Doctor of Philosophy

dissertationComputer simulations of biomolecules can provide insight into biological structure and dynamics at the atomic level. For simulations to be accurate and reliable, the underlying force eld that describes that system has to tested and assessed against experimental values. Evaluating the latest AMBER nucleic acids force elds at microsecond time scales is important for determining how updated force eld parameter sets compare to earlier models and updated, competing models. The latest two improvements to the AMBER nucleic acid force eld were compared to each other and previous, widely used versions. Both of the latest versions, bsc1 and OL15, showed improvement over earlier versions and reproduced many structural properties in agreement with nuclear magnetic resonance (NMR) and X-ray crystallography experiments. Having a force eld that accurately models duplex DNA is important, but it is also necessary to validate protein-nucleic acid simulations. To examine this, the E2-DNA system was chosen for simulations to see if DNA backbone substates observed in the X-ray structure were reproducible in simulations. In particular, the BI/BII substates were scrutinized. The BI substate is dominant in duplex DNA but and dihedrals populate both trans/gauche- (t/g-) and gauche-/trans (g-/t) conformations, the latter being the BII state. It was determined that dinucleotide steps crystallized in the BII were correspondingly highly-populated in simulations. Additionally, and dihedrals were manipulated to decoy states and found to converge to native distributions on the microsecond time scale in E2-bound DNA, and in less time for free DNA. During the investigation of BII substates in E2-DNA, the surprising observation was made that BI/BII transitions are dominant modes of motion in E2-bound DNA. This inspired research into whether these modes are sequence-dependent or completely induced by the E2 protein, and if the dynamics are conserved across E2 types. Simulations of E2-DNA found that the BII state is determined by a combination of DNA sequence and E2 binding partner

Women’s perspectives on the value of a father’s initiative in shifting gendered practices within families

This paper explores the qualitative perspectives of women about a community embedded fathers initiative in Northern England. Projects to improve the wellbeing of men and their children are less common within the landscape of parent and child support, with mothers more often being the target recipients. Asking women about their perceptions of an initiative for fathers then offers original insights from women who are positioned as ‘related outsiders’, in that they were ‘outside’ the project but ‘inside’ the family and community. Findings suggest that women are able to see the positive impact of such a project, identifying that it offers a shared space for men and children, time for mothers without their children and can help with shifting roles and attitudes around child care and emotional labour in the home. The initiative was also seen by the women as offering men more healthy means of coping, including men moving away from traditional hegemonic practices, which in turn shifted some women’s long held gendered beliefs about men as fathers. This research then offers a relational gendered backstory to a father’s initiative, demonstrating how such initiatives can potentially ‘undo’ gender and the positive implications this could have for families

Sources of uncertainty in future projections of the carbon cycle

This is the final version of the article. Available from the publisher via the DOI in this record.The inclusion of carbon cycle processes within CMIP5 Earth System Models provides the opportunity to explore the relative importance of differences in scenario and climate model representation to future land and ocean carbon fluxes. A two-way ANOVA approach was used to quantify the variability owing to differences between scenarios and between climate models at different lead times. For global ocean carbon fluxes, the variance attributed to differences between Representative Concentration Pathway scenarios exceeds the variance attributed to differences between climate models by around 2025, completely dominating by 2100. This contrasts with global land carbon fluxes, where the variance attributed to differences between climate models continues to dominate beyond 2100. This suggests that modelled processes that determine ocean fluxes are currently better constrained than those of land fluxes, thus we can be more confident in linking different future socio-economic pathways to consequences of ocean carbon uptake than for land carbon uptake. The apparent agreement in atmosphere-ocean carbon fluxes, globally, masks strong climate model differences at a regional level. The North Atlantic and Southern Ocean are key regions, where differences in modelled processes represent an important source of variability in projected regional fluxesMOHC authors were supported by the Joint DECC / Defra Met Office Hadley Centre Cli- mate Programme (GA01101). SY was supported by the Hong Kong Polytechnic University grant “Bayesian Modelling for Quantifying Uncertainty in Climate Predictions” (1-ZV9Z). We acknowl- edge use of R software package (R Core Team 2013). We acknowledge the World Climate Re- search Programme’s Working Group on Coupled Modelling, which is responsible for CMIP and we thank the climate modelling groups for providing their GCM output (listed in Table 1). Support of this dataset was provided by the Office of Science, U.S. Department of Energy

