Dutch influence in the urban landscape of Cork City pre-1800: Fact or myth?

The early years of the eighteenth century Irish port town, Cork saw an expansion of its city limits, an era of reconstruction both within and beyond the walls of its Medieval townscape and a reclamation of its marshlands to the east and west. New people, new ideas and the beginnings of new wealth infused the post Elizabethan character of the recently siege battered city. It also brought a desire for something different, something new, an opportunity to redefine the ambience and visual perception of the urban landscape and thereby make a statement about its intended cultural and social orientations. It brought an opportunity to re-imagine and model a new, continental style of place and surrounding environment.

The Irish credit union movement: member participation and organisational effectiveness

This thesis explores the relationship between organisational effectiveness and member participation in Irish credit unions. It is hypothesised that a positive relationship exists between both variables. Co-operative literature suggests that co-operatives require the involvement of the members in identifying and meeting their own needs in order to be effective organisations. Previous research studies into the issue across a variety of organisational types have shown mixed results. Related research into credit unions is sparse. The primary research undertaken is both quantitative and qualitative in approach. Organisational effectiveness is examined in both quantitative and qualitative terms. Member participation, being an organisational process, is examined in qualitative terms. Indicators of organisational effectiveness, specific to credit unions, are drawn up and form a framework through which effectiveness is examined. A typology and indicators of member participation are also developed and form a framework through which member participation is examined. The case study method is used primarily, to examine organisational effectiveness and member participation in Irish credit unions. A case study of a theoretical credit union, which is based on a composite of good practice in credit unions in Ireland and internationally, is also drawn up to develop the analysis further. The case studies allow an analysis of both organisational effectiveness and member participation, as well as an exploration of the relationship between the two. The findings support the hypothesis that there is a direct relationship between the two variables. In order to be effective, credit unions must involve their members in identifying their needs and in designing services to meet these needs. At present, they do not do this to any large extent. In order to continue to meet the needs of their members and to compete in the financial services sector, credit unions will need to find ways of involving members, drawing on good practice in other co-operatives. This will be critical to their continued success.

Phase estimation receiver for full-field detection: a novel receiver structure for electronic dispersion compensation of metropolitan area networks

The development of ultra high speed (~20 Gsamples/s) analogue to digital converters (ADCs), and the delayed deployment of 40 Gbit/s transmission due to the economic downturn, has stimulated the investigation of digital signal processing (DSP) techniques for compensation of optical transmission impairments. In the future, DSP will offer an entire suite of tools to compensate for optical impairments and facilitate the use of advanced modulation formats. Chromatic dispersion is a very significant impairment for high speed optical transmission. This thesis investigates a novel electronic method of dispersion compensation which allows for cost-effective accurate detection of the amplitude and phase of the optical field into the radio frequency domain. The first electronic dispersion compensation (EDC) schemes accessed only the amplitude information using square law detection and achieved an increase in transmission distances. This thesis presents a method by using a frequency sensitive filter to estimate the phase of the received optical field and, in conjunction with the amplitude information, the entire field can be digitised using ADCs. This allows DSP technologies to take the next step in optical communications without requiring complex coherent detection. This is of particular of interest in metropolitan area networks. The full-field receiver investigated requires only an additional asymmetrical Mach-Zehnder interferometer and balanced photodiode to achieve a 50% increase in EDC reach compared to amplitude only detection.

Understanding teacher collaboration in disadvantaged urban primary schools: uncovering practices that foster professional learning communities

This study is set in the context of disadvantaged urban primary schools in Ireland. It inquires into the collaborative practices of primary teachers exploring how class teachers and support teachers develop ways of working together in an effort to improve the literacy and numeracy levels of their student. Traditionally teachers have worked in isolation and therefore ‘collaboration’ as a practice has been slow to permeate the historically embedded assumption of how a teacher should work. This study aims to answer the following questions. 1). What are the dynamics of teacher collaboration in disadvantaged urban primary schools? 2). In what ways are teacher collaboration and teacher learning related? 3). In what ways does teacher collaboration influence students’ opportunities for learning? In answering these research questions, this study aims to contribute to the body of knowledge pertaining to teacher learning through collaboration. Though current policy and literature advocate and make a case for the development of collaborative teaching practices, key studies have identified gaps in the research literature in relation to the impact of teacher collaboration in schools. This study seeks to address some of those gaps by establishing how schools develop a collaborative environment and how teaching practices are enacted in such a setting. It seeks to determine what skills, relationships, structures and conditions are most important in developing collaborative environments that foster the development of professional learning communities (PLCs). This study uses a mixed method research design involving a postal survey, four snap-shot case studies and one in depth case study in an effort to establish if collaborative practice is a feasible practice resulting in worthwhile benefits for both teachers and students.

