http://hdl.handle.net/10379/1401 2017-10-29T22:40:50Z 2017-10-29T22:40:50Z Soldatou, Sylvia http://hdl.handle.net/10379/6935 2017-10-27T01:00:19Z 2017-08-23T00:00:00Z

Marine biodiscovery from Floridian mangrove forests and Irish waters Soldatou, Sylvia Natural products have been used since ancient times to treat illnesses and terrestrial organisms have been studied extensively from a chemical point of view. Marine organisms, on the other hand are definitely understudied compared to plants due to their difficult accessibility. However, technological advancements have made it possible for scientist to reach and sample from tropical waters to the deepest points of the world’s oceans. Ever since the discovery of spongouridine and spongothymidine, marine natural products have gained interest within the drug discovery community. The chemistry they produce has been shown beneficial for human health with many examples of marine-related compounds that made it into the market as potent drugs for severe diseases. This thesis is demonstrating the importance of marine microbes, corals and algae as a source of secondary metabolites and emphasis is also given on their biological activity. In particular, Chapter 2 is describing in detail the chemical investigation of an endophytic fungus isolated from a Floridian red-mangrove tree. As part of a high-throughput screening project which involved numerous fungal extracts that were screened against the ESKAPE pathogens, an Alternaria sp. isolate was chemically investigated. Bioassay-guided isolation of the fungal extract yielded a suite of new and known secondary metabolites which belong to the benzofuran (2.16-2.18) and benzopyrone (2.20) families and exhibited weak anti-MRSA activity. Part B of this thesis is focusing on the great unexplored potential of Irish Waters as source of new chemistry. Chapter 3 explores polyhalogenated monoterpenes produced by an Irish Plocamium cartilagineum sample. Six new and known linear and cyclic polyhalogenated monoterpenes were isolated and their structure elucidation process is thoroughly discussed. The cyclic polyhalogenated monoterpenes 3.2 and 3.3 have been previously described but this is the first report of crystal structure elucidation through X-ray analysis. The linear compounds 3.4 and 3.6 represent new polyhalogenated monoterpenes whereas compound 3.7 is a previously reported metabolite but full NMR data were not available until now. The new metabolite 3.4 exhibited significant cytotoxic activity when screened against cervical (HeLa) and pancreatic (MiaPaCa-2) cell lines. The next chapter, Chapter 4, investigates a deep-sea coral identified as Primona sp. which was collected in the Whittard canyon from various depths. A mixture of at least two ceramides (4.1) was isolated. Finally, Chapter 5 is focusing on the construction of a microbial library from Irish marine bacterial and fungal endosymbionts. One thousand seven hundred and fifty (1 750) endosymbiotic microbial strains were isolated from Irish algae, invertebrates and sediment samples. Priority was given to the fungal endosymbiotic isolates and each colony was cultured in a control treatment as well as in the presence of HDAC and DNMT inhibitors. More than fungal 1 200 extracts were screened against the ESKAPE pathogens and 10.8% of those showed antibacterial activity. The majority of the active extracts exhibited selective activity against only one of the ESKAPE pathogens. Interestingly, only 14 fungal cultures showed antimicrobial activity and for the majority of them only one treatment (control, HDAC or DNMT) was found active indicating that the each treatment should be treated as an independent sample/extract.

2017-08-23T00:00:00Z Morrissey, Ann-Marie http://hdl.handle.net/10379/6933 2017-10-26T01:02:00Z 2016-11-16T00:00:00Z

The need for and effectiveness of an individualised therapeutic programme for people living with prolonged disorders of consciousness in non-specialist care settings in the Republic of Ireland Morrissey, Ann-Marie Introduction: Disorders of consciousness are an increasing phenomena and people are living longer with these conditions. The care needs begin with acute medicine and ICU care and frequently end up with life-long nursing care (Royal College of Physicians [RCP], 2013). Little is known about the care and treatment this clinical population receive long-term. This group of patients will require care for many years following injury (Fins, 2013). This can place strain on budget limited healthcare systems. Interventions should be aimed at minimising carer burden and developing individualised programmes (Wheatley-Smith et al., 2012). Local, individualised, timely and integrated services which are flexible and responsive to personal need are the goal for future neuro-rehabilitation services (Health Service Executive [HSE], 2011). This study developed and implemented such local individualised programmes for people with prolonged disorders of consciousness (PDoC). Method: Firstly a nationwide cross sectional survey was conducted in order to evaluate current care services and determine if there was a need for the development of a specialised therapeutic programme. Following this, 5 in-depth case studies were conducted in 4 long-term residential care settings. An individualised therapeutic programme was developed and implemented for each participant. Each intervention was 3-6 months in duration. This study was evaluated from three perspectives: the participant with PDoC, their family and the professional staff caring for them. The behavioural changes for participants were measured using three standardised assessments, the Wessex Head Injury Matrix (WHIM), the Sensory Modality Assessment and Rehabilitation Technique (SMART) and the JFK Coma Recovery Scale Revised (CRS-R). Quantitative measures were also used to record changes in family members and professional care staff’s knowledge, anxiety, caregiver strain and attitudes towards people with PDoC. Results: Rehabilitation services for people with PDoC in this country for found to be very limited. There is a low level of follow up and re-assessment for this population also. When evaluating a therapeutic programme for people with PDoC significant positive statistical and clinical changes were recorded for participants, family members and care staff. This study highlights the value and importance of such non-pharmacological interventions for PDoC and their practical implementation in nursing home settings. Staff attitudes towards care were shown to have significantly changed following the study. Family strain and anxiety were also reduced as a result of this study. A positive impact on reducing misdiagnosis and increasing behavioural repertoire was shown for participants. Conclusion: People with PDoC are cared for in a multiple of residential care settings and there is considerable variation in the care and treatment services they receive long-term. In this study in-depth case study methodology contributed rich and valuable data to the study of treatment for PDoC. This study supports the provision of long-term rehabilitation for people with DoC and identifies how it can be implemented in non-specialist clinical environments.

