Genetic variation in the gene ZNF804A has been shown to be related to risk for psychopathology, especially schizophrenia and bipolar disorder. The main aim of this thesis was to characterise the behavioural effects of Zfp804a, the mouse orthologue of ZNF804A, in order to understand more about how this gene influences brain and psychological functioning, and hence provide clues as to its possible role in mediating risk for mental disorders. Prior to this work, two ENU-mutant mouse lines had been generated from a DNA library of ENU mutagenised mice with two non-synonymous mutations selected as viable candidates for further investigation. The C59X mutation encodes a premature stop codon in exon 2, thought to lead to a functional null of the gene, and the C417Y mutation is missense, substituting cysteine for tyrosine in exon 4. A first series of experiments examined the early development of the ENU-mutant lines and showed no gross developmental abnormalities, although the C59X mutants weighed significantly less than their WT littermate controls at weaning and during adulthood. A comprehensive series of behavioural tests then assayed aspects of emotion, motivation, hedonia, sensorimotor gating and response control. In general, the C59X mutants showed the greatest effects, displaying reduced anxiety, anhedonia, and sensorimotor gating deficits, together with evidence of enhanced response inhibition. The C417Y mutants only showed selective effects in terms of enhanced motivation. The data dissociate between the effects of the two ENU-induced mutations of Zfp804a. Furthermore, the findings with the C59X mutants would suggest, a priori, that genetic variance leading to alterations in ZNF804A expression may be an important mechanism contributing to risk for psychopathology.

The three aims of my interdisciplinary thesis are: - To develop a conceptual framework for re-thinking the gestures of neuro-atypical young people, that is non-traditional and non-representational - To develop qualitative analytical tools for the annotation and interpretation of gesture that can be applied inclusively to both neuro-atypical and neuro typical young people - To consider the conceptual framework in terms of its theoretical implications and practical applications Learning to communicate and work with neuro-atypical young people provides the rationale and continued impetus for my work. My approach is influenced by the limited social, physical and communicative experiences of young people with severe speech and motor impairment, due to cerebral palsy (CP). CP is described as: a range of non-progressive syndromes of posture and motor impairment. The aetiology is thought to result from damage to the developing central nervous system during gestation or in the neonate. Brain lesions involve the basal ganglia and the cerebellum; both these sites are known to support motor control and integration. However, a paucity of theoretical research and empirical data for this target group of young people necessitated the development of both an alternative theoretical framework and two new tools. Biological Dynamic Systems Theory is proposed as the best candidate structure for the re-consideration of gesture. It encompasses the global, synthetic and embodied nature of gesture. Gesture is re-defined and considered part of an emergent dynamic, complex, non-linear and self-organizing system. My construct of Cognition-in-Action (C-i-A) is derived from the notion of knowing-as-doing influenced by socio-biological paradigms; it places the Action-Ready-Body centre stage. It is informed by a theoretical synthesis of knowledge from the domains of Philosophy, Science and Technology, including practices in the clinical, technology design and performance arts arenas. The C-i-A is a descriptive, non-computational feature-based framework. Its development centred around two key questions that served as operational starting points: What can gestures reveal about children’s cognition-in-action? and Is there the potential to influence gestural capacity in children?. These are supported by my research objectives. In my empirical study I present three case studies that focus on the annotation and interpretative analyses of corporeal exemplars from a gesture corpus. These exemplars were contributed by neuro-atypical young people: two adolescent males aged 16.9 and 17.9 years, and one female girl aged 10.7 years. The Gesture-Action-Entity (GAE) is proposed as a unit of interest for the analysis of procedural, semantic and episodic aspects of our corporeal knowledge. A body-based-action-annotation-system (G-ABAS) and Interpretative Phenomenological Analysis methodology is applied for the first time to gesture (G-IPA). These tools facilitate fine-grained corporeal dynamic and narrative gesture feature analyses. These phenomenal data reveal that these young people have latent resources and capacities that they can express corporeally. Iteration of these interpretative findings with the Cognition-in-Action framework allows for the inference of processes that may underlie the strategies they use to achieve such social-motor-cognitive functions. In summary, their Cognition-in-Action is brought-forth, carried forward and has the potential to be culturally embodied. The utility of C-i-A framework lies in its explanatory power to contribute to a deeper understanding of child gesture. Furthermore, I discuss and illustrate its potential to influence practice in the domains of pedagogy, rehabilitation and the design of future intimate, assistive and perceptually sensitive technologies. Such technologies are increasingly mediating our social interactions. My thesis makes an original and significant contribution to the field of cognitive science, by offering an ecologically valid alternative to tradition conceptualization of perception, cognition and action.

