Disruption of Histone Modification and CARM1 Recruitment by Arsenic Represses Transcription at Glucocorticoid Receptor-Regulated Promoters

Chronic exposure to inorganic arsenic (iAs) found in the environment is one of the most significant and widespread environmental health risks in the U.S. and throughout the world. It is associated with a broad range of health effects from cancer to diabetes as well as reproductive and developmental anomalies. This diversity of diseases can also result from disruption of metabolic and other cellular processes regulated by steroid hormone receptors via aberrant transcriptional regulation. Significantly, exposure to iAs inhibits steroid hormone-mediated gene activation. iAs exposure is associated with disease, but is also used therapeutically to treat specific cancers complicating an understanding of iAs action. Transcriptional activation by steroid hormone receptors is accompanied by changes in histone and non-histone protein post-translational modification (PTM) that result from the enzymatic activity of coactivator and corepressor proteins such as GRIP1 and CARM1. This study addresses how iAs represses steroid receptor-regulated gene transcription. PTMs on histones H3 and H4 at the glucocorticoid receptor (GR)-activated mouse mammary tumor virus (MMTV) promoter were identified by chromatin immunoprecipitation analysis following exposure to steroid hormone 6 iAs. Histone H3K18 and H3R17 amino acid residues had significantly different patterns of PTMs after treatment with iAs. Promoter interaction of the coactivator CARM1 was disrupted, but the interaction of GRIP1, a p160 coactivator through which CARM1 interacts with a promoter, was intact. Over-expression of CARM1 was able to fully restore and GRIP1 partially restored iAs-repressed transcription indicating that these coactivators are functionally associated with iAs-mediated transcriptional repression. Both are essential for robust transcription at steroid hormone regulated genes and both are associated with disease when inappropriately expressed. We postulate that iAs effects on CARM1 and GRIP1 may underlie some of its therapeutic effects and as well be associated with its toxic effects

The number of transmission channels through a single-molecule junction

We calculate transmission eigenvalue distributions for Pt-benzene-Pt and Pt-butadiene-Pt junctions using realistic state-of-the-art many-body techniques. An effective field theory of interacting $\pi$-electrons is used to include screening and van der Waals interactions with the metal electrodes. We find that the number of dominant transmission channels in a molecular junction is equal to the degeneracy of the molecular orbital closest to the metal Fermi level.Comment: 9 pages, 8 figure

A Temporal Threshold for Formaldehyde Crosslinking and Fixation

Formaldehyde crosslinking is in widespread use as a biological fixative for microscopy and molecular biology. An assumption behind its use is that most biologically meaningful interactions are preserved by crosslinking, but the minimum length of time required for an interaction to become fixed has not been determined.Using a unique series of mutations in the DNA binding protein MeCP2, we show that in vivo interactions lasting less than 5 seconds are invisible in the microscope after formaldehyde fixation, though they are obvious in live cells. The stark contrast between live cell and fixed cell images illustrates hitherto unsuspected limitations to the fixation process. We show that chromatin immunoprecipitation, a technique in widespread use that depends on formaldehyde crosslinking, also fails to capture these transient interactions.Our findings for the first time establish a minimum temporal limitation to crosslink chemistry that has implications for many fields of research

Anthropometric and Physical Profiles of English Academy Rugby Union Players.

The purpose of the present study was to evaluate the anthropometric and physical characteristics of English regional academy rugby union academy players by age category (under 16, under 18 and under 21s). Data were collected on 67 academy players at the beginning of the pre-season period and comprised anthropometric (height, body mass and sum of 8 skinfolds) and physical (5 m, 10 m, 20 m & 40 m sprint, acceleration, velocity & momentum; agility 505; vertical jump; yo-yo intermittent recovery test level 1; 30-15 Intermittent Fitness Test; absolute and relative 3 repetition maximum (3RM) front squat, split squat, bench press, prone row and chin; and isometric mid-thigh pull). One way analysis of variance demonstrated significant increases across the three age categories (p < 0.05) for height (e.g., 16s = 178.8 ± 7.1; 18s = 183.5 ± 7.2; 21s = 186.7 ± 6.61 cm), body mass (e.g., 16s = 79.4 ± 12.8; 18s = 88.3 ± 11.9; 21s = 98.3 ± 10.4kg), countermovement jump height and peak power, sprint momentum, velocity and acceleration; absolute, relative and isometric (e.g., 16s = 2157.9 ± 309.9; 18s = 2561.3 ± 339.4; 21s = 3104.5 ± 354.0 N) strength. Momentum, maximal speed and the ability to maintain acceleration were all discriminating factors between age categories, suggesting that these variables may be more important to monitor rather than sprint times. These findings highlight that anthropometric and physical characteristics develop across age categories and provide comparative data for English academy Rugby Union players

Natural Inflation: Particle Physics Models, Power Law Spectra for Large Scale Structure, and Constraints from COBE

A pseudo-Nambu-Goldstone boson, with a potential of the form $V(\phi) = \Lambda^4[1 \pm \cos(\phi/f)], naturally gives rise to inflation if$f \sim M_{Pl}$and$\Lambda \sim M_{GUT}$. We show how this can arise in technicolor-like and superstring models, and work out an explicit string example in the context of multiple gaugino condensation models. We study the cosmology of this model in detail, and find that sufficient reheating to ensure that baryogenesis can take place requires$f > 0.3 M_{Pl}$. The primordial density fluctuation spectrum generated is a non-scale-invariant power law,$P(k) \propto k^{n_s}$, with$n_s \simeq 1 - (M^2_{Pl}/8\pi f^2)$, leading to more power on large length scales than the$n_s = 1$Harrison-Zeldovich spectrum. The standard CDM model with$0 \la n_s \la 0.6-0.7$could in principle explain the large-scale clustering observed in the APM and IRAS galaxy surveys as well as large-scale flows, but the COBE microwave anisotropy implies such low amplitudes (or high bias factors,$b>2$) for these CDM models that galaxy formation occurs too late to be viable; combining COBE with sufficiently early galaxy formation or the large-scale flows leads to$n_s >0.6$, or$f > 0.3 M_{Pl}$as well. For extended and power law inflation models, this constraint is even tighter,$n_s > 0.7$; combined with other bounds on large bubbles in extended inflation, this leaves little room for most extended models.Comment: 42 pages, (12 figures not included but available from the authors

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24&nbsp;months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500&nbsp;steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30&nbsp;minutes spent performing activities ≥500&nbsp;counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24&nbsp;months), both the number of steps per day (per 500&nbsp;steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500&nbsp;counts per minute (per 30&nbsp;minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score &gt;10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Anthropometric, Sprint, and High-Intensity Running Profiles of English Academy Rugby Union Players by Position

The purpose of the present study was to evaluate the anthropometric, sprint and high-intensity running profiles of English academy rugby union players by playing positions, and to investigate the relationships between anthropometric, sprint and high intensity running characteristics. Data was collected from 67 academy players following the off-season period and consisted of anthropometric (height, body mass, sum of 8 skinfolds [∑SF]), 40 m linear sprint (5, 10, 20 30 & 40 m splits), the Yo-Yo intermittent recovery test level 1(Yo-Yo IRTL-1) and the 30-15 intermittent fitness test (30-15IFT). Forwards displayed greater stature, body mass and ∑SF; sprint times and sprint momentum, with lower high-intensity running ability and sprint velocities than backs. Comparisons between age categories demonstrated body mass and sprint momentum to have the largest differences at consecutive age categories for forwards and backs; whilst 20-40 m sprint velocity was discriminate for forwards between Under 16s, 18s and 21s. Relationships between anthropometric, sprint velocity, momentum and high-intensity running ability demonstrated body mass to negatively impact upon sprint velocity (10 m; r = -0.34 to -0.46); positively affect sprint momentum (e.g., 5 m; r = 0.85 to 0.93), with large to very large negative relationships with the Yo-Yo IRTL-1 (r= -0.65 to -0.74) and 30-15IFT (r= -0.59 to -0.79). These findings suggest that there are distinct anthropometric, sprint and high-intensity running ability differences between and within positions in junior rugby union players. The development of sprint and high-intensity running ability may be impacted by continued increases in body mass as there appears to be a trade-off between momentum, velocity and the ability to complete high-intensity running

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie