Visualising ribosome profiling and using it for reading frame detection and exploration of eukaryotic translation initiation

Ribosome profiling (ribo-seq) is a recently developed technique that provides genomewide information on protein synthesis (GWIPS) in vivo. The high resolution of ribo-seq is one of the exciting properties of this technique. In Chapter 2, I present a computational method that utilises the sub-codon precision and triplet periodicity of ribosome profiling data to detect transitions in the translated reading frame. Application of this method to ribosome profiling data generated for human HeLa cells allowed us to detect several human genes where the same genomic segment is translated in more than one reading frame. Since the initial publication of the ribosome profiling technique in 2009, there has been a proliferation of studies that have used the technique to explore various questions with respect to translation. A review of the many uses and adaptations of the technique is provided in Chapter 1. Indeed, owing to the increasing popularity of the technique and the growing number of published ribosome profiling datasets, we have developed GWIPS-viz (http://gwips.ucc.ie), a ribo-seq dedicated genome browser. Details on the development of the browser and its usage are provided in Chapter 3. One of the surprising findings of ribosome profiling of initiating ribosomes carried out in 3 independent studies, was the widespread use of non-AUG codons as translation initiation start sites in mammals. Although initiation at non-AUG codons in mammals has been documented for some time, the extent of non-AUG initiation reported by these ribo-seq studies was unexpected. In Chapter 4, I present an approach for estimating the strength of initiating codons based on the leaky scanning model of translation initiation. Application of this approach to ribo-seq data illustrates that initiation at non-AUG codons is inefficient compared to initiation at AUG codons. In addition, our approach provides a probability of initiation score for each start site that allows its strength of initiation to be evaluated.

Assessment of dietary background exposure of the Irish adult population to dioxins and PCBs particularly taking into account additional exposure due to the 2008 Irish dioxin food contamination incident

Irish monitoring data on PCDD/Fs, DL-PCBs and Marker PCBs were collated and combined with Irish Adult Food Consumption Data, to estimate dietary background exposure of Irish adults to dioxins and PCBs. Furthermore, all available information on the 2008 Irish pork dioxin food contamination incident was collated and analysed with a view to evaluate any potential impact the incident may have had on general dioxin and PCB background exposure levels estimated for the adult population in Ireland. The average upperbound daily intake of Irish adults to dioxins Total WHO TEQ (2005) (PCDD/Fs & DLPCBs) from environmental background contamination, was estimated at 0.3 pg/kg bw/d and at the 95th percentile at 1 pg/kg bw/d. The average upperbound daily intake of Irish adults to the sum of 6 Marker PCBs from environmental background contamination ubiquitous in the environment was estimated at 1.6 ng/kg bw/d and at the 95th percentile at 6.8 ng/kg bw/d. Dietary background exposure estimates for both dioxins and PCBs indicate that the Irish adult population has exposures below the European average, a finding which is also supported by the levels detected in breast milk of Irish mothers. Exposure levels are below health based guidance values and/or Body Burdens associated with the TWI (for dioxins) or associated with a NOAEL (for PCBs). Given the current toxicological knowledge, based on biomarker data and estimated dietary exposure, general background exposure of the Irish adult population to dioxins and PCBs is of no human health concern. In 2008, a porcine fat sample taken as part of the national residues monitoring programme led to the detection of a major feed contamination incidence in the Republic of Ireland. The source of the contamination was traced back to the use of contaminated oil in a direct-drying feed operation system. Congener profiles in animal fat and feed samples showed a high level of consistency and pinpointed the likely source of fuel contamination to be a highly chlorinated commercial PCB mixture. To estimate additional exposure to dioxins and PCBs due to the contamination of pig and cattle herds, collection and a systematic review of all data associated with the contamination incident was conducted. A model was devised that took into account the proportion of contaminated product reaching the final consumer during the 90 day contamination incident window. For a 90 day period, the total additional exposure to Total TEQ (PCDD/F &DL-PCB) WHO (2005) amounted to 407 pg/kg bw/90d at the 95th percentile and 1911 pg/kg bw/90d at the 99th percentile. Exposure estimates derived for both dioxins and PCBs showed that the Body Burden of the general population remained largely unaffected by the contamination incident and approximately 10 % of the adult population in Ireland was exposed to elevated levels of dioxins and PCBs. Whilst people in this 10 % cohort experienced quite a significant additional load to the existing body burden, the estimated exposure values do not indicate approximation of body burdens associated with adverse health effects, based on current knowledge. The exposure period was also limited in time to approximately 3 months, following the FSAI recall of contaminated meat immediately on detection of the contamination. A follow up breast milk study on Irish first time mothers conducted in 2009/2010 did not show any increase in concentrations compared to the study conducted in 2002. The latter supports the conclusion that the majority of the Irish adult population was not affected by the contamination incident.

The political philosophy of Miki Kiyoshi: A close reading of the philosophical foundations of cooperative communitarianism

The thesis is a historical and philological study of the mature political theory of Miki Kiyoshi (1897-1945) focused on Philosophical Foundations of Cooperative Communitarianism (1939), a full translation of which is included. As the name suggests, it was a methodological and normative communitarianism, which critically built on liberalism, Marxism and Confucianism to realise a regional political community. Some of Miki’s Western readers have wrongly considered him a fascist ideologue, while he has been considered a humanist Marxist in Japan. A closer reading cannot support either view. The thesis argues that the Anglophone study of Japanese philosophy is a degenerating research programme ripe for revolution in the sense of returning full circle to an original point. That means returning to the texts, reading them contextually and philologically, in principle as early modern European political theory is read by intellectual historians, such as the representatives of Cambridge School history of political thought. The resulting reading builds critically on the Japanese scholarship and relates it to contemporary Western and postcolonial political theory and the East Asian tradition, particularly neo-Confucianism. The thesis argues for a Cambridge School perspective radicalised by the critical addendum of geo-cultural context, supplemented by Geertzian intercultural hermeneutics and a Saidian ‘return to philology’. As against those who have seen radical reorientations in Miki’s political thought, the thesis finds gradual progression and continuity between his neo-Kantian, existentialist, Marxian anthropology, Hegelian and finally communitarian phases. The theoretical underpinnings are his philosophical anthropology, a structurationist social theory of praxis, and a critique of liberalism, Marxism, nationalism and idealism emphasising concrete as opposed to abstract theory and the need to build on existing cultural traditions to modernise rather than westernise East Asia. This post-Western fusion was imagined to be the beginning of a true and pluralistic universalism.

Nihilism and emptiness: Nishitani's encounter with Nietzsche

In this thesis, I examine the relationship between the Kyoto School philosopher, Nishitani Keiji, and the work of Friedrich Nietzsche, focusing on the two thinkers’ respective approaches to the problem of nihilism. The work begins by positioning Nishitani’s interpretation of Nietzsche’s account of nihilism with reference to diverse readings of Nietzsche in Western scholarship. I then consider the development of Nishitani’s reading of Nietzsche from his lecture series on nihilism, The Self- Overcoming of Nihilism, through to his magnum opus, Religion and Nothingness. I make two key contributions to recent scholarly debate on Nishitani’s relationship to Nietzsche. The first is to emphasise the importance of Nishitani’s response to the idea of eternal recurrence for understanding his critical approach to Nietzsche’s thinking. I argue against the view, offered by Bret Davis, that Nishitani’s criticisms of Nietzsche are primarily based on the former’s negative assessment of the idea of will to power. The second contribution is to situate Nishitani’s critical approach to eternal recurrence within his broader attempt to formulate a Zen-influenced conception of temporality and historicity. I then argue for the necessity of this conceptual background for coming to grips with his conception of the ‘transhistorical’ grounds of historicity in emptiness (śūnyatā), as outlined in the later chapters of Religion and Nothingness.

Reading Lydgate's Troy Book: patronage, politics, and history in Lancastrian England

This thesis, Reading Lydgate's Troy Book: Patronage, Politics and History in Lancastrian England, discusses the relationship between John Lydgate as a court poet to his patron Henry V. I contend that the Troy Book is explored as a vehicle to propagate the idea that the House of Lancaster is the legitimate successor to King Richard II in order to smooth over the usurpation of 1399. Paul Strohm's England's Empty Throne was a key influence to the approach of this thesis' topic. I examine that although Chaucer had a definitive impact on Lydgate's writing, Lydgate is able to manipulate this influence for his own ambitions. In order to enhance his own fame, Lydgate works to promote Chaucer's canon so that as Chaucer's successor, he will inherit more prestige. The Trojan war is seen in context with the Hundred Years War, and can be applied contextually to political events. Lydgate presents characters that are vulnerable to human failings, and their assorted, complicated relationships. Lydgate modernises the Troy Book to reflect and enhance his Lancastrian society, and the thesis gives a contextual view of Lydgate's writing of the Troy Book. Lydgate writes for a more varied target audience than his thirteenth-century source, Guido delle Colonne, and there is a deliberation on the female characters of the Troy Book which promulgates the theory that Lydgate takes a proactive and empathetic interest in women's roles in society. Furthermore Lydgate has never really been accepted as a humanist, and I look at Lydgate's work from a different angle; he is a self-germinating humanist. Lydgate revives antiquity to educate his fifteenth-century audience, and his ambition is to create a memorial for his patron in the vernacular, and enhance his own fame as a poet separate from Chaucer's shadow.

Within the carnal: re-reading Merleau-Ponty through the language of drawing

In order to present visual art as a paradigm for philosophy, Merleau-Ponty investigated the creative processes of artists whose work corresponded closely with his philosophical ideas. His essays on art are widely valued for emphasising process over product, and for challenging the primacy of the written word in all spheres of human expression. While it is clear that he initially favoured painting, Merleau-Ponty began to develop a much deeper understanding of the complexities of how art is made in his late work in parallel with his advancement of a new ontology. Although his ontology remains unfinished and only exists as working notes and a manuscript entitled The Visible and Invisible, Merleau-Ponty had begun to appreciate the fundamental role drawing plays in the making of art and the creation of a language of expression that is as vital as the written or spoken word. Through an examination of Merleau-Ponty’s unfinished manuscript and working notes my thesis will investigate his working methods and use of materials and also explore how he processed his ideas by using my own art practice as the basis of my research. This research will take the form of an inquiry into how the unfinished and incomplete nature of text and artworks, while they are still ‘works in progress’, can often reveal the more human and carnal components of creative processes. Applying my experience as a practitioner and a teacher in an art school, I focus on the significance of drawing practice for Merleau-Ponty’s later work, in order to rebalance an overemphasis on painting in the literature. Understanding the differences between these two art forms, and how they are taught, can offer an alternative engagement with Merleau-Ponty’s later work and his struggle to find a language to express his developing new ontology. In addition, by re-reading his work through the language of drawing, I believe we gain new insights which reaffirm Merleau-Ponty's relevance to contemporary art making and aesthetics.