Investigating the innate immune barriers that constrain the transmission of coronaviruses

Since the turn of the century, the emergence of three highly pathogenic coronaviruses highlights the importance of understanding coronavirus-host interactions. If sufficient cellular factors are available for a virus to complete its life cycle, genome-encoded post-entry blocks to replication may determine whether virus replication is successful. One such barrier is the interferon response, a signalling pathway upregulating hundreds of interferon-stimulated genes (ISGs), many of which encode proteins with specific and potent antiviral activity. The presence and timing of a functional interferon response is important in controlling coronavirus infection. Thus, identifying ISGs with antiviral activity can provide insights into genetic risk factors associated with coronavirus disease severity and the barriers to coronavirus zoonosis. To identify ISGs that inhibit unmodified coronaviruses, I optimised an arrayed ISG expression screening protocol that utilises immunostaining of the dsRNA replication intermediate and quantification of virus infection by plate-based image cytometry. I screened the endemic coronavirus HCoV-OC43 against multiple ISG libraries encoded into lentiviral vectors, including three published species libraries (human, macaque, bovine) and two newly generated libraries (mouse, bat). This revealed ISGs with known and novel antiviral activity against coronaviruses, including 2’-5’-oligoadenylate synthetase 2 (OAS2). OAS proteins classically activate RNase L via the synthesis of 2’-5’-oligoadenylates, resulting in the degradation of cellular and viral RNA. Alternative splicing generates two OAS2 isoforms, p69 and p71, exhibiting differential antiviral activity. I show that the p69 isoform restricts HCoV-OC43,while the p71 isoform restricts the unrelated picornavirus Cardiovirus A (EMCV) via different mechanisms. The OAS gene family thus enhances antiviral breadth in the host genome by both gene duplication and alternative splicing. This research has provided insights into how coronaviruses interact with the innate immune system

An investigation into the influence of the systemic inflammatory response on treatment response to neoadjuvant chemoradiotherapy in rectal cancer

An abnormal systemic inflammatory response is associated with adverse short and long term outcomes in cancer. Systemic inflammation can be a surrogate maker of the interaction between host immune response and tumour. Systemic inflammation can influence treatment response to chemoradiotherapy. At present there is no reliable biomarker of response to chemoradiotherapy in rectal cancer. This thesis examines the influence of the systemic inflammatory response on treatment response to neoadjuvant chemoradiotherapy in rectal cancer. A dataset of patients receiving neoadjuvant long course chemoradiotherapy (CRT) for non metastatic disease followed by potentially curative resection for rectal cancer was compiled from two prospectively databases of patients treated at Glasgow Royal Infirmary from 2008-2014 and the wider West of Scotland between 2014-2016. Blood results and clinic-pathological data for these patients were collected from electronic patient records to create a comprehensive dataset. Biomarkers of systemic inflammation included: differential blood count; neutrophil to lymphocyte ratio (NLR); haemoglobin; C reactive protein; albumin; and modified Glasgow Prognostic Score(mGPS). Treatment response to chemoradiotherapy was quantified with tumour regression grade, pathological complete response and the neoadjuvant rectal score. I observed white cell count (WCC), NLR and mGPS were not associated with treatment response. Lower haemoglobin and elevated CEA were associated with poorer tumour response. There was no association with changes in WCC, NLR, CRP and tumour response. I observed the development of lymphopenia during treatment but no association with tumour response. I observed baseline anaemia was associated with poorer tumour response and an association between anaemia and systemic inflammation. A significant proportion of my time was in the recruitment and coordination of sample collection for a novel pilot study for the feasibility of protocolised blood and tumour sampling during neoadjuvant therapy. I have not demonstrated an association between serum markers of systemic inflammation and treatment response. I have demonstrated anaemia is a marker of poor response and the association between anaemia and systemic inflammation. This highlights the difficulty in measurements of the systemic inflammatory response from routine blood tests and the importance of more detailed study of markers of systemic inflammatory response which are being done in research settings rather than routine clinical practice. This would help identify reliable biomarkers of treatment response to neoadjuvant chemotherapy and organ preservation strategies

Understanding the role of genetic testing in parental adjustment to their child’s developmental and epileptic encephalopathy or treatment-resistant epilepsy diagnosis

Abstract available at each chapter

Spatial variability of meander characteristics in an avulsing distributive fluvial system