Molecular genetic analysis of DNA alterations in Irish colorectal cancer

Colorectal cancer is the most common cause of death due to malignancy in nonsmokers in the western world. In 1995 there were 1,757 cases of colon cancer in Ireland. Most colon cancer is sporadic, however ten percent of cases occur where there is a previous family history of the disease. In an attempt to understand the tumorigenic pathway in Irish colon cancer patients, a number of genes associated with colorectal cancer development were analysed in Irish sporadic and HNPCC colon cancer patients. The hereditary forms of colon cancer include Familial adenomatous polyposis coli (FAP) and Hereditary Non-Polyposis Colon Cancer (HNPCC). Genetic analysis of the gene responsible for FAP, (the APC gene) has been previously performed on Irish families, however the genetic analysis of HNPCC families is limited. In an attempt to determine the mutation spectrum in Irish HNPCC pedigrees, the hMSH2 and hMLHl mismatch repair genes were screened in 18 Irish HNPCC families. Using SSCP analysis followed by DNA sequencing, five mutations were identified, four novel and a previously reported mutation. In families where a mutation was detected, younger asyptomatic members were screened for the presence of the predisposing mutation (where possible). Detection of mutations is particularly important for the identification of at risk individuals as the early diagnosis of cancer can vastly improve the prognosis. The sensitive and efficient detection of multiple different mutations and polymorphisms in DNA is of prime importance for genetic diagnosis and the identification of disease genes. A novel mutation detection technique has recently been developed in our laboratory. In order to assess the efficacy and application of the methodology in the analysis of cancer associated genes, a protocol for the analysis of the K-ras gene was developed and optimised. Matched normal and tumour DNA from twenty sporadic colon cancer patients was analysed for K-ras mutations using the Glycosylase Mediated Polymorphism Detection technique. Five mutations of the K-ras gene were detected using this technology. Sequencing analysis verified the presence of the mutations and SSCP analysis of the same samples did not identify any additional mutations. The GMPD technology proved to be highly sensitive, accurate and efficient in the identification of K-ras gene mutations. In order to investigate the role of the replication error phenomenon in Irish colon cancer, 3 polyA tract repeat loci were analysed. The repeat loci included a 10 bp intragenic repeat of the TGF-β-RII gene. TGF-β-RII is involved in the TGF-β epithelial cell growth pathway and mutation of the gene is thought to play a role in cell proliferation and tumorigenesis. Due to the presence of a repeat sequence within the gene, TGFB-RII defects are associated with tumours that display the replication error phenomenon. Analysis of the TGF-β-RII 10 bp repeat failed to identify mutations in any colon cancer patients. Analysis of the Bat26 and Bat 40 polyA repeat sequences in the sporadic and HNPCC families revealed that instability is associated with HNPCC tumours harbouring mismatch repair defects and with 20 % of sporadic colon cancer tumours. No correlation between K-ras gene mutations and the RER+ phenotype was detected in sporadic colon cancer tumours.

The development of a computer model to optimize the performance of a 50kWp photovoltaic system

A computer model has been developed to optimize the performance of a 50kWp photovoltaic system which supplies electrical energy to a dairy farm at Fota Island in Cork Harbour. Optimization of the system involves maximising the efficiency and increasing the performance and reliability of each hardware unit. The model accepts horizontal insolation, ambient temperature, wind speed, wind direction and load demand as inputs. An optimization program uses the computer model to simulate the optimum operating conditions. From this analysis, criteria are established which are used to improve the photovoltaic system operation. This thesis describes the model concepts, the model implementation and the model verification procedures used during development. It also describes the techniques which are used during system optimization. The software, which is written in FORTRAN, is structured in modular units to provide logical and efficient programming. These modular units may also be used in the modelling and optimization of other photovoltaic systems.