Antisense oligonucleotide therapy is one of the most promising strategies for treatment of myotonic dystrophy type 1 (DM1), type 2 (DM2) and Duchene muscular dystrophy (DMD). These three diseases have nuclear retained mRNA, suitable for antisense therapy targeting. The delivery of oligonucleotides to their desired target has long been an obstacle in antisense therapy with a large number of delivery reagents or methods having adverse side effects. Promising work published detailing the successful delivery of various chemically modified oligonucleotides (CMOs) naked, via gymnosis, led to us investigating a number of these CMOs: deoxyribonucleic acids (DNA), Peptide nucleic acids (PNAs), 2’OMethyl (2’OMe), and Phosphorodiamidate morpholino (PMO) oligonucleotides. In DM1 expanded CUG repeat (CUGexp) mRNAs aggregate in the nucleus forming “foci”. Testing the CMOs effectiveness at disrupting nuclear foci in a cell based assay, using high content imaging to visualise the number, size and intensity of foci we initially discovered that PNA and 2’OMe, were seemingly taken up via gymnosis by DM1 cells, and removed nuclear foci at nanomolar concentrations. However further experimentation using live cell imaging indicated that although all CMOs could enter the cell, in all disease models tested, via gymnosis, the CMOs could not penetrate the nuclear membrane. In depth analysis led us to identify an artefact of the in-situ process used to identify these foci, explaining earlier positive results. As the target mRNA is trapped within the nuclear compartment we investigated several transfection reagents for their ability to deliver 2’OMe oligonucleotides to the nucleus using live cell fluorescent imaging and a modified northern blot based method. It was established that polyethylenimine could successfully deliver 2’OMe oligonucleotides to the cell, with a high abundance of the oligonucleotide residing within the nuclear compartment. It was observed that PEI degrades the expanded nuclear retained repeat in the DMPK transcript of a DM1 patient cell line alone, without the addition of an antisense agent, in a concentration dependent manner.

The ability to accurately perceive and respond to our visual environment is critical for optimising primate behaviour. A number of related cognitive functions, such as visual learning and longer-term memory, also depend upon an accurate percept of objects and their location within the visual environment. Understanding how the healthy brain supports higher-order visual perception is, therefore, a key goal for cognitive neuroscientist. A substantial body of research involving both humans and animals highlights a role for regions within the extrastriate cortex in visual perception, with many of these regions apparently exhibiting a high degree of functional specialisation for the processing of particular categories of complex stimuli (e.g. faces versus scenes). More recently, studies have found that patients with damage to structures within the medial temporal lobe, such as the hippocampus and perirhinal cortex, can also present with impairments in higher-level perception. More specifically, damage to perirhinal cortex has been linked to impairments in perception for complex objects and faces, whereas hippocampal damage has been linked to impairments in scene perception. Multiple regions distributed across the extrastriate cortex and medial temporal lobe may make individual category-sensitive contributions to visual perception, but it remains unclear how these regions interact with one another, and to what extent their ability to interact underpins successful visual perception. These issues are addressed here via a series of novel experiments involving a combination of behavioural paradigms and magnetic resonance imaging techniques in healthy human participants. These experiments aim to: a) investigate the functional and structural connections that support the category-sensitive contributions of the perirhinal cortex and hippocampus to higher-level visual perception; b) demonstrate that inter-individual variation in the structural properties of white matter pathways providing inputs/outputs to the perirhinal cortex or hippocampus is an important factor underpinning the contributions of these regions to successful higher-level perceptions.

