VictorJuiz/thesis huggingface dataset:
Template directed synthesis of porphyrin nanorings
Keywords: vernier templating
light harvesting complexes
porphyrins
template directed synthesis
molecular wires
nanorings

This thesis describes supramolecular approaches to porphyrin nanorings. Cyclic porphyrin arrays resemble natural light harvesting systems, and it is of interest to probe the photophysical effects of bending the porphyrin aromatic π-system.
A general overview of the synthesis and photophysical properties of porphyrins and their arrays is carried out in Chapter 1. The electronic structure of porphyrins is examined, and how conformational effects in oligomers, such as inter-porphyrin torsional angle and backbone bending influence the π-conjugation pathway. The structures of light harvesting complexes are discussed.
Chapter 2 describes the design and synthesis of a complementary 12-armed template designed to coordinate linear porphyrin oligomers in the correct conformation for cyclisation to give a cyclic porphyrin dodecamer.
Chapter 3 demonstrates two approaches to a cyclic porphyrin dodecamer ring. Firstly, a classical templating approach using the 12-armed template is described. The limitations of this approach in the quest for larger nanorings are discussed. Vernier templating, which utilises a mismatch in the number of binding sites between a ligand and its receptor is introduced as a general strategy to the synthesis of large nanorings. This is demonstrated by the synthesis of cyclic dodecamer from a linear porphyrin tetramer and a hexadentate template via a figure-of-eight intermediate.
The general utility of the Vernier method to large nanorings is explored in Chapter 4 with steps towards the synthesis of a cyclic tetracosamer, consisting of 24 porphyrin subunits. In preliminary experiments, an improved route to the cyclic porphyrin octamer is described.
Finally, the photophysical properties of the nanoring series are explored in Chapter 5 as a function of size and conformation. Femtosecond photoluminescence spectroscopy shows that even in cyclic dodecamer, exciton delocalisation over the entire porphyrin backbone occurs on a sub-picosecond timescale, and parallels are drawn with the dynamics of natural light harvesting complexes.
Derrida's return to Freud: from phenomenology to politics
Keywords: phenomenology
deconstruction
unconscious
influence
French thought
psychoanalysis
Freud
philosophy
Derrida
politics
theory

This thesis identifies and explores a ‘return to Freud’ in the work of Jacques Derrida. Resemblances between Derrida’s method of deconstruction and the therapeutic procedure of psychoanalysis have long been a source of debate among critics. Is deconstruction little more than a psychoanalytic reading of the history of philosophy, or is Freud a Derridean avant la lettre? Revealing this dilemma to be a false one, this thesis challenges major interpreters of Derrida such as Jonathan Culler and Gayatari Chakravorty Spivak. By developing Derrida’s well-known yet little understood concept of différance, it argues that this dilemma stems from an inadequate understanding of Derrida’s treatment of time. The structure of temporality implied by différance entails that the meaning of the past is continually reconstituted in its relationship to an ever-evolving present. Far from dissolving the importance of Freud’s contribution, this structure allows Derrida to circumvent nebulous notions of ‘influence’ and ‘indebtedness’ while still engaging psychoanalysis as a key theoretical resource in his own project of deconstruction. A productive engagement with psychoanalytic theory is shown to inform every major stage of the philosopher’s career, from his early phenomenological work to his later reflections on the terrorist attacks of 9/11. Derrida repeatedly turns to Freud as a crucial interlocutor in interrogating a number of philosophical problems encountered in his own work. These problems include the nature of time, space, and memory; the role of the fictive in scientific discourse; the question of the archive; the interdependence of the psyche and technology; and the relationship between politics and the unconscious. At a theoretical level, this thesis provides a detailed account of Derrida’s notion of spacing, arguing that the unconditional belatedness entailed by différance calls us to a difficult, dual responsibility: both towards the legator of an inheritance (that is, towards the textual legacy Freud has bequeathed to us) and towards the unforeseeable future contexts in which this inheritance will require transformation. The discourse of deconstruction, it concludes, enacts a careful negotiation of these two demands.
A discussion of the Canaanite mythological background to the Israelite concept of eschatological hope in Isaiah 24-27
Keywords: Israelite
Isaiah
Eschatology
Mythology
Canaanite

