ELUCIDATION OF KEY MEDIATORS OF TUMOUR CELL MIGRATION USING AN IN VIVO INHIBITORY RNA SCREEN

Metastatic disease, or the migration of cancer cells from the primary tumor to distant locations in the body, contributes to over 90% of cancer mortalities. Migration is a requirement of metastasis and involves the detachment of cancer cells from the primary tumour in vivo, followed by invasion of the cell into the surrounding stromal tissue. Tumour cells that are migration-deficient are incapable of detaching from the primary tumour and exhibit compact phenotypes in the chicken embryo model. Based on these findings, it was hypothesized that mediators of migration could be identified using an RNAi genomic library and screening for compact tumour phenotypes in the chicken embryo model. It was also postulated that knockdown of two proteins known to be involved in migration, rhoA and cortactin, would prevent migration of human epidermoid carcinoma (HEp3) cells in vivo, serving as a positive control and proof-of-principle for the RNAi screen. Results of this study identify rhoA and cortactin as positive regulators of migration, both in vitro and in vivo, and demonstrate the feasibility of the RNAi screen. Furthermore, execution of an RNAi screen, covering 5000 human genes, identified three novel mediators of tumour cell migration: MESCD1, KIF3B and ARHGAP12

The Evolution of Evolutionary Explanations of Culture: How and Why Can a Critical Evaluation of Costly Signalling Theory Enhance Our Understanding of Cultural Practices?

In the last two decades, evolutionary explanations of cultural practice have become prevalent within the social sciences and humanities, including religious studies. This thesis is a critical analysis and recension of one of these applications of evolutionary theory to cultural practice. Specifically, I analyse a secondary case study to investigate the explanatory power and politico-ethical considerations that arise from the application of costly signalling theory to Māori tā moko. Utilising primary and secondary source materials, this research was conducted within an interpretivist and inductive qualitative framework with the aim of offering a reflexive critique of the explanatory power that costly signalling theory carries for tā moko and, more broadly, of the illustrative efficacy of evolutionary explanations when applied to indigenous cultural practices. In a critique of the Cisco case study, I identify some of the more general, global deficiencies of evolutionary explanations of culture and explore the rich, indigenous narrative complexes which shape understandings of Māori tā moko. I maintain that the argument for moko as a costly signal, based, in part, upon Māori warfare is a reiteration of mythologised aspects of Māori culture which divorces tā moko from its ontological and epistemological underpinnings. In separating it from its Māori context, the reflexivity of tā moko is denied and Westernised and colonised conceptions of tā moko which etically view Māori cultural practice through a veil of alterity are perpetuated. In response to the concerns the application of costly signalling theory to tā moko generates, I propose an alternative model: transmissive assemblage. Drawing from actor-network theory, indigenous ontological perspectivism, and Kaupapa Māori, the transmissive assemblage model provides a symmetrical and decolonised framework which both challenges and enhances the dominant Western scientific paradigms used to explain indigenous practices. By focussing on the interactions between agents and the associations which circulate between them, rather than on the agents themselves, this integrative model makes an original contribution to scholarship in allowing the emergence of heteroglossia and by providing a balanced platform for indigenous voices and emic perspectives to be represented in the context of Western scientific research. In doing so, I argue that integrative, reflexive, and decolonised approaches to indigenous cultural practice which focus on process, as opposed to agency, enhance the explanatory power of evolutionary explanations by affording indigenous groups the opportunity to assert their own agency within the paradigm of Western science

Effects of a Combined Aquatic Exercise and Walking in Sedentary Obese Females Undergoing a Behavioral Weight-Loss Intervention

Background: The effects of the non-weight bearing method of aquatic exercise as a modality for weight loss have not been established. The purpose of this study was to examine the effects of a combined aquatic exercise and walking program compared to walking alone on body weight and selected variables in obese females undergoing a 16-week Standard Behavioral Treatment (SBT) program. Methods: Forty-four obese (BMI 34.9 ± 3.8 kg·m2) sedentary women (age=40.3 years ± 6.8 yrs) were randomly assigned to either an aquatic exercise (AE) group or a traditional walking (W) exercise only group. Both groups were also required to complete 3 sessions of home based walking per week, and reduce energy intake to facilitate weight loss. Results: In the AE group, total body weight, cardiorespiratory fitness, flexibility, strength, and health-related quality of life outcomes significantly improved over time similar to the W group. Significantly greater enjoyment scores also occurred in the AE group. Conclusion: Aquatic exercise in combination with walking can serve as an alternative to walking exercise alone for overweight women during periods of weight loss, and this can improve functional health status