Aims: Peer support has been incorporated into clinical and national stroke guidelines as an important component of community rehabilitation, yet there is a paucity of research in this area. This study aimed to evaluate the efficacy of a community-based stroke peer support intervention for survivors and carers. Design: Stroke survivors and carers (n=47) were randomly assigned to either a five-week peer support group intervention or a waiting-list comparison condition. Mixed multivariate (MANCOVA) and univariate (ANCOVA / ANOVA) analyses were used to compare mean scores over time on a range of self-report measures. Additionally, mediation analysis was used to explore the processes underlying peer support. Method: All participants completed measures of psychological distress (GHQ-30), perceived social support (Multidimensional Scale of Perceived Social Support), quality of life (EQ-5D-3L) and activities of daily living (Barthel Index). Intervention group participants completed a group process questionnaire (TFI-19). Assessments were completed at baseline, post-intervention (five-weeks) and at follow-up (four-weeks). Due to significant differences between the two groups on the Barthel Index at baseline, these scores were added as a covariate in the MANCOVA and follow-up ANCOVAs used in analysis with the outcome variables (i.e. GHQ-30 and EQ-5D-3L). Results: Participants in the peer support intervention group reported decreased psychological distress and increased perceived social support and quality of life over time. These changes were significantly greater when compared to the control group, over the same time period. Perceived social support was found to mediate the relationship between group condition and psychological distress. Conclusions: Peer support can facilitate improvements in psychosocial wellbeing for stroke survivors and carers. Social support was found to be an important mechanism underlying peer support. Theoretical and clinical implications of peer support in stroke are discussed and recommendations for future research are outlined.

This thesis broadly explores evidence-based practice (EBP) in mental health, with a particular focus on dissemination and implementation of research evidence regarding family intervention in psychosis. Chapter one comprises a review of evidence-based practice in mental health, including the uptake of evidence-based practice, the effects of training, research dissemination and implementation strategies. A brief narrative review is presented followed by a systematic review examining uptake of evidence-based therapies by mental health practitioners. Eleven papers were selected for review and were measured against the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines (von Elm, Altman, Egger, Pocock, Gøtzsche & Vandenbroucke, 2007). Following this, conclusions regarding the current evidence and areas which need to be developed are discussed, primarily the need for standardised measures, an indication of clinical change and provision of follow-up studies. Chapter Two comprises an empirical paper intended to be submitted to the journal ‘Implementation Science’. The aim was to address some of the issues identified in Chapter One, namely the use of standardised measures and the measure of a change in clinical practice. Mixed methods were used to assess attitudes to EBP in Trainee Clinical Psychologists and the effect that different dissemination methods had on their attitudes to a specific facet of EBP, family interventions in psychosis. A total of 104 trainee clinical psychologists from 23 UK training programmes participated in the online study, and were randomly allocated to one of four conditions. i. ‘Minimal information’: Participants viewed a brief summary of a fictitious service-user with psychosis, this served as the baseline condition. ii. ‘Case study’: Participants viewed a detailed case study describing the use of family interventions with a fictitious service-user with psychosis iii. ‘Research summary’: Participants viewed a detailed research summary showing research into the effectiveness of family interventions in psychosis iv. ‘Combined’, participants viewed both the case study and research summary Following this, participants completed a survey of their experience with different therapies and demographic information and a standardised measure of attitudes to EBP. Participants then viewed the minimal information about the fictitious client, followed by the summary specified in the condition they were allocated to. Participants then completed a questionnaire designed to assess their attitudes to family intervention in psychosis and their willingness to engage in further training. Responses to these served as the dependent variables. Participants were also given the opportunity to give their own views on the use of family interventions in clinical practice. Data were analysed using MANOVA and multiple regression, with thematic analysis (Braun & Clarke, 2006) employed for the qualitative data. Participants who viewed both case and research information showed a greater willingness to train than those who viewed research information alone. Chapter Three, the concluding section, consists of a general discussion of the research, focusing on the findings and their relation to previous findings in the area, the implications of the findings for research and clinical training and practice, as well as strengths and limitations of the research. The main limitations identified were the lack of a follow-up and the suitability of willingness to train as a measure in trainee clinical psychologists. Recommendations for future research in this area are made. Following the general discussion section a proposal for a follow-on study, extending the current study and improving the methodology is presented. Lastly, the research is presented in the form of a report intended for submission to ‘Clinical Psychology Forum’.

