Exploring the scope of asymmetric synthesis of β-Hydroxy-γ-lactams via Noyori-type reductions

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

This thesis details the design and implementation of novel chemical routes towards a series of highly propitious 7-azaindolyl derivatives of the indolocarbazole (ICZ) and bisindolylmaleimide (BIM) families, with subsequent evaluation for use as cancer chemotherapeutic agents. A robust synthetic strategy was devised to allow the introduction of a 7-azaindolyl moiety into our molecular template. This approach allowed access to a wide range of β-keto ester and β-keto nitrile intermediates. Critical analysis identified F-ring modulation as a major theme towards the advancement of ICZ and BIM derivatives in drug therapy. Thus, the employment of cyclocondensation methodology furnished a number of novel aminopyrazole, isoxazolone, pyrazolone and pyrimidinone analogues, considerably widening the scope of the prevalent maleimide functionality. Photochemical cyclisation provided for the first reported aza ICZ containing a six-membered F-ring. Another method towards achieving the aza ICZ core involved use of a Perkin-type condensation approach, with chemical elaboration of the headgroup instigated post-aromatisation. Subsequent use of a modified Lossen rearrangement allowed access to further analogues containing a six-membered F-ring. Extensive screening of the novel aza ICZ and BIM derivatives was carried out against the NCI-60 cancer cell array, with nine prospective candidates selected for continued biological evaluation. From these assays, a number of compounds were shown to inhibit cancer cell growth at concentrations of below 10 nM. Indeed, the most active aza ICZ tested is currently under assessment by the Biological Evaluation Committee of the NCI due to excellent antiproliferative activity demonstrated across the panel of cell lines, with a mean GI50 of 34 nM, a mean total growth inhibition (TGI) of 4.6 μM and a mean cytotoxicity (LC50) of 63.1 μM. Correlation to known topoisomerase I (topo I) inhibitors was revealed by COMPARE analysis, and subsequent topo I-mediated DNA cleavage assays showed inhibitory activity below 1 μM for several derivatives.

Development of food ingredients for modulation of glycemia

Starches are a source of digestible carbohydrate and are frequently used in formulated food products in the presence of other carbohydrates, proteins and fat. This thesis explored the effect of addition of neutral (Konjac glucomannan) or charged (milk proteins) polymers on the physical characteristics and digestion kinetics of waxy maize starch. The aim was to identify mechanisms to modulate the pasting properties and subsequent susceptibility to amylolytic digestion. Addition of αs- or β-caseinate protein fractions to waxy maize starch restricted granular swelling during gelatinisation, increasing granule integrity. It was shown that, while β-caseinate can adsorb to starch granules during pasting, αscaseinate can be absorbed into maize starch granules. The resultant effect was a reduction in granule size after heating, more intact granules and a subsequent decrease in starch digestion in vitro as determined by analysis of reducing sugars. The ability of αs-caseinate to reduce the level of amylolytic digestion was confirmed through in vivo pig (Teagasc, Moorepark) and human (University of Surrey, UK) trials. The scope of the thesis extended to the development of a new automated cell for attachment to a rheometer to measure digestion kinetics of starch-protein mixtures. In conclusion, the thesis offers new approaches to modulation of the physical characteristics of unmodified starch during gelatinisation and suggests that the type of protein and/or polysaccharide used in starch-based food systems may influence the ability of the food to modulate glycemia. This is an important consideration in the design of foods with positive health benefits.

Legal regulation of the software "patentable subject matter" requirement in the US and in Europe: The need for certainty, predictability and uniformity