The thesis begins with an overview of views concerning the dating of Isa 24–27 and its place within the genres of apocalyptic and eschatology, before stating its aim as showing how Canaanite myths were used by the author to give future hope rooted in cultic ideals. The second chapter looks at the image of the divine warrior, with particular emphasis on the chaos enemy as the dragon/serpent/sea, and the remarkable similarities between Isa 27:1 and the Ugaritic KTU 1.5.i.1–5. A possible cultic setting of the combat myth is examined, together with the question of why the myth appears here in an eschatological manner. The following chapter discusses the Israelite and Canaanite traditions concerning the holy mountain and divine banquet. Zion motifs are compared with those of Mt. Zaphon, and the nature of cultic feasts considered in Israelite and Canaanite literature, as well as later traditions. Chapter Four argues that the verses concerning death and resurrection represented exile/oppression and restoration, at a time when ideas of resurrection and judgment after death were emerging. The Israelite imagery of Mot/Death and Sheol are examined in relation to the nature of Ugaritic Mot, showing how Canaanite traditions were used to demonstrate Yahweh’s might and the possibility of individual and universal restoration. The following chapter places Israelite religion within the context of Canaanite fertility cults and popular practices. That myth and cult are connected is the basis for the view that the themes in Isa 24–27 were passed down to the post-exilic era via cultic activities and the reuse of myths to promote Yahweh, whether the author was aware that he was using ancient, mythological ideas or not. The sixth chapter gives a short overview of hope in the Hebrew Bible, before demonstrating how the universalism of Isa 24–27 combines with the ancient mythic themes to provide an eschatological hope in an all-encompassing deity. The paper concludes that the author of these chapters deliberately used Canaanite mythology to show how the final victory, rule, and celebration of Yahweh would bring about a personal and moral victory for all nations.
The effects of latitude on hominin social network maintenance
Keywords: modern humans
Neanderthals
gas model
hunter-gatherers
community cohesion

Social networks have been essential throughout hominin evolution, facilitating cooperative childrearing, transmission of cultural knowledge and the sharing of information and resources. As hominins dispersed out of Africa, these networks needed to be maintained at progressively higher latitudes.
The first part of this thesis explores the impact of latitude on brain organisation and the possible implications for social cognition. I hypothesise that the lower temperatures and light levels found at higher latitudes select for larger bodies and visual systems, which in turn necessitate larger somatic and visual brain areas. Using orbit size to index eye and visual cortex size, I demonstrate a robust positive relationship between absolute latitude and orbit volume in recent humans. I show that Neanderthals, who solely inhabited high latitudes, have significantly larger orbits than contemporary anatomically modern humans (AMH), who evolved in lower latitude Africa and had only relatively recently dispersed into higher latitudes. Since Neanderthals and AMH dated 27-75kya have almost identical endocranial volumes, I argue that if a greater proportion of the Neanderthal brain was required for somatic and visual processing, this would reduce the volume of neural tissue available for other functions. Since, according to the Social Brain Hypothesis, neocortex volume is positively associated with social complexity, I propose that Neanderthals might have been limited to smaller social networks than AMH.
The second part of the thesis explores the challenge of maintaining social networks across greater geographic distances at higher latitudes, where high travelling costs seem to prevent whole tribes from bonding during periodic aggregations. Using a gas model I predict that at lower latitudes daily subsistence mobility allows sufficient encounters between subgroups for the tribe to maintain connectivity, whereas in (Sub)Arctic biomes additional mechanisms are required to facilitate tribal cohesion. This may explain the apparent ‘explosion’ of Upper Palaeolithic art in Europe: symbolic representations allowed social ties to be sustained in the absence of frequent face-to-face contact.
Overall, this thesis demonstrates that latitude may influence both brain organisation and cultural expression and argues that both can have a substantial impact on the maintenance of hominin social networks at high latitudes.
Breast cancer related lymphedema
Keywords: tissue water concentration
lymphoedema
cancer
tissue dielectric constant
surgery
Breast
lymphedema