The transformation of Ireland 1958 - 93: the role of ideas in punctuating institutional path dependency at critical junctures

Ireland experienced two critical junctures when its economic survival was threatened: 1958/9 and 1986/7. Common to both crises was the supplanting of long established practices, that had become an integral part of the political culture of the state, by new ideas that ensured eventual economic recovery. In their adoption and implementation these ideas also fundamentally changed the institutions of state – how politics was done, how it was organised and regulated. The end result was the transformation of the Irish state. The main hypothesis of this thesis is that at those critical junctures the political and administrative elites who enabled economic recovery were not just making pragmatic decisions, their actions were influenced by ideas. Systematic content analysis of the published works of the main ideational actors, together with primary interviews with those actors still alive, reveals how their ideas were formed, what influenced them, and how they set about implementing their ideas. As the hypothesis assumes institutional change over time historical institutionalism serves as the theoretical framework. Central to this theory is the idea that choices made when a policy is being initiated or an institution formed will have a continuing influence long into the future. Institutions of state become ‘path dependent’ and impervious to change – the forces of inertia take over. That path dependency is broken at critical junctures. At those moments ideas play a major role as they offer a set of ready-made solutions. Historical institutionalism serves as a robust framework for proving that in the transformation of Ireland the role of ideas in punctuating institutional path dependency at critical junctures was central.

Differential and numerical models of hysteretic systems with stochastic and deterministic inputs

Many deterministic models with hysteresis have been developed in the areas of economics, finance, terrestrial hydrology and biology. These models lack any stochastic element which can often have a strong effect in these areas. In this work stochastically driven closed loop systems with hysteresis type memory are studied. This type of system is presented as a possible stochastic counterpart to deterministic models in the areas of economics, finance, terrestrial hydrology and biology. Some price dynamics models are presented as a motivation for the development of this type of model. Numerical schemes for solving this class of stochastic differential equation are developed in order to examine the prototype models presented. As a means of further testing the developed numerical schemes, numerical examination is made of the behaviour near equilibrium of coupled ordinary differential equations where the time derivative of the Preisach operator is included in one of the equations. A model of two phenotype bacteria is also presented. This model is examined to explore memory effects and related hysteresis effects in the area of biology. The memory effects found in this model are similar to that found in the non-ideal relay. This non-ideal relay type behaviour is used to model a colony of bacteria with multiple switching thresholds. This model contains a Preisach type memory with a variable Preisach weight function. Shown numerically for this multi-threshold model is a pattern formation for the distribution of the phenotypes among the available thresholds.

Ecotoxicology of marine biotoxins in bivalve shellfish

A small proportion of harmful algae produce toxins which are harmful to human health. Strict monitoring programmes are in place within Ireland and the EU to effectively manage risk to human consumers of shellfish species that have accumulated marine biotoxins in their tissues. However, little is known about the impacts of HABs on shellfish health. This study used Solid Phase Adsorption and Toxin Tracking (SPATT) for the passive sampling of algal biotoxins at Lough Hyne Marine Nature Reserve in West Cork, Ireland. Spatial and temporal monitoring of the incidence of a wide range of lipophilic toxins was assessed over a 4-month period. Active sampling accumulated sufficient quantities of toxin for use in subsequent experimentation. In addition to commonly occurring Diarrhetic Shellfish Poisoning (DSP) toxins, Dinophysis toxin-1 and Pinnatoxin-G were both detected in the samples. This is the first identification of these latter two toxins in Irish waters. The effects of the DSP toxin okadaic acid (OA) were investigated on three shellfish species: Mytilus edulis, Ruditapes philippinarum and Crassostrea gigas. Histological examination of the gill, mantle and hepatopancreas tissues revealed varying intensity of damage depending both on the tissue type and the species involved. At the cellular level, flow cytometric analysis of the differential cell population distribution was assessed. No change in cell population distribution was observed in Mytilus edulis or Ruditapes philippinarum, however significant changes were observed in Crassostrea gigas granulocytes at the lower levels of toxin exposure. This indicated a chemically-induced response to OA. DNA fragmentation was measured in the haemolymph and hepatopancreas cells post OA-exposure in Mytilus edulis and Crassostrea gigas. A significant increase in DNA fragmentation was observed in both species over time, even at the lowest OA concentrations. DNA fragmentation could be due to genotoxicity of OA and/or to the induction of cell apoptosis.

