14,510 research outputs found

    Modelling uncertainties for measurements of the H → γγ Channel with the ATLAS Detector at the LHC

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    The Higgs boson to diphoton (H → γγ) branching ratio is only 0.227 %, but this final state has yielded some of the most precise measurements of the particle. As measurements of the Higgs boson become increasingly precise, greater import is placed on the factors that constitute the uncertainty. Reducing the effects of these uncertainties requires an understanding of their causes. The research presented in this thesis aims to illuminate how uncertainties on simulation modelling are determined and proffers novel techniques in deriving them. The upgrade of the FastCaloSim tool is described, used for simulating events in the ATLAS calorimeter at a rate far exceeding the nominal detector simulation, Geant4. The integration of a method that allows the toolbox to emulate the accordion geometry of the liquid argon calorimeters is detailed. This tool allows for the production of larger samples while using significantly fewer computing resources. A measurement of the total Higgs boson production cross-section multiplied by the diphoton branching ratio (σ × Bγγ) is presented, where this value was determined to be (σ × Bγγ)obs = 127 ± 7 (stat.) ± 7 (syst.) fb, within agreement with the Standard Model prediction. The signal and background shape modelling is described, and the contribution of the background modelling uncertainty to the total uncertainty ranges from 18–2.4 %, depending on the Higgs boson production mechanism. A method for estimating the number of events in a Monte Carlo background sample required to model the shape is detailed. It was found that the size of the nominal γγ background events sample required a multiplicative increase by a factor of 3.60 to adequately model the background with a confidence level of 68 %, or a factor of 7.20 for a confidence level of 95 %. Based on this estimate, 0.5 billion additional simulated events were produced, substantially reducing the background modelling uncertainty. A technique is detailed for emulating the effects of Monte Carlo event generator differences using multivariate reweighting. The technique is used to estimate the event generator uncertainty on the signal modelling of tHqb events, improving the reliability of estimating the tHqb production cross-section. Then this multivariate reweighting technique is used to estimate the generator modelling uncertainties on background V γγ samples for the first time. The estimated uncertainties were found to be covered by the currently assumed background modelling uncertainty

    In her own words: exploring the subjectivity of Freud’s ‘teacher’ Anna von Lieben

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    This project is inspired by Roy Porter (1985), who draws attention to the patient-shaped gap in medical history, and Rita Charon (2006), who emphasises the need to bring the patient’s narrative to the fore in the practice of medicine. The principal aim was to devise a means of accessing the lived experience of a patient who is no longer alive in order to gain an understanding of her narrative. Anna von Lieben was identified as a suitable subject as she wrote a substantial quantity of autopathographical poetry suitable for analysis and her status as Freud’s patient makes her a person of significant interest to the history of medicine. The poems were analysed using Interpretative Phenomenological Analysis (IPA), an idiographic and inductive method of qualitative research, based on Heideggerian hermeneutic phenomenology, which explores the lived experience of individuals and is committed to understanding the first-person perspective from the third-person position. The main findings from the IPA study reveal that Anna experienced a prolonged period of malaise, starting in late adolescence which she believed to result, at least partly, from a traumatic experience which occurred at that time. The analysis also indicates that Anna suffered from deep and lasting feelings of guilt and shame. The discovery of additional family documentation enabled me to contextualise and add substance to the findings of the IPA study. Anna’s husband’s diaries in particular reveal that Anna: • had a severe and longstanding gynaecological disorder • suffered from severe morphinism • did not benefit from Freud’s treatment which seemed neither to ease her symptoms nor identify any cause • was treated in Paris, not by Jean-Martin Charcot as previously supposed, but by a French hydrotherapist, Theodore Keller, who appears to have become a person of considerable significance in her life. The above findings led me to investigate Anna’s comorbidities (gynaecological disease and morphinism) and to show how those could be responsible for much of the symptomatology identified by Freud as ‘hysteria’. I then explore the possibility that her psychotic-like experiences could have been iatrogenically induced by her treatment first by Keller and then by Freud. Finally, I propose a fourfold set of hypotheses as an alternative to Freud’s diagnosis of hysteria

