Chromatin modifications during repair of environmental exposure-induced DNA damage: a potential mechanism for stable epigenetic alterations

Exposures to environmental toxicants and toxins cause epigenetic changes that likely play a role in the development of diseases associated with exposure. The mechanism behind these exposure-induced epigenetic changes is currently unknown. One commonality between most environmental exposures is that they cause DNA damage either directly or through causing an increase in reactive oxygen species, which can damage DNA. Like transcription, DNA damage repair must occur in the context of chromatin requiring both histone modifications and ATP-dependent chromatin remodeling. These chromatin changes aid in DNA damage accessibility and signaling. Several proteins and complexes involved in epigenetic silencing during both development and cancer have been found to be localized to sites of DNA damage. The chromatin-based response to DNA damage is considered a transient event, with chromatin being restored to normal as DNA damage repair is completed. However, in individuals chronically exposed to environmental toxicants or with chronic inflammatory disease, repeated DNA damage-induced chromatin rearrangement may ultimately lead to permanent epigenetic alterations. Understanding the mechanism behind exposure-induced epigenetic changes will allow us to develop strategies to prevent or reverse these changes. This review focuses on epigenetic changes and DNA damage induced by environmental exposures, the chromatin changes that occur around sites of DNA damage, and how these transient chromatin changes may lead to heritable epigenetic alterations at sites of chronic exposure

An LED pulser for measuring photomultiplier linearity

A light-emitting diode (LED) pulser for testing the low-rate response of a photomultiplier tube (PMT) to scintillator-like pulses has been designed, developed, and implemented. This pulser is intended to simulate 80 ns full width at half maximum photon pulses over the dynamic range of the PMT, in order to precisely determine PMT linearity. This particular design has the advantage that, unlike many LED test rigs, it does not require the use of multiple calibrated LEDs, making it insensitive to LED gain drifts. Instead, a finite-difference measurement is made using two LEDs which need not be calibrated with respect to one another. These measurements give a better than 1% mapping of the response function, allowing for the testing and development of particularly linear PMT bases.Comment: 5 pages, 5 figure

A novel approach to light-front perturbation theory

We suggest a possible algorithm to calculate one-loop n-point functions within a variant of light-front perturbation theory. The key ingredients are the covariant Passarino-Veltman scheme and a surprising integration formula that localises Feynman integrals at vanishing longitudinal momentum. The resulting expressions are generalisations of Weinberg's infinite-momentum results and are manifestly Lorentz invariant. For n = 2 and 3 we explicitly show how to relate those to light-front integrals with standard energy denominators. All expressions are rendered finite by means of transverse dimensional regularisation.Comment: 10 pages, 5 figure

A tale of two tables

PostprintPeer reviewe

Reference priors for high energy physics

Bayesian inferences in high energy physics often use uniform prior distributions for parameters about which little or no information is available before data are collected. The resulting posterior distributions are therefore sensitive to the choice of parametrization for the problem and may even be improper if this choice is not carefully considered. Here we describe an extensively tested methodology, known as reference analysis, which allows one to construct parametrization-invariant priors that embody the notion of minimal informativeness in a mathematically well-defined sense. We apply this methodology to general cross section measurements and show that it yields sensible results. A recent measurement of the single top quark cross section illustrates the relevant techniques in a realistic situation

Mismatch Repair Proteins Initiate Epigenetic Alterations during Inflammation-Driven Tumorigenesis

Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared with normal epithelium and noninflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis

Bringing positional processes back in: occupational gender segregation in ‘non-academic’ work

This article highlights that organisations mask a 'gendered substructure' and a 'positional substructure', and reinforces the importance of (re)incorporating the effects of positional processes as an analytical concern in current analysis of occupational segregation. Drawing on the concept of 'inequality regimes', we use the case of 'non-academic' workers in Scottish higher education institutions as the context in which to explore how gendered and positional processes may be perpetuating occupational gender segregation ─ focusing on finance, registry, security and cleaning staff. Our findings show how embedded gendered and positional processes are reinforcing occupational gender segregation in many areas of non-academic work. We reveal that some gendered processes are position-sensitive and that stereotyped language use and related biases impact the progression and treatment of workers at the 'bottom' ─ and the compounding effects on women. We show that positions within organisational opportunity structures cannot merely be read off grading hierarchies and argue that any analysis of positional substructures necessitates uncovering the potential existence of multiple organisational hierarchies and other forms of positional advantage/disadvantage, whilst recognising that positional substructures are not static

Exposure assessment of process-related contaminants in food by biomarker monitoring

Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario’s and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment

High-Precision Measurement of the 19Ne Half-Life and Implications for Right-Handed Weak Currents

We report a precise determination of the 19Ne half-life to be $T_{1/2} = 17.262 \pm 0.007$ s. This result disagrees with the most recent precision measurements and is important for placing bounds on predicted right-handed interactions that are absent in the current Standard Model. We are able to identify and disentangle two competing systematic effects that influence the accuracy of such measurements. Our findings prompt a reassessment of results from previous high-precision lifetime measurements that used similar equipment and methods.Comment: 5 pages and 5 figures. Paper accepted for publication in Phys. Rev. Let

Towards an understanding of game software development processes: a case study

This paper aims to fill the gap that exists about software development processes in game development in the research literature, and address the gap in the research literature by investigating and reporting information about the software development processes used in game development. To investigate the role of the software development process in relation to the game development process, and to better understand the processes and practices used in game software development, a single industrial based case study was undertaken and reported to investigate in a real world context the software development processes and practices used in game development. This research contributes to our knowledge of the field of game development and potentially forms the foundation for further research in the area