Staircase-free acoustic sources for grid-based models of wave propagation

The k-Wave MATLAB toolbox is widely used to conduct medical ultrasound simulations. It uses a Fourier collocation method to numerically solve the governing model equations, and introduces sources by adding acoustic pressure at points on an orthogonal grid. This approach introduces two errors when sources don't exactly align with the grid. These are phase errors arising from shifting source points to nearby grid nodes, and amplitude errors arising from an angular dependence in the density of source points. These two errors are collectively referred to as `staircasing'. Staircasing errors can be overcome by considering the band-limited representation of sources that arises from the use of a Fourier collocation method. To do so, sources are discretised by convolving a band-limited point source with the desired source geometry. To validate this approach, a comparison is made with current k-Wave source algorithms and with the FOCUS ultrasound simulation code. The new sources are shown to eliminate staircasing errors

Observation of the thermal Casimir force

Quantum theory predicts the existence of the Casimir force between macroscopic bodies, due to the zero-point energy of electromagnetic field modes around them. This quantum fluctuation-induced force has been experimentally observed for metallic and semiconducting bodies, although the measurements to date have been unable to clearly settle the question of the correct low-frequency form of the dielectric constant dispersion (the Drude model or the plasma model) to be used for calculating the Casimir forces. At finite temperature a thermal Casimir force, due to thermal, rather than quantum, fluctuations of the electromagnetic field, has been theoretically predicted long ago. Here we report the experimental observation of the thermal Casimir force between two gold plates. We measured the attractive force between a flat and a spherical plate for separations between 0.7 $\mu$m and 7 $\mu$m. An electrostatic force caused by potential patches on the plates' surfaces is included in the analysis. The experimental results are in excellent agreement (reduced $\chi^2$ of 1.04) with the Casimir force calculated using the Drude model, including the T=300 K thermal force, which dominates over the quantum fluctuation-induced force at separations greater than 3 $\mu$m. The plasma model result is excluded in the measured separation range.Comment: 6 page

Pulpal sequelae after trauma to anterior teeth among adult Nigerian dental patients

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies show that about 11.6% to 33.0% of all boys and about 3.6% to 19.3% of all girls suffer dental trauma of varying severity before the age of 12 years. Moderate injuries to the periodontium such as concussion and subluxation are usually associated with relatively minor symptoms and hence may go unnoticed by the patient or the dentist, if consulted. Patients with these kinds of injuries present years after a traumatic accident most of the time with a single discoloured tooth. This study sets out to document the incidence of various posttraumatic sequelae of discoloured anterior teeth among adult Nigerian dental patients.</p> <p>Methods</p> <p>One hundred and sixty eight (168) traumatized discoloured anterior teeth in 165 patients were studied. Teeth with root canal treatment were excluded from the study. Partial obliteration was recorded when the pulp chamber or root canal was not discernible or reduced in size on radiographs, total obliteration was recorded when pulp chamber and root canal were not discernible. A retrospective diagnosis of concussion was made from patient's history of trauma to the tooth without abnormal loosening, while subluxation was made from patient's history of trauma to the tooth with abnormal loosening.</p> <p>Results</p> <p>Of the 168 traumatized discoloured anterior teeth, 47.6% and 31.6% had partial and total obliteration of the pulp canal spaces respectively, 20.8% had pulpal necrosis. Concussion and subluxation injuries resulted more in obliteration of the pulp canal space, while fracture of the teeth resulted in more pulpal necrosis (p < 0.001). Injuries sustained during the 1^stand 2^nddecade of life resulted more in obliteration of the pulp canal space, while injuries sustained in the 3^rddecade resulted in more pulpal necrosis.</p> <p>Conclusion</p> <p>Calcific metamorphosis developed more in teeth with concussion and subluxation injuries. Pulpal necrosis occurred more often in traumatized teeth including fractures.</p

Protocol for stage 1 of the GaP study (Genetic testing acceptability for Paget's disease of bone): an interview study about genetic testing and preventive treatment: would relatives of people with Paget's disease want testing and treatment if they were available?

