The Sonic hedgehog and Wnt signalling pathways in interstitial lung disease and CD4⁺T cell activation

The Sonic Hedgehog (Shh) signalling pathway plays an important role in lung development where it promotes branching morphogenesis through epithelialmesenchymal interactions. Increased Shh expression promotes epithelial and mesenchymal proliferation in vitro and in vivo. TGFß is also expressed in embryonic lung where it acts to inhibit branching morphogenesis. TGFß overexpression results in lung hypoplasia, a similar phenotype to that seen in Shh⁻/⁻ mutants; suggesting that Shh and TGFß have opposing roles. Evidence to date would suggest that although TGFß and Shh may not directly interact in lung development, they probably have common targets and may function in a shared regulatory circuit.Interstitial lung disease (ILD) is the end result of a multiplicity of pathological processes. It has been recently proposed that the commonest form, Idiopathic Pulmonary Fibrosis (IPF) or Usual Interstitial Pneumonia (UIP), is due to abnormal wound healing in the lung, characterized by epithelial-fibroblast interactions; a process similar to foetal lung branching and epithelialization. TGFß has been strongly linked with ELD in both animal models and human disease. Based on the link between TGFß and Shh in lung morphogenesis, the initial aim of this thesis was to determine whether or not Shh signalling was upregulated in ILD. The work presented confirms that Shh and TGFß expression are increased in the airway epithelium of fibrotic but not non-fibrotic lung both in the murine FITC model of ILD and in biopsy sections from patients with IPF. Expression of Patched (Ptc), the Shh receptor, is unchanged in epithelial cells. Notably, Ptc is present both in alveolar macrophages and lymphocytic infiltrates. However, there is no discernible difference in the fibrotic response in the lungs of mice containing heterozygous mutations of Gli2 and 3, used as models of dysregulated Shh signalling, nor in mice treated with intra-tracheal SPC-Shh cDNA.The Shh pathway has recently been shown to play a role in thymocyte development. The findings presented demonstrate that both Shh and Ptc are expressed in human T cells. In addition, upregulation of Shh signalling enhances and blocking of endogenous Shh inhibits T cell receptor mediated T cell activation, respectively, as determined by proliferation, cytokine production and CD25 and CD69 expressionWnt signalling is also thought to play a role in lung branching morphogenesis. It is known to interact both with Shh signalling and TGFß. However, using presently available antibodies, there is no evidence of upregulation of Wnt signalling in ILD. In an attempt to drive the Wnt Pathway, a replication-deficient adenovirus expressing Dvll (Ad5-MCMV-Dvll) was successfully rescued. Although the virus drives Dvll mRNA and protein expression in vitro and in vivo, it does not consistently mimic Wnt signalling, nor does it appear to affect Shh or TGFß signalling. Furthermore such Dvll overexpression has little effect on cell proliferation either in vitro or in vivo, and does not cause lung fibrosis in mice.Thus Shh signalling appears to be upregulated in fibrotic lung in mice and humans. However the work presented does not define whether or not the pathway plays a specific role in the pathogenesis of ILD. There is also no evidence relating Wnt signalling or Dvll upregulation to ILD. Finally, Shh is shown to influence TCR mediated signalling and clonal expansion. It may be that damaged epithelial cells and the immune system communicate via this pathway

Promoting Sustainable Lifestyles: a social marketing approach. Final Summary Report

Commissioned by Defra

Sustainable lifestyles: sites, practices and policy

Author's draft. Final version published in Environment and Planning A. Available online at http://www.envplan.com/A.htmlPro-environmental behaviour change remains a high priority for many governments and agencies and there are now numerous programmes aimed at encouraging citizens to adopt sustainable forms of living. However, although programmes for addressing behaviour change in and around the home are well developed, there has been significantly less attention paid to activities beyond this site of practice. This is despite the environmental implications of consumption choices for leisure, tourism and work-related activities. Notwithstanding the extensive literatures which have explored environmental practices at a wide range of specific sites, there has been little research on the relationships between sites of practice and environmental behaviours. Using data from a series of in-depth interviews, this paper identifies two major challenges for academics and practitioners concerned with understanding and promoting more environmentally-responsible behaviour. First, attention must shift beyond the home as a site of environmental practice to consider the ways in which individuals respond to exhortations towards ‘greener’ lifestyles in other high-consumption and carbon-intensive contexts, particularly leisure and tourism. Second, in broadening the scope of environmental practice, policy makers need to re-visit their reliance on segmentation models and related social marketing approaches. This is in the light of data that suggest those with strong environmental commitments in the home are often reluctant to engage in similar commitments in other sites of practice

‘Helping People Make Better Choices’: exploring the behaviour change agenda for environmental sustainability

This paper examines the emergence of market-orientated approaches to public participation in environmental issues through an exploration of recent empirical research into ‘sustainable lifestyles’ as a practical tool for encouraging pro-environmental behaviour. Using the notion of ‘sustainable lifestyles’, current social marketing policies seek to encourage behaviour change amongst citizens by identifying population segments with similar commitments to environmental practices as the basis for behaviour change initiatives. However, the use of static ‘lifestyle groups’ implies that that citizens replicate sustainable practices across different consumption contexts and this paper explores this line of argument through the use of data collected as part of a recent UK Department for the Environment, Food and Rural Affairs (DEFRA) funded research project on sustainable lifestyles and climate change. Through a series of focus group discussions, participants explored notions of sustainable practices using the home and leisure contexts as framing devices to explore issues of environmental responsibility and climate change. The emphasis placed on practices and context reveal that the comfortable notions of environmental responsibility and sustainable consumption in the home are often in conflict with the discourses of consumption reduction associated with climate change in leisure and tourism contexts. In many cases, these ‘paradoxes’ are explicitly referred to, reflected-upon and discussed by participants who demonstrate that notions of sustainable practice are mediated by practice and spaces of consumption. Accordingly, the paper argues that in conceptualising market-based approaches to behaviour change around the notion of ‘sustainable lifestyles’, researchers and policy makers need to address the role of context and recognise the importance of consumption spaces and the conflicts that may arise between these

