Identification of novel innate immune mechanisms regulating inflammation in the gastrointestinal tract

The Gastro-Intestinal (GI) tract is a unique region in the body. Our innate immune system retains a fine homeostatic balance between avoiding inappropriate inflammatory responses against the myriad commensal microbes residing in the gut while also remaining active enough to prevent invasive pathogenic attack. The intestinal epithelium represents the frontline of this interface. It has long been known to act as a physical barrier preventing the lumenal bacteria of the gastro-intestinal tract from activating an inflammatory immune response in the immune cells of the underlying mucosa. However, in recent years, an appreciation has grown surrounding the role played by the intestinal epithelium in regulating innate immune responses, both in the prevention of infection and in maintaining a homeostatic environment through modulation of innate immune signalling systems. The aim of this thesis was to identify novel innate immune mechanisms regulating inflammation in the GI tract. To achieve this aim, we chose several aspects of regulatory mechanisms utilised in this region by the innate immune system. We identified several commensal strains of bacteria expressing proteins containing signalling domains used by Pattern Recognition Receptors (PRRs) of the innate immune system. Three such bacterial proteins were studied for their potentially subversive roles in host innate immune signalling as a means of regulating homeostasis in the GI tract. We also examined differential responses to PRR activation depending on their sub-cellular localisation. This was investigated based on reports that apical Toll-Like Receptor (TLR) 9 activation resulted in abrogation of inflammatory responses mediated by other TLRs in Intestinal Epithelial Cells (IECs) such as basolateral TLR4 activation. Using the well-studied invasive intra-cellular pathogen Listeria monocytogenes as a model for infection, we also used a PRR siRNA library screening technique to identify novel PRRs used by IECs in both inhibition and activation of inflammatory responses. Many of the PRRs identified in this screen were previously believed not to be expressed in IECs. Furthermore, the same study has led to the identification of the previously uncharacterised TLR10 as a functional inflammatory receptor of IECs. Further analysis revealed a similar role in macrophages where it was shown to respond to intracellular and motile pathogens such as Gram-positive L.monocytogenes and Gram negative Salmonella typhimurium. TLR10 expression in IECs was predominantly intracellular. This is likely in order to avoid inappropriate inflammatory activation through the recognition of commensal microbial antigens on the apical cell surface of IECs. Moreover, these results have revealed a more complex network of innate immune signalling mechanisms involved in both activating and inhibiting inflammatory responses in IECs than was previously believed. This contribution to our understanding of innate immune regulation in this region has several direct and indirect benefits. The identification of several novel PRRs involved in activating and inhibiting inflammation in the GI tract may be used as novel therapeutic targets in the treatment of disease; both for inducing tolerance and reducing inflammation, or indeed, as targets for adjuvant activation in the development of oral vaccines against pathogenic attack.

The evolution of the medical professions in eighteenth-century Ireland: An institutional perspective