Introduction: Glucose-regulated protein 78-kDa (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone that is essential for correct protein folding and assembly in the ER lumen. Micro-environmental stress and a requirement for increased protein synthesis, typical of solid tumours, leads to a disruption of ER homeostasis, and accumulation of misfolded proteins. The ability of GRP78 to dissociate from several important ER-resident transmembrane proteins under conditions of ER stress leads to a cascade of signal transduction pathways, known as the unfolded protein response (UPR), that modulate cell survival or, if the stress is significantly severe, apoptosis. GRP78 has been found to be overexpressed in a variety of cancers compared with benign tissue and has been associated with poor outcome. In-vitro data indicate that GRP78 expression is often associated with aggressive phenotype and drug resistance. Thus, GRP78 has potential as a biomarker for tumour behaviour and treatment response. For stage III colorectal cancer, there is overwhelming evidence to recommend the use of fluoropyrimidine-based adjuvant chemotherapy. Unfortunately, a large proportion of patients do not benefit from adjuvant chemotherapy, and biomarkers that can determine the likelihood of response to chemotherapy remain elusive. The benefit of chemotherapy in stage II disease is less certain and markers that could reliably predict benefit would be particularly useful in this population. This study explores a potential mechanistic relationship between GRP78 and 5-FU sensitivity using both siRNA transfection and treatment with an engineered fusion protein, epidermal growth factor (EGF)-SubA, which has been demonstrated to cause highly selective cleavage of GRP78 at a single amino acid point. It was then examined whether GRP78 may have prognostic or predictive value in the context of colorectal cancer patients treated with fluoropyrimidine-based chemotherapy. The potential therapeutic value of targeting GRP78 in vitro using EGF-SubA is also examined. Methods: Colon cancer cell lines were used to examine response to 5-FU upon modulation of endogenous GRP78 using siRNA technology and EGF-SubA. Apoptosis and cell cycle progression were assessed using flow cytometry. Immunohistochemistry was used to characterise GRP78 expression in a large cohort of colorectal cancers on tissue microarrays and the results were correlated with clinicopathological parameters and with 5-year survival for the whole cohort and those treated with fluoropyrimidine-based (5-FU) adjuvant chemotherapy. The action of EGF-SubA upon colon cancer cells was examined using western blotting, MTT assay and flow cytometry. Results: GRP78 promotes apoptosis in response to 5-FU. Better overall 5-year survival was associated with high GRP78 expression (P=0.036). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (P=0.026), whereas patients with low GRP78 failed to benefit (P=0.805). Low GRP78 was an independent poor prognostic indicator of overall 5-year survival (P=0.005; HR=1.536; 95%CI 1.139-2.122). Colon cancer cells expressing EGFR were highly sensitive to EGF-SubA, demonstrating reduced proliferation and cell cycle arrest. However, EGF-SubA did not induce significant apoptosis and reduced the effectiveness of 5-FU in vitro. Conclusion: This study demonstrates a mechanistic relationship between GRP78 expression and response to 5-FU. GRP78 expression may provide a useful additional risk stratification to inform the adjuvant treatment of colorectal cancer. EGF-SubA does not have therapeutic value in colorectal cancer but is a useful tool for studying GRP78 and the UPR.

Objective: To develop a current understanding of the differences in how physicians communicate with Black and Minority Ethnic (BME) patients in comparison to non-BME patients. Methods: Systematic searches of electronic databases and references lists were performed. Data from the included studies were extracted in line with the review’s aims, and the studies’ quality was assessed using a standardised criteria. Results: Sixteen studies were included. The results indicated that physicians communicated differently with BME patients compared to non-BME patients as a consequence of patients’ race. Physicians were found to show less participative and affective behaviours towards BME patients and black patients received more information giving behaviours than other ethnicities. Additionally, BME patients displayed less conversational behaviours in comparison to non-BME patients. Studies have also begun to relate other culture related variables to communication but their relationship was less established. Conclusion: While physicians’ communication behaviours varied across patients’ race, there still continues to remain a gap in relation to the literature base being able to sufficiently explain, (a) how race exerts its effect on physician communication and (b) what other variables can account for the differences in physicians’ communication. This gap may reflect the complexity of communication and the measures used. The review firstly reinforces the need for a diverse workforce and the necessity to incorporate affective dimensions of communication in physicians’ cultural communication training, and secondly, calls for future research to expand explanations beyond patients’ race.