    Unraveling the effect of sex on human genetic architecture

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    Sex is arguably the most important differentiating characteristic in most mammalian species, separating populations into different groups, with varying behaviors, morphologies, and physiologies based on their complement of sex chromosomes, amongst other factors. In humans, despite males and females sharing nearly identical genomes, there are differences between the sexes in complex traits and in the risk of a wide array of diseases. Sex provides the genome with a distinct hormonal milieu, differential gene expression, and environmental pressures arising from gender societal roles. This thus poses the possibility of observing gene by sex (GxS) interactions between the sexes that may contribute to some of the phenotypic differences observed. In recent years, there has been growing evidence of GxS, with common genetic variation presenting different effects on males and females. These studies have however been limited in regards to the number of traits studied and/or statistical power. Understanding sex differences in genetic architecture is of great importance as this could lead to improved understanding of potential differences in underlying biological pathways and disease etiology between the sexes and in turn help inform personalised treatments and precision medicine. In this thesis we provide insights into both the scope and mechanism of GxS across the genome of circa 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits through the calculation of sex-specific heritability, genetic correlations, and sex-stratified genome-wide association studies (GWAS). We further investigated whether sex-agnostic (non-stratified) efforts could potentially be missing information of interest, including sex-specific trait-relevant loci and increased phenotype prediction accuracies. Finally, we studied the potential functional role of sex differences in genetic architecture through sex biased expression quantitative trait loci (eQTL) and gene-level analyses. Overall, this study marks a broad examination of the genetics of sex differences. Our findings parallel previous reports, suggesting the presence of sexual genetic heterogeneity across complex traits of generally modest magnitude. Furthermore, our results suggest the need to consider sex-stratified analyses in future studies in order to shed light into possible sex-specific molecular mechanisms

    Probing the Intergalactic medium properties using X-ray absorption from multiple tracers

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    Based on the Lambda Cold Dark Matter concordance cosmological model (ΛCDM), the majority of baryons exist in the Intergalactic medium (IGM). It is extremely challenging to observationally trace the IGM, especially at higher temperatures and low densities. Post reionisation, the vast majority of hydrogen and helium is ionized in the IGM and therefore, the observation of metals is essential for parametrising the IGM properties. My hypothesis is that there is significant absorption in the diffuse highly ionisied IGM and that this IGM column density increases with redshift. I use X-ray absorption in multiple tracers which yields information on the total absorbing column density of the matter between the observer and the source. Clear IGM detections require tracer sources that are bright, distant, and common enough to provide a good statistical sample of IGM lines of sight (LOS). To more accurately isolate any IGM contribution to spectral absorption, I examine each tracer host type to realistically model it, in addition to using appropriate intrinsic continuum curvature models. I test the robustness of the result from a number of perspectives. I examine the impact of the key underlying assumptions that affect the column density calculations including metallicity, ionisation and location of absorption. I look for any evidence of evolution in the parameters. In Chapters 2, 3, 4 and 5, I use gamma-ray bursts (GRBs), blazars and quasars (QSOs) to estimate IGM baryon column densities, metallicity, temperature, ionisation parameters and redshift distributions. My results for each tracer are presented in each of the respective chapters and collectively in Chapter 5 which includes comparative analysis. In conclusion, through the work in this thesis I demonstrate a consistent case for strong X-ray absorption in the IGM on the LOS to three different tracer types and that it is related to redshift. The results are consistent with the ΛCDM model for density, temperature and metallicity. Given these results, I would recommend that studies of distant objects should not follow the convention of assuming all X-ray absorption in excess of our Galaxy is attributed to the host galaxy, that the host is neutral and has solar metallicity. Instead, particularly at higher redshift, absorption in the IGM should be accounted for to give more accurate results for the tracer host properties

    How to Be a God

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    When it comes to questions concerning the nature of Reality, Philosophers and Theologians have the answers. Philosophers have the answers that can’t be proven right. Theologians have the answers that can’t be proven wrong. Today’s designers of Massively-Multiplayer Online Role-Playing Games create realities for a living. They can’t spend centuries mulling over the issues: they have to face them head-on. Their practical experiences can indicate which theoretical proposals actually work in practice. That’s today’s designers. Tomorrow’s will have a whole new set of questions to answer. The designers of virtual worlds are the literal gods of those realities. Suppose Artificial Intelligence comes through and allows us to create non-player characters as smart as us. What are our responsibilities as gods? How should we, as gods, conduct ourselves? How should we be gods

