National geological screening : the Hampshire Basin and adjoining areas

This report is the published product of one of a series of studies covering England, Wales and Northern Ireland commissioned by Radioactive Waste Management (RWM) Ltd. The report provides geological information about the Hampshire Basin and adjoining areas region to underpin the process of national geological screening set out in the UK’s government White Paper Implementing geological disposal: a framework for the long-term management of higher activity radioactive waste (DECC, 2014). The report describes geological features relevant to the safety requirements of a geological disposal facility (GDF) for radioactive waste emplaced onshore and up to 20 km offshore at depths between 200 and 1000 m from surface. It is written for a technical audience but is intended to inform RWM in its discussions with communities interested in finding out about the potential for their area to host a GDF

Investigating genome wide dna methylation in airway smooth muscle cells from asthmatic and non-asthmatic donors

Rationale: Genetic mechanisms fail to fully explain asthma pathogenesis and environmental factors are considered to play an important role. Environmental factors may lead to permanent changes in epigenetic patterns and contribute to asthma. Epigenetics is the study of heritable changes in gene expression that are not due to changes in DNA sequence. DNA methylation is a reversible modification of DNA structure in which a methyl group is added to cytosine residues. Parental smoking affects the methylation of buccal cell DNA from children and children with early onset wheeze have an altered blood DNA methylation profile to healthy individuals. No studies have compared DNA methylation profiles in the disease relevant cell type of airway smooth muscle (ASM) cells. Methods: DNA was isolated from ASM cells at passage 5 and bisulphite treated to convert epigenetic information into sequence-based information. Site specific, quantitative genome wide methylation was determined using the Illumina 450K Infinium Methylation BeadChip array. Hits were validated by Pyrosequencing. RNA was extracted simultaneously for mRNA expression analysis by real time PCR. Results: There were no independent CpG sites associated with asthmatic status of ASM cells following multiple test correction. Without correction over 13000 CpG sites showed a significant difference in methylation (linear modelling, p value >0.05) between asthmatic and non-asthmatic cells, and a biologically relevant difference in methylation of greater that 10% (β value >0.1 ). 10 of these sites were selected as top hits. 7 sites positively validated by pyrosequencing. They were associated with 7 different genes; LGALS3BP, ATP11A, ZNF696, KLF6, TBX1, RUNX3, and SPINT2. Expression of these genes was measured in ASM cells isolated from asthmatic and non-asthmatic donors. LGALS3BP expression was undetectable while ATP11A and ZNF696 displayed no difference in expression between cells from asthmatic and non-asthmatic donors. KLF6 and SPINT2 showed a trend towards increased expression in cells from asthmatic donors while RUNX3 and TBX1 showed a trend towards decreased expression. Conclusions: Differences in CpG methylation exist between ASM isolated from asthmatic and non-asthmatic donors. Future work will focus on identifying differentially methylated regions of DNA and further defining the association to gene and protein expression

National geological screening : the Wealden district

This report is the published product of one of a series of studies covering England, Wales and Northern Ireland commissioned by Radioactive Waste Management (RWM) Ltd. The report provides geological information about the Wealden district region to underpin the process of national geological screening set out in the UK’s government White Paper Implementing geological disposal: a framework for the long-term management of higher activity radioactive waste (DECC, 2014). The report describes geological features relevant to the safety requirements of a geological disposal facility (GDF) for radioactive waste emplaced onshore and up to 20 km offshore at depths between 200 and 1000 m from surface. It is written for a technical audience but is intended to inform RWM in its discussions with communities interested in finding out about the potential for their area to host a GDF

National geological screening : the Pennines and adjacent areas

This report is the published product of one of a series of studies covering England, Wales and Northern Ireland commissioned by Radioactive Waste Management (RWM) Ltd. The report provides geological information about the Pennines and adjacent areas region to underpin the process of national geological screening set out in the UK’s government White Paper Implementing geological disposal: a framework for the long-term management of higher activity radioactive waste (DECC, 2014). The report describes geological features relevant to the safety requirements of a geological disposal facility (GDF) for radioactive waste emplaced onshore and up to 20 km offshore at depths between 200 and 1000 m from surface. It is written for a technical audience but is intended to inform RWM in its discussions with communities interested in finding out about the potential for their area to host a GDF

National geological screening : Northern England region

This report is the published product of one of a series of studies covering England, Wales and Northern Ireland commissioned by Radioactive Waste Management (RWM) Ltd. The report provides geological information about the Northern England region to underpin the process of national geological screening set out in the UK’s government White Paper Implementing geological disposal: a framework for the long-term management of higher activity radioactive waste (DECC, 2014). The report describes geological features relevant to the safety requirements of a geological disposal facility (GDF) for radioactive waste emplaced onshore and up to 20 km offshore at depths between 200 and 1000 m from surface. It is written for a technical audience but is intended to inform RWM in its discussions with communities interested in finding out about the potential for their area to host a GDF

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma

The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects – using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function – and its response to pharmacological intervention – to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures

The utility of exhaled nitric oxide in patients with suspected asthma

The value of FENO measurements in patients with symptoms suggestive of asthma is unclear. We performed an observational study to assess the ability of FENO to diagnose asthma and to predict response to inhaled corticosteroids (ICS). Our findings suggest FENO is not useful for asthma diagnosis but is accurate at predicting ICS response

National geological screening : Bristol and Gloucester region

This report is the published product of one of a series of studies covering England, Wales and Northern Ireland commissioned by Radioactive Waste Management (RWM) Ltd. The report provides geological information about the Bristol and Gloucester region to underpin the process of national geological screening set out in the UK’s government White Paper Implementing geological disposal: a framework for the longterm management of higher activity radioactive waste (DECC, 2014). The report describes geological features relevant to the safety requirements of a geological disposal facility (GDF) for radioactive waste emplaced onshore and up to 20 km offshore at depths between 200 and 1000 m from surface. It is written for a technical audience but is intended to inform RWM in its discussions with communities interested in finding out about the potential for their area to host a GDF