Search

Although the role of the cerebellum has historically been associated with motoric function, more recently it has become clear that the cerebellum also has a role in many cognitive functions, such as learning, perception, verbal working memory and emotion. Of particular interest to this thesis is how the cerebellum is involved in predictive language processing. Studies employing transcranial magnetic stimulation to examine the role of the cerebellum in language have primarily indicated that it is in some way associative or predictive, and have used methodologies that principally rely upon associative priming. The aims of this thesis are to: a) replicate previous findings as regards the role of the cerebellum in associative as compared to categorical priming, but with stimuli where the categorical relationship is controlled for across both types (namely, opposite pairs as compared to categorical pairs), and to determine whether these behavioural modulations are reflected in language specific event-related potentials that index language prediction, b) examine whether the role of the cerebellum in associative priming extends to backward priming, whose models imply a differing process as compared to forward priming, and c) examine whether the predictive or associative role of the cerebellum in language can be extended to more complex sentences and how modulation of this function affects later language specific event-related potentials that index language prediction. In Chapter 4, the opposite stimuli, and not the categorical, displayed a priming effect. This was reflected by the phonological mismatch negativity wave, implying that this task required only phonological access to be completed. There was no effect of the cTBS, possibly because this task did not require semantic access. This indirectly supports the literature that suggests the cerebellum plays a role in semantic prediction. In Chapter 5 I show for the first time, beyond fMRI activation, that the left cerebellar hemisphere is actively involved in backward priming. Modulation of the left cerebellar hemisphere through cTBS selectively enhanced backward as compared to forward priming, indicating that the cerebellum has a role in backward priming that is localized to the left cerebellar hemisphere. Additionally, this finding provides a potential explanation for the presence and mechanism of short stimulus onset asynchrony backward priming. Finally, Chapter 6 shows that modulation of right cerebellar function through cTBS results in easier processing of incongruent endings of highly predictable sentences, as indexed by the N400 event-related potential. I hypothesise that the effect of cTBS exhibited here is caused by modulation of the process through which errors are fed back in order to update cerebellar internal models. For the first time, we have shown that modulation of cerebellar predictive language function impacts upon later electrophysiological measures, and that this method might be an effective way to further elucidate the role of the cerebellum in language. Overall, this thesis supports the evidence that the cerebellum is involved in predictive language function, and that it applies a similar set of computations or internal models here as it does in motoric function and other cognitive functions. Additionally, we have proposed mechanisms through which cTBS may be affecting these internal models attributed to the cerebellum.

The Endosomal Sorting Complex Required for Transport (ESCRT) proteins are a series of four protein complexes (numbered ESCRT-0 to III) which aid the endosome in sorting internalised receptors. The ESCRT proteins recognise receptors which have been tagged with ubiquitin to help sort between receptors which need to be recycled from those which are to be degraded. The ESCRT proteins are aided in their function by HDPTP, a Bro1-domain protein which can act as a scaffold by replacing one ESCRT complex with another on the Epidermal Growth Factor Receptor (EGFR).The proteins Endofin and SARA both bind to the endosome membrane using a FYVE domain, and were identified in a commercial yeast-2-hybrid screen as potential interacting partners for HDPTP. Functionally, SARA has been suggested as a signalling anchor in the Transforming Growth Factor β (TGFβ) pathway; Endofin performs the same role in the related Bone Morphogenic Protein (BMP) pathway. Additionally, both Endofin and SARA have been suggested to have roles in EGFR signalling and have independently been implicated as members of alternative complexes to the first ESCRT complex, ESCRT-0.The results presented in this thesis confirm that Endofin and SARA can both interact with the Bro1-V domain of HDPTP. Both Endofin and SARA can recruit exogenously expressed, full length HDPTP to structures which contain endocytic markers. Further characterisation shows that Endofin requires an α-helix at its N-terminus to interact with several regions in the HDPTP Bro1-V domain. Knockdown studies show that Endofin co-operates with SARA and possibly ESCRT-0 in regulating HDPTP localisation to the endosome. It is also shown that Endofin and SARA can influence positioning of certain organelles, especially lysosomes. However, no influence of either Endofin or SARA on endosome morphology or distribution has been found. The results also indicate that Endofin can bind to the EGFR and is phosphorylated downstream of EGFR signalling but does not directly influence EGFR trafficking or signalling. Overall, this project has discovered two novel interacting partners for HDPTP: Endofin and SARA. The results also contribute to the understanding of the functions that Endofin and SARA perform at the endosome and during cell signalling.

