Prospective Investigation of Pesticide Applicators' Health (PIPAH) study: a cohort study of professional pesticide users in Great Britain

PURPOSE: The purpose of the study is to monitor the exposure and health of workers in Great Britain who use pesticides as a part of their job, and to gain a better understanding of the relationship between long-term exposure to pesticides and health. PARTICIPANTS: Study participants are professional pesticide users who are certified in the safe use of pesticides or who were born before 1965 and apply pesticides under 'grandfather rights'. Overall response rate was 20%; participants are mostly male (98%) and the average age is 54 years, ranging from 17 to over 80 years. FINDINGS TO DATE: Participants have completed a baseline general questionnaire and three follow-up questionnaires on the use of pesticides. These data will enable investigations into the relationship between occupational pesticide exposure and health outcomes taking into account non-occupational confounding factors. FUTURE PLANS: There is no set end date for data collection. Recruitment into the cohort will continue, and for the foreseeable future there will be annual pesticide use questionnaires and five yearly follow-up general questionnaires.The intention is to validate the pesticide use questionnaire, and to develop a crop/job exposure matrix (C/JEM) which can be updated regularly. This C/JEM will be able to look at general categories of pesticide, such as insecticides, structurally related pesticides, such as organochlorines, or individual active ingredients. Data collected on use of personal protective equipment and method of application will provide information on how potential exposure to pesticide during application may have been modified. The study will be able to estimate changes in individual pesticide use over time, and to examine the associations between pesticide use and both baseline and long-term health outcomes.The cohort members will be linked to national databases for notification of hospital episode statistics, cancer incidence and mortality for follow-up of health outcomes

An experimental scale-model study of seismic response of an underground opening in jointed rock mass

This report describes an experimental investigation conducted by the Center for Nuclear Waste Regulatory Analyses (CNWRA) to (i) obtain a better understanding of the seismic response of an underground opening in a highly-fractured and jointed rock mass and (ii) generate a data set that can be used to evaluate the capabilities (analytical methods) to calculate such response. This report describes the design and implementation of simulated seismic experiments and results for a 1/15 scale model of a jointed rock mass with a circular tunnel in the middle. The discussion on the design of the scale model includes a description of the associated similitude theory, physical design rationale, model material development, preliminary analytical evaluation, instrumentation design and calibration, and model assembly and pretest procedures. The thrust of this discussion is intended to provide the information necessary to understand the experimental setup and to provide the background necessary to understand the experimental results. The discussion on the experimental procedures and results includes the seismic input test procedures, test runs, and measured excitation and response time histories. The closure of the tunnel due to various levels of seismic activity is presented. A threshold level of seismic input amplitude was required before significant rock mass motion occurred. The experiment, though designed as a two-dimensional representation of a rock mass, behaved in a somewhat three-dimensional manner, which will have an effect on subsequent analytical model comparison

Donor Centers and Absorption Spectra in Quantum Dots

We have studied the electronic properties and optical absorption spectra of three different cases of donor centers, D^{0}, D^{-} and D^{2-}, which are subjected to a perpendicular magnetic field, using the exact diagonalization method. The energies of the lowest lying states are obtained as function of the applied magnetic field strength B and the distance zeta between the positive ion and the confinement xy-plane. Our calculations indicate that the positive ion induces transitions in the ground-state, which can be observed clearly in the absorption spectra, but as zeta goes to 0 the strength of the applied magnetic field needed for a transition to occur tends to infinity.Comment: 5 pages, 4 figures, REVTeX 4, gzipped tar fil

Single stranded fully Modified-Phosphorothioate oligonucleotides can induce structured nuclear inclusions, alter nuclear protein localization and disturb the transcriptome In Vitro

Oligonucleotides and nucleic acid analogues that alter gene expression are now showing therapeutic promise in human disease. Whilst the modification of synthetic nucleic acids to protect against nuclease degradation and to influence drug function is common practice, such modifications may also confer unexpected physicochemical and biological properties. Gapmer mixed-modified and DNA oligonucleotides on a phosphorothioate backbone can bind non-specifically to intracellular proteins to form a variety of toxic inclusions, driven by the phosphorothioate linkages, but also influenced by the oligonucleotide sequence. Recently, the non-antisense or other off-target effects of 2′ O- fully modified phosphorothioate linkage oligonucleotides are becoming better understood. Here, we report chemistry-specific effects of oligonucleotides composed of modified or unmodified bases, with phosphorothioate linkages, on subnuclear organelles and show altered distribution of nuclear proteins, the appearance of highly stable and strikingly structured nuclear inclusions, and disturbed RNA processing in primary human fibroblasts and other cultured cells. Phosphodiester, phosphorodiamidate morpholino oligomers, and annealed complimentary phosphorothioate oligomer duplexes elicited no such consequences. Disruption of subnuclear structures and proteins elicit severe phenotypic disturbances, revealed by transcriptomic analysis of transfected fibroblasts exhibiting such disruption. Our data add to the growing body of evidence of off-target effects of some phosphorothioate nucleic acid drugs in primary cells and suggest alternative approaches to mitigate these effects

Radiative Corrections to One-Photon Decays of Hydrogenic Ions

Radiative corrections to the decay rate of n=2 states of hydrogenic ions are calculated. The transitions considered are the M1 decay of the 2s state to the ground state and the E1(M2) decays of the $2p_{1/2}$ and $2p_{3/2}$ states to the ground state. The radiative corrections start in order $\alpha (Z \alpha)^2$, but the method used sums all orders of $Z\alpha$. The leading $\alpha (Z\alpha)^2$ correction for the E1 decays is calculated and compared with the exact result. The extension of the calculational method to parity nonconserving transitions in neutral atoms is discussed.Comment: 22 pages, 2 figure

Negatively Charged Excitons and Photoluminescence in Asymmetric Quantum Well

We study photoluminescence (PL) of charged excitons ($X^-$) in narrow asymmetric quantum wells in high magnetic fields B. The binding of all $X^-$ states strongly depends on the separation $\delta$ of electron and hole layers. The most sensitive is the ``bright'' singlet, whose binding energy decreases quickly with increasing $\delta$ even at relatively small B. As a result, the value of B at which the singlet--triplet crossing occurs in the $X^-$ spectrum also depends on $\delta$ and decreases from 35 T in a symmetric 10 nm GaAs well to 16 T for $\delta=0.5$ nm. Since the critical values of $\delta$ at which different $X^-$ states unbind are surprisingly small compared to the well width, the observation of strongly bound $X^-$ states in an experimental PL spectrum implies virtually no layer displacement in the sample. This casts doubt on the interpretation of PL spectra of heterojunctions in terms of $X^-$ recombination

ALS-linked FUS mutations confer loss and gain of function in the nucleus by promoting excessive formation of dysfunctional paraspeckles

Mutations in the FUS gene cause amyotrophic lateral sclerosis (ALS-FUS). Mutant FUS is known to confer cytoplasmic gain of function but its effects in the nucleus are less understood. FUS is an essential component of paraspeckles, subnuclear bodies assembled on a lncRNA NEAT1. Paraspeckles may play a protective role specifically in degenerating spinal motor neurons. However it is still unknown how endogenous levels of mutant FUS would affect NEAT1/paraspeckles. Using novel cell lines with the FUS gene modified by CRISPR/Cas9 and human patient fibroblasts, we found that endogenous levels of mutant FUS cause accumulation of NEAT1 isoforms and paraspeckles. However, despite only mild cytoplasmic mislocalisation of FUS, paraspeckle integrity is compromised in these cells, as confirmed by reduced interaction of mutant FUS with core paraspeckle proteins NONO and SFPQ and increased NEAT1 extractability. This results in NEAT1 localisation outside paraspeckles, especially prominent under conditions of paraspeckle-inducing stress. Consistently, paraspeckle-dependent microRNA production, a readout for functionality of paraspeckles, is impaired in cells expressing mutant FUS. In line with the cellular data, we observed paraspeckle hyper-assembly in spinal neurons of ALS-FUS patients. Therefore, despite largely preserving its nuclear localisation, mutant FUS leads to loss (dysfunctional paraspeckles) and gain (excess of free NEAT1) of function in the nucleus. Perturbed fine structure and functionality of paraspeckles accompanied by accumulation of non-paraspeckle NEAT1 may contribute to the disease severity in ALS-FUS

Scaling Rule for Nonperturbative Radiation in a Class of Event Shapes

We discuss nonperturbative radiation for a recently introduced class of infrared safe event shape weights, which describe the narrow-jet limit. Starting from next-to-leading logarithmic (NLL) resummation, we derive an approximate scaling rule that relates the nonperturbative shape functions for these weights to the shape function for the thrust. We argue that the scaling reflects the boost invariance implicit in NLL resummation, and discuss its limitations. In the absence of data analysis for the new event shapes, we compare these predictions to the output of the event generator PYTHIA.Comment: 23 pages, 3 figures, uses JHEP3.cls (included); v2 - version to appear in JHE

Paraspeckle subnuclear bodies depend on dynamic heterodimerisation of DBHS RNA-binding proteins via their structured domains

RNA-binding proteins of the DBHS (Drosophila Behavior Human Splicing) family, NONO, SFPQ, and PSPC1 have numerous roles in genome stability and transcriptional and posttranscriptional regulation. Critical to DBHS activity is their recruitment to distinct subnuclear locations, for example, paraspeckle condensates, where DBHS proteins bind to the long noncoding RNA NEAT1 in the first essential step in paraspeckle formation. To carry out their diverse roles, DBHS proteins form homodimers and heterodimers, but how this dimerization influences DBHS localization and function is unknown. Here, we present an inducible GFP-NONO stable cell line and use it for live-cell 3D-structured illumination microscopy, revealing paraspeckles with dynamic, twisted elongated structures. Using siRNA knockdowns, we show these labeled paraspeckles consist of GFP-NONO/endogenous SFPQ dimers and that GFP-NONO localization to paraspeckles depends on endogenous SFPQ. Using purified proteins, we confirm that partner swapping between NONO and SFPQ occurs readily in vitro. Crystallographic analysis of the NONOSFPQ heterodimer reveals conformational differences to the other DBHS dimer structures, which may contribute to partner preference, RNA specificity, and subnuclear localization. Thus overall, our study suggests heterodimer partner availability is crucial for NONO subnuclear distribution and helps explain the complexity of both DBHS protein and paraspeckle dynamics through imaging and structural approaches.Pei Wen Lee, Andrew C. Marshall, Gavin J. Knott, Simon Kobelke, Luciano Martelotto, Ellie Cho, Paul J. McMillan, Mihwa Lee, Charles S. Bond, and Archa H. Fo