    The labour supply and retirement of older workers: an empirical analysis

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    This thesis examines the labour supply of older workers, their movement into retirement, and any movement out of retirement and back into work. In particular the labour force participation, labour supply and wage elasticity and other income elasticity of work hours are estimated for older workers and compared to younger workers. The thesis goes on to look at the movement into retirement for older workers as a whole by examining cohorts by gender, wave and age. The thesis also presents a descriptive and quantitative • examination of the changes in income and happiness that occur as an individual retires. Finally the thesis examines the reasons why an individual may return to work from v . retirement. The results of the findings suggest: that younger workers are significantly more responsive to wage and household income changes than older worker

    Breaking Ub with Leishmania mexicana: a ubiquitin activating enzyme as a novel therapeutic target for leishmaniasis

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    Leishmaniasis is a neglected tropical disease, which inflicts a variety of gruesome pathologies on humans. The number of individuals afflicted with leishmaniasis is thought to vary between 0.7 and 1.2 million annually, of whom it is estimated that 20 to 40 thousand die. This problem is exemplary of inequality in healthcare – current leishmaniasis treatments are inadequate due to toxicity, cost, and ineffectiveness, so there is an urgent need for improved chemotherapies. Ubiquitination is a biochemical pathway that has received attention in cancer research. It is the process of adding the ubiquitin protein as a post-translational modification to substrate proteins, using an enzymatic cascade comprised of enzymes termed E1s, E2s, and E3s. Ubiquitination can lead to degradation of substrate proteins, or otherwise modulate their function. As the name suggests, this modification can be found across eukaryotic cell biology. As such, interfering with ubiquitination may interfere with essential biological processes, which means ubiquitination may present a new therapeutic target for leishmaniasis. Before ubiquitination inhibitors can be designed, components of the ubiquitination system must be identified. To this end, a bioinformatic screening campaign employed BLASTs and hidden Markov models, using characterised orthologs from model organisms as bait, to screen publicly-available Leishmania mexicana genome sequence databases, searching for genes encoding putative E1s, E2s, and E3s. To confirm some of these identifications on a protein level, activity-based probes, protein pulldowns, and mass spectrometry were used. Using an activity-based probe that emulates the structure of adenylated ubiquitin, E1s were identified, and their relative abundance quantified. A chemical crosslinker extended the reach of this probe, allowing the identification of an E2 (LmxM.33.0900). It is noted that L. mexicana has two E1s – unusual for a single celled organism. Of these E1s, LmxM.34.3060 was considerably more abundant than LmxM.23.0550 in both major life cycle stages of the in vitro Leishmania cultures. It is important to describe the wider context of these enzymes – what is their interactome, what are their substrates? To study this, CRISPR was used to fuse a proximity-based labelling system, BioID, on genes of interest – LmxM.34.3060 and LmxM.33.0900. The E2 (LmxM.33.0900) was shown to interact with the E1 (LmxM.34.3060), validating the results from the activity-based probe and crosslinker experiments. Due to sequence homology with characterised orthologs, the E2 was hypothesised to function in the endoplasmic reticulum degradation pathway. Immunoprecipitations of a ubiquitin motif, diglycine, were conducted with a view to gathering information on the substrates of ubiquitin. Anti-diglycine peptides included some of those identified by BioID. Experiments examining ubiquitin’s role in the DNA damage response were also initiated, as were improvements to the proximity-based labelling system, however these were not followed to completion due to a lack of time and resources. To examine the possibility of finding novel drug targets in the ubiquitination cascade, recombinant proteins were expressed. LmxM.34.3060 was expressed in a functional form, while a putative SUMO E2 (LmxM.02.0390) was functional after refolding. Expressed LmxM.33.0900 was not functional and could not be refolded into a functional form. Drug assays were conducted on LmxM.34.3060, which found an inhibitor of the human ortholog, TAK-243, to be 20-fold less effective against the Leishmania enzyme. Additional assays found an inhibitor that was 50-fold more effective at inhibiting the Leishmania enzyme as opposed to its human equivalent - 5'O-sulfamoyl adenosine. Furthermore, a new mechanism of action, inhibiting the E1, for was identified for drugs previously characterised to inhibit protein synthesis. LmxM.34.3060 underwent biophysical characterisation, with structural information obtained using SAXS and protein crystallography. A crystal structure was solved to 3.1 Å, with the in-solution SAXS structure complementary to this. TAK-243 was modelled into the LmxM.34.3060 structure and clashes were predicted, concurring with TAK-243’s reduced efficacy against the Leishmania enzyme in the drug assays. This project aimed to characterise the potential of an understudied biochemical system to provide novel therapeutic targets for a neglected tropical pathogen. To achieve this aim it presents the identifications of two E1s, an interactome, a structure, and a potent, selective inhibitor of a Leishmania ubiquitin activating enzyme

