Design and evaluation of novel microencapsulation technologies to enhance delivery of Ciclosporin

Drug delivery systems influence the various processes of release, absorption, distribution and elimination of drug. Conventional delivery methods administer drug through the mouth, the skin, transmucosal areas, inhalation or injection. However, one of the current challenges is the lack of effective and targeted oral drug administration. Development of sophisticated strategies, such as micro- and nanotechnology that can integrate the design and synthesis of drug delivery systems in a one-step, scalable process is fundamental in advancing the limitations of conventional processing techniques. Thus, the objective of this thesis is to evaluate novel microencapsulation technologies in the production of size-specific and target-specific drug-loaded particles. The first part of this thesis describes the utility of PDMS and silicon microfluidic flow focusing devices (MFFDs) to produce PLGA-based microparticles. The formation of uniform droplets was dependent on the surface of PDMS remaining hydrophilic. However, the durability of PDMS was limited to no more than 1 hour before wetting of the microchannel walls with dichloromethane and subsequent swelling occurred. Critically, silicon MFFDs revealed very good solvent compatibility and was sufficiently robust to withstand elevated fluid flow rates. Silicon MFFDs facilitated experiments to run over days with continuous use and re-use of the device with a narrower microparticle size distribution, relative to conventional production techniques. The second part of this thesis demonstrates an alternative microencapsulation technology, SmPill® minispheres, to target CsA delivery to the colon. Characterisation of CsA release in vitro and in vivo was performed. By modulating the ethylcellulose:pectin coating thickness, release of CsA in-vivo was more effectively controlled compared to current commercial CsA formulations and demonstrated a linear in-vitro in-vivo relationship. Coated minispheres were shown to limit CsA release in the upper small intestine and enhance localised CsA delivery to the colon.

The cloud personal assistant for providing services to mobile clients

This paper introduces the original concept of a cloud personal assistant, a cloud service that manages the access of mobile clients to cloud services. The cloud personal assistant works in the cloud on behalf of its owner: it discovers services, invokes them, stores the results and history, and delivers the results to the mobile user immediately or when the user requests them. Preliminary experimental results that demonstrate the concept are included.

Ironworking in late medieval Ireland, c. AD. 1200 to 1600

The landscape of late medieval Ireland, like most places in Europe, was characterized by intensified agricultural exploitation, the growth and founding of towns and cities and the construction of large stone edifices, such as castles and monasteries. None of these could have taken place without iron. Axes were needed for clearing woodland, ploughs for turning the soil, saws for wooden buildings and hammers and chisels for the stone ones, all of which could not realistically have been made from any other material. The many battles, waged with ever increasingly sophisticated weaponry, needed a steady supply of iron and steel. During the same period, the European iron industry itself underwent its most fundamental transformation since its inception; at the beginning of the period it was almost exclusively based on small furnaces producing solid blooms and by the turn of the seventeenth century it was largely based on liquid-iron production in blast-furnaces the size of a house. One of the great advantages of studying the archaeology of ironworking is that its main residue, slag, is often produced in copious amounts both during smelting and smithing, is virtually indestructible and has very little secondary use. This means that most sites where ironworking was carried out are readily recognizable as such by the occurrence of this slag. Moreover, visual examination can distinguish between various types of slag, which are often characteristic for the activity from which they derive. The ubiquity of ironworking in the period under study further means that we have large amounts of residues available for study, allowing us to distinguish patterns both inside assemblages and between sites. Disadvantages of the nature of the remains related to ironworking include the poor preservation of the installations used, especially the furnaces, which were often built out of clay and located above ground. Added to this are the many parameters contributing to the formation of the above-mentioned slag, making its composition difficult to connect to a certain technology or activity. Ironworking technology in late medieval Ireland has thus far not been studied in detail. Much of the archaeological literature on the subject is still tainted by the erroneous attribution of the main type of slag, bun-shaped cakes, to smelting activities. The large-scale infrastructure works of the first decade of the twenty-first century have led to an exponential increase in the amount of sites available for study. At the same time, much of the material related to metalworking recovered during these boom-years was subjected to specialist analysis. This has led to a near-complete overhaul of our knowledge of early ironworking in Ireland. Although many of these new insights are quickly seeping into the general literature, no concise overviews on the current understanding of the early Irish ironworking technology have been published to date. The above then presented a unique opportunity to apply these new insights to the extensive body of archaeological data we now possess. The resulting archaeological information was supplemented with, and compared to, that contained in the historical sources relating to Ireland for the same period. This added insights into aspects of the industry often difficult to grasp solely through the archaeological sources, such as the people involved and the trade in iron. Additionally, overviews on several other topics, such as a new distribution map of Irish iron ores and a first analysis of the information on iron smelting and smithing in late medieval western Europe, were compiled to allow this new knowledge on late medieval Irish ironworking to be put into a wider context. Contrary to current views, it appears that it is not smelting technology which differentiates Irish ironworking from the rest of Europe in the late medieval period, but its smithing technology and organisation. The Irish iron-smelting furnaces are generally of the slag-tapping variety, like their other European counterparts. Smithing, on the other hand, is carried out at ground-level until at least the sixteenth century in Ireland, whereas waist-level hearths become the norm further afield from the fourteenth century onwards. Ceramic tuyeres continue to be used as bellows protectors, whereas these are unknown elsewhere on the continent. Moreover, the lack of market centres at different times in late medieval Ireland, led to the appearance of isolated rural forges, a type of site unencountered in other European countries during that period. When these market centres are present, they appear to be the settings where bloom smithing is carried out. In summary, the research below not only offered us the opportunity to give late medieval ironworking the place it deserves in the broader knowledge of Ireland's past, but it also provided both a base for future research within the discipline, as well as a research model applicable to different time periods, geographical areas and, perhaps, different industries..

Human intestinal microbiota and metabolites they produce in relation to host health

The aim of this thesis was to identify selected potential probiotic characteristics of Bifidobacterium longum strains isolated from human sources, and to examine these characteristics in detail using genomic and phenotypic techniques. One strain in particular Bifidobacterium longum DPC 6315 was the main focus of the thesis and this strain was used in both the manufacture of yoghurt and an animal study. In total, 38 B. longum strains, obtained from infants and adults, were assessed in vitro for the selected probiotic traits using a combined phenotypic and molecular approach. Differentiation of the 38 strains using amplified ribosomal DNA restriction analysis (ARDRA) into subspecies indicated that of the 38 bifidobacterial strains tested, 34 were designated B. longum subsp. longum and four B. longum subsp. infantis.

High speed optical communication systems: From modulation formats to radically new fibres

High volumes of data traffic along with bandwidth hungry applications, such as cloud computing and video on demand, is driving the core optical communication links closer and closer to their maximum capacity. The research community has clearly identifying the coming approach of the nonlinear Shannon limit for standard single mode fibre [1,2]. It is in this context that the work on modulation formats, contained in Chapter 3 of this thesis, was undertaken. The work investigates the proposed energy-efficient four-dimensional modulation formats. The work begins by studying a new visualisation technique for four dimensional modulation formats, akin to constellation diagrams. The work then carries out one of the first implementations of one such modulation format, polarisation-switched quadrature phase-shift keying (PS-QPSK). This thesis also studies two potential next-generation fibres, few-mode and hollow-core photonic band-gap fibre. Chapter 4 studies ways to experimentally quantify the nonlinearities in few-mode fibre and assess the potential benefits and limitations of such fibres. It carries out detailed experiments to measure the effects of stimulated Brillouin scattering, self-phase modulation and four-wave mixing and compares the results to numerical models, along with capacity limit calculations. Chapter 5 investigates hollow-core photonic band-gap fibre, where such fibres are predicted to have a low-loss minima at a wavelength of 2μm. To benefit from this potential low loss window requires the development of telecoms grade subsystems and components. The chapter will outline some of the development and characterisation of these components. The world's first wavelength division multiplexed (WDM) subsystem directly implemented at 2μm is presented along with WDM transmission over hollow-core photonic band-gap fibre at 2μm. References: [1]P. P. Mitra, J. B. Stark, Nature, 411, 1027-1030, 2001 [2] A. D. Ellis et al., JLT, 28, 423-433, 2010.