Improvements in the treatment of breast cancer have resulted in better survival rates and less breast cancer related morbidity. Nevertheless, a significant group of patients still experience a diminished quality of life as a result of lymphedema. In the early, often reversible, stage of lymphedema patients can experience subjective changes in the affected area. However, with the traditionally available tools the lymphedema often remains clinically undetectable and patients are denied essential care that can prevent worsening. Furthermore, most lymphedema assessment tools fail to support a clear unambiguous definition of lymphedema. This underlines the need for a sensitive objective measurement method that can assess lymphedema in a subclinical stage.
In this study we demonstrated that measuring tissue dielectric constant (TDC) using the MoistureMeter-D is an effective method to detect tissue water changes and could potentially provide a cost-effective adequate tool to measure the early onset of breast cancer related lymphedema (BCRL). Secondarily, we established the correlation between the novel TDC method and the frequently used arm volume measurements and self-assessment questionnaires. A group of 20 female patients with clinically BCRL were included. TDC measurements in both arms and all quadrant of both breast were recorded along with volumetric measurements of both arms. All patients were asked to complete a self-report questionnaire.
The novel TDC method detected significantly higher tissue water levels in the affected arm and breast compared to the control side. The TDC ratio between control and affected side showed significant correlation with self-reported pain and discomfort in both arm and breast. In the arm, the TDC method also showed correlation with the volume measurement method. The TDC value of the arm was correlated to age, but not to BMI. This study demonstrates that measuring TDC using the MMD is an effective method for quantifying lymphedema in arm and breast and is an important tool in detecting early TWC changes.
The impact of HIV-1 disease and its treatment on mycobacterium tuberculosis-specific immunity
Keywords: Antiretroviral
Tuberculosis
HIV/AIDS
Reconstitution
Immunology
CD8
Cytomegalovirus
CD4
TB

Human immunodeficiency virus-1 (HIV-1) and tuberculosis (TB) are significant global health issues today and the immunological correlates of protection to both diseases remain poorly defined. HIV-1 is the greatest risk factor for the development of TB and HIV-associated TB contributes significantly to the global TB burden, particularly in sub-Saharan Africa. The host T cell response to Mycobacterium tuberculosis (Mtb) is critical for control and is weakened in HIV-1 disease. However, the extent and precise mechanisms remain incompletely elucidated. Antiretroviral therapy (ART) for HIV-1 reduces TB risk in treated individuals significantly, although not to levels seen in HIV-uninfected individuals.
This thesis studies HIV- and Mtb-specific T cell responses in 2 cohorts of individuals from a community with high HIV-1 and TB prevalence in Bloemfontein, South Africa. An analysis of HIV-specific CD8 T cell responses in Chapter 4, confirms the superior role of HIV-1 Gag-specific CD8 responses in controlling HIV-1 viraemia and demonstrates that the loss of such responses contributes to HIV-1 disease progression and likely susceptibility to opportunistic infection.
I investigated the impact of HIV-1 infection on the Mtb-specific T cell response through a cross-sectional comparison of T cell responses in HIV-infected and HIV-uninfected individuals (Chapters 5 and 6). HIV-infected individuals had a significant depletion of both Th1 and Th17 CD4 responses to Mtb-specific antigens as well inhibition of Mtb-specific CD8 T cell responses, in comparison to those uninfected with HIV-1. PPD- and Rv2031c-specific responses were particularly reduced in HIV-infected individuals.
Over a 12 month period of therapy, ART partially restored the Mtb-specific CD4 T cell response (Chapters 5 and 7). This effect was greater for Th1 than Th17 responses and had no detectable effect on the Mtb-specific CD8 response. However, despite some evident restoration, there remains a significant quantitative deficit in individuals on ART that is likely to contribute to persistent elevated TB risk.
Overall, these data contribute to a better understanding of the mechanisms of susceptibility to TB during HIV-1 disease and ART, as well as of the correlates of protective immune responses to both pathogens.
Structure and function studies of K2P channels
Keywords: potassium channels
TREK-1
K2P

Members of the two-pore potassium-selective (K2P) ion channel superfamily control cell excitability by contributing to the resting membrane potential. Through this, K2P channels are involved in a variety of physiological processes and dysfunction of these channels has been linked to diseases such as epilepsy, depression and migraine. The aim of this study was to develop a greater understanding of how K2P channels, in particular TREK-1, are gated.
In the initial stage of this study we hoped to identify mutations which alter the function of the TREK-1 channel by screening a random mutant library using a K+-auxotrophic strain of S. cerevisiae, SGY1528. From the assay we identified a number of gain-of-function (GoF) mutations, primarily distributed through the pore-lining transmembrane (TM) helices TM2 and TM4. The clustering of mutations in these regions suggested a major role for these helices in channel gating.
Subsequent electrophysiological characterisation of these mutations revealed an increase in basal channel activity and altered sensitivity to modulation by extracellular pH, as well as by activators DEPC and BL-1249.
The publication of two K2P channel crystal structures, TWIK-1 (pdb code: 3UKM) and TRAAK (3UM7), enabled us to build an accurate homology model of TREK-1 and more accurately interpret these functional studies. This approach revealed a number of interesting points, the most important being an interaction between TM4 and pore-helix 1 (PH1). Further mutagenesis studies of this region confirmed that this interaction is essential for normal channel function. Another interaction was identified involving a number of residues within the interface between TM helices TM2, TM3 and TM4 emphasised the importance of helical movements for gating TREK-1 channels.
Based on our findings we therefore present a model for gating of the TREK-1 channel, which suggests that the movement of TM4 in particular, is transduced to the selectivity filter gate via PH1.
Mechanistic Studies of JMJD6, Fe(II) and 2OG dependent lysyl hydroxylase
Keywords: lysine hydroxykase
oxygenases
histone modification
mRNA splicing
amino acid analysis

JMJD6 or PSR (phosphatidyl serine receptor) was initially proposed to be a membrane receptor involved in apoptotic cell clearance by recognition of apoptotic cells. However, sequence analyses implied the presence of a jelly roll or double stranded beta helix (DSBH) structural domain in PSR/JMJD6 and similarity with JmjC family of enzymes which are involved in chromatin regulation. Subsequently, PSR was renamed as JMJD6 and was reported to be a histone arginine demethylase. Previous work from our group has shown that JMJD6 is a lysine hydroxylase that interacts with nuclear proteins including CROP and U2AF65 which are involved in mRNA splicing. Peptide screening and cell based assays led to the conclusion that JMJD6 catalyses lysine hydroxylation of splicing regulatory proteins containing arginine serine rich domains (SR proteins) including U2AF65 and Luc7like-2.
Studies were carried out to investigate the putative arginine demethylation activity of JMJD6 using MS analysis of histone peptides and luminescence-based assays. New substrates from SR proteins were identified by immunoprecipitation of JMJD6 expressed in human cell lines followed by LC-MS/MS analysis and MALDI-MS based assays of synthesised peptide substrates. Work then focussed on studying the mechanism of lysyl-hydroxylation from substrate and enzyme perspective. A crystal structure of seleno-methionine labelled JMJD6 was obtained and it provided insights into the JMJD6 active site and its substrate interactions. Based on this data, single point variants of JMJD6 were prepared and their substrate binding properties were studied by MALDI-MS and 2OG turnover assays.
Collagen lysyl-hydroxylases are also 2OG dependent oxygenases. Efforts to investigate the stereochemistry of JMJD6 catalysed hydroxylation, employing NMR and amino acid analyses were carried out. These studies led to the interesting finding that the C-5 stereochemistry of hydroxylysine in LUC7L2 peptide is opposite (2S,5S-hydroxylysine) to that present in collagen (2S,5R-hydroxylysine). It was found that JMJD6 undergoes autocatalytic self-hydroxylation. Lysine residues from both recombinant JMJD6 and that from HeLa cells at endogenous level were identified to be hydroxylated by amino acid and LC-MS/MS analyses.
JMJD6 has a strong tendency to form aggregates and gel electrophoresis always reveals multimeric bands of various JMJD6 constructs. Characterisation and identification of oligomeric states of JMJD6 was carried out using Electron Microscopy. Studies were initiated to identify possible inhibitors by screening a set of 2OG analogues. The results from this preliminary inhibition studies have identified the tricarboxylic acid (TCA) cycle intermediates, succinate and fumarate to be JMJD6 inhibitors and form a basis of further studies aimed at identifying selective inhibitors.
Generation, regulation and function of morphology in Leishmania and Trypanosoma
Keywords: mitosis
leishmaniasis
motility
Leishmania
life cycle
flagellum
parasitology
Trypanosoma
trypanosomiasis
cell cycle
evolution
automated image analysis
morphology
selection pressure
trypanosome

