Studies towards an enhanced understanding of electron beams and their diagnostics

A large part of current research and innovation capacity depends on high quality electron beams. Electron accelerators are found in many applications from cancer therapy, cargo scanners, high energy particle colliders, synchrotron light sources to free electron lasers. Electron beams also offer exciting opportunities for developments at the cutting edge of science, for example on novel accelerating schemes which promise accelerating gradients several orders of magnitude higher than what can be realised with conventional radiofrequency accelerators. Whilst R&D into the optimisation of electron accelerators has been performed over many decades, further improvements are still required so their potential can be fully exploited. This includes studies into advanced instrumentation to yield more precise information about the beam itself, novel simulation tools that model the physics of emission and interaction processes, as well as improved beam generation and shaping schemes to enhance the achievable beam brightness. In the frame of this PhD work, different areas of electron beams and associated technologies have been studied whilst still pertaining to the same question: How can we better understand the generation, control and use of electron beams? The thesis is split into three main sections: After a general introduction to the subject, studies into electron emission and initial beam shaping are covered in chapter 2, before the results from investigations into novel beam loss detection techniques are presented in chapter 3. In any accelerator based light source, maintaining the beam quality is crucial. The electron source itself is a key element that determines the achievable beam quality. A variety of source materials are currently under test across many institutes to better understand emission characteristics and to identify the best materials and optimum preparation methods. Here, one experimental set-up at the Cockcroft Institute has been considered. The Transverse Energy Spread Spectrometer (TESS) apparatus uses electrostatic elements to measure both the transverse and longitudinal energy properties of electron beams generated from photocathodes. This then provides detailed information about the electron emission process and allows optimisation of beam generation schemes. To enhance the understanding of the experimental data, a dedicated particle tracking code has been developed which uses accurate maps obtained from simulation or experiment to represent all electromagnetic fields of the set-up. This code has then been used to study two different techniques to measure the longitudinal energy spread of electrons emitted from gallium arsenide. The first technique was to use a wire mesh as an energy filter which the electrons must pass through, the second was to generate a potential difference between the cathode source and detector system. Experimental results are presented for both techniques and the analysis is supplemented with simulations. Monte Carlo results are in good agreement with experimental data, however, through this analysis it is found that using the meshes as a wire filter may not be an efficient method of measuring the longitudinal energy distribution curve as a result of the potential distribution surrounding the wire meshes. The second method is sufficient to the task however the resolution of the technique may be affected by focusing effects around the meshes. Measurement and detection of beam loss is important for any accelerator as unwanted losses yield reduced beam transmission and cause higher background noise. It is crucial in high energy accelerators where unwanted loss particles could easily damage parts of the accelerator and the experiments. Currently used techniques, however, are often limited in their dynamic range, spatial and time resolution, radiation hardness and can be expensive. A detector based on optical fibres with photodetector readout has been studied as part of this work as a detector for a future electron-positron collider. It can cover large distances at the expense of many smaller localised detectors. The ultimate performance of this detector is strongly affected by the light sensor at the fibre end. This in turn limits the performance to locate beam loss intensity and position and hence ultimately limits the understanding of beam loses along an accelerator. To this end Silicon Photomultipliers have been studied as an advanced light sensor that shows great promise for beam loss applications. Preliminary models are compared to experimental data and it is shown that the detector performance in this application is limited by the finite number of pixels available to fire along with pixel recovery/dead time. Measurements carried out at the CLIC Test Facility at CERN using an optical fibre systems are presented and used to assess the system’s performance to specific beam structures. Several techniques are used to analyses signals recorded by multiple detectors however it is found that the layout of optical fibres, which could not be changed, limited full understanding, however, these results are the basis of later experiments which fully measure the effect of a fibre optic beam loss monitor to different beam structures and additional changes to the set-up, which may aid further tests, are covered

Measurements of the longitudinal energy distribution of low energy electrons

The Transverse Energy Spread Spectrometer (TESS) is an ASTeC experiment designed to measure the energy of electrons from different cathode materials. It is a dedicated test stand for future light sources. A full particle tracking code has been developed in the QUASAR Group, which simulates particle trajectories through TESS. Using this code it is possible to simulate different operational conditions of the experiment and cathode materials. The simulation results can then be benchmarked against experimental data to test the validity of the emission and beam transport model. Within this paper, results from simulation studies are presented and compared against experimental data as a collaboration within the Cockcroft Institute between ASTeC and the QUASAR Group for the case of measuring the longitudinal velocity distribution of electrons emitted from a gallium arsenide cathode using a grid structure as an energy filter

Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding

Background: Atherosclerosis is an inflammatory process that develops in individuals with known risk factors that include hypertension and hyperlipidaemia, influenced by diet. However, the interplay between diet, inflammatory mechanisms and vascular risk factors requires further research. We hypothesised that interleukin-1 (IL-1) signaling in the vessel wall would raise arterial blood pressure and promote atheroma. Methodology/Principal Findings: Apoe(-/-) and Apoe(-/-)/IL-1R1(-/-) mice were fed high fat diets for 8 weeks, and their blood pressure and atherosclerosis development measured. Apoe(-/-)/IL-R1(-/-) mice had a reduced blood pressure and significantly less atheroma than Apoe(-/-) mice. Selective loss of IL-1 signaling in the vessel wall by bone marrow transplantation also reduced plaque burden (p<0.05). This was associated with an IL-1 mediated loss of endothelium-dependent relaxation and an increase in vessel wall Nox 4. Inhibition of IL-1 restored endothelium-dependent vasodilatation and reduced levels of arterial oxidative stress. Conclusions/Significance: The IL-1 cytokine system links atherogenic environmental stimuli with arterial inflammation, oxidative stress, increased blood pressure and atherosclerosis. This is the first demonstration that inhibition of a single cytokine can block the rise in blood pressure in response to an environmental stimulus. IL-1 inhibition may have profound beneficial effects on atherogenesis in man

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS

More frequent, more costly? Health economic modelling aspects of monitoring glaucoma patients in England

BACKGROUND: Chronic open angle glaucoma (COAG) is an age-related eye disease causing irreversible loss of visual field (VF). Health service delivery for COAG is challenging given the large number of diagnosed patients requiring lifelong periodic monitoring by hospital eye services. Yet frequent examination better determines disease worsening and speed of VF loss under treatment. We examine the cost-effectiveness of increasing frequency of VF examinations during follow-up using a health economic model. METHODS: Two different VF monitoring schemes defined as current practice (annual VF testing) and proposed practice (three VF tests per year in the first 2 years after diagnosis) were examined. A purpose written health economic Markov model is used to test the hypothesis that cost effectiveness improves by implementing proposed practice on groups of patients stratified by age and severity of COAG. Further, a new component of the model, estimating costs of visual impairment, was added. Results were derived from a simulated cohort of 10000 patients with quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) used as main outcome measures. RESULTS: An ICER of £21,392 per QALY was derived for proposed practice improving to a value of £11,382 once savings for prevented visual impairment was added to the model. Proposed practice was more cost-effective in younger patients. Proposed practice for patients with advanced disease at diagnosis generated ICERs > £60,000 per QALY; these cases would likely be on the most intensive treatment pathway making clinical information on speed of VF loss redundant. Sensitivity analysis indicated results to be robust in relation to hypothetical willingness to pay threshold identified by national guidelines, although greatest uncertainty was allied to estimates of implementation and visual impairment costs. CONCLUSION: Increasing VF monitoring at the earliest stages of follow-up for COAG appears to be cost-effective depending on reasonable assumptions about implementation costs. Our health economic model highlights benefits of stratifying patients to more or less monitoring based on age and stage of disease at diagnosis; a prospective study is needed to prove these findings. Further, this works highlights gaps in knowledge about long term costs of visual impairment

UGT1A1 is a major locus influencing bilirubin levels in African Americans

Total serum bilirubin is associated with several clinical outcomes, including cardiovascular disease, diabetes and drug metabolism. We conducted a genome-wide association study in 619 healthy unrelated African Americans in an attempt to replicate reported findings in Europeans and Asians and to identify novel loci influencing total serum bilirubin levels. We analyzed a dense panel of over two million genotyped and imputed SNPs in additive genetic models adjusting for age, sex, and the first two significant principal components from the sample covariance matrix of genotypes. Thirty-nine SNPs spanning a 78 kb region within the UGT1A1 displayed P-values <5 × 10−8. The lowest P-value was 1.7 × 10−22 for SNP rs887829. None of SNPs in the UGT1A1 remained statistically significant in conditional association analyses that adjusted for rs887829. In addition, SNP rs10929302 located in phenobarbital response enhancer module was significantly associated with bilirubin level with a P-value of 1.37 × 10−11; this enhancer module is believed to have a critical role in phenobarbital treatment of hyperbilirubinemia. Interestingly, the lead SNP, rs887829, is in strong linkage disequilibrium (LD) (r2≥0.74) with rs10929302. Taking advantage of the lower LD and shorter haplotypes in African-ancestry populations, we identified rs887829 as a more refined proxy for the causative variant influencing bilirubin levels. Also, we replicated the reported association between variants in SEMA3C and bilirubin levels. In summary, UGT1A1 is a major locus influencing bilirubin levels and the results of this study promise to contribute to understanding of the etiology and treatment of hyperbilirubinaemia in African-ancestry populations

The Role of the BMP Signaling Antagonist Noggin in the Development of Prostate Cancer Osteolytic Bone Metastasis

Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma-derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases