Characterisation of the role of canonical BMP-Smad 1/5/8 signalling in the development of ventral midbrain dopaminergic neurons

Ventral midbrain (VM) dopaminergic (DA) neurons, which project to the dorsal striatum via the nigrostriatal pathway, are progressively degenerated in Parkinson’s disease (PD). The identification of the instructive factors that regulate midbrain DA neuron development, and the subsequent elucidation of the molecular bases of their effects, is vital. Such an understanding would facilitate the generation of transplantable DA neurons from stem cells and the identification of developmentally-relevant neurotrophic factors, the two most promising therapeutic approaches for PD. Two related members of the bone morphogenetic protein (BMP) family, BMP2 and growth/differentiation factor (GDF) 5, which signal via a canonical Smad 1/5/8 signalling pathway, have been shown to have neurotrophic effects on midbrain DA neurons both in vitro and in vivo, and may function to regulate VM DA neuronal development. However, the molecular (signalling pathway(s)) and cellular (direct neuronal or indirect via glial cells) mechanisms of their effects remain to be elucidated. The present thesis hypothesised that canonical Smad signalling mediates the direct effects of BMP2 and GDF5 on the development of VM DA neurons. By activating, modulating and/or inhibiting various components of the BMP-Smad signalling pathway, this research demonstrated that GDF5- and BMP2-induced neurite outgrowth from midbrain DA neurons is dependent on BMP type I receptor activation of the Smad signalling pathway. The role of glial cell-line derived neurotrophic factor (GDNF)-signalling, dynamin-dependent endocytosis and Smad interacting protein-1 (Sip1) regulation, in the neurotrophic effects of BMP2 and GDF5 were determined. Finally, the in vitro development of VM neural stem cells (NSCs) was characterised, and the ability of GDF5 and BMP2 to induce these VM NSCs towards DA neuronal differentiation was investigated. Taken together, these experiments identify GDF5 and BMP2 as novel regulators of midbrain DA neuronal induction and differentiation, and demonstrate that their effects on DA neurons are mediated by canonical BMPR-Smad signalling.

Action design research: a comparison with canonical action research and design science

This research in progress paper addresses the IS issue in relation to conducting relevant research while keeping academic rigor. In particular, it contributes to the ongoing academic conversation around the investigation on how to incor-porate action in design science research. In this document the philosophical underpinnings of the recently proposed methodology called Action Design Re-search [1] are derived, outlined and integrated into Burrel and Morgan’s Par-adigmatic Framework (1979)[6]. The results so far show how Action Design Research can be considered as a particular case of Design Science Research (rather than a methodology closely related to Action Research) although they can assume two different epistemological positions. From these philosophical perspectives, future works will involve the inclusion of actual research projects using the three different methodologies. The final goal is to outline and structure the divergences and similarities of Action Design Research with Design Science Research and Canonical Action Research.

Claude McKay and the transnational novel

This thesis considers the three works of fiction of the Jamaican author Claude McKay (1889-1948) as a coherent transnational trilogy which dramatises the semi-autobiographical complexities of diasporic exile and return in the period of the 1920s and 1930s. Chapter One explores McKay’s urban North American novel, Home to Harlem (1928). I suggest that we need to ‘reworld’ conceptions of McKay’s writing in order to release him from his canonical confinement in the Harlem Renaissance. Querying the problematics of the city space, of sexuality and of race as they emerge in the novel, this chapter considers McKay’s percipient understanding of the need to reconfigure diasporic identity beyond the limits set by American nationalism. Chapter Two engages with McKay’s novel of portside Marseilles, Banjo (1929), and considers the homosocial interactions of the vagabond collective. A comparison of North America and France as supposed exemplars of individual liberty highlights the unsuitability of nationalistic prerogatives to an internally diverse black diaspora. Paul Gilroy’s Black Atlantic construct provides a suggestive space in which to re-imagine the possibilities of affiliation in the port. The latter section of the chapter examines McKay’s particular influence on, and relationship, to the Négritude movement and Pan-African philosophies. Chapter Three focuses on McKay’s third novel, Banana Bottom (1933). I suggest here that the three novels comprise a coherent New World Trilogy comparable to Edward (Kamau) Brathwaite’s trilogy, The Arrivants. This chapter considers both the Caribbean and the transnational dimensions to McKay’s work.