Epilepsy is a chronic neurological disorder which can arise following an initial insult that over time, progresses into a condition characterised by recurrent spontaneous seizures. During a latent period between the initial insult and the epilepsy condition proper, major changes occur within the brain at both a cellular and molecular level, in a process known as epileptogenesis. It is postulated that during epileptogenesis, signal transduction pathways are perturbed following the initial insult, which may bring about long term changes in gene expression profiles. For example, the expression of a host of neuropeptides is known to be modulated in response to an initial insult, including the up-regulation of the pro-convulsant tachykinins Substance P and Neurokinin B, encoded by the TAC1 and TAC3 genes, respectively. In this thesis I have explored the regulation of both of these genes by two distinct transcription factor (TF) families; the Neuron Restrictive Silencing Factor (NRSF) isoforms, and the Upstream Stimulatory Factor (USF) proteins. I demonstrate that both NRSF and USF variants regulate TAC3 promoter activity, and that NRSF isoforms can modulate endogenous NKB expression in a human neuroblastoma cell line. Furthermore, these distinct TF families are shown to work in cooperation to regulate the activity of the rat TAC1 promoter. Thus, both NRSF and USF variants are shown to be important in the regulation of pro-convulsant neuropeptides and as both NRSF and USF proteins have been shown to be induced by pro-convulsant stresses here, they are potential key TFs in epileptogenesis, responding to an initial insult, and orchestrating downstream gene expression changes. Consistent with such a model, I have also revealed that both NRSF and USF variants are modulated by anti-convulsant drug treatment. Here, three distinct anti-convulsant drugs, were found to differentially modulate the expression of both the full-length NRSF, and its truncated isoform, as well as the USF proteins USF1 and USF2. Furthermore, whilst the drugs had limited impact upon the localisation of these TFs in human neuroblastoma cells, they did affect the binding of these TFs to target DNA sequences, particularly NRSF binding to its recognition DNA sequence, the NRSE, in a number of genes. In addition, due to an increasingly appreciation of the role of cocaine and the dopaminergic pathways in seizure progression, I explored the impact of cocaine treatment on the expression of these TFs. Cocaine was found to modulate both NRSF and USF variant expression, and NRSF binding to target DNA sequences. These findings suggest that both NRSF and USF variants are important in epileptogenesis and are targets for modulation by the anti-convulsant drugs investigated here. To further explore the significance of NRSF expression in seizure progression, I explored the impact of over-expression of NRSF isoforms, modelling that which occurs in response to seizure in animal models, on global gene expression pathways. I reveal that NRSF isoform over-expression significantly modulates the expression of a host of genes with known associations with epilepsy, supporting a model that NRSF isoforms are key TFs which respond to the initial insult and coordinate long-term changes in gene expression. These findings may help our understanding of the molecular mechanisms at work during epileptogenesis, and may better our understanding of the progression of epilepsy.

Theory and research in the field of persecutory beliefs have identified a number of important psychological processes involved in clinical and non-clinical paranoia. This dissertation set out to investigate some of these processes. Firstly, the empirical evidence for the distinction of 'Poor Me' and 'Bad Me' paranoia (Trower & Chadwick, 1995) was reviewed systematically. Secondly, an empirical study with two phases aimed to investigate the contribution of key processes to paranoia in clinical and non-clinical samples. Investigated factors were: anxiety, depression, anger, attachment anxiety, attachment avoidance, deservedness, submissiveness, self-attacking, self-compassion and experiential avoidance. The review found the distinction of 'Poor Me' and 'Bad Me' paranoia to have some validity and clinical usefulness; however, as yet not all of the theoretical predictions have been borne out in the empirical literature. The importance of the role of deservedness and its measurement was discussed. A series of one-way ANCOVAs found levels of a number of processes to distinguish clinical and non-clinical paranoid groups. Hierarchical regression revealed experiential avoidance to be a significant predictor of paranoia in the final model. A concluding section synthesised these findings and consideration was given to future directions.