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

A prototype system for detecting the radio-frequency pulse associated with cosmic ray air showers

The development of a system to detect the radio-frequency (RF) pulse associated with extensive air showers of cosmic rays is described. This work was performed at the CASA/MIA array in Utah, with the intention of designing equipment that can be used in conjunction with the Auger Giant Array. A small subset of data (less than 40 out of a total of 600 hours of running time), taken under low-noise conditions, permitted upper limits to be placed on the rate for pulses accompanying showers of energies around $10^{17}$ eV.Comment: 53 pages, LaTeX, 19 figures, published in Nuclear Instruments and Methods. Revised version; some references update

Physics Results from RICH Detectors

RICH detectors have become extraordinarily useful. Results include measurement of solar neutrino rates, evidence for neutrino oscillations, measurement of TeV gamma-rays from gravitational sources, properties of QCD, charm production and decay, and measurement of the CKM matrix elements Vcs, Vcb and Vub. A new value |Vub/Vcb|=0.087+/-0.012 is determined.Comment: Invited talk at ``The 3rd International Workshop on Ring Imaging Cherenkov Detectors," Ein-Gedi, Dead-Sea, Israel, Nov. 15-20, 1998, 21 pages, 22 fig

Chlorpyrifos Accumulation Patterns for Child-Accessible Surfaces and Objects and Urinary Metabolite Excretion by Children for 2 Weeks after Crack-and-Crevice Application

The Children’s Post-Pesticide Application Exposure Study (CPPAES) was conducted to look at the distribution of chlorpyrifos within a home environment for 2 weeks after a routine professional crack-and-crevice application and to determine the amount of the chlorpyrifos that is absorbed by a child living within the home. Ten residential homes with a 2- to 5-year-old child in each were selected for study, and the homes were treated with chlorpyrifos. Pesticide measurements were made from the indoor air, indoor surfaces, and plush toys. In addition, periodic morning urine samples were collected from each of the children throughout the 2-week period. We analyzed the urine samples for 3,5,6-trichloropyridinol, the primary urinary metabolite of chlorpyrifos, and used the results to estimate the children’s absorbed dose. Average chlorpyrifos levels in the indoor air and surfaces were 26 (pretreatment)/120 (posttreatment) ng/m(3) and 0.48 (pretreatment)/2.8 (posttreatment) ng/cm(2), respectively, reaching peak levels between days 0 and 2; subsequently, concentrations decreased throughout the 2-week period. Chlorpyrifos in/on the plush toys ranged from 7.3 to 1,949 ng/toy postapplication, with concentrations increasing throughout the 2-week period, demonstrating a cumulative adsorption/absorption process indoors. The daily amount of chlorpyrifos estimated to be absorbed by the CPPAES children postapplication ranged from 0.04 to 4.8 μg/kg/day. During the 2 weeks after the crack-and-crevice application, there was no significant increase in the amount of chlorpyrifos absorbed by the CPPAES children

Composite model with neutrino large mixing

We suggest a simple composite model that induces the large flavor mixing of neutrino in the supersymmetric theory. This model has only one hyper-color in addition to the standard gauge group, which makes composite states of preons. In this model, {\bf 10} and {\bf 1} representations in SU(5) grand unified theory are composite states and produce the mass hierarchy. This explains why the large mixing is realized in the lepton sector, while the small mixing is realized in the quark sector. This model can naturally solve the atmospheric neutrino problem. We can also solve the solar neutrino problem by improving the model.Comment: 20 pages, Latex, no figure

Proconvertase Furin Is Downregulated in Postural Orthostatic Tachycardia Syndrome.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular autonomic disorder characterized by orthostatic intolerance and high prevalence among young women. The etiology of POTS is uncertain, though autoimmunity and inflammation may play an important role. We aimed to identify novel inflammatory biomarkers associated with POTS. Methods and Results: In the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort, we identified 396 patients (age range, 15-50 years) with either POTS (n = 113) or normal haemodynamic response during passive head-up-tilt test (n = 283). Blood samples were analyzed using antibody-based Proximity Extension Assay technique simultaneously measuring 57 inflammatory protein biomarkers. The discovery algorithm was a sequential two-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. POTS patients were younger (26 vs. 31 years; p < 0.001) and there was no significant difference in sex distribution (74% vs. 67% females, p = 0.24). PCA and Bonferroni-adjusted ANOVA identified proconvertase furin as the most robust biomarker signature for POTS. Plasma level of proconvertase furin was lower (6.38 vs. 6.58 of normalized protein expression units (NPX); p < 0.001 in POTS, compared with the reference group. Proconvertase furin met Bonferroni-adjusted significance criteria in both uni- and multivariable regression analyses. Conclusion: Patients with POTS have lower plasma level of proconvertase furin compared with individuals with normal postural hemodynamic response. This finding suggests the presence of a specific autoimmune trait with disruption of immune peripheral tolerance in this hitherto unexplained condition. Further studies are needed for external validation of our results.This study was supported by grants from the Swedish Heart-Lung Foundation, the Swedish Heart and Lung Association, the Medical Faculty of Lund University, ALF funds, Skne University Hospital Funds, Crafoord Foundation, Ernhold Lundstrms Research Foundation, Region Skåne, Hulda and Conrad Mossfelt Foundation, and Anna-Lisa and Sven Eric Lundgrens Foundation for Medical Research

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Review of Pesticide Urinary Biomarker Measurements from Selected US EPA Children’s Observational Exposure Studies

Children are exposed to a wide variety of pesticides originating from both outdoor and indoor sources. Several studies were conducted or funded by the EPA over the past decade to investigate children’s exposure to organophosphate and pyrethroid pesticides and the factors that impact their exposures. Urinary metabolite concentration measurements from these studies are consolidated here to identify trends, spatial and temporal patterns, and areas where further research is required. Namely, concentrations of the metabolites of chlorpyrifos (3,5,6-trichloro-2-pyridinol or TCPy), diazinon (2-isopropyl-6-methyl-4-pyrimidinol or IMP), and permethrin (3-phenoxybenzoic acid or 3-PBA) are presented. Information on the kinetic parameters describing absorption and elimination in humans is also presented to aid in interpretation. Metabolite concentrations varied more dramatically across studies for 3-PBA and IMP than for TCPy, with TCPy concentrations about an order of magnitude higher than the 3-PBA concentrations. Temporal variability was high for all metabolites with urinary 3-PBA concentrations slightly more consistent over time than the TCPy concentrations. Urinary biomarker levels provided only limited evidence of applications. The observed relationships between urinary metabolite levels and estimates of pesticide intake may be affected by differences in the contribution of each exposure route to total intake, which may vary with exposure intensity and across individuals

Changing behaviour: Increasing the effectiveness of workplace interventions in creating pro-environmental behaviour change

There is a great deal of research outlining interventions to increase pro-environmental behaviour, many of which are aimed at employees. However, to date the results for these have not lived up to their initial promise. Instead of offering another intervention, we propose a model which identifies psychological conditions under which these interventions are most likely to succeed. Through the integration of previously separate literatures from experimental social psychology, organisational psychology, organisational behaviour and environmental psychology, we suggest that the degree to which the intervention-related goal is efficacious and attractive, self-concordant, in conflict with other goals, and perceived to be completed will affect the level and type of behaviour change. Our model aims to provide actionable knowledge that extends our understanding of the effectiveness of workplace interventions designed to increase green organisational behaviour

Evoking context with contrastive stress: effects on pragmatic enrichment

Although it is widely acknowledged that context influences a variety of pragmatic phenomena, it is not clear how best to articulate this notion of context and thereby explain the nature of its influence. In this paper, we target contextual alternatives that are evoked via focus placement and test how the same contextual manipulation can influence three different phenomena that involve pragmatic enrichment: scalar implicature, presupposition, and coreference. We argue that focus placement influences these three phenomena indirectly by providing the listener with information about the likely question under discussion (QUD) that a particular utterance answers (Roberts, 1996/2012). In three listening experiments, we find that the predicted interpretations are indeed made more available when focus placement is added to the final element (to the scalar adjective, to an entity embedded under the negated presupposition trigger, and to the predicate of a pronoun). These findings bring together several distinct strands of work on the effect of focus placement on interpretation all in the domain of pragmatic enrichment. Together they advance our empirical understanding of the relation between focus placement and QUD and highlight commonalities between implicature, presupposition, and coreference