Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society

Inhibition of nuclear PTEN tyrosine phosphorylation enhances glioma radiation sensitivity through attenuated DNA repair

Ionizing radiation (IR) and chemotherapy are standard of care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240FPten knock-in mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy

CANDELS Visual Classifications: Scheme, Data Release, and First Results

We have undertaken an ambitious program to visually classify all galaxies in the five CANDELS fields down to H \u3c 24.5 involving the dedicated efforts of over 65 individual classifiers. Once completed, we expect to have detailed morphological classifications for over 50,000 galaxies spanning 0 \u3c z \u3c 4 over all the fields, with classifications from 3 to 5 independent classifiers for each galaxy. Here, we present our detailed visual classification scheme, which was designed to cover a wide range of CANDELS science goals. This scheme includes the basic Hubble sequence types, but also includes a detailed look at mergers and interactions, the clumpiness of galaxies, k-corrections, and a variety of other structural properties. In this paper, we focus on the first field to be completed—GOODS-S, which has been classified at various depths. The wide area coverage spanning the full field (wide+deep+ERS) includes 7634 galaxies that have been classified by at least three different people. In the deep area of the field, 2534 galaxies have been classified by at least five different people at three different depths. With this paper, we release to the public all of the visual classifications in GOODS-S along with the Perl/Tk GUI that we developed to classify galaxies. We present our initial results here, including an analysis of our internal consistency and comparisons among multiple classifiers as well as a comparison to the Sérsic index. We find that the level of agreement among classifiers is quite good (\u3e70% across the full magnitude range) and depends on both the galaxy magnitude and the galaxy type, with disks showing the highest level of agreement (\u3e50%) and irregulars the lowest (k-corrections between the V-band and H-band observations and find that a small fraction (84 galaxies in total) are classified as being very different between these two bands. These galaxies typically have very clumpy and extended morphology or are very faint in the V-band

The Lyman Continuum Escape Fraction of Star-forming Galaxies at 2.4≲z≲3.72.4\lesssim z\lesssim3.7 from UVCANDELS

The UltraViolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) survey is a Hubble Space Telescope (HST) Cycle-26 Treasury Program, allocated in total 164 orbits of primary Wide-Field Camera 3 Ultraviolet and Visible light F275W imaging with coordinated parallel Advanced Camera for Surveys F435W imaging, on four of the five premier extragalactic survey fields: GOODS-N, GOODS-S, EGS, and COSMOS. We introduce this survey by presenting a thorough search for galaxies at $z\gtrsim2.4$ that leak significant Lyman continuum (LyC) radiation, as well as a stringent constraint on the LyC escape fraction ($f_{\rm esc}$) from stacking the UV images of a population of star-forming galaxies with secure redshifts. Our extensive search for LyC emission and stacking analysis benefit from the catalogs of high-quality spectroscopic redshifts compiled from archival ground-based data and HST slitless spectroscopy, carefully vetted by dedicated visual inspection efforts. We report a sample of five galaxies as individual LyC leaker candidates, showing $f_{\rm esc}^{\rm rel}\gtrsim60\%$ estimated using detailed Monte Carlo analysis of intergalactic medium attenuation. We develop a robust stacking method to apply to five samples of in total 85 non-detection galaxies in the redshift range of $z\in[2.4,3.7]$. Most stacks give tight 2-$\sigma$ upper limits below $f_{\rm esc}^{\rm rel}<6\%$. A stack for a subset of 32 emission-line galaxies shows tentative LyC leakage detected at 2.9-$\sigma$, indicating $f_{\rm esc}^{\rm rel}=5.7\%$ at $z\sim2.65$, supporting the key role of such galaxies in contributing to the cosmic reionization and maintaining the UV ionization background. These new F275W and F435W imaging mosaics from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes.Comment: 33 pages, 21 figures, and 5 tables. Resubmitted after addressing the referee repor

A path forward in the debate over health impacts of endocrine disrupting chemicals

Several recent publications reflect debate on the issue of “endocrine disrupting chemicals” (EDCs), indicating that two seemingly mutually exclusive perspectives are being articulated separately and independently. Considering this, a group of scientists with expertise in basic science, medicine and risk assessment reviewed the various aspects of the debate to identify the most significant areas of dispute and to propose a path forward. We identified four areas of debate. The first is about the definitions for terms such as “endocrine disrupting chemical”, “adverse effects”, and “endocrine system”. The second is focused on elements of hormone action including “potency”, “endpoints”, “timing”, “dose” and “thresholds”. The third addresses the information needed to establish sufficient evidence of harm. Finally, the fourth focuses on the need to develop and the characteristics of transparent, systematic methods to review the EDC literature. Herein we identify areas of general consensus and propose resolutions for these four areas that would allow the field to move beyond the current and, in our opinion, ineffective debate

Morphological Analysis of Galaxies in the CANDELS Fields

Knowledge of the morphology of galaxies is essential in studying galaxy formation and evolution. When combined with other observable characteristics, a detailed understanding of the properties of galaxies can be acquired. In this study, I analyze parametric morphology using the code GALFIT of two galaxy samples in the CANDELS fields by applying a single Sérsic function and a two-component fit to the surface brightness distribution of the galaxies. I quantify morphological properties, such as galaxy Sérsic index, bulge-to-total flux ratio, and size to study the evolution and correlation with other galaxy properties. When my parametric measurements are compared with non-parametric techniques, such as the Gini-M20 diagram, I find that the different methods show overall agreement.I find that galaxies selected with MIPS 24 μm detection, characteristic of dusty, star-forming galaxies, in the GOODS-S field are primarily disk galaxies with a range of bulge fractions, although some galaxies with elliptical profiles are present. Many of these galaxies have AGN candidates, another source of 24 μm emission, while the remaining elliptical galaxies could contain obscured AGN. In comparison, I find that galaxies without 24μm emission are primarily disks but with a larger sample of elliptical galaxies that show an observed evolution is bulge-dominance with redshift.For galaxies observed in the MOSDEF survey, I find little to no correlation between the relations of SFR-M* and MZR with galaxy n. The star forming main sequence is observed to form a tighter, steeper correlation for galaxies with low B/T than other populations indicating that higher mass, disky galaxies have higher SFRs with smaller bulge fractions. This relation also shows that galaxies with high B/T have much flatter slopes indicating that they may be evolving to quiescence. I examine the necessity for a morphological k-correction when studying morphology across multiple redshifts, and discover that galaxy n and re show wavelength dependence when comparing observed optical and infrared morphologies, while the B/T shows significant scatter in all wavelengths and redshifts. Overall I find that a morphological k-correction is necessary when studying galaxies across a wide redshift range

Human impacts on mammal communities in Rio Campo Nature Reserve, Equatorial Guinea

Equatorial Guinea in central Africa hosts rich biodiversity and a network of protected areas (PAs). However, infrastructure development has facilitated access to previously remote forests. This has likely increased poaching in PAs, thereby complicating efforts of agencies tasked with protecting threatened mammals. Reserva Natural de Río Campo (RNRC) in Equatorial Guinea was previously identified as a priority area for large mammals due to the presence of elephants and great apes and includes habitat for a diverse mammal community of commonly hunted species. To assess mammalian diversity in RNRC, we conducted a camera trap survey in 2017 and 2019. We used a two-step modelling approach to quantify environmental and anthropogenic factors influencing mammal groups. We detected 32 terrestrial mammal species, including endangered forest elephant, western gorilla, chimpanzee, giant pangolin and white-bellied pangolin. We found bushbuck and sitatunga closer to human-dominated areas, while other common species were, in general, further from development. Monkey and pangolin abundance increased inward from the RNRC boundary. Endangered species appear restricted to northeast RNRC which connects to Campo Ma'an National Park in Cameroon. We recommend using our inventory and distributions of threatened mammals as starting points to determine effectiveness of future anti-poaching and management strategies on mammal populations