PRMT5 is a critical regulator of breast cancer stem cell function via Histone Methylation and FOXP1 expression

Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the argininemethyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient- derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population

Hemispherical power asymmetry: parameter estimation from CMB WMAP5 data

We reexamine the evidence of the hemispherical power asymmetry, detected in the CMB WMAP data using a new method. At first, we analyze the hemispherical variance ratios and compare these with simulated distributions. Secondly, working within a previously-proposed CMB bipolar modulation model, we constrain model parameters: the amplitude and the orientation of the modulation field as a function of various multipole bins. Finally, we select three ranges of multipoles leading to the most anomalous signals, and we process corresponding 100 Gaussian, random field (GRF) simulations, treated as observational data, to further test the statistical significance and robustness of the hemispherical power asymmetry. For our analysis we use the Internally-Linearly-Coadded (ILC) full sky map, and KQ75 cut-sky V channel, foregrounds reduced map of the WMAP five year data (V5). We constrain the modulation parameters using a generic maximum a posteriori method. In particular, we find differences in hemispherical power distribution, which when described in terms of a model with bipolar modulation field, exclude the field amplitude value of the isotropic model A=0 at confidence level of ~99.5% (~99.4%) in the multipole range l=[7,19] (l=[7,79]) in the V5 data, and at the confidence level ~99.9% in the multipole range l=[7,39] in the ILC5 data, with the best fit (modal PDF) values in these particular multipole ranges of A=0.21 (A=0.21) and A=0.15 respectively. However, we also point out that similar or larger significances (in terms of rejecting the isotropic model), and large best-fit modulation amplitudes are obtained in GRF simulations as well, which reduces the overall significance of the CMB power asymmetry down to only about 94% (95%) in the V5 data, in the range l=[7,19] (l=[7,79]).Comment: 24 pages, 10 figures; few typos corrected; published in JCA

Evaluation of anti-biofilm activity of acidic amino acids and synergy with ciprofloxacin on Staphylococcus aureus biofilms

Acidic amino acids, aspartic acid (Asp) and glutamic acid (Glu) can enhance the solubility of many poorly soluble drugs including ciprofloxacin (Cip). One of the mechanisms of resistance within a biofilm is retardation of drug diffusion due to poor penetration across the matrix. To overcome this challenge, this work set to investigate novel counter ion approach with acidic amino acids, which we hypothesised will disrupt the biofilm matrix as well as simultaneously improve drug effectiveness. The anti-biofilm activity of D-Asp and D-Glu was studied on Staphylococcus aureus biofilms. Synergistic effect of combining D-amino acids with Cip was also investigated as a strategy to overcome anti-microbial resistance in these biofilms. Interestingly at equimolar combinations, D-Asp and D-Glu were able to significantly disperse (at 20 mM and 40 mM) established biofilms and inhibit (at 10 mM, 20 mM and 40 mM) new biofilm formation in the absence of an antibiotic. Moreover, our study confirmed L-amino acids also exhibit anti-biofilm activity. The synergistic effect of acidic amino acids with Cip was observed at lower concentration ranges (<40 mM amino acids and <90.54 µM, respectively), which resulted in 96.89% (inhibition) and 97.60% (dispersal) reduction in CFU with exposure to 40 mM amino acids. Confocal imaging indicated that the amino acids disrupt the honeycomb-like extracellular DNA (eDNA) meshwork whilst also preventing its formation

Human Gastrointestinal Juices Intended for Use in In Vitro Digestion Models

The aim of this study was to characterise the individual human gastric and duodenal juices to be used in in vitro model digestion and to examine the storage stability of the enzymes. Gastroduodenal juices were aspirated, and individual variations in enzymatic activities as well as total volumes, pH, bile acids, protein and bilirubin concentrations were recorded. Individual pepsin activity in the gastric juice varied by a factor of 10, while individual total proteolytic activity in the duodenal juice varied by a factor of 5. The duodenal amylase activity varied from 0 to 52.6 U/ml, and the bile acid concentration varied from 0.9 to 4.5 mM. Pooled gastric and duodenal juices from 18 volunteers were characterised according to pepsin activity (26.7 U/ml), total proteolytic activity (14.8 U/ml), lipase activity (951.0 U/ml), amylase activity (26.8 U/ml) and bile acids (4.5 mM). Stability of the main enzymes in two frozen batches of either gastric or duodenal juice was studied for 6 months. Pepsin activity decreased rapidly and adjusting the pH of gastric juice to 4 did not protect the pepsin from degradation. Lipase activity remained stable for 4 months, however decreased rapidly thereafter even after the addition of protease inhibitors. Glycerol only marginally stabilised the survival of the enzymatic activities. These results of compositional variations in the individual gastrointestinal juices and the effect of storage conditions on enzyme activities are useful for the design of in vitro models enabling human digestive juices to simulate physiological digestion