Ireland, in the eighteenth century, followed the classic tripartite division of regular medical practitioners into physicians, surgeons and apothecaries. At the beginning of the century surgeons and apothecaries were regarded as mere tradesmen, but by the end of the century both were regarded as professionals and had the right to regulate their respective professions. Practitioners in different regions of Europe developed in a different manner, and eighteenth-century practitioners in Ireland developed independently from their English counterparts. In common with Britain and Europe in the eighteenth century, the total number of practitioners increased in Ireland, and by the end of the century, apothecaries were the largest group in Dublin, closely followed by the surgeons. Surgeons and apothecaries at the start of the eighteenth century belonged to the same guild. However in mid-century, St Luke's guild of apothecaries was established and this provided the apothecaries with a new identity that allowed them to pursue auto regulation, rather than hitherto, when they had been regulated by the physicians. This was vital to the apothecaries as they were in direct commercial competition with both the physicians and the surgeons and faced increasing pressure from both druggists and the disparate group of practitioners known as the irregulars. The 1765 County Infirmaries Act established a hospital in virtually every county in Ireland, and cast the surgeon as the primary medical officer in the countrywide network of hospitals. This legislation, which was unique in Europe, had the unintended consequence of elevating the status of the surgeons, as prior to this physicians were always in the ascendancy in the voluntary hospitals in Ireland and Britain, in contrast to France. The status of the surgeons was further enhanced by the establishment of the College of Surgeons in Ireland in 1784, which provided them with a new corporate identity, the authority to regulate the profession countrywide, and, also, the ability to educate surgeons in Ireland. The establishment of the College of Surgeons placed further pressure on the apothecaries to demonstrate that they also had a recognisable identity, and the authority to regulate their own profession. This was achieved with the 1791 Apothecaries Act which established the Apothecaries Hall and give the apothecaries the right to regulate themselves. This innovative legislation deemed the apothecaries a profession, and was enacted twenty-four years prior to similar legislation in Britain. Commercial pressure from druggists and, probably, irregulars expedited the requirement of the apothecaries to establish a new corporate identity, in order to distance themselves from these groups. The changing status of both apothecaries and surgeons had little effect on the physicians as a group, and, despite being the beneficiaries of a generous bequest from Sir Patrick Dun in 1711 to provide medical chairs in Dublin, the physicians displayed an inertia during the eighteenth century that was not in keeping with the developments that occurred in the contemporary Dublin medical world. The fact that it took ninety-five years, and that five acts of parliament, two House of Commons enquiries and a House of Lords enquiry were required to ensure that Dun's wishes were brought to fruition demonstrates that the physicians did not develop at the same pace as the other medical groups in the city. Had Dun’s bequest been implemented as he desired, Dublin, with a number of voluntary hospitals, would have been well placed to provide comprehensive tuition for medical students in the eighteenth century. It was not until the nineteenth century that the city, and the populace, benefited from this legacy. This thesis will trace these developments in the context of changes that occurred in contemporary medical education and diagnosis in Ireland, Britain and France. It will demonstrate that Irish practitioners developed independently, influenced mainly by local issues, but also by those who had travelled abroad and returned to Ireland with new concepts and ideas, ensuring that Irish medical practitioners had the institutional structure that could encompass the diagnostic and regulatory changes that would become accepted in the nineteenth century.

Designing tools that enhance communication and understanding between multiple stakeholders: the case of mobile payment value networks

The pervasive use of mobile technologies has provided new opportunities for organisations to achieve competitive advantage by using a value network of partners to create value for multiple users. The delivery of a mobile payment (m-payment) system is an example of a value network as it requires the collaboration of multiple partners from diverse industries, each bringing their own expertise, motivations and expectations. Consequently, managing partnerships has been identified as a core competence required by organisations to form viable partnerships in an m-payment value network and an important factor in determining the sustainability of an m-payment business model. However, there is evidence that organisations lack this competence which has been witnessed in the m-payment domain where it has been attributed as an influencing factor in a number of failed m-payment initiatives since 2000. In response to this organisational deficiency, this research project leverages the use of design thinking and visualisation tools to enhance communication and understanding between managers who are responsible for managing partnerships within the m-payment domain. By adopting a design science research approach, which is a problem solving paradigm, the research builds and evaluates a visualisation tool in the form of a Partnership Management Canvas. In doing so, this study demonstrates that when organisations encourage their managers to adopt design thinking, as a way to balance their analytical thinking and intuitive thinking, communication and understanding between the partners increases. This can lead to a shared understanding and a shared commitment between the partners. In addition, the research identifies a number of key business model design issues that need to be considered by researchers and practitioners when designing an m-payment business model. As an applied research project, the study makes valuable contributions to the knowledge base and to the practice of management.

Politics, Power, PISA: a genealogy of mathematics education policy at second level in Ireland at the beginning of the 21st century

This thesis traces a genealogy of the discourse of mathematics education reform in Ireland at the beginning of the twenty first century at a time when the hegemonic political discourse is that of neoliberalism. It draws on the work of Michel Foucault to identify the network of power relations involved in the development of a single case of curriculum reform – in this case Project Maths. It identifies the construction of an apparatus within the fields of politics, economics and education, the elements of which include institutions like the OECD and the Government, the bureaucracy, expert groups and special interest groups, the media, the school, the State, state assessment and international assessment. Five major themes in educational reform emerge from the analysis: the arrival of neoliberal governance in Ireland; the triumph of human capital theory as the hegemonic educational philosophy here; the dominant role of OECD/PISA and its values in the mathematics education discourse in Ireland; the fetishisation of western scientific knowledge and knowledge as commodity; and the formation of a new kind of subjectivity, namely the subjectivity of the young person as a form of human-capital-to-be. In particular, it provides a critical analysis of the influence of OECD/PISA on the development of mathematics education policy here – especially on Project Maths curriculum, assessment and pedagogy. It unpacks the arguments in favour of curriculum change and lays bare their ideological foundations. This discourse contextualises educational change as occurring within a rapidly changing economic environment where the concept of the State’s economic aspirations and developments in science, technology and communications are reshaping both the focus of business and the demands being put on education. Within this discourse, education is to be repurposed and its consequences measured against the paradigm of the Knowledge Economy – usually characterised as the inevitable or necessary future of a carefully defined present.