Characterization of TRAF6 mediated ubiquitination of presenilins and γ-secretase substrates

Post-translational modification of the γ-secretase protease complexes and their substrates has an important role in controlling receptor-initiated signalling events, which are critically important in the pathogenesis of cancer, inflammatory and Alzheimer’s disease. Our lab has previously characterised an interaction between TRAF6 and presenilin-1, which lead to the identification of interleukin-1 (IL-1) receptor type 1 (IL-1R1) and Toll-like receptor-4 (TLR4) as novel γ-secretase substrates. Subsequently our group showed that TRAF6 promoted ubiquitination and γ-secretase cleavage of IL-1R1. The aim of this project is to study the association between TRAF6 and the presenilins, the critical γ-secretase complex components, and to determine the functional importance of TRAF6-mediated ubiquitination of γ-secretase substrates. Firstly, we show that the full-length presenilins are novel substrates of TRAF6-mediated Lysine-63-linked polyubiquitination. Secondly, we show that co-expression of TRAF6 and the presenilins increases the stability and alters the turnover of the presenilins. Thirdly, we reveal that TRAF6-mediated ubiquitination of presenilin does not affect γ-secretase enzyme activity, but may regulate the full-length presenilin functions such as ER Ca2+ signalling. Previously, we have reported IL-1R1 as a novel substrate of TRAF6-mediated ubiquitination. In this study, we identified five lysine residues in the IL-1R1 intracellular domain targeted by TRAF6-mediated polyubiquitination. Furthermore, mutagenesis of these five lysine residues led to decreased IL-1R1 cell surface expression, precluded the ectodomain shedding and attenuated the responsiveness to IL-1β stimulation, demonstrating the critical role of TRAF6 in IL-1R1 trafficking.

Synthesis and evaluation of novel azaindolocarbazole derivatives as cancer chemotherapeutics

This thesis details the design and implementation of novel chemical routes towards a series of highly propitious 7-azaindolyl derivatives of the indolocarbazole (ICZ) and bisindolylmaleimide (BIM) families, with subsequent evaluation for use as cancer chemotherapeutic agents. A robust synthetic strategy was devised to allow the introduction of a 7-azaindolyl moiety into our molecular template. This approach allowed access to a wide range of β-keto ester and β-keto nitrile intermediates. Critical analysis identified F-ring modulation as a major theme towards the advancement of ICZ and BIM derivatives in drug therapy. Thus, the employment of cyclocondensation methodology furnished a number of novel aminopyrazole, isoxazolone, pyrazolone and pyrimidinone analogues, considerably widening the scope of the prevalent maleimide functionality. Photochemical cyclisation provided for the first reported aza ICZ containing a six-membered F-ring. Another method towards achieving the aza ICZ core involved use of a Perkin-type condensation approach, with chemical elaboration of the headgroup instigated post-aromatisation. Subsequent use of a modified Lossen rearrangement allowed access to further analogues containing a six-membered F-ring. Extensive screening of the novel aza ICZ and BIM derivatives was carried out against the NCI-60 cancer cell array, with nine prospective candidates selected for continued biological evaluation. From these assays, a number of compounds were shown to inhibit cancer cell growth at concentrations of below 10 nM. Indeed, the most active aza ICZ tested is currently under assessment by the Biological Evaluation Committee of the NCI due to excellent antiproliferative activity demonstrated across the panel of cell lines, with a mean GI50 of 34 nM, a mean total growth inhibition (TGI) of 4.6 μM and a mean cytotoxicity (LC50) of 63.1 μM. Correlation to known topoisomerase I (topo I) inhibitors was revealed by COMPARE analysis, and subsequent topo I-mediated DNA cleavage assays showed inhibitory activity below 1 μM for several derivatives.

An examination of the construction of meanings for obesity in Ireland

Obesity has been defined as a consequence of energy imbalance, where energy intake exceeds energy expenditure and results in a build-up of adipose tissue. However, this scientific definition masks the complicated social meanings associated with the condition. This research investigated the construction of meaning around obesity at various levels of inquiry to inform how obesity is portrayed and understood in Ireland. A multi-paradigmatic approach was adopted, drawing on theory and methods from psychology and sociology and an analytical framework combining the Common Sense Model and framing theory was employed. In order to examine the exo-level meanings of obesity, content analysis was performed on two media data sets (n=479, n=346) and a thematic analysis was also performed on the multiple newspaper sample (n=346). At the micro-level, obesity discourses were investigated via the thematic analysis of comments sampled from an online message board. Finally, an online survey assessed individual-level beliefs and understandings of obesity. The media analysis revealed that individual blame for obesity was pervasive and the behavioural frame was dominant. A significant increase in attention to obesity over time was observed, manifestations of weight stigma were common, and there was an emotive discourse of blame directed towards the parents of obese children. The micro-level analysis provided insight into the weight-based stigma in society and a clear set of negative ‘default’ judgements accompanied the obese label. The survey analysis confirmed that the behavioural frame was the dominant means of understanding obesity. One of the strengths of this thesis is the link created between framing and the Common Sense Model in the development of an analytical framework for application in the examination of health/illness representations. This approach helped to ascertain the extent of the pervasive biomedical and individual blame discourse on obesity, which establishes the basis for the stigmatisation of obese persons.