Evaluation of containers as a virtualisation alternative for HEP workloads

In this paper the emerging technology of Linux containers is examined and evaluated for use in the High Energy Physics (HEP) community. Key technologies required to enable containerisation will be discussed along with emerging technologies used to manage container images. An evaluation of the requirements for containers within HEP will be made and benchmarking will be carried out to asses performance over a range of HEP workflows. The use of containers will be placed in a broader context and recommendations on future work will be given

Sources of non-methane volatile organic compounds in Delhi, India

Cities in India consistently feature amongst the most polluted in the world, with air quality problems driven by rapid and poorly regulated economic growth and development. Many sources emit non-methane volatile organic compounds (NMVOCs), which degrade local and regional air quality through the photochemical formation of tropospheric ozone and secondary organic aerosol (SOA). Large uncertainties in the understanding of NMVOC sources specific to India result in poorly constrained regional policy and global chemical transport models. Consequently, the drivers of the consistently observed poor air quality remain poorly understood. This thesis presents measurements of NMVOCs made in Delhi during pre- and post-monsoon seasons in 2018. The sources of NMVOCs were examined, which showed that NMVOC emissions were principally from petrol and diesel related sources. Very high NMVOC concentrations were measured at night during the post-monsoon campaign. These were shown to be emissions from the local area and were enhanced due to stagnant conditions caused by very low planetary boundary layer heights and windspeeds. Solid fuels represent a large energy source to India, with potentially significant impacts to air quality. Consequently, a detailed source study of organic emissions from solid-fuel combustion sources was conducted. Firstly, a new method for collecting intermediate-volatility and semi-volatile organic gases and particles onto solid-phase extraction disks and Teflon filters, followed by solvent extraction with analysis by two-dimensional gas chromatography coupled to time-of-flight mass spectrometry was evaluated. Secondly, an extremely detailed set of emission factors of NMVOCs were measured with a range of online gas-phase techniques. These results were then mapped onto a volatility-basis dataset and the SOA production potential and OH reactivity of different sources compared. Finally, a high-resolution bottom-up emission inventory was developed for India from 1993-2016. This found that burning of cow dung cake had a disproportionately large impact to NMVOCs from residential combustion

Behavioral and other phenotypes in a cytoplasmic Dynein light intermediate chain 1 mutant mouse

The cytoplasmic dynein complex is fundamentally important to all eukaryotic cells for transporting a variety of essential cargoes along microtubules within the cell. This complex also plays more specialized roles in neurons. The complex consists of 11 types of protein that interact with each other and with external adaptors, regulators and cargoes. Despite the importance of the cytoplasmic dynein complex, we know comparatively little of the roles of each component protein, and in mammals few mutants exist that allow us to explore the effects of defects in dynein-controlled processes in the context of the whole organism. Here we have taken a genotype-driven approach in mouse (Mus musculus) to analyze the role of one subunit, the dynein light intermediate chain 1 (Dync1li1). We find that, surprisingly, an N235Y point mutation in this protein results in altered neuronal development, as shown from in vivo studies in the developing cortex, and analyses of electrophysiological function. Moreover, mutant mice display increased anxiety, thus linking dynein functions to a behavioral phenotype in mammals for the first time. These results demonstrate the important role that dynein-controlled processes play in the correct development and function of the mammalian nervous system

Using the Autopilot pattern to deploy container resources at a WLCG Tier-2

Containers are becoming ubiquitous within the WLCG, with CMS announcing a requirement for its sites to provide Singularity during 2018. The ubiquity of containers means it is now possible to reify the combination of an application and its configuration into a single easy-to-deploy unit, avoiding the need to make use of a myriad of configuration management tools such as Puppet, Ansible or Salt. This allows use to be made of industry-standard devops techniques within the operations domain, such as Continuous Integration (CI) and Continuous Deployment (CD), which can lead to faster upgrades and greater system security. One interesting technique is the Autopilot pattern, which provides mechanisms for application life-cycle management which are accessible from within the container itself. Using modern service discovery techniques, each container manages its own configuration, monitors its own health, and adapts to changing requirements through the use of event triggers. In this paper, we expand on previous work to create and deploy resources to a WLCG Tier-2 via containers, and investigate the viability of using the Autopilot pattern at a WLCG site to deploy and manage computational resources

Low carbon oil production: Enhanced oil recovery with CO 2 from North Sea residual oil zones

Residual Oil Zones (ROZ) form when oil has leaked or migrated from a reservoir trap through geological time, leaving a zone of immobile oil. Here we assess the feasibility of ROZ production with CO2 flooding, in a North Sea oil field for the first time. We identify a hydrodynamically produced ROZ, with an oil saturation of 26%, in the Pierce Oil Field of the Central North Sea and adapt established recovery factors for Carbon Dioxide Enhanced Oil Recovery (CO2 EOR) from onshore fields, to estimate oil resource and CO2 storage potential. Our mid case results show that CO2 utilisation increases commercial reserves by 5–20% while storing 15 M t CO2. Based on our calculations CO2 EOR can produce low carbon intensity crude oil from a mature basin and could store more CO2 than is released from the production, transport, refining and final combustion of oil