Environmental monitoring : phase 5 final report (April 2019 - March 2020)

This report presents the results and interpretation for Phase 5 of an integrated environmental monitoring programme that is being undertaken around two proposed shale gas sites in England – Preston New Road, Lancashire and Kirby Misperton, North Yorkshire. The report should be read in conjunction with previous reports freely available through the project website1 . These provide additional background to the project, presentation of earlier results and the rationale for establishment of the different elements of the monitoring programme

Australia Day, flags on cars and Australian nationalism

This article reports the results of research into the recent popular phenomenon of flying Australian flags on one’s car for Australia Day. A survey was undertaken in Western Australia in 2011 to ascertain who flies the flag and why. Results indicate the phenomenon was widespread, with a quarter of those surveyed displaying car-flags. A clear relationship between car-flag-flying and exclusionary nationalism is demonstrated. Car-flag-flyers rate more highly on measures of patriotism and nationalism, and feel more negative towards Muslims and asylum seekers, and more positive about the White Australia Policy. They are also significantly more likely to feel their culture and values are in danger, and have a nativist vision of Australian identity. While both groups are positive about Australia’s diversity, car-flag-flyers are more likely to feel that migrants should assimilate. The results support other literature that suggests that in some contexts the Australian flag has come to be associated with exclusionary nationalism

Environmental monitoring : phase 4 final report (April 2018 - March 2019)

This report describes the results of activities carried out as part of the Environmental Monitoring Project (EMP) led by the British Geological Survey (BGS) in areas around two shale gas sites in England – Kirby Misperton (Vale of Pickering, North Yorkshire) and Preston New Road (Fylde, Lancashire). It focuses on the monitoring undertaken during the period April 2018–March 2019 but also considers this in the context of earlier monitoring results that have been covered in reports for earlier phases of the project (Phases I–IV) 2 . The EMP project is a multi-partner project involving BGS together with Public Health England (PHE), University of Birmingham, University of Bristol, University of Manchester, Royal Holloway University of London (RHUL) and University of York. The work has been enabled by funding from a combination of the BGS National Capability programme, a grant awarded by the UK Government’s Department for Business Energy & Industrial Strategy (BEIS) and additional benefit-in-kind contributions from all partners. The project comprises the comprehensive monitoring of different environment compartments and properties at and around the two shale-gas sites. The component parts of the EMP are all of significance when considering environmental and human health risks associated with shale gas development. Included are seismicity, ground motion, water (groundwater and surface water), soil gas, greenhouse gases, air quality, and radon. The monitoring started before hydraulic fracturing had taken place at the two locations, and so the results obtained before the initiation of operations at the shale-gas sites represent baseline conditions. It is important to characterise adequately the baseline conditions so that any future changes caused by shale gas operations, including hydraulic fracturing, can be identified. This is also the case for any other new activities that may impact those compartments of the environment being monitored as part of the project. In the period October 2018–December 2018, an initial phase of hydraulic fracturing took place at the Preston New Road (PNR) shale-gas site (shale gas well PNR1-z) in Lancashire. This was followed by a period of flow testing of the well to assess its performance (to end of January 2019). The project team continued monitoring during these various activities and several environmental effects were observed. These are summarised below and described in more detail within the report. The initiation of operations at the shale-gas site signified the end of baseline monitoring. At the Kirby Misperton site (KMA), approval has not yet been granted for hydraulic fracturing of the shale gas well (KM8), and so no associated operations have taken place during the period covered by this report. The effects on air quality arising from the mobilisation of equipment in anticipation of hydraulic fracturing operations starting was reported in the Phase III report, and in a recently published paper3 . Following demobilisation of the equipment and its removal from the site, conditions returned to baseline and the on-going monitoring (reported in this report) is effectively a continuation of baseline monitoring

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Whole genome sequence analysis of platelet traits in the NHLBI Trans-Omics for Precision Medicine (TOPMed) initiative

Platelets play a key role in thrombosis and hemostasis. Platelet count (PLT) and mean platelet volume (MPV) are highly heritable quantitative traits, with hundreds of genetic signals previously identified, mostly in European ancestry populations. We here utilize whole genome sequencing (WGS) from NHLBI's Trans-Omics for Precision Medicine initiative (TOPMed) in a large multi-ethnic sample to further explore common and rare variation contributing to PLT (n = 61 200) and MPV (n = 23 485). We identified and replicated secondary signals at MPL (rs532784633) and PECAM1 (rs73345162), both more common in African ancestry populations. We also observed rare variation in Mendelian platelet-related disorder genes influencing variation in platelet traits in TOPMed cohorts (not enriched for blood disorders). For example, association of GP9 with lower PLT and higher MPV was partly driven by a pathogenic Bernard-Soulier syndrome variant (rs5030764, p.Asn61Ser), and the signals at TUBB1 and CD36 were partly driven by loss of function variants not annotated as pathogenic in ClinVar (rs199948010 and rs571975065). However, residual signal remained for these gene-based signals after adjusting for lead variants, suggesting that additional variants in Mendelian genes with impacts in general population cohorts remain to be identified. Gene-based signals were also identified at several genome-wide association study identified loci for genes not annotated for Mendelian platelet disorders (PTPRH, TET2, CHEK2), with somatic variation driving the result at TET2. These results highlight the value of WGS in populations of diverse genetic ancestry to identify novel regulatory and coding signals, even for well-studied traits like platelet traits