Chiroptical spectroscopy of biomolecules using chiral plasmonic nanostructures

This thesis explores the potential of chiral plasmonic nanostructures for the ultrasensitive detection of protein structure. These nanostructures support the generation of fields with enhanced chirality relative to circularly polarised light and are an extremely incisive probe of protein structure. In chapter 4 we introduce a nanopatterned Au film (Templated Plasmonic Substrate, TPS) fabricated using a high through-put injection moulding technique which is a viable alternative to expensive lithographically fabricated nanostructures. The optical and chiroptical properties of TPS nanostructures are found to be highly dependent on the coupling between the electric and magnetic modes of the constituent solid and inverse structures. Significantly, refractive index based measurements of strongly coupled TPSs display a similar sensitivity to protein structure as previous lithographic nanostructures. We subsequently endeavour to improve the sensing properties of TPS nanostructures by developing a high through-put nanoscale chemical functionalisation technique. This process involves a chemical protection/deprotection strategy. The protection step generates a self-assembled monolayer (SAM) of a thermally responsive polymer on the TPS surface which inhibits protein binding. The deprotection step exploits the presence of nanolocalised thermal gradients in the water surrounding the TPS upon irradiation with an 8ns pulsed laser to modify the SAM conformation on surfaces with high net chirality. This allows binding of biomaterial in these regions and subsequently enhances the TPS sensitivity levels. In chapter 6 an alternative method for the detection of protein structure using TPS nanostructures is introduced. This technique relies on mediation of the electric/magnetic coupling in the TPS by the adsorbed protein. This phenomenon is probed through both linear reflectance and nonlinear second harmonic generation (SHG) measurements. Detection of protein structure using this method does not require the presence of fields of enhanced chirality whilst it is also sensitive to a larger array of secondary structure motifs than the measurements in chapters 4 and 5. Finally, a preliminary investigation into the detection of mesoscale biological structure is presented. Sensitivity to the mesoscale helical pitch of insulin amyloid fibrils is displayed through the asymmetry in the circular dichroism (CD) of lithographic gammadions of varying thickness upon adsorption of insulin amyloid fibril spherulites and fragmented fibrils. The proposed model for this sensitivity to the helical pitch relies on the vertical height of the nanostructures relative to this structural property as well as the binding orientation of the fibrils.

Our own language: Scots verse translation and the second-generation Scottish renaissance

This thesis examines the role of Scots language verse translation in the second-generation or post-war Scottish Renaissance. The translation of European poetry into Scots was of central importance to the first-generation Scottish Renaissance of the nineteen twenties and thirties. As Margery Palmer McCulloch has shown, the wider cultural climate of Anglo-American modernism was key to MacDiarmid’s conception of the interwar Scottish Renaissance. What was the effect on second-generation poet-translators as the modernist moment passed? Are the many translations undertaken by the younger poets who emerged in the course of the nineteen forties and fifties a faithful reflection of this cultural inheritance? To what extent are they indicative of a new set of priorities and international influences? The five principal translators discussed in this thesis are Douglas Young (1913-1973), Sydney Goodsir Smith (1915-1975), Robert Garioch (1909-1981), Tom Scott (1918-1995) and William J. Tait (1918-1992). Each is the subject of a chapter, in many cases providing the first or most extensive treatment of particular translations. While the pioneering work of John Corbett, Bill Findlay and J. Derrick McClure, among other scholars, has drawn attention to the long history of literary translation into Scots, this thesis is the first extended critical work to take the verse translations of the post-MacDiarmid makars as its subject. The nature and extent of MacDiarmid’s influence is considered throughout, as are the wider discourses around language and translation in twentieth-century Scottish poetry. Critical engagement with a number of key insights from theoretical translation studies helps to situate these writers’ work in its global context. This thesis also explores the ways in which the specific context of Scots translation allows scholars to complicate or expand upon theories of translation developed in other cultural situations (notably Lawrence Venuti’s writing on domestication and foreignisation). The five writers upon whom this thesis concentrates were all highly individual, occasionally idiosyncratic personalities. Young’s polyglot ingenuity finds a foil in Garioch’s sharp, humane wit. Goodsir Smith’s romantic ironising meets its match in Scott’s radical certainty of cause. Tait’s use of the Shetlandic tongue sets him apart. Nonetheless, despite the great variety of style, form and tone shown by each of these translators, this thesis demonstrates that there are meaningful links to be made between them and that they form a unified, coherent group in the wider landscape of twentieth-century Scottish poetry. On the linguistic level, each engaged to some extent in the composition of a ‘synthetic’ or ‘plastic’ language deriving partly from literary sources, partly from the spoken language around them. On a more fundamental level, each was committed to enriching this language through translation, within which a number of key areas of interest emerge. One of the most important of these key areas is Gaelic – especially the poetry of Sorley MacLean, which Young, Garioch and Goodsir Smith all translated into Scots. This is to some extent an act of solidarity on the part of these Scots poets, acknowledging a shared history of marginalisation as well as expressing shared hopes for the future. The same is true of Goodsir Smith’s translations from a number of Eastern European poets (and Edwin Morgan’s own versions, slightly later in the century). The translation of verse drama by poets is another key theme sustained throughout the thesis, with Garioch and Young attempting to fill what they perceived as a gap in the Scots tradition through translation from other languages (another aspect of these writers’ legacy continued by Morgan). Beyond this, all of the writers discussed in this thesis translated extensively from European poetries from Ancient Greece to twentieth-century France. Their reasons for doing so were various, but a certain cosmopolitan idealism figures highly among them. So too does a desire to see Scotland interact with other European nations, thus escaping the potentially narrowing influence of post-war British culture. This thesis addresses the legacy of these writers’ translations, which, it argues, continue to exercise a perceptible influence on the course of poetry in Scotland. This work constitutes a significant contribution to a much-needed wider critical re-assessment of this pivotal period in modern Scottish writing, offering a fresh perspective on the formal and linguistic merits of these poets’ verse translations. Drawing upon frequently obscure book, pamphlet and periodical sources, as well as unpublished manuscripts in the National Library of Scotland and the Shetland Archives, this thesis breaks new ground in its investigation of the role of Scots verse translation in the second-generation Scottish Renaissance.

Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources