Numerous studies have demonstrated the normal tissue-sparing effects of ultra-high dose rate 'FLASH' irradiation in vivo, with an associated reduction in damage burden being reported in vitro. ...Towards this, two key radiochemical mechanisms have been proposed: radical-radical recombination (RRR) and transient oxygen depletion (TOD), with both being proposed to lead to reduced levels of induced damage. Previously, we reported that FLASH induces lower levels of DNA strand break damage in whole-blood peripheral blood lymphocytes (WB-PBL) ex vivo, but our study failed to distinguish the mechanism(s) involved. A potential outcome of RRR is the formation of crosslink damage (particularly, if any organic radicals recombine), whilst a possible outcome of TOD is a more anoxic profile of induced damage resulting from FLASH. Therefore, the aim of the current study was to profile FLASH-induced damage via the Comet assay, assessing any DNA crosslink formation as a putative marker of RRR and/or anoxic DNA damage formation as an indicative marker of TOD, to determine the extent to which either mechanism contributes to the "FLASH effect". Following FLASH irradiation, we see no evidence of any crosslink formation; however, FLASH irradiation induces a more anoxic profile of induced damage, supporting the TOD mechanism. Furthermore, treatment of WB-PBLs pre-irradiation with BSO abrogates the reduced strand break damage burden mediated by FLASH exposures. In summary, we do not see any experimental evidence to support the RRR mechanism contributing to the reduced damage burden induced by FLASH. However, the observation of a greater anoxic profile of damage following FLASH irradiation, together with the BSO abrogation of the reduced strand break damage burden mediated by FLASH, lends further support to TOD being a driver of the reduced damage burden plus a change in the damage profile mediated by FLASH.
This paper reviews clinical and asymptomatic
Toxoplasma gondii infection in humans and other animals in the USA. Seroprevalence of
T. gondii in humans and pigs is declining. Modes of transmission, ...epidemiology and environmental contamination with oocysts on land and sea are discussed.
First measurements of the in-flight shape of imploding inertial confinement fusion (ICF) capsules at the National Ignition Facility (NIF) were obtained by using two-dimensional x-ray radiography. The ...sequence of area-backlit, time-gated pinhole images is analyzed for implosion velocity, low-mode shape and density asymmetries, and the absolute offset and center-of-mass velocity of the capsule shell. The in-flight shell is often observed to be asymmetric even when the concomitant core self-emission is round. A ∼ 15 μm shell asymmetry amplitude of the Y(40) spherical harmonic mode was observed for standard NIF ICF hohlraums at a shell radius of ∼ 200 μm (capsule at ∼ 5× radial compression). This asymmetry is mitigated by a ∼ 10% increase in the hohlraum length.
We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been ...used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10(-3) from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10(-4)) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10(-9), odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10(-8), OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.
► Introduces the Agricultural Model Intercomparison and Improvement Project (AgMIP). ► Describes AgMIP Protocols for consistent research activities. ► Demonstrates AgMIP approaches using climate, ...crop, and economic model analyses. ► Wheat pilot results elucidate the relative uncertainties from crop and climate models. ► Outlines AgMIP crop-specific, regional, and global research activities.
The Agricultural Model Intercomparison and Improvement Project (AgMIP) is a major international effort linking the climate, crop, and economic modeling communities with cutting-edge information technology to produce improved crop and economic models and the next generation of climate impact projections for the agricultural sector. The goals of AgMIP are to improve substantially the characterization of world food security due to climate change and to enhance adaptation capacity in both developing and developed countries. Analyses of the agricultural impacts of climate variability and change require a transdisciplinary effort to consistently link state-of-the-art climate scenarios to crop and economic models. Crop model outputs are aggregated as inputs to regional and global economic models to determine regional vulnerabilities, changes in comparative advantage, price effects, and potential adaptation strategies in the agricultural sector. Climate, Crop Modeling, Economics, and Information Technology Team Protocols are presented to guide coordinated climate, crop modeling, economics, and information technology research activities around the world, along with AgMIP Cross-Cutting Themes that address uncertainty, aggregation and scaling, and the development of Representative Agricultural Pathways (RAPs) to enable testing of climate change adaptations in the context of other regional and global trends. The organization of research activities by geographic region and specific crops is described, along with project milestones.
Pilot results demonstrate AgMIP's role in assessing climate impacts with explicit representation of uncertainties in climate scenarios and simulations using crop and economic models. An intercomparison of wheat model simulations near Obregón, Mexico reveals inter-model differences in yield sensitivity to CO2 with model uncertainty holding approximately steady as concentrations rise, while uncertainty related to choice of crop model increases with rising temperatures. Wheat model simulations with mid-century climate scenarios project a slight decline in absolute yields that is more sensitive to selection of crop model than to global climate model, emissions scenario, or climate scenario downscaling method. A comparison of regional and national-scale economic simulations finds a large sensitivity of projected yield changes to the simulations’ resolved scales. Finally, a global economic model intercomparison example demonstrates that improvements in the understanding of agriculture futures arise from integration of the range of uncertainty in crop, climate, and economic modeling results in multi-model assessments.
Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has ...been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.
The Southern Parkes Large-Area Survey in Hydroxyl (SPLASH) is a sensitive, unbiased, and fully sampled survey of the southern Galactic plane and Galactic Centre in all four ground-state transitions ...of the hydroxyl (OH) radical. The survey provides a deep census of 1612-, 1665-, 1667-, and 1720-MHz OH absorption and emission from the Galactic interstellar medium, and is also an unbiased search for maser sources in these transitions. We present here first results from the SPLASH pilot region, which covers Galactic longitudes 334° to 344° and latitudes ±2°. Diffuse OH is widely detected in all four transitions, with optical depths that are always small (averaged over the Parkes beam), and with departures from local thermodynamic equilibrium common even in the 1665- and 1667-MHz main lines. To a 3σ sensitivity of ∼30 mK, we find no evidence of OH envelopes extending beyond the CO-bright regions of molecular cloud complexes, and conclude that the similarity of the OH excitation temperature and the level of the continuum background is at least partly responsible for this. We detect masers and maser candidates in all four transitions, approximately 50 per cent of which are new detections. This implies that SPLASH will produce a substantial increase in the known population of ground-state OH masers in the southern Galactic plane.
Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by ...single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
Genome-wide association studies (GWAS) have identified a number of loci that have strong support for their association with bipolar disorder (BD). The Psychiatric Genome-Wide Association Study (GWAS) ...Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis of BD GWAS data sets and replication samples identified evidence (P=6.7 × 10⁻⁷, odds ratio (OR)=1.147) of association with the risk of BD at the polymorphism rs9371601 within SYNE1, a gene which encodes nesprin-1. Here we have tested this polymorphism in an independent BD case (n=1527) and control (n=1579) samples, and find evidence for association (P=0.0095) with similar effect sizes to those previously observed in BD (allelic OR=1.148). In a combined (meta) analysis of PGC-BD data (both primary and replication data) and our independent BD samples, we found genome-wide significant evidence for association (P=2.9 × 10⁻⁸, OR=1.104). We have also examined the polymorphism in our recurrent unipolar depression cases (n=1159) and control (n=2592) sample, and found that the risk allele was associated with risk for recurrent major depression (P=0.032, OR=1.118). Our findings add to the evidence that association at this locus influences susceptibility to bipolar and unipolar mood disorders.
Abstract
STUDY QUESTION
What is the prevalence of infertility and of help seeking among women and men in Britain?
SUMMARY ANSWER
One in eight women and one in ten men aged 16–74 years had experienced ...infertility, defined by unsuccessfully attempting pregnancy for a year or longer, and little more than half of these people sought medical or professional help.
WHAT IS KNOWN ALREADY
Estimates of infertility and help seeking in Britain vary widely and are not easily comparable because of different definitions and study populations.
STUDY DESIGN, SIZE, DURATION
A cross-sectional population survey was conducted between 2010 and 2012 with a sample of 15 162 women and men aged 16–74 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Participants completed the Natsal-3 questionnaire, using computer-assisted personal interviewing (CAPI) and computer-assisted self-interview (CASI).
MAIN RESULTS AND THE ROLE OF CHANCE
The reported prevalence of infertility was 12.5% (CI 95% 11.7–13.3) among women and 10.1% (CI 95% 9.2–11.1) among men. Increased prevalence was associated with later cohabitation with a partner, higher socio-economic status and, for those who had a child, becoming parents at older ages. The reported prevalence of help seeking was 57.3% (CI 95% 53.6–61.0) among women and 53.2% (CI 95% 48.1–58.1) among men. Help seekers were more likely to be better educated and in higher status occupations and, among those who had a child, to have become parents later in life.
LIMITATIONS, REASONS FOR CAUTION
These data are cross-sectional so it is not possible to establish temporality or infer causality. Self-reported data may be subject to recall bias.
WIDER IMPLICATIONS OF THE FINDINGS
The study provides estimates of infertility and help seeking in Britain and the results indicate that the prevalence of infertility is higher among those delaying parenthood. Those with higher educational qualifications and occupational status are more likely to consult with medical professionals for fertility problems than others and these inequalities in help seeking should be considered by clinical practice and public health.
STUDY FUNDING/COMPETING INTEREST(S)
Funding was provided by grants from the Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health. AMJ is a Governor of the Wellcome Trust. Other authors have no competing interests.
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