Background: An estimated one in ten adolescents living in the community will engage in deliberately self-harming (DSH) during their lifetime. This perplexing behaviour is of growing clinical concern and appears to be increasing in prevalence, yet continues to be without definitive understanding. There are multiple theories on the underlying mechanisms of DSH, however, there is limited empirical evidence to support these theories. The present study aimed to investigate whether Young’s schema theory could provide a comprehensive framework to understand DSH in adolescents from the general community. This study aimed take a unique perspective on DSH by investigating the theorised unconscious cognitive constructs, known as Early Maladaptive Schema’s (EMS’s), which may underlie this behaviour. It also explored the relationship between EMS’s and psychopathology within this sample. Methodology: 252 adolescents recruited from internet forums and social networking sites completed a series of self-report questionnaires online. DSH was measured using the Deliberate Self-Harm Inventory. Early Maladaptive Schema’s were measured using an age downward version of the Young’s Schema Questionnaire-short form. The Brief Symptoms Inventory was used to measure psychopathology, and a demographics questionnaire was designed to gather pertinent additional information. Results: Correlational analyses indicated positive relationships between frequency of DSH behaviours and intensity of 13 of the 15 EMS’s. Despite no association found between the overall EMS score and general psychological distress, when each EMS was considered individually, relationships were found between the intensity of each of the 15 EMS’s and the general measure of psychological distress. Hierarchical multiple regression, controlling for gender and general psychopathology, indicated that the Emotional Deprivation, Vulnerability to Harm, Subjugation and Self-Sacrifice EMS’s accounted for a unique proportion of the variance in DSH behaviour. Conclusions: These finding are unique in that they extend the research into both DSH and EMS’s in adolescents. From the findings one could broadly conclude that, as Schema Theory states, DSH is a coping strategy used to manage unbearable memories, emotions, cognitions, and bodily sensations associated with EMS’s, with positive correlations between the intensity of the EMS’s and the frequency of DSH, and the intensity of the EMS’s and increased psychological distress. Further, during this time the EMS’s Emotional Deprivation, Vulnerability to Harm, Self-Sacrifice and Subjugation are more predictive of DSH than alternative EMS’s. When comparing these findings to the wider literature, one could conclude that EMS’s are unstable in adolescents, as those EMS’s causing distress in an individual’s adolescence may not continue to do so into their adulthood, yet the coping strategy may remain the same. This highlights the role of social, environmental and biological changes in the stability of EMS’s. The pertinence of these findings to adolescents who DSH, the overlap with broader psychological symptomotology, and its relevance to clinical practice is discussed.

This thesis examines the changes in health governance at both global and country levels brought by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund), a self-described public/private partnership intended as a financing mechanism to achieve Millennium Development Goal (MDG) 6. Since the G8 announced the Global Fund's creation in 2001, it has succeeded in mobilising over US$30 bn in commitments, primarily from donor governments. This thesis is rooted in the 'high politics' of International Relations (IR), and in particular its literature on globalisation, governance and international institutions. Where this literature has failures or gaps, it draws from the Development Studies and International Political Economy (IPE) literatures. It also relies on key informant interviews undertaken in Geneva, Lilongwe and Zomba with executives of international institutions, and those involved in Malawi's HIV/AIDS response including government representatives and staff from the National AIDS Commission, donors, NGOs and those working on the front line. This thesis relies on a descriptive, single case study to create a 'thick' narrative. Rather than deriving generalisations, it provides a basis for further research into the nature and effects of systemic change in how health is governed that the Global Fund signals. This thesis makes three contributions to knowledge: 1) It provides a basis to evolve the IR literature on globalisation, governance and international institutions to consider the nature, significance and effects of the Global Fund as a form of institutional innovation which is disrupting the traditional multilateral order, particularly for international institutions working in health; 2) It challenges the use of the term 'country ownership' to mean 'putting the country in the driver's seat', and instead notes the double deficit in external accountability that arises when global politics and country evidence collide in a Global Fund convened elite, mediated space for country ownership; and 3) It synthesises observations from field work in Malawi on the exercise of the Global Fund's authority and its dislocation from external accountability when failures occur. The IR literature is silent on the rise of the Global Fund's authority. It fails to contend with the notion that country ownership is as much about the burden of responsibility as it is about agenda setting. This highlights the dislocation between the loci for authority and accountability despite the Global Fund's growing authoritative territorial claims.

This study sets out to explore parents'l experiences of part-time nurture groups within three primary schools in a large urban authority in the North of England. Six parents were interviewed using a semi-structured narrative approach, to explore their experiences, perceptions, expectations and feelings about the nurture group intervention. A discussion of the findings using interpretative phenomenological analysis offers insights into the nature of relationships between parents, nurture group staff and children, and the impact of the intervention and its influence on parents' behaviour. Key themes which emerged from the data concerned the parents' relationships with nurture group staff. They perceived staff to be friendly, caring and trustworthy. They were encouraged by the individual, personalised attention given to their child and felt positive about the holistic, caring nature of the intervention. The gains that parents perceived their child had made included a positive attitude to school, engagement with learning and the development of constructive relationships with school staff and children. Key areas of concern centred on aspects of withdrawal/re-integration and limited information sharing with parents, and communication between nurture group staff and teachers. Findings were related to the theoretical notion of 'educational attachment' and collaborative models of parent partnership. The study concludes by identifying ways in which schools could further develop effective collaborative practice with parents of children with social, emotional and behavioural difficulties. Future research issues are also highlighted.

The main aim of this project was to determine the potential of increased chitin content as a mechanism of resistance to caspofungin in different fungal pathogens. C. albicans wild-type cells were pre-grown with a combination of CaCl2 and CFW prior to caspofungin treatment. This result sin a three-fold increase in cell wall chitin. Wild-type cells, which had elevated chitin content, were less susceptible to caspofungin. Priming cells to activated chitin synthesis was also able to compensate for the loss of the normally essential CaCHS1, through formation of three novel forms of salvage septa. In the absence of both CaChs1 and CaChs3, which are typically involved in septum formation, the class I chitin synthases, CaChs2 and CaChs8, could be stimulated to synthesise a proximally offset salvage septum. When CaChs3 was the only remaining chitin synthase, treatment with CaCl2 and CFW, led to the formation of thick chitin-rich salvage septa. CaChs2 and CaChs3 could be stimulated by treatment with CaCl2 and CFW to synthesise a thin salvage septum similar to the septum of wild-type cells. All three salvage septa were capable of restoring viability and cell division in C. albicans. The compensatory increase in chitin content in response to caspofungin treatment was not specific to C. albicans because clinical isolates of C. tropicalis, C. parapsilosis and C. guilliermondii and the filamentous fungus, A. fumigatus, also demonstrated an increase in chitin content after treatment with caspofungin. Isolates of C. glabrata and C. krusei showed no change in chitin content when exposed to caspofungin. The results of this thesis highlight the potential for using chitin synthase inhibitors in combination therapy with the echinocandins.