Developing Multimodal Spectroscopic Imaging Techniques to Study Metal Dyshomeostasis and Altered Brain Biochemistry During Ageing

Cognitive decline and neurodegenerative diseases such as Alzheimer’s disease, pose significant concerns for the ageing population. Increased understanding of the biochemical processes that occur during ageing, may help to reveal pathways for prevention or treatment. There has been interest in the potential role that metal dis-homeostasis plays during ageing and cognitive decline, so this thesis has focussed on developing and applying spectroscopic methods to study metal dis-homeostasis and concomitant biochemical changes during ageing

Regulation of Transcription and Stress Response by CarD in Mycobacteria

Mycobacterium tuberculosis, the causative agent of Tuberculosis, infects over one third of the world\u27s population. To control this epidemic, we must develop new chemotherapeutic strategies for treatment, which requires further insight into the physiology of this bacterium. Previous studies have identified CarD as a transcriptional regulator essential during both acute and persistent infection. Depletion of CarD sensitizes strains to a diverse panel of stresses and deregulates several hundred genes and ribosomal RNA (rRNA) which suggested that CarD may be a transcriptional regulator. Chromatin immunoprecipitation sequencing experiments showed that CarD was localized to promoters throughout the genome, suggesting that CarD regulates transcription initiation. In collaboration with the Darst Lab, we published the first crystal structure of a CarD homolog. CarD\u27s N-terminal domain was homologous to a known RNA polymerase (RNAP) interacting domain and C-terminal domain with a novel fold. Modeling CarD onto initiation structures of RNAP position CarD\u27s C-terminal domain to interact with DNA. We identified three independent activities of CarD: binding RNAP, binding DNA, and the activity of a highly conserved tryptophan residue that we predict stabilizes the transcription bubble. Using a panel of single mutations in carD that attenuate one of these three activities, I characterized the roles of each of CarD\u27s activities in vivo and in vitro. All three of CarD\u27s activities are necessary for optimal growth, antibiotic resistance, stabilizing RNAP-promoter complexes, and activating transcription from rRNA promoters. This work contributed to a model in which CarD slows the rate of transcription initiation DNA bubble collapse and accelerates DNA opening. In further studies of CarD, I discovered a correlation between the cellular concentration of CarD and growth rate and showed that this growth rate dependence is not due to an effect on the rRNA content of the cell. This separated CarD\u27s effect on growth rate from its effect on rRNA content for the first time, which indicates that this growth defect is a result of deregulation of non-rRNA promoters. Additionally, I elucidated a new mechanism of regulating CarD activity through turnover of free protein. Most recently, I discovered the extent of CarD regulation in mycobacteria through RNA sequencing experiments. These studies revealed that more than 80% of the transcripts in the genome are significantly affected by alterations in CarD activity. Furthermore, there are transcript-dependent effects of CarD that imply that CarD is responsive qualities of the promoters but showed that the promoter sequence only partial explains this specificity. My thesis work has dramatically advanced our understanding of the mechanism of transcriptional regulation by CarD. CarD\u27s activity at transcription initiation complexes is an entirely novel mechanism of transcriptional regulation, creating a new paradigm of transcriptional regulation in prokaryotes. Furthermore, as CarD is conserved in many bacteria, its function has broad implications for bacterial transcription beyond mycobacteria. Finally, since CarD is essential in mycobacteria and absent from eukaryotes, my work will inform the development of new strategies to inhibit CarD activity as novel therapies to treat tuberculosis

Development of a Faculty Learning Community to support Scholarship and Feedback

In an effort to explore the ideas of Scholarship of Learning and Teaching, and to comply with Glasgow’s University’s career development programme, a small group of academics from the College of Medicine, Veterinary and Life Sciences established a Learning Community. The LC has several aims: • To create and design a Learning Community to support scholarship and progression for lecturers on learning & teaching track • To understand how a Learning Community can be used to support staff on career development pathways • To empower participants to engage in the University’s career development programme through peer support and peer mentorship within the Learning Community • provide practical support for scholarship projects (it is hoped that all members will be supported to drive their scholarship ‘from idea to manuscript’) It is hoped that through the sharing of ideas, and collaboration between schools, the LC hope to publish and disseminate scholarship, and provide a series of recommendations regarding scholarship support. Planned scholarship outputs include papers in educational journals, conference abstracts and presentations, and a significant ambition to influence policy within the university regarding scholarship and career development

Barriers to entry: social exclusion is rife in elite professions in the UK

Research by Louise Ashley, Hilary Sommerlad and Jo Duberley highlights the structural nature of social exclusion and its connections to unequal access to educational opportunities

A qualitative evaluation of non-educational barriers to the elite professions: June 2015

This report sets out the findings from a qualitative study, focusing on two main areas. The first (Study A) examines the barriers to entry for people from less privileged socioeconomic backgrounds to elite law and accountancy firms, with a particular focus on London. The second (Study B) examines the barriers to entry for people from similar backgrounds to elite financial service firms (inclu ding accountancy) located in Scotland

Dredged Sediments Contain Potentially Beneficial Microorganisms for Agriculture and Little Harmful Cyanobacteria