Genetic evaluation of a proposed introduction: the case of the greater prairie chicken and the extinct heath hen.

Population introduction is an important tool for ecosystem restoration. However, before introductions should be conducted, it is important to evaluate the genetic, phenotypic and ecological suitability of possible replacement populations. Careful genetic analysis is particularly important if it is suspected that the extirpated population was unique or genetically divergent. On the island of Martha's Vineyard, Massachusetts, the introduction of greater prairie chickens (Tympanuchus cupido pinnatus) to replace the extinct heath hen (T. cupido cupido) is being considered as part of an ecosystem restoration project. Martha's Vineyard was home to the last remaining heath hen population until its extinction in 1932. We conducted this study to aid in determining the suitability of greater prairie chickens as a possible replacement for the heath hen. We examined mitochondrial control region sequences from extant populations of all prairie grouse species (Tympanuchus) and from museum skin heath hen specimens. Our data suggest that the Martha's Vineyard heath hen population represents a divergent mitochondrial lineage. This result is attributable either to a long period of geographical isolation from other prairie grouse populations or to a population bottleneck resulting from human disturbance. The mtDNA diagnosability of the heath hen contrasts with the network of mtDNA haplotypes of other prairie grouse (T. cupido attwateri, T. pallidicinctus and T. phasianellus), which do not form distinguishable mtDNA groupings. Our findings suggest that the Martha's Vineyard heath hen was more genetically isolated than are current populations of prairie grouse and place the emphasis for future research on examining prairie grouse adaptations to different habitat types to assess ecological exchangeability between heath hens and greater prairie chickens.

Genetic Studies Identify Critical Biomarkers and Refine the Classification of Malignant Gliomas

Gliomagenesis is driven by a complex network of genetic alterations and while the glioma genome has been a focus of investigation for many years; critical gaps in our knowledge of this disease remain. The identification of novel molecular biomarkers remains a focus of the greater cancer community as a method to improve the consistency and accuracy of pathological diagnosis. In addition, novel molecular biomarkers are drastically needed for the identification of targets that may ultimately result in novel therapeutics aimed at improving glioma treatment. Through the identification of new biomarkers, laboratories will focus future studies on the molecular mechanisms that underlie glioma development. Here, we report a series of genomic analyses identifying novel molecular biomarkers in multiple histopathological subtypes of glioma and refine the classification of malignant gliomas. We have completed a large scale analysis of the WHO grade II-III astrocytoma exome and report frequent mutations in the chromatin modifier, alpha thalassemia mental retardation x-linked (ATRX), isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), and mutations in tumor protein 53 (TP53) as the most frequent genetic mutations in low grade astrocytomas. Furthermore, by analyzing the status of recurrently mutated genes in 363 brain tumors, we establish that highly recurrent gene mutational signatures are an effective tool in stratifying homogeneous patient populations into distinct groups with varying outcomes, thereby capable of predicting prognosis. Next, we have established mutations in the promoter of telomerase reverse transcriptase (TERT) as a frequent genetic event in gliomas and in tissues with low rates of self renewal. We identify TERT promoter mutations as the most frequently mutated gene in primary glioblastoma. Additionally, we show that TERT promoter mutations in combination with IDH1 and IDH2 mutations are able to delineate distinct clinical tumor cohorts and are capable of predicting median overall survival more effectively than standard histopathological diagnosis alone. Taken together, these data advance our understanding of the genetic alterations that underlie the transformation of glial cells into neoplasms and we provide novel genetic biomarkers and multi – gene mutational signatures that can be utilized to refine the classification of malignant gliomas and provide opportunity for improved diagnosis.

Evolution of networks and sequences in eukaryotic cell cycle control.

The molecular networks regulating the G1-S transition in budding yeast and mammals are strikingly similar in network structure. However, many of the individual proteins performing similar network roles appear to have unrelated amino acid sequences, suggesting either extremely rapid sequence evolution, or true polyphyly of proteins carrying out identical network roles. A yeast/mammal comparison suggests that network topology, and its associated dynamic properties, rather than regulatory proteins themselves may be the most important elements conserved through evolution. However, recent deep phylogenetic studies show that fungal and animal lineages are relatively closely related in the opisthokont branch of eukaryotes. The presence in plants of cell cycle regulators such as Rb, E2F and cyclins A and D, that appear lost in yeast, suggests cell cycle control in the last common ancestor of the eukaryotes was implemented with this set of regulatory proteins. Forward genetics in non-opisthokonts, such as plants or their green algal relatives, will provide direct information on cell cycle control in these organisms, and may elucidate the potentially more complex cell cycle control network of the last common eukaryotic ancestor.

The role of stimulus salience and attentional capture across the neural hierarchy in a stop-signal task.

Inhibitory motor control is a core function of cognitive control. Evidence from diverse experimental approaches has linked this function to a mostly right-lateralized network of cortical and subcortical areas, wherein a signal from the frontal cortex to the basal ganglia is believed to trigger motor-response cancellation. Recently, however, it has been recognized that in the context of typical motor-control paradigms those processes related to actual response inhibition and those related to the attentional processing of the relevant stimuli are highly interrelated and thus difficult to distinguish. Here, we used fMRI and a modified Stop-signal task to specifically examine the role of perceptual and attentional processes triggered by the different stimuli in such tasks, thus seeking to further distinguish other cognitive processes that may precede or otherwise accompany the implementation of response inhibition. In order to establish which brain areas respond to sensory stimulation differences by rare Stop-stimuli, as well as to the associated attentional capture that these may trigger irrespective of their task-relevance, we compared brain activity evoked by Stop-trials to that evoked by Go-trials in task blocks where Stop-stimuli were to be ignored. In addition, region-of-interest analyses comparing the responses to these task-irrelevant Stop-trials, with those to typical relevant Stop-trials, identified separable activity profiles as a function of the task-relevance of the Stop-signal. While occipital areas were mostly blind to the task-relevance of Stop-stimuli, activity in temporo-parietal areas dissociated between task-irrelevant and task-relevant ones. Activity profiles in frontal areas, in turn, were activated mainly by task-relevant Stop-trials, presumably reflecting a combination of triggered top-down attentional influences and inhibitory motor-control processes.

Simulation of 2-D metal cutting by means of a distributed algorithm

Temperature distributions involved in some metal-cutting or surface-milling processes may be obtained by solving a non-linear inverse problem. A two-level concept on parallelism is introduced to compute such temperature distribution. The primary level is based on a problem-partitioning concept driven by the nature and properties of the non-linear inverse problem. Such partitioning results to a coarse-grained parallel algorithm. A simplified 2-D metal-cutting process is used as an example to illustrate the concept. A secondary level exploitation of further parallel properties based on the concept of domain-data parallelism is explained and implemented using MPI. Some experiments were performed on a network of loosely coupled machines consist of SUN Sparc Classic workstations and a network of tightly coupled processors, namely the Origin 2000.

The centrality of groups and classes

This paper extends the standard network centrality measures of degree, closeness and betweenness to apply to groups and classes as well as individuals. The group centrality measures will enable researchers to answer such questions as ‘how central is the engineering department in the informal influence network of this company?’ or ‘among middle managers in a given organization, which are more central, the men or the women?’ With these measures we can also solve the inverse problem: given the network of ties among organization members, how can we form a team that is maximally central? The measures are illustrated using two classic network data sets. We also formalize a measure of group centrality efficiency, which indicates the extent to which a group's centrality is principally due to a small subset of its members.

Performance evaluation of a distributed algorithm for an inverse heat conduction problem

Numerical solutions of realistic 2-D and 3-D inverse problems may require a very large amount of computation. A two-level concept on parallelism is often used to solve such problems. The primary level uses the problem partitioning concept which is a decomposition based on the mathematical/physical problem. The secondary level utilizes the widely used data partitioning concept. A theoretical performance model is built based on the two-level parallelism. The observed performance results obtained from a network of general purpose Sun Sparc stations are compared with the theoretical values. Restrictions of the theoretical model are also discussed.

