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Humans display a 90% population level bias towards right-handedness, implying the vast majority of people have a left-hemisphere dominant for motor control. Although handedness presents a weak, but very consistent heritability across the literature (estimated to be approximately 25%), to date few genetic loci associated with this complex trait have been identified and replicated in subsequent studies. One such gene which has been found to be associated with handedness and subsequently replicated is PCSK6, most recently through a quantitative GWAS (P < 0.5*10−8, Brandler et al. (2013)). Interestingly, PCSK6 is known to activate Nodal, a morphogen involved in a highly conserved bilaterian pathway known to regulate left-right body axis determination. Here I present the first molecular characterisation of a handedness-associated region by conducting a detailed functional analysis of the PCSK6 locus, combining genetic analysis, in silico prediction and molecular assays to investigate how common genetic variants influence handedness-related phenotypes. Specifically, I defined the associated locus to be 12.7 kb in size, spanning a predicted 1.8 kb bidirectional promoter which controls the expression of both an antisense long non-coding RNA (lncRNA), and a novel short PCSK6 isoform. A series of luciferase-expressing constructs were generated to characterise the promoter, identifying a minimal sequence capable of driving transcription in a sense strand direction. I have demonstrated experimentally that one of the top associated markers in previous GWA studies, rs11855145, directly creates/disrupts a suspected transcription factor bind site in the vicinity of this bidirectional promoter. Further functional studies of the genetic variation within PCSK6 may help explain the molecular regulatory mechanisms affecting gene expression. This project provides a model for assays to study other GWAS-nominated candidate genes, and in particular for establishing the role of noncoding variants. The findings from this study support the role of common variants in influencing complex phenotypes, such as handedness.

In near-Earth space, highly spatio-temporally variant magnetic fields result from solar-terrestrial magnetic interaction. These near-Earth external fields currently represent the largest source of error in efforts to model the magnetic field produced in the Earth’s interior. Starting in 1999, the Decade of Geopotential Field Research (Friis-Christensen et al., 2009) has greatly increased the amount of available low-Earth orbit (LEO) satellite magnetic data. These data have driven many advances in field modelling, yet have highlighted that LEO measurements are particularly susceptible to contamination from external fields. This thesis presents a series of studies attempting to describe the external fields in more detail, in order that they can be more effectively separated from the internal fields in magnetic modelling efforts. A range of analysis methods, different for each study, are applied to satellite and ground-based observatory data. Mandea and Olsen’s (2006) method of estimating the secular variation (SV) of the internal field from satellite data via ‘Virtual Observatories’ (VOs) is applied to synthetic data from the upcoming Swarm constellation satellite mission of the European Space Agency. Beggan (2009) found VOs constructed from CHAMP satellite data to be contaminated with external field signals which appeared to have a significant local time (LT) dependence. I find that utilising the increased coverage of LT sectors offered by the Swarm constellation geometry does not significantly decrease the contamination. Following this surprising result I tested a wide range of methods aimed at reducing the VO contamination from each parameterised external field source region. In anticipation of future studies using real data, I used the results of the tests to provide a more complete description of the external field variations affecting analyses of geographically-fixed magnetic phenomena when using satellite data and spherical harmonic analysis (SHA). Ionospheric electric currents flowing at LEO altitudes are known to violate the assumption of measurements taken in a source-free space, required in SHA-based models of the magnetic field. In order to better describe the electromagnetic environment at LEO altitudes, I use data from the Ørsted and CHAMP satellites to calculate the current density from Amp`ere’s integral. Vector magnetic data from discrete overflights of the two satellites (at different altitudes) are rotated into the along-track frame to define the integral loop and its ‘surface area’, permitting estimation of the predominantly zonal current density flowing in the region between the two orbital paths. I designed selection criteria to extract geometrically-stable overflights spanning the range of LTs twice in the 6 years of mutually available satellite vector data. From these overflights I resolve current densities in the range 0:1 μA=m2, with the distribution of current largely matching the LT progression of the Appleton anomaly. I applied detailed tests to check for biases intrinsic to the method, and present results free of systematic errors. The results are compared with the predictions of the CTIP (Coupled Thermosphere-Ionosphere-Plasmasphere) model of ionospheric composition and temperature, showing a typically good spatiotemporal agreement. I find persistent current intensifications between geomagnetic latitudes of 30 and 50 in the post-midnight, pre-dawn sector, a region which has been previously considered to be relatively free of currents. External fields induce currents in the Earth’s conducting mantle, the magnetic fields of which add to the field measured at and above the Earth’s surface. The morphology of the long-period inducing field is poorly resolved on timescales of months to years, reducing the accuracy of mantle induction studies (a key part of the Swarm mission). I improve the description of its morphology via the method of Empirical Orthogonal Functions (EOFs), which I apply to over a decade of ground-based observatory data. EOFs provide a decomposition of the spatiotemporal structures contained in the magnetic field data, with partitions arising from the data themselves, overcoming the relatively simplistic assumptions made about the inducing field morphology in LT. The results of vector data EOF analyses are presented, but I rely primarily on scalar analyses which are more fitting for this study. I overcome the limitations of the irregular observatory distribution with a novel spatial weighting matrix, combining the output from multiple EOF analyses to greatly improve the data coverage in LT. I find that the seasonal variation of the inducing field is more important than the variation of the symmetric ring current on annual periods, and that dawn-dusk asymmetry should be accounted for to increase the accuracy of mantle conductivity estimates based on data covering the decadal timescales of the solar cycle.

This dissertation is designed to re-illuminate the figures of William Davenant and Abraham Cowley and to begin to suggest some of the ways in which neglected works dating from the period of the English republic might fruitfully be read. It focuses on the work Davenant and Cowley published in the middle decades of the seventeenth century and attempts to trace the course of their artistic and political waverings in the face of republican iconoclasm. Where English history is customarily squeamish about the idea of political collaboration, the dissertation examines how Davenant and Cowley vacillated between the desire to remain in the royalist literary underground and the temptation to collaborate with the godly authorities. It analyses their work in terms of these twin forces and attempts to assess how far they continued to make 'Lawrels for the Conquered, as Cowley described it, and to what extent they tried to accommodate the revolutionary and godly spirit in their art. 1 The dissertation falls into two parts. The first is largely concerned with the poetry published b)'. Davenant and Cowley in the period, in particular Davenant's Gondibert (1651) and his panegyrics to various Commonwealth grandees and Cowley's lyric sequence The Mistress (1647) and his Poems (1656). In order to offer properly contextualized readings I also look at work published by iconoclasts such as Milton and Wither, by royalist apostates such as Edmund Waller, and by faithful cavaliers such as John Denham. The second part of the dissertation revolves around Davenant's attempts to revive the outlawed stage. It reviews the degree to which the theatre was identified with the court and the monarchy before investigating Davenant's pamphlet arguing for the restoration of the drama, A Proposition for Advancement of Moralitie (1654). It then examines Davenant's subsequent 'operatic' entertainments in terms of the ideological requirement to disinherit the stage of its Caroline legacy. It explores important works by James Shirley and Richard Flecknoe and attempts to shed new light on Cowley's involvement in Davenant's projects. Finally, but perhaps most revealingly, it looks at some of the self-exculpatory accounts offered by fallen royalists on the stage after the Restoration.