The use of fault detection and diagnostics to reduce air handling unit energy consumption

The contribution of buildings towards total worldwide energy consumption in developed countries is between 20% and 40%. Heating Ventilation and Air Conditioning (HVAC), and more specifically Air Handling Units (AHUs) energy consumption accounts on average for 40% of a typical medical device manufacturing or pharmaceutical facility’s energy consumption. Studies have indicated that 20 – 30% energy savings are achievable by recommissioning HVAC systems, and more specifically AHU operations, to rectify faulty operation. Automated Fault Detection and Diagnosis (AFDD) is a process concerned with potentially partially or fully automating the commissioning process through the detection of faults. An expert system is a knowledge-based system, which employs Artificial Intelligence (AI) methods to replicate the knowledge of a human subject matter expert, in a particular field, such as engineering, medicine, finance and marketing, to name a few. This thesis details the research and development work undertaken in the development and testing of a new AFDD expert system for AHUs which can be installed in minimal set up time on a large cross section of AHU types in a building management system vendor neutral manner. Both simulated and extensive field testing was undertaken against a widely available and industry known expert set of rules known as the Air Handling Unit Performance Assessment Rules (APAR) (and a later more developed version known as APAR_extended) in order to prove its effectiveness. Specifically, in tests against a dataset of 52 simulated faults, this new AFDD expert system identified all 52 derived issues whereas the APAR ruleset identified just 10. In tests using actual field data from 5 operating AHUs in 4 manufacturing facilities, the newly developed AFDD expert system for AHUs was shown to identify four individual fault case categories that the APAR method did not, as well as showing improvements made in the area of fault diagnosis.

Human interfaces to structured documents

This research investigates some of the reasons for the reported difficulties experienced by writers when using editing software designed for structured documents. The overall objective was to determine if there are aspects of the software interfaces which militate against optimal document construction by writers who are not computer experts, and to suggest possible remedies. Studies were undertaken to explore the nature and extent of the difficulties, and to identify which components of the software interfaces are involved. A model of a revised user interface was tested, and some possible adaptations to the interface are proposed which may help overcome the difficulties. The methodology comprised: 1. identification and description of the nature of a ‘structured document’ and what distinguishes it from other types of document used on computers; 2. isolation of the requirements of users of such documents, and the construction a set of personas which describe them; 3. evaluation of other work on the interaction between humans and computers, specifically in software for creating and editing structured documents; 4. estimation of the levels of adoption of the available software for editing structured documents and the reactions of existing users to it, with specific reference to difficulties encountered in using it; 5. examination of the software and identification of any mismatches between the expectations of users and the facilities provided by the software; 6. assessment of any physical or psychological factors in the reported difficulties experienced, and to determine what (if any) changes to the software might affect these. The conclusions are that seven of the twelve modifications tested could contribute to an improvement in usability, effectiveness, and efficiency when writing structured text (new document selection; adding new sections and new lists; identifying key information typographically; the creation of cross-references and bibliographic references; and the inclusion of parts of other documents). The remaining five were seen as more applicable to editing existing material than authoring new text (adding new elements; splitting and joining elements [before and after]; and moving block text).

