Characterization of new interaction partners of the DNA double-strand break repair protein DNA-PKcs

Unrepaired DNA double-strand breaks can lead to apoptosis or tumorigenesis. In mammals double-strand breaks are repaired mainly by nonhomologous end joining mediated by the DNA-PK complex. The core protein of this complex, DNA-PKcs, is a DNA-dependent serine/threonine kinase that phosphorylates protein targets as well as itself. To identify new proteins, which contribute to double-strand break repair by nonhomologous end joining, we previously performed a yeast two-hybrid screen with fragments of human DNA-PKcs as bait. From the identified putative interaction partners of DNA-PKcs we chose two for further characterization: Protein phosphatase 5 (PP5) and Ku70 binding protein 3 (Kub3). With PP5 we have identified the first protein phosphatase with a function in doublestrand break repair. We show that protein phosphatase 5 interacts with DNA-PKcs and dephosphorylates with surprising specificity at least two functional sites of it. Cells with either hypo or hyperphosphorylation of DNA-PKcs at these sites show increased radiation sensitivity. For the characterization of Kub3 we describe its correct reading frame and a putative metalloprotease domain. Using a rabbit polyclonal antibody against human Kub3 we demonstrate that Kub3 is a nuclear protein which co-precipitates with DNA-PKcs. When Kub3 is overexpressed in HeLa cells, DNA-PKcs phosphorylation at T2609 is increased after ionizing radiation. However, when Kub3 is knocked down in drosophila cells by RNAi, cell survival after ionizing radiation is not affected. In summary, with PP5 and Kub3 we have characterized two new interaction partners of DNA-PKcs. While PP5 clearly functions in double-strand break repair, further experiments are necessary to confirm such a role for Kub3

Balancing Independence and Accountability: Proposals to Reform Special Counsel Investigations

Investigations of the president and other high-ranking officials must be free from political interference yet cannot devolve into “runaway” inquiries. This report recommends reforms to the rules for every stage of special counsel investigations. Among the proposals is a requirement that federal judges oversee the attorney general’s appointment and removal of special counsels. Additionally, a special counsel should be mandatory when the president is suspected of a crime and reports on investigations should go directly to Congress

Investigating whether adverse prenatal and perinatal events are associated with non-clinical psychotic symptoms at age 12 years in the ALSPAC birth cohort

Background. Non-clinical psychosis-like symptoms (PLIKS) occur in about 15% of the population. It is not clear whether adverse events during early development alter the risk of developing PLIKS. We aimed to examine whether maternal infection, diabetes or pre-eclampsia during pregnancy, gestational age, perinatal cardiopulmonary resuscitation or 5-min Apgar score were associated with development of psychotic symptoms during early adolescence. Method. A longitudinal study of 6356 12-year-old adolescents who completed a semi-structured interview for psychotic symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Prenatal and perinatal data were obtained from obstetric records and maternal questionnaires completed during pregnancy. Results. The presence of definite psychotic symptoms was associated with maternal infection during pregnancy [adjusted odds ratio (OR) 1.44, 95% confidence interval (CI) 1.11–1.86, p=0.006], maternal diabetes (adjusted OR 3.43, 95% CI 1.14–10.36, p=0.029), need for resuscitation (adjusted OR 1.50, 95% CI 0.97–2.31, p=0.065) and 5-min Apgar score (adjusted OR per unit decrease 1.30, 95% CI 1.12–1.50, p<0.001). None of these associations were mediated by childhood IQ score. Most associations persisted, but were less strong, when including suspected symptoms as part of the outcome. There was no association between PLIKS and gestational age or pre-eclampsia. Conclusions. Adverse events during early development may lead to an increased risk of developing PLIKS. Although the status of PLIKS in relation to clinical disorders such as schizophrenia is not clear, the similarity between these results and findings reported for schizophrenia indicates that future studies of PLIKS may help us to understand how psychotic experiences and clinical disorders develop throughout the life-course

The Aemulus Project I: Numerical Simulations for Precision Cosmology

The rapidly growing statistical precision of galaxy surveys has lead to a need for ever-more precise predictions of the observables used to constrain cosmological and galaxy formation models. The primary avenue through which such predictions will be obtained is suites of numerical simulations. These simulations must span the relevant model parameter spaces, be large enough to obtain the precision demanded by upcoming data, and be thoroughly validated in order to ensure accuracy. In this paper we present one such suite of simulations, forming the basis for the AEMULUS Project, a collaboration devoted to precision emulation of galaxy survey observables. We have run a set of 75 (1.05 h^-1 Gpc)^3 simulations with mass resolution and force softening of 3.51\times 10^10 (Omega_m / 0.3) ~ h^-1 M_sun and 20 ~ h^-1 kpc respectively in 47 different wCDM cosmologies spanning the range of parameter space allowed by the combination of recent Cosmic Microwave Background, Baryon Acoustic Oscillation and Type Ia Supernovae results. We present convergence tests of several observables including spherical overdensity halo mass functions, galaxy projected correlation functions, galaxy clustering in redshift space, and matter and halo correlation functions and power spectra. We show that these statistics are converged to 1% (2%) for halos with more than 500 (200) particles respectively and scales of r>200 ~ h^-1 kpc in real space or k ~ 3 h Mpc^-1 in harmonic space for z\le 1. We find that the dominant source of uncertainty comes from varying the particle loading of the simulations. This leads to large systematic errors for statistics using halos with fewer than 200 particles and scales smaller than k ~ 4 h^-1 Mpc. We provide the halo catalogs and snapshots detailed in this work to the community at https://AemulusProject.github.io.Comment: 16 pages, 12 figures, 3 Tables Project website: https://aemulusproject.github.io

