerful AGN jets have a wide range of Lorentz factors up to ∼40, while intrinsically weak jets are only mildly relativistic

Search for supersymmetry in events with four or more leptons in √s =13 TeV pp collisions with ATLAS

Results from a search for supersymmetry in events with four or more charged leptons (electrons, muons and taus) are presented. The analysis uses a data sample corresponding to 36.1 fb −1 of proton-proton collisions delivered by the Large Hadron Collider at s √ =13 TeV and recorded by the ATLAS detector. Four-lepton signal regions with up to two hadronically decaying taus are designed to target a range of supersymmetric scenarios that can be either enriched in or depleted of events involving the production and decay of a Z boson. Data yields are consistent with Standard Model expectations and results are used to set upper limits on the event yields from processes beyond the Standard Model. Exclusion limits are set at the 95% confidence level in simplified models of General Gauge Mediated supersymmetry, where higgsino masses are excluded up to 295 GeV. In R -parity-violating simplified models with decays of the lightest supersymmetric particle to charged leptons, lower limits of 1.46 TeV, 1.06 TeV, and 2.25 TeV are placed on wino, slepton and gluino masses, respectively

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level

Measurement of the cross section for inclusive isolated-photon production in pp collisions at √s=13TeV using the ATLAS detector

Inclusive isolated-photon production in pp collisions at a centre-of-mass energy of 13TeVis studied with the ATLAS detector at the LHC using a data set with an integrated luminosity of 3.2fb−1. The cross section is measured as a function of the photon transverse energy above 125GeVin different regions of photon pseudorapidity. Next-to-leading-order perturbative QCD and Monte Carlo event-generator predictions are compared to the cross-section measurements and provide an adequate description of the data

Operation and performance of the ATLAS Tile Calorimeter in Run 1

The Tile Calorimeter is the hadron calorimeter covering the central region of the ATLAS experiment at the Large Hadron Collider. Approximately 10,000 photomultipliers collect light from scintillating tiles acting as the active material sandwiched between slabs of steel absorber. This paper gives an overview of the calorimeter’s performance during the years 2008–2012 using cosmic-ray muon events and proton–proton collision data at centre-of-mass energies of 7 and 8TeV with a total integrated luminosity of nearly 30 fb−1. The signal reconstruction methods, calibration systems as well as the detector operation status are presented. The energy and time calibration methods performed excellently, resulting in good stability of the calorimeter response under varying conditions during the LHC Run 1. Finally, the Tile Calorimeter response to isolated muons and hadrons as well as to jets from proton–proton collisions is presented. The results demonstrate excellent performance in accord with specifications mentioned in the Technical Design Report