This thesis critically investigates the divergent international approaches to the legal regulation of the patentability of computer software inventions, with a view to identifying the reforms necessary for a certain, predictable and uniform inter-jurisdictional system of protection. Through a critical analysis of the traditional and contemporary US and European regulatory frameworks of protection for computer software inventions, this thesis demonstrates the confusion and legal uncertainty resulting from ill-defined patent laws and inconsistent patent practices as to the scope of the “patentable subject matter” requirement, further compounded by substantial flaws in the structural configuration of the decision-making procedures within which the patent systems operate. This damaging combination prevents the operation of an accessible and effective Intellectual Property (IP) legal framework of protection for computer software inventions, capable of securing adequate economic returns for inventors whilst preserving the necessary scope for innovation and competition in the field, to the ultimate benefit of society. In exploring the substantive and structural deficiencies in the European and US regulatory frameworks, this thesis develops to ultimately highlight that the best approach to the reform of the legal regulation of software patentability is two-tiered. It demonstrates that any reform to achieve international legal harmony first requires the legislature to individually clarify (Europe) or restate (US) the long-standing inadequate rules governing the scope of software “patentable subject matter”, together with the reorganisation of the unworkable structural configuration of the decision-making procedures. Informed by the critical analysis of the evolution of the “patentable subject matter” requirement for computer software in the US, this thesis particularly considers the potential of the reforms of the European patent system currently underway, to bring about certainty, predictability and uniformity in the legal treatment of computer software inventions.

Landscapes of kingship in early medieval Ireland, AD 400–1150

This thesis explores the evolution of kingship in early medieval Ireland (AD 400–1150) through a kingdom based and multi-scalar approach to royal landscapes. Through exploring the role of place and landscape in the construction of early medieval Irish kingship, this study will assess the relationship between the social, economic and ideological roles of the king in Irish society. Kingship in Ireland was vested in places, such that royal landscapes were the pre-eminent symbol of regality and authority. As such, an interdisciplinary study of kingship grounded in archaeological methodologies has a unique potential to contribute to our knowledge of the practice of kingship. Consequently, this research considers the material apparatus of different scales of kingships and explores the role of landscape in the construction of kingship and the evolution of kingdoms. It takes two major case studies; (i) Cashel, Munster and the Éoganachta federation; and (ii) the Uí Néill, Tara and the Síl nÁedo Sláine kingdom of Brega. Through interdisciplinary methodologies it charts the genesis and development of political federations, focusing specifically on the role that royal landscapes’ played in their evolution. Similarly, this thesis engages critically with the nature of assembly places and practices in Ireland, and focuses specifically on issues pertaining to the nature of assembly and the archaeological manifestation of such practices. It includes a list of 115 landscapes identified as assembly places, and through the analysis of this material, this thesis examines the ways in which different types of royal sites articulated together to create royal landscapes implicated in the exercise of kingship, and the construction and maintenance of authority. Moreover, through the analysis of assembly places within the context of the development of kingdoms, and structures of jurisdiction and administration, it also investigates the evolution of supra-regional scales of identity and community associated with the emergence of major political federations in early medieval Ireland.

An exploration of leadership in Irish post-primary education

The purpose of this study is to explore the nature and how of leadership in Irish post-primary schools. It considers school leadership within the context of contemporary Distributed Leadership theory. Associated concepts such as Distributed Cognition and Activity Theory are used to frame the study. From a distributed perspective, it is now widely accepted that other agents (e.g. teachers) have a leadership role, as part of collaborative, participative and supportive learning communities. Thus, this study considers how principals interact and build leadership capacity throughout the school. The study draws on two main sources of evidence. In analysing the implications of accountability agendas for school leadership, there is an exploration and focus on the conceptualisations of school leadership that are fore-grounded in 21 WSE reports. Elements of Critical Discourse Analysis are employed as an investigative tool to decipher how the construction of leadership practice is produced. The second prong of the study explores leadership in 3 case-study post-primary schools. Leadership is a complex phenomenon and not easy to describe. The findings clarify, however, that school leadership is a construct beyond the scope of the principal alone. While there is widespread support for a distributed model of leadership, the concept does not explicitly form part of the discourse in the case-study schools. It is also evident that any attempt to understand leadership practice must connect local interpretations with broader discourses. The understanding and practice of leadership is best understood in its sociohistorical context. The study reveals that, in the Irish post-primary school, the historical dimension is very influential, while the situational setting, involving a particular set of agents and agendas, strongly shapes thinking and practices. This study is novel as it synthesises two key sources of evidence. It is of great value in that it teases out the various historical and situational aspects to enhance understandings of school leadership in contemporary Ireland. It raises important questions for policy, practice and further research.

Ontological representation of design science research publications

A search result provided by existing digital library and web search systems typically comprises only a prioritised list of possible publications or web pages that meet the search criteria, possibly with excerpts and possibly with search terms highlighted. The research in progress reported in this poster contributes to a larger research effort to provide a readable summary of search results that synthesise relevant publications or web pages to provide results that meet four C’s: comprehensive, concise, coherent, and correct, as a more useful alternative to un-synthesised result lists. The scope of this research is limited to searching for and synthesising Design Science Research (DSR) publications that present the results of DSR, as an example problem domain.

"I have nothing to say, only to show": appropriation in the poetries of Trevor Joyce, Alan Halsey, and Susan Howe

This thesis studies contemporary poetry’s innovations in textual borrowing and the range and scope of its appropriative practices. The restrictions of the inherited definitions of appropriation include a limited capacity for expression and meaningfulness, a partial concept of appropriation’s critical capacity, and an inadequate sense of the poet’s individual and unique practice of appropriation. This thesis resolves the problematic constraints limiting contemporary definitions of appropriation by tracing the history of the practice to reveal an enduring relation between appropriation and poetic expression. Close readings of Trevor Joyce’s, Alan Halsey’s, and Susan Howe’s poetry serve as evidence of contemporary poetry’s development of appropriation beyond the current ascriptions and offer some direction on how the critical understanding of appropriation might be extended and redefined. Here, appropriation is recognized as another source of lyric expression, critical innovation, and conceptual development in contemporary poetry. This thesis encourages a new perspective on the purpose and processes of poetic appropriation and the consequences of its declarative potential for both poet and poem.

A tight-binding analysis of the electronic properties of III-nitride semiconductors

This thesis divides into two distinct parts, both of which are underpinned by the tight-binding model. The first part covers our implementation of the tight-binding model in conjunction with the Berry phase theory of electronic polarisation to probe the atomistic origins of spontaneous polarisation and piezoelectricity as well as attempting to accurately calculate the values and coefficients associated with these phenomena. We first develop an analytic model for the polarisation of a one-dimensional linear chain of atoms. We compare the zincblende and ideal wurtzite structures in terms of effective charges, spontaneous polarisation and piezoelectric coefficients, within a first nearest neighbour tight-binding model. We further compare these to real wurtzite structures and conclude that accurate quantitative results are beyond the scope of this model but qualitative trends can still be described. The second part of this thesis deals with implementing the tight-binding model to investigate the effect of local alloy fluctuations in bulk AlGaN alloys and InGaN quantum wells. We calculate the band gap evolution of Al1_xGaxN across the full composition range and compare it to experiment as well as fitting bowing parameters to the band gap as well as to the conduction band and valence band edges. We also investigate the wavefunction character of the valence band edge to determine the composition at which the optical polarisation switches in Al1_xGaxN alloys. Finally, we examine electron and hole localisation in InGaN quantum wells. We show how the built-in field localises the carriers along the c-axis and how local alloy fluctuations strongly localise the highest hole states in the c-plane, while the electrons remain delocalised in the c-plane. We show how this localisation affects the charge density overlap and also investigate the effect of well width fluctuations on the localisation of the electrons.

Processes of social flourishing and their liminal collapse: elements to a genealogy of globalization

This article aims at exploring a long-term historical perspective on which contemporary globalization can be more meaningfully situated. A central problem with established approaches to globalization is that they are even more presentist than the literature on modernization was. Presentism not only means the ignoring of history, but also the unreflective application to history of concepts taken from the study of the modern world. In contrast, it is argued that contemporary globalization is not a unique development, but rather is a concrete case of a historical type. Taking as its point of departure the spirit, rather than the word, of Max Weber, this article extends the scope of sociological investigation into archaeological evidence. Having a genealogical design and introducing the concept of ‘liminality’, the article approaches the modern process of globalization through reconstructing the internal dynamics of another type of historical change called ‘social flourishing’. Taking up the Weberian approach continued by Eisenstadt in his writings on ‘axial age’, it moves away from situations of crisis as reference point, shifting attention to periods of revival by introducing the term ‘epiphany’. Through the case of early Mesopotamia, it shows how social flourishing can be transmogrified into globalizing growth, gaining a new perspective concerning the kind of ‘animating spirit’ that might have driven the shift from Renaissance to Reformation, the rise of modern colonialism, or contemporary globalization. More generally, it will retrieve the long-term historical background of the axial age and demonstrate the usefulness and importance of archaeological evidence for sociology.