Little is known about the generation of Leishmania morphology and the function of morphology in trypanosomatids, despite every species having characteristic cell shapes and undergoing changes in morphology between life cycle stages. To address this I analysed morphogenesis of the cell body and flagellum through the cell cycle of the Leishmania insect (promastigote) life cycle stage using a novel method for determining cell cycle stage from cell size and DNA content. This showed cell body morphology is generated by growth and then remodelling of cell shape around mitosis and cytokinesis. Mathematical modelling of flagellum growth indicated flagellum length continues to increase over multiple cell cycles and does not reach a defined length. I also observed little link between the cell cycle and flagellum length regulation during differentiation to the mammalian macrophage-inhabiting (amastigote) life cycle stage. Analysis of motility showed the diverse flagellar lengths of promastigote Leishmania cells bestow different swimming abilities, and the capacity of Leishmania promastigotes for highly directional swimming differs sharply from trypomastigote Trypanosoma brucei. This difference did not arise from altered flagellar beating therefore appeared to be linked to morphology. Together these indicate the mechanisms of cell body morphogenesis, flagellum length regulation, life cycle stage differentiation and the swimming abilities of the cells the morphogenetic processes generate differ significantly between Leishmania and T. brucei. These insights motivated the programming of automated micrograph analysis tools based on a new DNA staining method to support similar future morphometric analyses. This is the first comprehensive comparison of morphogenesis and function of morphology in a promastigote and a trypomastigote and, by considering these new insights in the context of existing molecular biology and the morphological diversity across many trypanosomatid species, give insight into basic Leishmania biology, the shared molecular mechanisms underlying morphogenesis and the potential functions of the diverse morphologies which are seen in different trypanosomatid species and life cycle stages.
Early modern literary afterlives
Keywords: Sir Philip Sidney
Edmund Spenser
posthumous editions
literary biography
Robert Greene
biography
George Herbert
biographical reading
John Donne
Izaak Walton

My thesis explores the posthumous literary life in the early modern period by examining responses to ‘dead poets’ shortly after their deaths. Analysing responses to a series of literary figures, I chart a pre-history of literary biography. Overall, I argue for the gradual emergence of a linkage between an individual’s literary output and the personal life that predates the eighteenth century. Chapter 1 frames the critical investigation by contrasting examples of Lives written for authors living before and after my chosen period of specialisation. Both these Lives reflect changed attitudes towards the writing of poets’ lives as a result of wider discourses that the following chapters examine in more detail. Chapter 2 focuses on the events following the death of Robert Greene, an author often described as the first ‘professional’ English writer. The chapter suggests that Greene’s notoriety is for the most part a posthumous construct resulting from printed responses to his death. Chapter 3 is concerned with the problem of reconciling a poet’s life-narrative with the vita activa model and examines potential causes for the ‘gap’ between Sir Philip Sidney’s public life and his works, which continues to pose a challenge for biographers. Chapter 4 examines the evolution of Izaak Walton’s Life of Donne. The ‘life history’ of Walton’s Lives, particularly the Life of Donne, reflects an accidental discovery of a biographical technique that anticipates literary biography.
My method is mainly based on bibliographical research, comparing editions and making distinctions between them which have not been made before, while paying particular attention to paratextual materials, such as dedications, prefaces and title pages. By investigating assumptions about individual authors, and also authorship in general, I hope to shed some light on a promising new area of early modern scholarship and direct greater scrutiny towards the assumptions brought into literary biography.