Access to modified geiparvarins using Pd(0)-mediated C-C bond forming reactions

Geiparvarin is a natural product which contains both a 3(2H)-furanone and a coumarin moiety in its structure. The aim of this project was to investigate the use of Pd(0)-mediated C–C bondforming reactions to produce structurally modified geiparvarins. Chapter 1 consists of a review of the relevant literature, including that pertaining to the syntheses of selected naturally occurring 3(2H)-furanones. The known syntheses of geiparvarin and closely related analogues are examined, along with the documented biological activity of these compounds. The synthetic routes which allow access to 4-substituted-3(2H)-furanones are also described. Chapter 2 describes in detail the synthesis of a variety of novel structurally modified geiparvarins by two complementary routes, both approaches utilising Pd(0)-mediated crosscoupling reactions, and discusses the characterisation of these compounds. The preparation of 5-ethyl-3(2H)-furanones is described, as is their incorporation into geiparvarin and the corresponding 5″-alkylgeiparvarin analogues via formation and dehydration of intermediate alcohols. Halogenation of 5-ethyl-3(2H)-furanones and the corresponding geiparvarin derivatives is discussed, along with further reactions of the resulting halides. Preparation of 3″-arylgeiparvarins involving both Suzuki–Miyura and Stille reactions, using the appropriate intermediate iodides and bromides, is described. The application of Stille and Heck conditions to give 3″-ethenylgeiparvarin analogues and Sonogashira conditions to produce 3″-ethynylgeiparvarin analogues, using the relevant intermediate iodides, is also extensively outlined. Chapter 3 contains all of the experimental data and details of the synthetic methods employed for the compounds prepared during the course of this research. All novel compounds prepared were fully characterised using NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; the details of which are included.

Formatting information: A beginner's introduction to typesetting with LATEX

This book originally accompanied a 2-day course on using the LATEX typesetting system. It has been extensively revised and updated and can now be used or self-study or in the classroom. It is aimed at users of Linux, Macintosh, or Microsoft Windows but it can be used with LATEX systems on any platform, including other Unix workstations, mainframes, and even your Personal Digital Assistant (PDA).

Multi-party actions as a route to collective redress for mass arm, having particular regard to environmental mass harm

Accepted Version

A cultural study on communication and technology with specific reference to media in China

This dissertation examines the role of communications technology in social change. It examines secondary data on contemporary China arguing that many interpretations of events in China are unsuitable at best and at worst conceptually damages our understanding of social change in China. This is especially the case in media studies under the ‘democratic framework’. It proposes that there is an alternative framework in studying the media and social change. This alternative conceptual framework is termed a zone of interpretative development offering a means by which to discuss events that take place in a mediated environment. Taking a theoretical foundation using the philosophy of Mikhail Bakhtin this dissertation develops a platform with which to understand communication technology from an anthropological perspective. Three media events from contemporary China are examined. The first examines the Democracy Wall event and the implications of using a public sphere framework. The second case examines the phenomenon of the Grass Mud Horse, a symbol that has gained popular purchase as a humorous expression of political dissatisfaction and develops the problems seen in the first case but with some solutions. Using a modification of Lev Vygotskiĭ’s zone of proximal development this symbol is understood as an expression of the collective recognition of a shared experience. In the second example from the popular TV talent show contests in China further expressions of collective experience are introduced. With the evidence from these media events in contemporary China this dissertation proposes that we can understand certain modes of communication as occurring in a zone of interpretative development. This proposed anthropological feature of social change via communication and technology can fruitfully describe meaning-formation in society via the expression and recognition of shared experiences.

Hearing family carers: ‘Going from bad to worse’

This report provides an update to research conducted in 2008 on the experiences and access to supports available to family carers in Cork and published as Hearing Family Carers (O’Riordan, O’hAdhmaill and Duggan 2010). It includes additional research carried out in 2013 with some of the original participants who partook in the earlier research. Given the more recent changes in supports in the context of austerity measures it was considered necessary to consult carers again with reference to their more current experiences, supports and the challenges they face in their informal caring roles.

The contribution of warlordism to the disintegration of the western Roman army (c. AD 395-480)

My thesis investigates the dynamics behind the changing nature of the leadership of the western Roman army in the fifth century through the concept of ‘warlordism’. I carried this out by analyzing those cases of insubordination and military unrest in the officer class of the western Roman army, which can be shown to be linked to the slow decline of central authority and the imperial office in the period 395-480. My thesis demonstrates that theories of ‘Warlordism’, as developed in social sciences, can be useful for both the late Imperial west as for other eras of ancient history, such as the late Roman republic. Warlordism was a way of continuing politics, if necessary by military means, when commanders found themselves outside the legitimate framework. Unlike the case of usurpation of the imperial office, when there was little hope of achieving permanent recognition and acceptance, it offered insubordinate officers a chance of returning to the ruling imperial regime depending on circumstances and the success of their resistance. I propose that warlordism functioned as an alternative to usurpation, a tool for military dissidence, fuelled by an economy of violence. Contrary to modern warlordism, the warlordism of the fifth century AD represented a transient phase which no imperial commander was willing to prolong indefinitely. At some stage, given the means, warlords in the western Roman army wanted to become part of the imperial echelon again. Yet these alternative methods of violent opposition, and the acquisition of force through private means, ensured the breakdown of the state’s monopoly on violence and the disintegration of centralized armies. What started as an accidental revolution became a new form of military rule.