Monasticism and its limits: rematerialising monastic space in early medieval Ireland

This thesis creates a multi-faceted archaeological context for early Irish monasticism, so as to ‘rematerialise’ a phenomenon that has been neglected by recent archaeological scholarship. Following revision of earlier models of the early Irish Church, archaeologists are now faced with redefining monasticism and distinguishing it from other diverse forms of Christian lifestyle. This research addresses this challenge, exploring the ways in which material limits can be set on the monastic phenomenon. The evidence for early Irish monasticism does not always conform to modern expectations of its character, and monastic space must be examined as culturally unique in its own right - though this thesis demonstrates that early Irish monasticism was by no means as unorthodox in its contemporary European setting as has previously been suggested. The research is informed by theories of the body, habitus and space, drawing on a wide body of archaeological, religious, sociological and anthropological thought. The data-set comprises evidences gathered through field-survey, reassessment of archaeological scholarship, historical research and cartographic research, enabling consideration of the ways in which early Irish monastics engaged with their environments. A sample of thirty-one early Irish ecclesiastical sites plus Iona forms the basis for discussion of the location and layout of monastic space, the ways in which monastics used buildings and space in their daily lives, the relationship of monasticism and material culture, the setting of mental and physical limits on monastic space and monastic bodies, and the variety of monastic lifestyles that pertained in early medieval Ireland. The study then examines the Christian landscapes of two case-studies in mid-Western Ireland in order to illustrate how monasticism functioned on the ground in these areas. As this research shows, the material complexities of early Irish monastic life are capable of archaeological definition in terms of both communal and personal lived experience.

An evaluation of orogenic kinematic evolution utilizing crystalline and magnetic anisotropy in granitoids

