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Synthesis of PfCLK1 inhibitors
Get PDFDespite international efforts to deal with malaria, it remains a serious health concern on a global scale, contributing to a considerable number of deaths worldwide, especially in LEDCs (less economically developed countries) on the African and Asian continents. Unfortunately, a lack of research has resulted in no new antimalarial drugs being introduced into the market since 1996. Current treatment strategies against malaria have been seen in the form of artemisinin; however, due to constant usage, this drug has become compromised, as the most virulent malaria parasite strain, Plasmodium falciparum, has developed resistance. As a result, significant efforts must be targeted towards the development of new antimalarial drugs that target not only the symptomatic blood stage of infection, but all stages of the parasite life cycle to prevent transmission and hopefully allow the eradication of malaria.
In recent times, a four-membered protein kinase family known as ‘Plasmodium falciparum cyclin-like kinase’ (PfCLK1-4) has been identified as an essential eukaryotic protein for the survival of the parasite during the ‘blood stage’ of its lifecycle. Studies have shown these kinases to be pivotal in regulating RNA expression throughout the asexual and sexual stages of the parasite lifecycle, which are important in parasite survival. As a result, efforts have been made to focus on this protein kinase family to see if targeting these protein kinases could offer a novel therapeutic strategy to treat malaria. Henceforth, this project aims to validate one of these family members ‘PfCLK1 as a new therapeutic target against malaria by synthesizing tool compounds that selectively inhibit PfCLK1.
As this project is still in the early ‘hit to lead’ stage of the drug discovery process, the focus so far has been on developing a synthetic route towards the ‘hit’ molecules identified from a HTS (high throughput screen) that showed biological activity against PfCLK1. As a result, the main discussion of this report will outline the synthetic route used to synthesize two of the four hit molecules, compounds A & B
Tracing the origin of methane using clumped isotope geochemistry
Get PDFMethane (CH4) is the main component of natural gas and the second most abundant greenhouse gas produced by natural and anthropogenic sources. Stable isotopic compositions of carbon and hydrogen (δ13C and δD) have improved our understanding on the production and sink pathways of methane in the atmosphere, subsurface, freshwater and marine environments. However, the overlapping of δ13C and δD values between diverse sources, produce ambiguous results difficult to interpret. Due to technological advancements, the clumped isotopic compositions Δ13CH3D and Δ12CH2D2 can be measured using HR-IRMS, providing additional insights into the formation temperature and origin of methane. This PhD thesis includes a description of the work carried out for testing, establishing, and validating methods for the purification of methane, the preparation of the equilibrated aliquots, and the measurement of bulk and clumped isotopologues at the Clumped Isotope Laboratory in SUERC. In this thesis, those methods were applied to understand the methane formation in a world-class helium deposit in Virginia gas field (Witwatersrand basin). The results suggest a dominant microbial source of the gas with smaller but ultimately significant contribution from abiotic sources. The data suggest negligible at best contributions from thermogenic sources. The large Δ13CH3D values (>7‰) and the trend identified were consistent with a scenario for anaerobic oxidation of methane by methanotrophs, with no more than ~1.6% CH4 consumption. Additionally, this PhD thesis includes work on calcite veins associated with a fracture network, in order to identify any potential relationship between calcites and methane in the Virginia gas field. The origin of carbon was assessed in the calcites through measuring the δ13C, and has been suggested to be a mixture of marine sources and carbon deriving from the oxidation of organic matter. The δ18O of the calcites and the precipitation temperatures of the calcites T47, indicate a mixture of two precipitating fluids; one related to hydrothermal sources and one consistent with a palaeometeoric origin. The T47 of the calcites veins indicate that the calcite precipitation has preceded the formation of the dominant microbial CH4, as the precipitation temperatures are in average greater than the limit of life at 122oC. Overall, no clear relationship between the calcites and methane is identified, however I discuss the different scenarios
Design, properties, and potential applications of Group IV metal oxo clusters
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Developing a Theory- and Evidence-Based Self-Management Intervention for Multimorbidity in Thailand (M-SMiTh): an intervention mapping approach
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On-orbit manufacturing using solid foams
Get PDFThere is growing interest in the development of processes that can enable the manufacturing of products in space. In-space manufacturing could remove the limitations imposed by terrestrial manufacturing and the launch environment on products used in space and enable large-scale space infrastructure that could further develop in-space capabilities. Examples of large-scale space infrastructure, that could be enabled by in-space manufacturing, include large solar arrays, or orbital reflectors, to increase the amount of light on terrestrial solar arrays. Given the large scale of the proposed infrastructure made using in-space manufacturing and the large energy demands that such construction would place on a space mission, materials that have a low energy consumption for each unit of volume or mass constructed could present advantages for an in-space manufacturing facility. This thesis examines the use of solid foams, which typically require much less energy to apply, to construct an equivalent volume of engineered plastics or metals.
To explore the development of in-space manufacturing and solid foam manufacturing, this thesis presents a literature review based on these fields. A trade-off review is also conducted to compare the material properties and process characteristics of a range of potential in space manufacturing processes and the materials that they are capable of producing, to understand what characteristics are important for an in-space manufacturing facility. Case studies were used to understand if solid foams could provide an advantage for products manufactured in space. Two generalised use cases were explored, one structural and one thermal, where each was an abstract use case that was not bound by a specific mission, as well as a specific use case, in which the solid foam was intended for a specific mission application. The structural generalised use case compared constructing and using solid foams for a structural beam with constructing and using stainless steel and PEEK beams using a direct energy deposition process and a fused filament fabrication process, respectively. It was found that, while the solid foam beam required more volume than the other beams, it could be produced with significantly less energy and over a much shorter time span. The generalised thermal use case compared the construction and use of a solid foam insulator with a multi-layer insulator made of a PEEK frame and aluminium film, constructed using a fused filament fabrication and a physical vapour deposition process. It was found that, while a large mass of foam was required to produce that insulating layer, when compared to the multi-layer system, the foam layer took less energy to produce. The specific use case considered an aerocapture around Mars, in which solid foam was used to construct an aeroshell. This solid foam aeroshell was compared with an inflatable system and a chemical propulsion system to understand if it could provide a reduction in the proportion of mission mass required for the aerocapture. It was found that, for lighter missions a foam aeroshell could be used in a similar fashion to the inflatable system, however, it was noted, that the heat flux on the aeroshell would be significant, and further development would be needed to understand to protect the foam system form this high heat flux.
The thesis presents a plan for the future development of this research with a focus on verifying the material properties that a solid foam, produced in space, would have and developing a system capable of producing solid foams in vacuum and in microgravity. Two lines of enquiry are proposed, a practical experimental enquiry and computational analysis. The results of either enquiry could be used to further the understanding of solid foams made in space and which applications they may provide an advantage too
Sensi litterales et spirituales, lignum vitaeque: the literal and spiritual senses of the scriptures with reference to the Tree of Life in the works of Thomas Aquinas
Get PDF“That first meaning, therefore, [in] which words signify things, pertains to the first sense, which is the ‘historical’ or ‘literal’ sense. Then, that second meaning, [in] which things which are signified through words also signify things, is called the ‘spiritual sense’; which is founded upon the ‘literal’, and presupposes it”. (ST Ia.q1.a10.co. My translation).
Thus runs Thomas Aquinas’ theory of meaning of the Scriptures. Wrestling with this seemingly simple statement, however, interpreters of the Angelic Doctor have argued much over what, precisely, Thomas sought to communicate in this pronouncement. Is it truly appropriate to understand Thomas to be speaking of multiple distinct kinds of meaning to be accessible in and through the text of the Scriptures? How much weight, in the friar’s mind, ought the interpreter of the Scriptures to rest on readings following the literal sense of the text, as opposed to those following the spiritual senses communicated through the words on the page? And does Thomas’ method of interpretation, as evidenced throughout his body of work, belie his celebrated statement at the opening of the ST?
This present work holds that Thomas does indeed insist upon the necessity of interpretation of the Scriptures according to both the literal and spiritual senses. The opening of the ST is no mere lip-service to a stock medieval formula. This work bears this thesis out through detailed examination of Thomas’ polymorphic readings of the Scriptural entity of the Tree of Life.
The first chapter of the present work rigorously examines the nature of Scripture itself in Thomas’ thought, focussing upon his understanding of the literal sense (the kind of meaning communicated through conventional signs, i.e., words) and the spiritual senses (the kinds of meaning communicated through the things referred to by the conventional signs which fill the pages of the Scriptures). While the first category of meaning inheres in all texts, regardless of authorship, the second category is the sole province of works authored by both God and man.
The following chapters of the present work demonstrate the significant role which this distinction bears throughout Thomas’ body of work by way of numerous examples. The second chapter outlines Thomas’ readings, which follow the literal sense, of Scriptural passages referencing the Tree of Life. The third chapter examines Thomas’ readings, which follow the spiritual senses, of Scriptural passages referencing the Tree of Life
In bed with Kierkegaard
Get PDFFor the creative part of this thesis, I have submitted a novel in the genre of autofiction, titled In Bed with Kierkegaard. It is a fictionalised account of my initiation in a BDSM community in Athens, Greece, between the years 2007 – 2009, and an account of a long-distance relationship I developed with a dominant man, with the nickname Morpheus. The themes of the novel are: domination/submission and sadism/masochism in our modern digital age, the quest for a female identity defined by sexuality, and writing erotic memoirs. The novel is based on detailed notes kept during the narrated events and follows closely on the advice on seduction offered by the Danish philosopher Søren Kierkegaard in the text, The Seducer’s Diary.
The critical part of this thesis provides a background account of writing a novel of autofiction on sadomasochism and seeking its publication. It also provides a comparative analysis of two literary works on similar themes, Dominique Aury’s Story of O, and Garth Greenwell’s Cleanness, especially as they pertain to the way in which erotic fantasy encroaches on reality, as well as the quest for what Kierkegaard called a ‘God-relationship’: a love and devotion so deep it may offer one a sense of transcendence beyond the limitations of human existence as grounded on the quotidian
An analysis of the early French violin school
Get PDFThis research examines one of the less studied sides of eighteenth century music and performance: French violin playing. By answering the three following questions, this research seeks to provide insight concerning just one of the aspects of musical learning in the late seventeenth and early eighteenth century:
• What specifically constitutes French violin posture of the early period of development as recommended by these primary sources?
• What were the general trends in ornamentation that a French violin player might have observed in this period?
• And the final area: how did French violin methods and treatises define and teach the application of the French practice of notes inégales?
This research examines one of the unexamined sides of eighteenth century music and performance studies: French violin playing. Focusing on an immersive analysis of the violin methods of early French authors of violin playing, one is able to better understand how these violin players would probably have learned to play music in the early half of the eighteenth century.Here, the key French concept of rhythmic inequality was examined from another angle from both 1711 Méthode Facile of Montéclair and the later, more modern L’école d’Orphée of Corrette which offered the most encyclopædic definition of inequality. Correspondent to inequality, the use of ornamental and technical musical practices in these methods shows how the French curated a national violin school.
Interestingly, this research was able to explain the emerging trends in the eighteenth century of both an increase in designated violin music from sonatas to concertos, and the increase of private instructors in Paris with the rise of printed violin methods and treatises. Furthermore this research provided an immersive understanding into the manner of learning to play music from the perspective of an early eighteenth century French violin player
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