2016-11-16T00:00:00Z Hennessy, Conor http://hdl.handle.net/10379/6926 2017-10-21T01:02:31Z 2017-10-20T00:00:00Z

Investigating the epigenetic regulation of toll-like receptor 3 Hennessy, Conor Toll-like receptors are a family of pattern recognition receptors (PRRs), which have evolved to recognise structurally conserved components of microorganisms. They form an important part of the innate immune system, yet in spite of their importance, there is still a paucity of information regarding the expression and regulation of these receptors. Epigenetics is a field of genetics which focuses on non-nucleotide based changes in gene expression, and highlights the implications that changes in chromatin structure and function have for gene expression and regulation. We theorised that TLRs might be susceptible to changes in the epigenetic state, and we theorised that epigenetic modifications may alter the regulation and function of TLRs, most notably TLR3. Our studies were centred on two cell lines, epithelial HCT 116 cells and monocytic THP-1 cells, two cell lines which play important but distinct roles in the innate immune system. We targeted two families of enzymes involved in remodelling chromatin structure, DNA methyltransferases (DNMTs) and histone deacetylase complexes (HDACs). We initially showed that knockout of DNA methyltransferases in HCT 116 cells produced significant decreases in TLR3 expression, with less dramatic results seen in other TLRs. This finding was replicated with pharmacological inhibition of DNMTs with 5-aza-2-dc and inhibition of HDACs with SAHA. Inhibition of DNMTs and HDACs also inhibited TLR3 function, with no signalling cascade or cytokine release seen with enzyme inhibition. TLR3 function was markedly different in THP-1 and HCT 116 cells, with THP-1 cells not expressing TLR3. This difference in expression led us to search for a potential regulator common to both cell lines. Literature vi i searches led to IRF8, a potential negative regulator of TLR3, which is known to be highly expressed in THP-1 cells. We determined that high IRF8 expression was correlated with low TLR3 expression, and lack of functional responses. Overexpression of IRF8 in HCT 116 cells, which prevented TLR3 functional responses, suggested that IRF8 may indeed be an epigenetically controlled regulator of TLR3. Our studies show the immunomodulatory capabilities of these epigenetic drugs, with decreased viral receptor function and inhibition of inflammatory cytokine release seen with inhibition of DNMTs and HDACs. Furthermore, our studies suggest a potential role for epigenetic modifications, which may alter IRF8 expression, in indirectly regulating TLR3 expression and function.

2017-10-20T00:00:00Z Mouton Kinyon, Chanté http://hdl.handle.net/10379/6925 2017-10-21T01:02:08Z 2016-12-09T00:00:00Z

Analogous states: John Millington Synge, Zora Neale Hurston, and the performance of ethnography Mouton Kinyon, Chanté The thesis presents J. M. Synge and Zora Neale Hurston as autoethnographic researcher-practitioners who employed important cultural forms in their theatre, such as the keen and the cakewalk, in order to challenge the representational caricatures that contributed to the racialization of both the Irish and African Americans. Using ethnographic material, Synge and Hurston locate such performative rituals in their proper cultural contexts, thereby giving a representation of them that audiences might consider authentic, while also writing against the stereotypes associated with the cultures under discussion. Yet Synge and Hurston’s claims to authenticity and cultural intimacy, through the use of ethnographic practices, is undermined as the material created was intended for the theatre, an artificial space. Thus, Synge’s and Hurston’s flawed research practices reveal moral binds of performance ethnography as cross-cultural studies was becoming a significant aspect of anthropology prior to the development of performance studies. This intervention not only impacts the fields of Irish studies and African American studies but also has broader implications in performance studies. Further, this project has the potential to impact the way in which cultural anthropologists incorporate literary criticism and theory into their work.

2016-12-09T00:00:00Z