The Silurian-Devonian Galway Granite Complex (GGC ~425-380Ma) is defined here as a suite of granitoid plutons that comprise the Main Galway Granite Batholith and the Earlier Plutons. The Main Batholith is a composite of the Carna Pluton in the west and the Kilkieran Pluton in the east and extends from Galway City ~130km to the west. The Earlier Plutons are spatially, temporally and structurally distinct, situated northwest of the Main Batholith and include the Roundstone, Omey, Inis and Letterfrack Plutons. The majority of isotopic and structural data currently available pertain to the Kilkieran Pluton, several tectonic models have already been devised for this part of the complex. These relate emplacement of the Kilkieran Pluton to extension across a large east-west Caledonian lineament, i.e. the Skird Rocks Fault, during late Caledonian transtension. No chronological data have been published that directly and accurately date the emplacement of the Carna Pluton or any of the Earlier Plutons. There is also a lack of data pertaining to the internal structure of these intrusions. Accordingly, no previous study has established the mechanisms of emplacement for the Earlier Plutons and only limited work is available for the Carna Pluton. As a consequense of this, constituents of the GGC have not previously been placed in a context relative to each other or to regional scale Silurio-Devonian kinematics. The current work focuses on the Omey, Roundstone and Carna Plutons. Here, results of detailed field and Anisotropy of Magnetic Susceptibiliy (AMS) fabric studies are presented. This work is complemented by geological mapping that focuses on fault dynamics and contact relationships. Interpretation of AMS data is aided by rock magnetic experiment data and petrographic microstructural evaluations of representative samples. A new geological map of the the Omey Pluton demonstrates that this intrusion has a defined roof and base which are gently inclined parallel to the fold hinge of the Connemara Antiform. AMS and petrographic data show the intrusion is cross cut by NNW-SSE shear zones that extend into the country rock. These pre-date and were active during magma emplacement. It is proposed that the Omey pluton was emplaced as a discordant phacolith. Pre-existing subvertical D5 faults in the host rock were reactived during emplacement, due to regional sinistral transpression, and served as centralised ascent conduits. A central portion of the Roundstone Pluton was mapped in detail for the first time. Two facies are identified, G1 forms the majority of the pluton and coeval G2 sheets cross cut G1 at the core of the pluton. NNW-SSE D5 faults mapped in the country rock extend across the pluton. These share a geometrical relationship with the distribution of submagmatic strain in the pluton and parallel the majoity of mapped subvertical G2 dykes. These data indicate that magma ascent was controlled by NNW-SSE conduits that are inherently related to those identifed in the Omey Pluton. It is proposed that the Roundstone Pluton is a punched laccolith, the symmetry and structure of which was controlled by pre-exising host rock structures and regional sinistral transpressive stress which presided during emplacement. Field relationships show the long axis of the Carna Pluton lies parallel to mulitple NNW-SSE shear zones. These are represented on a regional scale by the Clifden-Mace Fault which cross cuts the core of this intrusion. AMS and petrographic data show concentric emplacement fabrics were tectonically overprinted as magma cooled from the magmatic state due to this faulting. It is proposed that the Clifden-Mace Fault system was active during ascent and emplacement of the magma and that pluton inflation only terminated as this controlling structure went into compression due to the onset of regional transtension. U-Pb zircon laser ablation inductively coupled mass spectrometry (LA-ICP-MS) data has been compiled from four sample sites. New geochronological data from the Roundstone Pluton (RD1 = ± 3.2Ma) represent the oldest age determination obtained from any member of the GGC and demonstrates that this pluton predates the Carna Pluton by ~10Ma and probably intruded synchronously with the Omey Pluton (~422.5 ± 1.7Ma). Chronological data from the Carna Pluton (CN2 = 412.9 ± 2.5Ma; CN3 = 409.8 ± 7.2Ma; CN4 = 409.6 ± 3.6Ma) represent the first precise magma crystallisation age for this intrusion. This work shows this pluton is 10Ma older than the Kilkieran Pluton and that the supply of magma into the Carna Pluton had terminated by ~409Ma. Chronological, magnetic and field data have been utilised to evaluate the kinematic evolution of the Caledonides of western Ireland throughout the construction of the GGC. It is proposed that the GGC was constructed during four distinct episodes. The style of emplacement and the conduits used for magma transport to the site of emplacement was dependent on the orientation of local structures relative to the regional ambiant stress field. This philosophy is used to critically evaluate and progress existing hypotheses on the transition from regional transpression to regional transtension at the end of the Caledonian Orogeny.

Investigation of toll-like receptor tolerance in the regulation of inflammation

Inflammation is a complex and highly organised immune response to microbes and tissue injury. Recognition of noxious stimuli by pathogen recognition receptor families including Toll-like receptors results in the expression of hundreds of genes that encode cytokines, chemokines, antimicrobials and regulators of inflammation. Regulation of TLR activation responses is controlled by TLR tolerance which induces a global change in the cellular transcriptional expression profile resulting in gene specific suppression and induction of transcription. In this thesis the plasticity of TLR receptor tolerance is investigated using an in vivo, transcriptomics and functional approach to determine the plasticity of TLR tolerance in the regulation of inflammation. Firstly, using mice deficient in the negative regulator of TLR gene transcription, Bcl-3 (Bcl-3-/-) in a model of intestinal inflammation, we investigated the role of Bcl-3 in the regulation of intestinal inflammatory responses. Our data revealed a novel role for Bcl-3 in the regulation of epithelial cell proliferation and regeneration during intestinal inflammation. Furthermore this data revealed that increased Bcl-3 expression contributes to the development of inflammatory bowel disease (IBD). Secondly, we demonstrate that lipopolysaccharide tolerance is transient and recovery from LPS tolerance results in polarisation of macrophages to a previously un-described hybrid state (RM). In addition, we identified that RM cells have a unique transcriptional profile with suppression and induction of genes specific to this polarisation state. Furthermore, using a functional approach to characterise the outcomes of TLR tolerance plasticity, we demonstrate that cytokine transcription is uncoupled from cytokine secretion in macrophages following recovery from LPS tolerance. Here we demonstrate a novel mechanism of regulation of TLR tolerance through suppression of cytokine secretion in macrophages. We show that TNF-α is alternatively trafficked towards a degradative intracellular compartment. These studies demonstrate that TLR tolerance is a complex immunological response with the plasticity of this state playing an important role in the regulation of inflammation.