The application of computer modelling to develop a methodology for ‘existing building’ upgrades to move towards carbon-neutral buildings

The retrofitting of existing buildings for decreased energy usage, through increased energy efficiency and for minimum carbon dioxide emissions throughout their remaining lifetime is a major area of research. This research area requires development to provide building professionals with more efficient building retrofit solution determination tools. The overarching objective of this research is to develop a tool for this purpose through the implementation of a prescribed methodology. This has been achieved in three distinct steps. Firstly, the concept of using the degree-days modelling method as an adequate means of basing retrofit decision upon was analysed and the results illustrated that the concept had merit. Secondly, the concept of combining the degree-days modelling method and the Genetic Algorithms optimisation method is investigated as a method of determining optimal thermal energy retrofit solutions. Thirdly, the combination of the degree-days modelling method and the Genetic Algorithms optimisation method were packaged into a building retrofit decision-support tool and named BRaSS (Building Retrofit Support Software). The results demonstrate clearly that, fundamental building information, simplified occupancy profiles and weather data used in a static simulation modelling method is a sufficient and adequate means to base retrofitting decisions upon. The results also show that basing retrofit decisions upon energy analysis results are the best means to guide a retrofit project and also to achieve results which are optimum for a particular building. The results also indicate that the building retrofit decision-support tool, BRaSS, is an effective method to determine optimum thermal energy retrofit solutions.

Redox remodelling in diaphragm muscle adaptation to chronic sustained hypoxia

Chronic sustained hypoxia (CH) induces functional weakness, atrophy, and mitochondrial remodelling in the diaphragm muscle. Animal models of CH present with changes similar to patients with respiratory-related disease, thus, elucidating the molecular mechanisms driving these adaptations is clinically important. We hypothesize that ROS are pivotal in diaphragm muscle adaptation to CH. C57BL6/J mice were exposed to CH (FiO2=0.1) for one, three, and six weeks. Sternohyoid (upper airway dilator), extensor digitorum longus (EDL), and soleus were studied as reference muscles as well as the diaphragm. The diaphragm was profiled using a redox proteomics approach followed by mass spectrometry. Following this, redox-modified metabolic enzyme activities and atrophy signalling were assessed using spectrophotometric assays and ELISA. Diaphragm isotonic performance was assessed after six weeks of CH ± chronic antioxidant supplementation. Protein carbonyl and free thiol content in the diaphragm were increased and decreased respectively after six weeks of CH – indicative of protein oxidation. These changes were temporally modulated and muscle specific. Extensive remodelling of metabolic proteins occurred and the stress reached the cross-bridge. Metabolic enzyme activities in the diaphragm were, for the most part, decreased by CH and differential muscle responses were observed. Redox sensitive chymotrypsin-like proteasome activity of the diaphragm was increased and atrophy signalling was observed through decreased phospho-FOXO3a and phospho-mTOR. Phospho-p38 MAPK content was increased and this was attenuated by antioxidant treatment. Hypoxia decreased power generating capacity of the diaphragm and this was restored by N-acetyl-cysteine (NAC) but not by tempol. Redox remodelling is pivotal for diaphragm adaptation to chronic sustained hypoxia. Muscle changes are dependent on duration of the hypoxia stimulus, activity profile of the muscle, and molecular composition of the muscle. The working respiratory muscles and slow oxidative fibres are particularly susceptible. NAC (antioxidant) may be useful as an adjunct therapy in respiratory-related diseases characterised by hypoxic stress.