Abstract Introduction Soils worldwide are degrading, raising concerns about our ability to feed the growing global population. Soil amendments that can alleviate degradation are gaining attention. The application of sediments dredged from waterways to agricultural fields has increasing promise as a means for improving degraded soils. However, herbaceous plant species may have difficulty establishing on dredged material because of low nutrient availability, inhibitory levels of toxins, unsuitable moisture conditions and lack of microorganisms capable of ameliorating these characteristics. To counteract these issues, we sought to understand if the use of a cover crop would increase the abundance, diversity and function of beneficial soil microorganisms compared to harmful microorganisms in dredged sediments. Materials and Methods We collected soil samples from two 100% dredged sediment plots, one where winter cereal rye (Secale cereal) was grown as a winter cover crop and one left fallow over the winter, followed by traditional corn (Zea mays) planting. We sampled both plots three times during the growing season: before cover crop application, following cover crop application but before corn planting and following final corn harvest. We then used high‐throughput sequencing to identify the bacterial and fungal communities present in the samples. Results Our data show that cover crop application did not alter the microbial community in these plots. However, sampling time decreased species diversity and altered the composition of both fungal and bacterial communities recovered from these plots. Across both plots, microorganisms associated with carbon cycling were more abundant than those associated with harmful effects, including microcystin‐producing cyanobacteria, which were an extremely small portion of the overall community. Conclusion Our work suggests that dredged sediments have the potential to improve soil function through the addition of microorganisms associated with nutrient cycling, but a cover crop is not necessary to incur these benefits

MHC-dependent inhibition of uterine NK cells impedes fetal growth and decidual vascular remodelling.

NK cells express variable receptors that engage polymorphic MHC class I molecules and regulate their function. Maternal NK cells accumulate at the maternal-fetal interface and can interact with MHC class I molecules from both parents. The relative contribution of the two sets of parental MHC molecules to uterine NK cell function is unknown. Here we show that, in mice, maternal and not paternal MHC educates uterine NK cells to mature and acquire functional competence. The presence of an additional MHC allele that binds more inhibitory than activating NK cell receptors results in suppressed NK cell function, compromised uterine arterial remodelling and reduced fetal growth. Notably, reduced fetal growth occurs irrespectively of the parental origin of the inhibitory MHC. This provides biological evidence for the impact of MHC-dependent NK inhibition as a risk factor for human pregnancy-related complications associated with impaired arterial remodelling.This work was supported by the Wellcome Trust, the Medical Research Council, the Centre for Trophoblast Research and the British Heart Foundation.This is the final version of the article. It first appeared from Nature Publishing Group at http://dx.doi.org/10.1038/ncomms4359

Manipulation of the Immune Response by Human Cytomegalovirus

Human cytomegalovirus (HCMV) is an endemic betaherpesvirus whose persistence can be attributed to evasion of the immune response. The intrinsic immune response, the first to be activated, is mediated by endogenously expressed antiviral proteins. The core proteins of Nuclear Domain 10 (ND10) - Promyelocytic leukemia factor (PML), speckled protein of 100kDa (Sp100) and human death domain associated protein 6 (hDaxx) - are key effectors of the intrinsic response to HCMV. This thesis demonstrates that PML and Sp100 are upregulated by type I interferons (IFNs) during HCMV infection and that this contributes significantly to the antiviral capacity of type I IFNs. Type I IFNs are proinflammatory cytokines produced during the innate immune response to HCMV. Type I IFNs induce an antiviral state by upregulation of IFN stimulated genes (ISGs). This thesis explores IFN-independent regulation of ISGs by HCMV, using cell lines lacking the ability to produce or respond to IFNs. The ISGs identified as being regulated independently of IFN are: IFIT1, IFIT2, IFIT3, ISG15, CXCL10, Mx1 and Mx2. The antigen presenting molecule, major histocompatibility complex class I (MHC) I is also an ISG. Levels of MHC I and MHC I-like molecules are extensively regulated by HCMV. Therefore, this thesis explored the regulation of MHC I related molecule 1 (MR1) that had not previously been studied during HCMV infection. Although MR1 was not an ISG, its expression was regulated by HCMV. In the absence of exogenous MR1 ligand, HCMV infected cells upregulated MR1 cell surface expression, while in the presence of MR1 ligand, HCMV infection impaired MR1 cell surface expression. Some ligands bound by MR1 activate innate-like mucosal-associated invariant T (MAIT) cells. To date, MR1-dependent activation of MAIT cells is known to protect against bacterial and fungal pathogens. In the context of viral infection, MAIT cells can be activated in an MR1-independent manner by proinflammatory cytokines. However, this thesis demonstrates that HCMV infection can inhibit MR1-dependent MAIT cell activation, a finding suggests HCMV could alter the pathogenesis of bacterial or fungal co-infections. This thesis also raises the possibility that HCMV-associated MR1 ligands exist, and that MAIT cells may play a role in monitoring HCMV infection

An annotated Afrikaans/English list of words and phrases used on the floor of the Johannesburg stock exchange

The object of this project is to provide translators with a standardized list of Afrikaans/English words and phrases used on the floor of The Johannesburg Stock Exchange. The Introduction sets out the compilation method and prescriptive approach adopted. The list is preceded by a Forward for prospective users. In the Annotations selected problems relating to a word or phrase are discussed and wherever necessary definitions provided to substantiate arguments. The Conclusion contains comments on the compilation method and prescriptive approach