PKS 1502+106: a new and distant gamma-ray blazar in outburst discovered by the Fermi Large Area Telescope

The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope discovered a rapid (about 5 days duration), high-energy (E >100 MeV) gamma-ray outburst from a source identified with the blazar PKS 1502+106 (OR 103, S3 1502+10, z=1.839) starting on August 05, 2008 and followed by bright and variable flux over the next few months. Results on the gamma-ray localization and identification, as well as spectral and temporal behavior during the first months of the Fermi all-sky survey are reported here in conjunction with a multi-waveband characterization as a result of one of the first Fermi multi-frequency campaigns. The campaign included a Swift ToO (followed up by 16-day observations on August 07-22, MJD 54685-54700), VLBA (within the MOJAVE program), Owens Valley (OVRO) 40m, Effelsberg-100m, Metsahovi-14m, RATAN-600 and Kanata-Hiroshima radio/optical observations. Results from the analysis of archival observations by INTEGRAL, XMM-Newton and Spitzer space telescopes are reported for a more complete picture of this new gamma-ray blazar.Comment: 17 pages, 11 figures, accepted for The Astrophysical Journa

Early Fermi Gamma-ray Space Telescope Observations of the Quasar 3C 454.3

This is the first report of Fermi Gamma-ray Space Telescope observations of the quasar 3C 454.3, which has been undergoing pronounced long-term outbursts since 2000. The data from the Large Area Telescope (LAT), covering 2008 July 7 - October 6, indicate strong, highly variable gamma-ray emission with an average flux of ~3 x 10^{-6} photons cm^{-2} s^{-1}, for energies above 100 MeV. The gamma-ray flux is variable, with strong, distinct, symmetrically-shaped flares for which the flux increases by a factor of several on a time scale of about three days. This variability indicates a compact emission region, and the requirement that the source is optically thin to pair-production implies relativistic beaming with Doppler factor delta > 8, consistent with the values inferred from VLBI observations of superluminal expansion (delta ~ 25). The observed gamma-ray spectrum is not consistent with a simple power-law, but instead steepens strongly above ~2 GeV, and is well described by a broken power-law with photon indices of ~2.3 and ~3.5 below and above the break, respectively. This is the first direct observation of a break in the spectrum of a high luminosity blazar above 100 MeV, and it is likely direct evidence for an intrinsic break in the energy distribution of the radiating particles. Alternatively, the spectral softening above 2 GeV could be due to gamma-ray absorption via photon-photon pair production on the soft X-ray photon field of the host AGN, but such an interpretation would require the dissipation region to be located very close (less than 100 gravitational radii) to the black hole, which would be inconsistent with the X-ray spectrum of the source.Comment: Accepted by the Astrophysical Journal; corresponding authors: Greg Madejski ([email protected]) and Benoit Lott ([email protected]

Fermi observations of TeV-selected AGN

We report on observations of TeV-selected AGN made during the first 5.5 months of observations with the Large Area Telescope (LAT) on-board the Fermi Gamma-ray Space Telescope (Fermi). In total, 96 AGN were selected for study, each being either (i) a source detected at TeV energies (28 sources) or (ii) an object that has been studied with TeV instruments and for which an upper-limit has been reported (68 objects). The Fermi observations show clear detections of 38 of these TeV-selected objects, of which 21 are joint GeV-TeV sources and 29 were not in the third EGRET catalog. For each of the 38 Fermi-detected sources, spectra and light curves are presented. Most can be described with a power law of spectral index harder than 2.0, with a spectral break generally required to accommodate the TeV measurements. Based on an extrapolation of the Fermi spectrum, we identify sources, not previously detected at TeV energies, which are promising targets for TeV instruments. Evidence for systematic evolution of the $\gamma$-ray spectrum with redshift is presented and discussed in the context of interaction with the EBL.Comment: 51 pages, 6 figures, accepted for The Astronomical Journa

Fermi/LAT discovery of gamma-ray emission from a relativistic jet in the narrow-line quasar PMN J0948+0022