Hardware design of cryptographic accelerators

With the rapid growth of the Internet and digital communications, the volume of sensitive electronic transactions being transferred and stored over and on insecure media has increased dramatically in recent years. The growing demand for cryptographic systems to secure this data, across a multitude of platforms, ranging from large servers to small mobile devices and smart cards, has necessitated research into low cost, flexible and secure solutions. As constraints on architectures such as area, speed and power become key factors in choosing a cryptosystem, methods for speeding up the development and evaluation process are necessary. This thesis investigates flexible hardware architectures for the main components of a cryptographic system. Dedicated hardware accelerators can provide significant performance improvements when compared to implementations on general purpose processors. Each of the designs proposed are analysed in terms of speed, area, power, energy and efficiency. Field Programmable Gate Arrays (FPGAs) are chosen as the development platform due to their fast development time and reconfigurable nature. Firstly, a reconfigurable architecture for performing elliptic curve point scalar multiplication on an FPGA is presented. Elliptic curve cryptography is one such method to secure data, offering similar security levels to traditional systems, such as RSA, but with smaller key sizes, translating into lower memory and bandwidth requirements. The architecture is implemented using different underlying algorithms and coordinates for dedicated Double-and-Add algorithms, twisted Edwards algorithms and SPA secure algorithms, and its power consumption and energy on an FPGA measured. Hardware implementation results for these new algorithms are compared against their software counterparts and the best choices for minimum area-time and area-energy circuits are then identified and examined for larger key and field sizes. Secondly, implementation methods for another component of a cryptographic system, namely hash functions, developed in the recently concluded SHA-3 hash competition are presented. Various designs from the three rounds of the NIST run competition are implemented on FPGA along with an interface to allow fair comparison of the different hash functions when operating in a standardised and constrained environment. Different methods of implementation for the designs and their subsequent performance is examined in terms of throughput, area and energy costs using various constraint metrics. Comparing many different implementation methods and algorithms is nontrivial. Another aim of this thesis is the development of generic interfaces used both to reduce implementation and test time and also to enable fair baseline comparisons of different algorithms when operating in a standardised and constrained environment. Finally, a hardware-software co-design cryptographic architecture is presented. This architecture is capable of supporting multiple types of cryptographic algorithms and is described through an application for performing public key cryptography, namely the Elliptic Curve Digital Signature Algorithm (ECDSA). This architecture makes use of the elliptic curve architecture and the hash functions described previously. These components, along with a random number generator, provide hardware acceleration for a Microblaze based cryptographic system. The trade-off in terms of performance for flexibility is discussed using dedicated software, and hardware-software co-design implementations of the elliptic curve point scalar multiplication block. Results are then presented in terms of the overall cryptographic system.

Who pays and who plays? Mapping the discourse of publicly funded instrumental music education in Ireland

Instrumental music education is provided as an extra-curricular activity on a fee-paying basis by a small number of Education and Training Boards, formerly Vocational Education Committees (ETB/VECs) through specialist instrumental Music Services. Although all citizens’ taxes fund the public music provision, participation in instrumental music during school-going years is predominantly accessed by middle class families. A series of semistructured interviews sought to access the perceptions and beliefs of instrumental music education practitioners (N=14) in seven publicly-funded music services in Ireland. Canonical dispositions were interrogated and emergent themes were coded and analysed in a process of Grounded theory. The study draws on Foucault’s conception of discourse as a lens with which to map professional practices, and utilises Bourdieu’s analysis of the reproduction of social advantage to examine cultural assumptions, which may serve to privilege middle-class cultural choice to the exclusion of other social groups. Study findings show that within the Music Services, aesthetic and pedagogic discourses of the 19th century Conservatory system exert a hegemonic influence over policy and practice. An enduring ‘examination culture’ located within the Western art music tradition determines pedagogy, musical genre, and assessment procedures. Ideologies of musical taste and value reinforce the more tangible boundaries of fee-payment and restricted availability as barriers to access. Practitioners are aware of a status duality whereby instrumental teachers working as visiting specialists in primary schools experience a conflict between specialist and generalist educational aims. Nevertheless, study participants consistently advocated siting the point of access to instrumental music education in the primary schools as the most equitable means of access to instrumental music education. This study addresses a ‘knowledge gap’ in the sociology of music education in Ireland. It provides a framework for rethinking instrumental music education as equitable in-school musical participation. The conclusions of the study suggest starting-points for further educational research and may provide key ‘prompts’ for curriculum planning.