Explorations in a meaning making system: Kerry as an entrepreneurial platform and the equine sector as a cluster

This Portfolio is about the changes that can be supported and achieved through transformational education that impacts on personal, professional and organisational levels. Having lived through an era of tremendous change over the second half of the twentieth century and into the twenty-first the author has a great drawing board to contemplate in the context of professional career experience as an engineer. The ability to engage in ‘subject-object’ separation is the means by which Kegan (1994, 2009) explains that transformation takes place and the Essays in this Portfolio aim to support and bring about such change. Exploration of aspects of ‘Kerry’ is the material selected to both challenge support change in the way of knowing from being subject to certain information and knowledge that to being able to consider it more objectively. The task of being able to distance judgement about the economy and economic development of Kerry was facilitated by various readings around of a number of key thinkers including Kegan, Drucker, Porter and Penrose. The central themes of Kerry or the potential for economic development are built into each Essay. Essay One focuses on reflections of Kerry life - on Kerry people within and without Kerry - and events as they affected understandings of how people related to and worked with one another. These reflections formed the basis for transformational goals identified which required a shift from an engineering mindset to encompass an economics-based view. In Essay Two knowledge of economic concepts is developed by exploring the writings of Drucker, Penrose, and Porter with pertinence to considering economic development generally, and for Kerry in particular in the form of an ‘entrepreneurial platform’. The concepts and theories were the basis of explorations presented in Essays Three and Four. Essay Three focuses on Kerry’s potential for economic development give its current economic profile and includes results from interviews with selected businesses. Essay Four is an exercise in the application of Porter’s ‘Cluster’ concept to the equine sector.

Synthesis and reactivity of alpha-thio-beta-chloroacrylamides and alpha-thio-beta-chloroenones

Development of novel synthetic methodology for selective transformation of organic compounds is a central element underpinning organic synthesis with control of chemo-, regio- and stereoselectivity a very high priority. Reactions which can be conducted under mild reaction conditions and, ideally in an environmentally attractive manner, are particularly advantageous. The principal objective of this thesis was to explore the synthesis, reactivity and synthetic utility of a series of α,β-thio-β-chloroenones. The stereochemical features of these transformations and the potential of this novel series of compounds in the synthesis of bioactive compounds were of particular interest. In exploring the reactivity of these compounds, the key transformations included nucleophilic additions and Stille cross-coupling at the β-carbon. Chapter 1 reviews the literature relevant to the research conducted, and focuses in particular on the synthesis of β-chloroenones and related unsaturated carbonyl compounds. The synthesis of chalcone compounds from various precursors is also discussed, with particular emphasis on the use of palladium cross-coupling reactions in the preparation of these compounds. The biological activity of chalcones is also summarised in this chapter. The second chapter delineates the stereoselective synthesis of the novel α-thio-β-chloroenones from the corresponding α-thioketones in a multistep reaction cascade initiated by a NCS-mediated chlorination. A range of both alkyl and aryl β-chloroenones were prepared in this work and the oxidation of these compounds to the corresponding sulfoxides and sulfones is also outlined. The electrophilicity of the β-carbon of the enones was examined in nucleophilic addition/substitution reactions with successful access to a variety of synthetically useful novel adducts including acetals and enaminoketones. Investigation of the synthetic potential of the Stille cross-coupling reaction with the novel α-thio-β-chloroenones was explored and provided an efficient route for the synthesis of a novel series of chalcones. Most importantly this new methodology provided a new and synthetically powerful approach for carbon-carbon bond formation at the β-carbon under mild neutral conditions. A preliminary investigation into the use of these β-chloroenones as dienophiles in Diels-Alder cycloaddition reactions is also discussed in this chapter. Chapter 2 also reports the nucleophilic addition of N, O, S and C nucleophiles to previously described β-chloroacrylamides and their corresponding sulfoxide derivatives. This work builds on previous research carried out in this programme and the reactivity of these β-chloroacrylamides at the sulfide and sulfoxide level is compared. Comparison of the reactivity of the β-chloroacrylamides, in nucleophilic substitution and Stille-coupling, with that of the novel β-chloroenones is of interest. Finally, the biological activity of both the β-chloroenones and the β-chloroacrylamides in terms of cytotoxicity is summarised in Chapter 2. The final chapter, Chapter 3, details the full experimental procedures, including spectroscopic and analytical data for the compounds prepared during this research.

Catalyst, additive and substrate effects in intramolecular aromatic additions of alpha-diazoketones

This thesis is focused on transition metal catalysed reaction of α-diazoketones leading to aromatic addition to form azulenones, with particular emphasis on enantiocontrol through use of chiral copper catalysts. The first chapter provides an overview of the influence of variation of the substituent at the diazo carbon on the outcome of subsequent reaction pathways, focusing in particular on C-H insertion, cyclopropanation, aromatic addition and ylide formation drawing together for the first time input from a range of primary reports. Chapter two describes the synthesis of a range of novel α-diazoketones. Rhodium and copper catalysed cyclisation of these to form a range of azulenones is described. Variation of the transition metal catalyst was undertaken using both copper and rhodium based systems and ligand variation, including the design and synthesis of a novel bisoxazoline ligand. The influence of additives, especially NaBARF, on the enantiocontrol was explored in detail and displayed an interesting impact which was sensitive to substituent effects. Further exploration demonstrated that it is the sodium cation which is critical in the additive effects. For the first time, enantiocontrol in the aromatic addition of terminal diazoketones was demonstrated indicating enantiofacial control in the aromatic addition is feasible in the absence of a bridgehead substituent. Determination of the enantiopurity in these compounds was particularly challenging due to the lability of the products. A substantial portion of the work was focused on determining the stereochemical outcome of the aromatic addition processes, both the absolute stereochemistry and extent of enantiopurity. Formation of PTAD adducts was beneficial in this regard. The third chapter contains the full experimental details and spectral characterisation of all novel compounds synthesised in this project, while details of chiral stationary phase HPLC and 1H NMR analysis are included in the appendix.

Investigation of the genetic susceptibility to osteoporosis in the Irish population

Osteoporosis is a complex skeletal disorder characterized by compromised bone strength. Variation in bone mineral density (BMD) is a contributing factor. The aim of this research as to select informative single nucleotide polymorphisms (SNPs) in potential candidate genes from loci suggestively linked to BMD variation for fine mapping. The gene regulated by oestrogen in breast cancer 1 (GREB1), located at 2p25.1, was selected. GREB1 transcription is initiated early in the oestrogen receptor alpha regulated pathway. There was significant association between GREB1_03 and BMD variation at the lumbar spine and femoral neck (FN) in the discovery cohort. Significant association was observed between GREB1_04 and FN BMD in the replication cohort. The development and differentiation enhancing factor 2, the integrin cytoplasmic domain associated protein 1 and A-disintegrin and metalloprotease 17 were selected due to their respective roles in cell mobility and adhesion. There was no linkage or association observed between the Chr2 cluster SNPs and BMD. Two factors in bone remodelling are the attraction of bone cell precursors and endocrine regulation of the process, primarily through the action of parathyroid hormone (PTH). The C-C chemokine receptor type 3 (CCR3) encodes a CC chemokine receptor expressed in osteoclast precursors. The PTH receptor type 1 (PTHR1) encodes a G-protein coupled receptor for PTH. Association was observed between CCR3 haplotypes and BMD variation at the FN. There was no linkage or association observed between PTHR1 SNPs and BMD variation. Population genetic studies with complex phenotypes endeavour to elucidate the traits genetic architecture. This study presents evidence of association between GREB1 and BMD variation and as such, introduces GREB1 as a novel gene target for osteoporosis genetics studies. It affirms that common genomic variants in PTHR1 are not associated with BMD variation in Caucasians and supports the evidence that CCR3 may be contributing to BMD variation

Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells

Cytokine-driven signalling shapes immune homeostasis and guides inflammatory responses mainly through induction of specific gene expression programmes both within and outside the immune cell compartment. These transcriptional outputs are often amplified via cytokine synergy, which sets a stimulatory threshold that safeguards from exacerbated inflammation and immunopathology. In this study, we investigated the molecular mechanisms underpinning synergy between two pivotal Th1 cytokines, IFN-γ and TNF-α, in human intestinal epithelial cells. These two proinflammatory mediators induce a unique state of signalling and transcriptional synergy implicated in processes such as antiviral and antitumour immunity, intestinal barrier and pancreatic β-cell dysfunction. Since its discovery more than 30 years ago, this biological phenomenon remains, however, only partially defined. Here, using a functional genomics approach including RNAi perturbation screens and small-molecule inhibitors, we identified two new regulators of IFN-γ/TNF-α-induced chemokine and antiviral gene and protein expression, a Bcl-2 protein BCL-G and a histone demethylase UTX. We also discovered that IFN-γ/TNF-α synergise to trigger a coordinated shutdown of major receptor tyrosine kinases expression in colon cancer cells. Together, these findings extend our current understanding of how IFN-γ/TNF-α synergy elicits qualitatively and quantitatively distinct outputs in the intestinal epithelium. Given the well-documented role of this synergistic state in immunopathology of various disorders, our results may help to inform the identification of high quality and biologically relevant druggable targets for diseases characterised by an IFN-γ/TNF-α high immune signature