We report the discovery by the Large Area Telescope (LAT) onboard the Fermi Gamma-ray Space Telescope of high-energy gamma-ray emission from the peculiar quasar PMN J0948+0022 (z=0.5846). The optical spectrum of this object exhibits rather narrow Hbeta (FWHM(Hbeta) ~ 1500 km s^-1), weak forbidden lines and is therefore classified as a narrow-line type I quasar. This class of objects is thought to have relatively small black hole mass and to accrete at high Eddington ratio. The radio loudness and variability of the compact radio core indicates the presence of a relativistic jet. Quasi simultaneous radio-optical-X-ray and gamma-ray observations are presented. Both radio and gamma-ray emission (observed over 5-months) are strongly variable. The simultaneous optical and X-ray data from Swift show a blue continuum attributed to the accretion disk and a hard X-ray spectrum attributed to the jet. The resulting broad band spectral energy distribution (SED) and, in particular, the gamma-ray spectrum measured by Fermi are similar to those of more powerful FSRQ. A comparison of the radio and gamma-ray characteristics of PMN J0948+0022 with the other blazars detected by LAT shows that this source has a relatively low radio and gamma-ray power, with respect to other FSRQ. The physical parameters obtained from modelling the SED also fall at the low power end of the FSRQ parameter region discussed in Celotti & Ghisellini (2008). We suggest that the similarity of the SED of PMN J0948+0022 to that of more massive and more powerful quasars can be understood in a scenario in which the SED properties depend on the Eddington ratio rather than on the absolute power.Comment: 10 pages, 5 figures, accepted for publication on ApJ Main Journal. Corresponding author: L. Foschin

Bright AGN Source List from the First Three Months of the Fermi Large Area Telescope All-Sky Survey

The first three months of sky-survey operation with the Fermi Gamma Ray Space Telescope (Fermi) Large Area Telescope (LAT) reveals 132 bright sources at |b|>10 deg with test statistic greater than 100 (corresponding to about 10 sigma). Two methods, based on the CGRaBS, CRATES and BZCat catalogs, indicate high-confidence associations of 106 of these sources with known AGNs. This sample is referred to as the LAT Bright AGN Sample (LBAS). It contains two radio galaxies, namely Centaurus A and NGC 1275, and 104 blazars consisting of 57 flat spectrum radio quasars (FSRQs), 42 BL Lac objects, and 5 blazars with uncertain classification. Four new blazars were discovered on the basis of the LAT detections. Remarkably, the LBAS includes 10 high-energy peaked BL Lacs (HBLs), sources which were so far hard to detect in the GeV range. Another 10 lower-confidence associations are found. Only thirty three of the sources, plus two at |b|>10 deg, were previously detected with EGRET, probably due to the variable nature of these sources. The analysis of the gamma-ray properties of the LBAS sources reveals that the average GeV spectra of BL Lac objects are significantly harder than the spectra of FSRQs. No significant correlation between radio and peak gamma-ray fluxes is observed. Blazar log N - log S and luminosity functions are constructed to investigate the evolution of the different blazar classes, with positive evolution indicated for FSRQs but none for BLLacs. The contribution of LAT-blazars to the total extragalactic gamma-ray intensity is estimated.Comment: Submitted to ApJ. Not yet refereed. 61 pages, 26 figure

Fermi Large Area Telescope Measurements of the Diffuse Gamma-Ray Emission at Intermediate Galactic Latitudes

The diffuse Galactic gamma-ray emission is produced by cosmic rays (CRs) interacting with the interstellar gas and radiation field. Measurements by the Energetic Gamma-Ray Experiment Telescope (EGRET) instrument on the Compton Gamma-Ray Observatory indicated excess gamma-ray emission > 1 GeV relative to diffuse Galactic gamma-ray emission models consistent with directly measured CR spectra (the so-called ``EGRET GeV excess''). The excess emission was observed in all directions on the sky, and a variety of explanations have been proposed, including beyond-the-Standard-Model scenarios like annihilating or decaying dark matter. The Large Area Telescope (LAT) instrument on the Fermi Gamma-ray Space Telescope has measured the diffuse gamma-ray emission with improved sensitivity and resolution compared to EGRET. We report on LAT measurements of the diffuse gamma-ray emission for energies 100 MeV to 10 GeV and Galactic latitudes 10 deg. <= |b| <= 20 deg. The LAT spectrum for this region of the sky is well reproduced by a diffuse Galactic gamma-ray emission model that is consistent with local CR spectra and inconsistent with the EGRET GeV excess.Comment: 2 figures, 1 table, accepted by Physical Review Letters, available online Dec. 18th, 200