Aberrant Neuronal Dynamics during Working Memory Operations in the Aging HIV-Infected Brain

Impairments in working memory are among the most prevalent features of HIV-associated neurocognitive disorders (HAND), yet their origins are unknown, with some studies arguing that encoding operations are disturbed and others supporting deficits in memory maintenance. The current investigation directly addresses this issue by using a dynamic mapping approach to identify when and where processing in working memory circuits degrades. HIV-infected older adults and a demographically-matched group of uninfected controls performed a verbal working memory task during magnetoencephalography (MEG). Significant oscillatory neural responses were imaged using a beamforming approach to illuminate the spatiotemporal dynamics of neuronal activity. HIV-infected patients were significantly less accurate on the working memory task and their neuronal dynamics indicated that encoding operations were preserved, while memory maintenance processes were abnormal. Specifically, no group differences were detected during the encoding period, yet dysfunction in occipital, fronto-temporal, hippocampal, and cerebellar cortices emerged during memory maintenance. In addition, task performance in the controls covaried with occipital alpha synchronization and activity in right prefrontal cortices. In conclusion, working memory impairments are common and significantly impact the daily functioning and independence of HIV-infected patients. These impairments likely reflect deficits in the maintenance of memory representations, not failures to adequately encode stimuli

Aberrant Neuronal Dynamics during Working Memory Operations in the Aging HIV-Infected Brain.

Impairments in working memory are among the most prevalent features of HIV-associated neurocognitive disorders (HAND), yet their origins are unknown, with some studies arguing that encoding operations are disturbed and others supporting deficits in memory maintenance. The current investigation directly addresses this issue by using a dynamic mapping approach to identify when and where processing in working memory circuits degrades. HIV-infected older adults and a demographically-matched group of uninfected controls performed a verbal working memory task during magnetoencephalography (MEG). Significant oscillatory neural responses were imaged using a beamforming approach to illuminate the spatiotemporal dynamics of neuronal activity. HIV-infected patients were significantly less accurate on the working memory task and their neuronal dynamics indicated that encoding operations were preserved, while memory maintenance processes were abnormal. Specifically, no group differences were detected during the encoding period, yet dysfunction in occipital, fronto-temporal, hippocampal, and cerebellar cortices emerged during memory maintenance. In addition, task performance in the controls covaried with occipital alpha synchronization and activity in right prefrontal cortices. In conclusion, working memory impairments are common and significantly impact the daily functioning and independence of HIV-infected patients. These impairments likely reflect deficits in the maintenance of memory representations, not failures to adequately encode stimuli

The impact of patient and public involvement in the SlowMo study: reflections on peer innovation

Background The SlowMo study demonstrated the effects of SlowMo, an eight-session digitally supported reasoning intervention, on paranoia in a large-scale randomized-controlled trial with 362 participants with schizophrenia-spectrum psychosis. Aim The current evaluation aimed to investigate the impact of Patient and Public Involvement (PPI) in the SlowMo study. Method PPI members were six women and three men from Sussex, Oxford and London with experience of using mental health services for psychosis. They received training and met at least 3-monthly throughout the project. The impact of PPI was captured quantitatively and qualitatively through (i) a PPI log of recommendations and implementation; (ii) written subjective experiences of PPI members; (iii) meeting minutes; and (iv) outputs produced. Results The PPI log revealed 107 recommendations arising from PPI meetings, of which 87 (81%) were implemented. Implementation was greater for recruitment-, data collection- and organization-related actions than for dissemination and emergent innovations. Qualitative feedback revealed impacts on study recruitment, data collection, PPI participants' confidence, knowledge, career aspirations and society more widely. Outputs produced included a film about psychosis that aired on BBC primetime television, novel webpages and journal articles. Barriers to PPI impact included geography, travel, funding, co-ordination and well-being. Discussion A future challenge for PPI impact will be the extent to which peer innovation (innovative PPI-led ideas) can be supported within research study delivery. Patient and Public Contribution Planned Patient and Public Contribution in SlowMo comprised consultation and collaboration in (i) design, (ii) recruitment, (iii) qualitative interviews and analysis of service users' experiences of SlowMo therapy and (iv) dissemination

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin