The Metagalactic Ionizing Radiation Field at Low Redshift

We compute the ionizing radiation field at low redshift, arising from Seyferts, QSOs, and starburst galaxies. This calculation combines recent Seyfert luminosity functions, extrapolated ultraviolet fluxes from our IUE-AGN database, and a new intergalactic opacity model based on Hubble Space Telescope and Keck Ly-alpha absorber surveys. At z = 0 for AGN only, our best estimate for the specific intensity at 1 Ryd is I_0 = 1.3 (+0.8/-0.5) x 10^-23 ergs/cm^2/s/Hz/sr, independent of H_0, Omega_0, and Lambda. The one-sided ionizing photon flux is Phi_ion = 3400 (+2100/-1300) photons/cm^2/s, and the H I photoionization rate is Gamma_HI = 3.2 (+2.0/-1.2) x 10^-14 s^-1 for alpha_s = 1.8. We also derive Gamma_ HI for z = 0 - 4. These error ranges reflect uncertainties in the spectral indexes for the ionizing EUV (alpha_s = 1.8 +/- 0.3) and the optical/UV (alpha_UV = 0.86 +/- 0.05), the IGM opacity model, the range of Seyfert luminosities (0.001 - 100 L*) and the completeness of the luminosity functions. Our estimate is a factor of three lower than the most stringent upper limits on the ionizing background (Phi_ion < 10^4 photons/cm^2/s) obtained from H-alpha observations in external clouds, and it lies within the range implied by other indirect measures. Starburst galaxies with a sufficiently large Lyman continuum escape fraction, f_ esc > 0.05, may provide a comparable background to AGN, I_0 (z=0) = 1.1 (+1.5/-0.7) x 10^{-23). An additional component of the ionizing background of this magnitude would violate neither upper limits from H-alpha observations nor the acceptable range from other measurements.Comment: 30 pages, 9 figures, accepted for Astronomical J. (Oct. 1999

Associations of negative affective biases and depressive symptoms in a community-based sample

Acknowledgements. We thank professor Jonathan Roiser (University College London, UK) and professor emeritus Ian Deary (University of Edinburgh, UK) for their input on task selection and statistical analysis. We also acknowledge all researchers who have contributed to the collection of data for the current study. Most importantly, we would like to thank all participants of Generation Scotland, and particularly those of the STRADL subcohort, for their participation in the research. Financial support. Stratifying Resilience and Depression Longitudinally is supported by the Wellcome Trust through a Strategic Award (Grant No. 104036/Z/14/Z) and through an Investigator Award (Grant No. 220857/Z/ 20/Z). The Chief Scientist Office of the Scottish Government Health Department (Grant No. CZD/16/6), Scottish Funding Council (Grant No. HR03006) and Wellcome Trust (Grant No. 216767/Z/19/Z) provided core support for Generation Scotland.Peer reviewedPublisher PD

Associations of negative affective biases and depressive symptoms in a community-based sample

Background: Major depressive disorder (MDD) was previously associated with negative affective biases. Evidence from larger population-based studies, however, is lacking, including whether biases normalise with remission. We investigated associations between affective bias measures and depressive symptom severity across a large community-based sample, followed by examining differences between remitted individuals and controls. Methods: Participants from Generation Scotland (N = 1109) completed the: (i) Bristol Emotion Recognition Task (BERT), (ii) Face Affective Go/No-go (FAGN), and (iii) Cambridge Gambling Task (CGT). Individuals were classified as MDD-current (n = 43), MDD-remitted (n = 282), or controls (n = 784). Analyses included using affective bias summary measures (primary analyses), followed by detailed emotion/condition analyses of BERT and FAGN (secondary analyses). Results: For summary measures, the only significant finding was an association between greater symptoms and lower risk adjustment for CGT across the sample (individuals with greater symptoms were less likely to bet more, despite increasingly favourable conditions). This was no longer significant when controlling for non-affective cognition. No differences were found for remitted-MDD v. controls. Detailed analysis of BERT and FAGN indicated subtle negative biases across multiple measures of affective cognition with increasing symptom severity, that were independent of non-effective cognition [e.g. greater tendency to rate faces as angry (BERT), and lower accuracy for happy/neutral conditions (FAGN)]. Results for remitted-MDD were inconsistent. Conclusions: This suggests the presence of subtle negative affective biases at the level of emotion/condition in association with depressive symptoms across the sample, over and above those accounted for by non-affective cognition, with no evidence for affective biases in remitted individuals

Systematic identification of signaling pathways with potential to confer anticancer drug resistance

Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)–mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF[superscript V600E] melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.National Institutes of Health (U.S.) (Grant CA103866)National Institutes of Health (U.S.) (Grant AI07389

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Cohort profile for the STratifying Resilience and Depression Longitudinally (STRADL) study:A depression-focused investigation of Generation Scotland, using detailed clinical, cognitive, and neuroimaging assessments

Grant information: STRADL is supported by the Wellcome Trust through a Strategic Award (104036/Z/14/Z). GS:SFHS received core support from the CSO of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). ADM is supported by Innovate UK, the European Commission, the Scottish Funding Council via the Scottish Imaging Network SINAPSE, and the CSO. HCW is supported by a JMAS SIM Fellowship from the Royal College of Physicians of Edinburgh, by an ESAT College Fellowship from the University of Edinburgh, and has received previous funding from the Sackler Trust. LR has previously received financial support from Pfizer (formerly Wyeth) in relation to imaging studies of people with schizophrenia and bipolar disorder. JDH is supported by the MRC. DJM is an NRS Clinician, funded by the CSO. RMR is supported by the British Heart Foundation. ISP-V and MRM are supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health; and MRM is also supported by the MRC MC_UU_12013/6). JMW is supported by MRC UK Dementia Research Institute and MRC Centre and project grants, EPSRC, Fondation Leducq, Stroke Association, British Heart Foundation, Alzheimer Society, and the European Union H2020 PHC-03-15 SVDs@Target grant agreement (666881). DJP is supported by Wellcome Trust Longitudinal Population Study funding (216767/Z/19/Z) the Eva Lester bequest to the University of Edinburgh. AMM is additionally supported by the MRC (MC_PC_17209, MC_PC_MR/R01910X/1, MR/S035818/1), The Wellcome Trust (216767/Z/19/Z ), The Sackler Trust, and has previously received research funding from Pfizer, Eli Lilly, and Janssen. Both AMM and IJD are members of The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross council Lifelong Health and Wellbeing Initiative (MR/K026992/1); funding from the BBSRC and MRC is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscriptPeer reviewedPublisher PD

An HST/COS Survey of the Low-Redshift IGM. I. Survey, Methodology, & Overall Results

We use high-quality, medium-resolution {\it Hubble Space Telescope}/Cosmic Origins Spectrograph (\HST/COS) observations of 82 UV-bright AGN at redshifts $z_{AGN}<0.85$ to construct the largest survey of the low-redshift intergalactic medium (IGM) to date: 5343 individual extragalactic absorption lines in HI and 25 different metal-ion species grouped into 2610 distinct redshift systems at $z_{abs}<0.75$ covering total redshift pathlengths $\Delta z_{HI}=21.7$ and $\Delta z_{OVI}=14.5$. Our semi-automated line-finding and measurement technique renders the catalog as objectively-defined as possible. The cumulative column-density distribution of HI systems can be parametrized $dN(>N)/dz=C_{14}(N/10^{14} cm^{-2})^{-(\beta-1)}$, with $C_{14}=25\pm1$ and $\beta=1.65\pm0.02$. This distribution is seen to evolve both in amplitude, $C_{14}\sim(1+z)^{2.0\pm0.1}$, and slope $\beta(z)=1.73-0.26 z$ for $z<0.47$. We observe metal lines in 427 systems, and find that the fraction of IGM absorbers detected in metals is strongly dependent on N_{HI}. The distribution of OVI absorbers appear to evolve in the same sense as the Lya forest. We calculate contributions to $\Omega_b$ from different components of the low-$z$ IGM and determine the Lya decrement as a function of redshift. IGM absorbers are analyzed via a two-point correlation function (TPCF) in velocity space. We find substantial clustering of \HI\ absorbers on scales of $\Delta v=50-300$ km/s with no significant clustering at $\Delta v>1000$ km/s. Splitting the sample into strong and weak absorbers, we see that most of the clustering occurs in strong, $N_{HI}>10^{13.5} cm^{-2}$, metal-bearing IGM systems. The full catalog of absorption lines and fully-reduced spectra is available via MAST as a high-level science product at http://archive.stsci.edu/prepds/igm/.Comment: This is the accepted version (v3) of the paper. Previous versions (July 2015 and Feb. 2014) should be replaced by this one. In particular, please note that the associated MAST high-level-science product has been updated to reflect the of the final state of the paper. It is available at: http://archive.stsci.edu/prepds/igm

The Sno Oncogene Antagonizes Wingless Signaling during Wing Development in Drosophila

The Sno oncogene (Snoo or dSno in Drosophila) is a highly conserved protein and a well-established antagonist of Transforming Growth Factor-β signaling in overexpression assays. However, analyses of Sno mutants in flies and mice have proven enigmatic in revealing developmental roles for Sno proteins. Thus, to identify developmental roles for dSno we first reconciled conflicting data on the lethality of dSno mutations. Then we conducted analyses of wing development in dSno loss of function genotypes. These studies revealed ectopic margin bristles and ectopic campaniform sensilla in the anterior compartment of the wing blade suggesting that dSno functions to antagonize Wingless (Wg) signaling. A subsequent series of gain of function analyses yielded the opposite phenotype (loss of bristles and sensilla) and further suggested that dSno antagonizes Wg signal transduction in target cells. To date Sno family proteins have not been reported to influence the Wg pathway during development in any species. Overall our data suggest that dSno functions as a tissue-specific component of the Wg signaling pathway with modest antagonistic activity under normal conditions but capable of blocking significant levels of extraneous Wg, a role that may be conserved in vertebrates

Different Vocal Parameters Predict Perceptions of Dominance and Attractiveness

Low mean fundamental frequency (F0) in men’s voices has been found to positively influence perceptions of dominance by men and attractiveness by women using standardized speech. Using natural speech obtained during an ecologically valid social interaction, we examined relationships between multiple vocal parameters and dominance and attractiveness judgments. Male voices from an unscripted dating game were judged by men for physical and social dominance and by women in fertile and non-fertile menstrual cycle phases for desirability in short-term and long-term relationships. Five vocal parameters were analyzed: mean F0 (an acoustic correlate of vocal fold size), F0 variation, intensity (loudness), utterance duration, and formant dispersion (Df, an acoustic correlate of vocal tract length). Parallel but separate ratings of speech transcripts served as controls for content. Multiple regression analyses were used to examine the independent contributions of each of the predictors. Physical dominance was predicted by low F0 variation and physically dominant word content. Social dominance was predicted only by socially dominant word content. Ratings of attractiveness by women were predicted by low mean F0, low Df, high intensity, and attractive word content across cycle phase and mating context. Low Df was perceived as attractive by fertile-phase women only. We hypothesize that competitors and potential mates may attend more strongly to different components of men’s voices because of the different types of information these vocal parameters provide