BACKGROUND: Paget's disease of bone (PDB) is characterised by focal increases in bone turnover, affecting one or more bones throughout the skeleton. This disrupts normal bone architecture and causes pain, deformity, deafness, osteoarthritis, and fractures. Genetic factors are recognised to play a role in PDB and it is now possible to carry out genetic tests for research. In view of this, it is timely to investigate the clinical potential for a programme of genetic testing and preventative treatment for people who have a family history of PDB, to prevent or delay the development of PDB. Evidence from non-genetic conditions, that have effective treatments, demonstrates that patients' beliefs may affect the acceptability and uptake of treatment. Two groups of beliefs (illness and treatment representations) are likely to be influential. Illness representations describe how people see their illness, as outlined in Leventhal's Self-Regulation Model. Treatment representations describe how people perceive potential treatment for their disease. People offered a programme of genetic testing and treatment will develop their own treatment representations based on what is offered, but the beliefs rather than the objective programme of treatment are likely to determine their willingness to participate. The Theory of Planned Behaviour is a theoretical model that predicts behaviours from people's beliefs about the consequences, social pressures and perceived control over the behaviour, including uptake of treatment. METHODS/DESIGN: This study aims to examine the acceptability of genetic testing, followed by preventative treatment, to relatives of people with PDB. We aim to interview people with Paget's disease, and their families, from the UK. Our research questions are: 1. What do individuals with Paget's disease think would influence the involvement of their relatives in a programme of genetic testing and preventative treatment? 2. What do relatives of Paget's disease sufferers think would influence them in accepting an offer of a programme of genetic testing and preventative treatment? DISCUSSION: Our research will be informed by relevant psychological theory: primarily the Self-Regulation Model and the Theory of Planned Behaviour. The results of these interviews will inform the development of a separate questionnaire-based study to explore these research questions in greater detail

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

Transient disruption of M1 during response planning impairs subsequent offline consolidation

Transcranial magnetic stimulation (TMS) was used to probe the involvement of the left primary motor cortex (M1) in the consolidation of a sequencing skill. In particular we asked: (1) if M1 is involved in consolidation of planning processes prior to response execution (2) whether movement preparation and movement execution can undergo consolidation independently and (3) whether sequence consolidation can occur in a stimulus specific manner. TMS was applied to left M1 while subjects prepared left hand sequential finger responses for three different movement sequences, presented in an interleaved fashion. Subjects also trained on three control sequences, where no TMS was applied. Disruption of subsequent consolidation was observed, but only for sequences where subjects had been exposed to TMS during training. Further, reduced consolidation was only observed for movement preparation, not movement execution. We conclude that left M1 is causally involved in the consolidation of effective response planning for left hand movements prior to response execution, and mediates consolidation in a sequence specific manner. These results provide important new insights into the role of M1 in sequential memory consolidation and sequence response planning

On the Adaptive Partition Approach to the Detection of Multiple Change-Points

With an adaptive partition procedure, we can partition a “time course” into consecutive non-overlapped intervals such that the population means/proportions of the observations in two adjacent intervals are significantly different at a given level . However, the widely used recursive combination or partition procedures do not guarantee a global optimization. We propose a modified dynamic programming algorithm to achieve a global optimization. Our method can provide consistent estimation results. In a comprehensive simulation study, our method shows an improved performance when it is compared to the recursive combination/partition procedures. In practice, can be determined based on a cross-validation procedure. As an application, we consider the well-known Pima Indian Diabetes data. We explore the relationship among the diabetes risk and several important variables including the plasma glucose concentration, body mass index and age