The development of parallel implementation for a CFD based fire field model utilising conventional office based PCs

Parallel processing techniques have been used in the past to provide high performance computing resources for activities such as fire-field modelling. This has traditionally been achieved using specialized hardware and software, the expense of which would be difficult to justify for many fire engineering practices. In this article we demonstrate how typical office-based PCs attached to a Local Area Network has the potential to offer the benefits of parallel processing with minimal costs associated with the purchase of additional hardware or software. It was found that good speedups could be achieved on homogeneous networks of PCs, for example a problem composed of ~100,000 cells would run 9.3 times faster on a network of 12 800MHz PCs than on a single 800MHz PC. It was also found that a network of eight 3.2GHz Pentium 4 PCs would run 7.04 times faster than a single 3.2GHz Pentium computer. A dynamic load balancing scheme was also devised to allow the effective use of the software on heterogeneous PC networks. This scheme also ensured that the impact between the parallel processing task and other computer users on the network was minimized.

Emergent self-organisation of wireless sensor networks

This paper describes a protocol for dynamically configuring wireless sensor nodes into logical clusters. The concept is to be able to inject an overlay configuration into an ad-hoc network of sensor nodes or similar devices, and have the network configure itself organically. The devices are arbitrarily deployed and have initially have no information whatsoever concerning physical location, topology, density or neighbourhood. The Emergent Cluster Overlay (ECO) protocol is totally self-configuring and has several novel features, including nodes self-determining their mobility based on patterns of neighbour discovery, and that the target cluster size is specified externally (by the sensor network application) and is not directly coupled to radio communication range or node packing density. Cluster head nodes are automatically assigned as part of the cluster configuration process, at no additional cost. ECO is ideally suited to applications of wireless sensor networks in which localized groups of sensors act cooperatively to provide a service. This includes situations where service dilution is used (dynamically identifying redundant nodes to conserve their resources).

Journal citation among heterodox economists 1995-2007: Dynamics of community emergence

Purpose – This study aims to investigate the pattern among 17 heterodox economic journals over a prolonged period to provide evidence about the social dynamics among the group of researchers who publish in them and the extent to which they hold or develop a collective identity as heterodox economists. Design/methodology/approach – Traditional approaches to citation analysis are extended by the use of techniques from social network analysis. In addition to citation counts, measures of network position and clique membership are used to identify key journals and turning points in a longitudinal analysis. Findings – Important shifts in the nature of citation within the network of journals are identified in the 1998-2001 period and evidence is found of the emergence of a collective identity. Research limitations/implications – The methods prove a valuable extension of citation analysis and also focus greater consideration on the social relationships that citations represent. They are well suited to addressing the principal limitation of the study, its restriction to journals within the defined community rather than journals in general. Originality/value – This extends traditional approaches to citation analysis, provides an important new technique in identifying emergent collective identities and provides insight into the history and nature of the heterodox economic community.

An overview of Calanus helgolandicus ecology in European waters

We review current knowledge and understanding of the biology and ecology of the calanoid copepod Calanus helgolandicus in European waters, as well as provide a collaborative synthesis of data from 18 laboratories and 26 sampling stations in areas distributed from the northern North Sea to the Aegean and Levantine Seas. This network of zooplankton time-series stations has enabled us to collect and synthesise seasonal and multi-annual data on abundance, body size, fecundity, hatching success and vertical distribution of C. helgolandicus. An aim was to enable comparison with its congener Calanus finmarchicus, which has been studied intensively as a key component of European and north east Atlantic marine ecosystems. C. finmarchicus is known to over-winter at depth, whereas the life-cycle of C. helgolandicus is less well understood. Overwintering populations of C. helgolandicus have been observed off the Atlantic coast between 400 and 800 m, while in the Mediterranean there is evidence of significant deep-water populations at depths as great as 4200 m. The biogeographical distribution of C. helgolandicus in European coastal waters covers a wide range of habitats, from open ocean to coastal environments, and its contribution to mesozooplankton biomass ranges from 6% to 93%. Highest abundances were recorded in the Adriatic and off the west coast of Spain. C. helgolandicus is generally found in 9-20 C water, with maximum abundances from 13-17 C. In contrast, C. finmarchicus is found in cooler water between 0 and 15 C, with peak abundances from 0 to 9 C. As water has warmed in the North Atlantic over recent decades, the range of C. helgolandicus and its abundance on the fringes of its expanding range have increased. This review will facilitate development of population models of C. helgolandicus. This will not only help answer remaining questions but will improve our ability to forecast future changes, in response to a warming climate, in the abundance and distribution of this important species.