Targeting Chromatin Readers

Modulation of gene expression through epigenetic signaling has recently emerged as a novel approach in treating human disease. Specifically, chromatin reader proteins, which mediate protein–protein interactions via binding to modified lysine residues, are gaining traction as potential therapeutic targets. Herein, we review recent efforts to understand and modulate the activity of chromatin reader proteins with small-molecule ligands

Path integral evaluation of Dbrane amplitudes

We extend Polchinski's evaluation of the measure for the one-loop closed string path integral to open string tree amplitudes with boundaries and crosscaps embedded in Dbranes. We explain how the nonabelian limit of near-coincident Dbranes emerges in the path integral formalism. We give a careful path integral derivation of the cylinder amplitude including the modulus dependence of the volume of the conformal Killing group.Comment: Extended version replacing hep-th/9903184, includes discussion of nonabelian limit, Latex, 10 page

CLASH-VLT: Insights on the mass substructures in the Frontier Fields Cluster MACS J0416.1-2403 through accurate strong lens modeling

We present a detailed mass reconstruction and a novel study on the substructure properties in the core of the CLASH and Frontier Fields galaxy cluster MACS J0416.1-2403. We show and employ our extensive spectroscopic data set taken with the VIMOS instrument as part of our CLASH-VLT program, to confirm spectroscopically 10 strong lensing systems and to select a sample of 175 plausible cluster members to a limiting stellar mass of log(M_*/M_Sun) ~ 8.6. We reproduce the measured positions of 30 multiple images with a remarkable median offset of only 0.3" by means of a comprehensive strong lensing model comprised of 2 cluster dark-matter halos, represented by cored elliptical pseudo-isothermal mass distributions, and the cluster member components. The latter have total mass-to-light ratios increasing with the galaxy HST/WFC3 near-IR (F160W) luminosities. The measurement of the total enclosed mass within the Einstein radius is accurate to ~5%, including systematic uncertainties. We emphasize that the use of multiple-image systems with spectroscopic redshifts and knowledge of cluster membership based on extensive spectroscopic information is key to constructing robust high-resolution mass maps. We also produce magnification maps over the central area that is covered with HST observations. We investigate the galaxy contribution, both in terms of total and stellar mass, to the total mass budget of the cluster. When compared with the outcomes of cosmological $N$-body simulations, our results point to a lack of massive subhalos in the inner regions of simulated clusters with total masses similar to that of MACS J0416.1-2403. Our findings of the location and shape of the cluster dark-matter halo density profiles and on the cluster substructures provide intriguing tests of the assumed collisionless, cold nature of dark matter and of the role played by baryons in the process of structure formation.Comment: 26 pages, 22 figures, 7 tables; accepted for publication in the Astrophysical Journal. A high-resolution version is available at https://sites.google.com/site/vltclashpublic/publications/Grillo_etal_2014.pd

RELICS: The Reionization Lensing Cluster Survey and the Brightest High-z Galaxies

Massive foreground galaxy clusters magnify and distort the light of objects behind them, permitting a view into both the extremely distant and intrinsically faint galaxy populations. We present here the z ~ 6-8 candidate high-redshift galaxies from the Reionization Lensing Cluster Survey (RELICS), a Hubble and Spitzer Space Telescope survey of 41 massive galaxy clusters spanning an area of ≈200 arcmin². These clusters were selected to be excellent lenses, and we find similar high-redshift sample sizes and magnitude distributions as the Cluster Lensing And Supernova survey with Hubble (CLASH). We discover 257, 57, and eight candidate galaxies at z ~ 6, 7, and 8 respectively, (322 in total). The observed (lensed) magnitudes of the z ~ 6 candidates are as bright as AB mag ~23, making them among the brightest known at these redshifts, comparable with discoveries from much wider, blank-field surveys. RELICS demonstrates the efficiency of using strong gravitational lenses to produce high-redshift samples in the epoch of reionization. These brightly observed galaxies are excellent targets for follow-up study with current and future observatories, including the James Webb Space Telescope

Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32–p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development

First Results from The GlueX Experiment

The GlueX experiment at Jefferson Lab ran with its first commissioning beam in late 2014 and the spring of 2015. Data were collected on both plastic and liquid hydrogen targets, and much of the detector has been commissioned. All of the detector systems are now performing at or near design specifications and events are being fully reconstructed, including exclusive production of $\pi^{0}$, $\eta$ and $\omega$ mesons. Linearly-polarized photons were successfully produced through coherent bremsstrahlung and polarization transfer to the $\rho$ has been observed.Comment: 8 pages, 6 figures, Invited contribution to the Hadron 2015 Conference, Newport News VA, September 201

Feedback and metal enrichment in cosmological SPH simulations I. A model for chemical enrichment

We discuss a model for treating chemical enrichment by SNII and SNIa explosions in simulations of cosmological structure formation. Our model includes metal-dependent radiative cooling and star formation in dense collapsed gas clumps. Metals are returned into the diffuse interstellar medium by star particles using a local SPH smoothing kernel. A variety of chemical abundance patterns in enriched gas arise in our treatment owing to the different yields and lifetimes of SNII and SNIa progenitor stars. In the case of SNII chemical production, we adopt metal-dependent yields. Because of the sensitive dependence of cooling rates on metallicity, enrichment of galactic haloes with metals can in principle significantly alter subsequent gas infall and the build up of the stellar components. Indeed, in simulations of isolated galaxies we find that a consistent treatment of metal-dependent cooling produces 25% more stars outside the central region than simulations with a primordial cooling function. In the highly-enriched central regions, the evolution of baryons is however not affected by metal cooling, because here the gas is always dense enough to cool. A similar situation is found in cosmological simulations because we include no strong feedback processes which could spread metals over large distances and mix them into unenriched diffuse gas. We demonstrate this explicitly with test simulations which adopt super-solar cooling functions leading to large changes both in the stellar mass and in the metal distributions. We also find that the impact of metallicity on the star formation histories of galaxies may depend on their particular evolutionary history. Our results hence emphasise the importance of feedback processes for interpreting the cosmic metal enrichment.Comment: 15 pages, 15 figures, MNRAS, modified to match published versio