    Intervening on hypertension in Zambia: development of a culturally sensitized lifestyle programme to reduce disease incidence in urban areas

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    Background/purpose: Hypertension, like other non-communicable diseases, is becoming a major public health problem for Sub-Saharan Africa (SSA). Its increasing prevalence is driven by an epidemiological transition with more people leading unhealthy lifestyles, including poor diet and physical inactivity. This project aimed to explore the use of participatory methods with an urban community in Zambia in co-developing a culturally sensitized hypertension prevention intervention. Methods: The intervention development study was divided into four phases. I scoped and synthesized existing literature on risk factors (non-modifiable and modifiable) for hypertension in SSA in Phase One. The identified risk factors and their drivers informed Phase Two community members focus group discussions and stakeholder interviews to explore the local context in the study site to clarify the problem, identify which hypertension risk factors were malleable (potential factors to target), the mechanism of change, and how to deliver this. The findings informed the development of the causal pathway, the intervention theory of change and the Phase Three co-development of the intervention core components and small-scale evaluation. Five co-development workshops (four with local residents and one with local stakeholders) iteratively informed identification of priority risk factors, the delivery format and setting, and finalization of intervention core components. The pilot intervention was then tested with volunteer participants (N=34) to assess feasibility, acceptability and potential effectiveness in Phase four. Results: The scoping review identified the most common risk factors for hypertension in SSA. Residents FGDs and key stakeholder interviews, informed by the scoping review findings, identified a number of potentially malleable hypertension risk factors at individual and interpersonal levels, including high salt intake and other dietary factors, low physical activity, excess body weight, central obesity, high alcohol intake and smoking. From these, the workshops prioritised intervening on salt intake, other dietary factors, and physical inactivity. Using these suggestions, an 8-week group-based intervention (CHiPI) was codeveloped. Stakeholders proposed evaluation of the CHiPI on a small scale and delivery through churches: “nearly all residents belong to a church”. Stakeholders also identified community health workers and church leaders as delivery facilitators. The intervention core components were agreed and refined in close consultation with residents. These included linguistic and cultural adaptations of SMART goal setting and self-monitoring tools, which were iteratively tested and refined to reflect the local socio-cultural context. The small-scale evaluation of the intervention showed high acceptability, feasibility and potential effectiveness in improving health literacy, adoption of healthier diets (less salt added during cooking [p=0.014], reduction in added salt to the plate at mealtimes [p=0.001], increased fruit intake [p=0.001], reduced fried meals [p = 0.001]), increased physical activity [p=0.01] and reduced sedentary lifestyle [p = 0.001]. Reductions in body weight [p = 0.002], BMI [p = 0.001], WC [p = 0.001], SBP [-3mmHg, p=0.003] and DBP [-4mmHg, p = 0.001] were also observed. Conclusions and implications: Participatory methods succeeded in engaging local residents and stakeholders in the development of a potentially effective culturally sensitized, 8-week, group-based hypertension prevention lifestyle intervention for delivery through churches in Zambia. Having demonstrated high feasibility, acceptability and potential effectiveness, taking this intervention to a larger evaluation to obtain evidence of effectiveness can inform hypertension prevention intervention development in Zambia and other SSA countries
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