The Aemulus Project III: Emulation of the Galaxy Correlation Function

Using the N-body simulations of the AEMULUS Project, we construct an emulator for the non-linear clustering of galaxies in real and redshift space. We construct our model of galaxy bias using the halo occupation framework, accounting for possible velocity bias. The model includes 15 parameters, including both cosmological and galaxy bias parameters. We demonstrate that our emulator achieves ~ 1% precision at the scales of interest, 0.1<r<10 h^{-1} Mpc, and recovers the true cosmology when tested against independent simulations. Our primary parameters of interest are related to the growth rate of structure, f, and its degenerate combination fsigma_8. Using this emulator, we show that the constraining power on these parameters monotonically increases as smaller scales are included in the analysis, all the way down to 0.1 h^{-1} Mpc. For a BOSS-like survey, the constraints on fsigma_8 from r<30 h^{-1} Mpc scales alone are more than a factor of two tighter than those from the fiducial BOSS analysis of redshift-space clustering using perturbation theory at larger scales. The combination of real- and redshift-space clustering allows us to break the degeneracy between f and sigma_8, yielding a 9% constraint on f alone for a BOSS-like analysis. The current AEMULUS simulations limit this model to surveys of massive galaxies. Future simulations will allow this framework to be extended to all galaxy target types, including emission-line galaxies.Comment: 14 pages, 8 figures, 1 table; submitted to ApJ; the project webpage is available at https://aemulusproject.github.io ; typo in Figure 7 and caption updated, results unchange

The Aemulus Project II: Emulating the Halo Mass Function

Existing models for the dependence of the halo mass function on cosmological parameters will become a limiting source of systematic uncertainty for cluster cosmology in the near future. We present a halo mass function emulator and demonstrate improved accuracy relative to state-of-the-art analytic models. In this work, mass is defined using an overdensity criteria of 200 relative to the mean background density. Our emulator is constructed from the AEMULUS simulations, a suite of 40 N-body simulations with snapshots from z=3 to z=0. These simulations cover the flat wCDM parameter space allowed by recent Cosmic Microwave Background, Baryon Acoustic Oscillation and Type Ia Supernovae results, varying the parameters w, Omega_m, Omega_b, sigma_8, N_{eff}, n_s, and H_0. We validate our emulator using five realizations of seven different cosmologies, for a total of 35 test simulations. These test simulations were not used in constructing the emulator, and were run with fully independent initial conditions. We use our test simulations to characterize the modeling uncertainty of the emulator, and introduce a novel way of marginalizing over the associated systematic uncertainty. We confirm non-universality in our halo mass function emulator as a function of both cosmological parameters and redshift. Our emulator achieves better than 1% precision over much of the relevant parameter space, and we demonstrate that the systematic uncertainty in our emulator will remain a negligible source of error for cluster abundance studies through at least the LSST Year 1 data set.Comment: https://aemulusproject.github.io

Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring

Background Adverse effects of maternal substance use during pregnancy on fetal development may increase risk of psychopathology. Aims To examine whether maternal use of tobacco, cannabis or alcohol during pregnancy increases risk of offspring psychotic symptoms. Method A longitudinal study of 6356 adolescents, age 12, who completed a semi-structured interview for psychotic symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Results Frequency of maternal tobacco use during pregnancy was associated with increased risk of suspected or definite psychotic symptoms (adjusted odds ratio 1.20, 95% CI 1.05–1.37, P = 0.007). Maternal alcohol use showed a non-linear association with psychotic symptoms, with this effect almost exclusively in the offspring of women drinking >21 units weekly. Maternal cannabis use was not associated with psychotic symptoms. Results for paternal smoking during pregnancy and maternal smoking post-pregnancy lend some support for a causal effect of tobacco exposure in utero on development of psychotic experiences. Conclusions These findings indicate that risk factors for development of non-clinical psychotic experiences may operate during early development. Future studies of how in utero exposure to tobacco affects cerebral development and function may lead to increased understanding of the pathogenesis of psychotic phenomena

Perceptual grouping abilities in individuals with Autism Spectrum Disorder: exploring patterns of ability in relation to grouping type and levels of development

This study further investigates findings of impairment in Gestalt, but not global processing in Autism Spectrum Disorder (ASD) [Brosnan, Scott, Fox, & Pye, 2004]. Nineteen males with ASD and nineteen typically developing (TD) males matched by nonverbal ability, took part in five Gestalt perceptual grouping tasks. Results showed that performance differed according to grouping type. The ASD group showed typical performance for grouping by proximity and by alignment, impairment on low difficulty trials for orientation and luminance similarity, and general impairment for grouping by shape similarity. Group differences were also observed developmentally; for the ASD group, with the exception of grouping by shape similarity, perceptual grouping performance was poorer at lower than higher levels of nonverbal ability. In contrast, no developmental progression was observed in the TD controls