Previous studies of meandering fluvial systems have mainly focused on meanders at a localised ‘reach’ scale within a river system, without consideration of the spatial context. As such, much of the research has focused on exhumed meander deposits instead of active meanders. More research is therefore required on the spatial variability of meander deposits across a single system or sedimentary basin. Recent research has found meandering fluvial systems to be a dominant planform type in modern-day sedimentary basins; meander deposits are consequently assumed to be more dominant than originally perceived in the fluvial rock record. Distributive fluvial systems (DFSs) have also been shown to dominate sedimentation patterns in modern-day aggradational sedimentary basins and therefore warrant further study due to their abundance. Due to the prevalence of meandering systems and distributive fluvial systems in modern-day sedimentary basins, this study aims to fill a critical literature gap with regards to the spatial and temporal variability of meander characteristics across a modern-day distributive fluvial system (i.e., from apex to toe of a DFS). This study uses satellite imagery of Brazil, acquired through Google Earth Engine and analysed in ArcGIS software, to conduct a spatial analysis of the meandering Taquari DFS. The Taquari DFS is a well-documented, dominantly meandering system, which provides a good spatial context for the study of meander characteristics across the DFS. Spatial changes in: channel width, channel belt width, meander deposit dimensions and sinuosity are quantified on the Taquari DFS to explore downstream changes in meander characteristics within this system. Polygons are created in ArcGIS using the available satellite imagery, which allows for detailed measurements of meander dimensions downstream. This study also explores the temporal changes in channel width, channel belt width, meander deposit dimensions, and sinuosity on the Taquari DFS since the initiation of the large Caronal avulsion (initiation between 1996 to 1997) by comparing meander dimensions pre-avulsion and during-avulsion. The Caronal avulsion is ongoing and continues to divert flow from the parent channel to the avulsed channel. Using the oldest and most modern satellite imagery available from 1985 and 2022, respectively, fluvial dimensions are compared between pre-avulsion (1985) and during-avulsion (2022) imagery, to understand the impact of the avulsion on the parent channel (active channel) and its associated channel belt and meander deposits. On the modern Taquari DFS (2022), active variables (i.e., active channel width, active channel belt width, and active meander deposit dimensions) show a decrease in dimensions downstream, with a significant decrease in dimensions downstream of the avulsion point (where flow is diverted to the avulsed channel). Pre avulsion variables were also identified on the 2022 satellite imagery including pre avulsion channel belt width and abandoned meander deposit dimensions. Pre-avulsion channel belt width displays weak downstream trends and abandoned meander deposit dimensions display no downstream trends. Important differences in downstream trends were identified between active and abandoned meander deposit dimensions along the Taquari DFS. The active meander deposits are larger in size than the abandoned meander deposits upstream of the Caronal avulsion point and the abandoned meander deposits are larger than active meander deposits downstream of the avulsion point. The active meander deposits also show clear changes in size and shape downstream as they change from larger, more rounded deposits, to much smaller crescent-shaped deposits. The abandoned deposits however, display a range of shapes and sizes downstream and show no clear decrease in size, especially between medial and distal DFS zones. The decrease in active meander dimensions (active channel width, active channel belt width, and active meander deposit dimensions) is due to a decrease in discharge downstream as a result of typical DFS bifurcation processes in addition to the diversion of flow from the parent channel to the avulsed channel. Active meander deposit size and shape change downstream as sediment load, and therefore deposition, decrease as discharge decreases. The weak downstream trends displayed by the channel belt relate to confinement in the upper DFS where channel belt migration capacity is limited. The lack of downstream trends displayed by the abandoned meander deposits is due to the range of conditions under which these deposits were formed over time. This research has important implications for the understanding of avulsing rivers due to the significant decrease in width of the parent channel and the size of active deposit dimensions downstream, which influence the redistribution of water and sediment resources within modern DFS. In addition, this research creates an important database on the spatial variability of meander deposit dimensions on a modern DFS which can contribute to the understanding of sandstone-body reservoir dimensions which is important for resource exploration or hydrocarbon storage

Strengthening of concrete columns with pseudo-ductile hybrid FRP

Abstract not currently available

Mitochondrial targeting for inhibition of fumarate hydratase

Abstract not currently available

Broken brotherhood: understanding child sexual abuse by Marist brothers and former Marist brothers in Australia

The purpose of this research was to interview four Marist brothers and four former Marist brothers who had abused children to ascertain their understanding of the factors that contributed to the abuse. Interpretive phenomenological analysis was used as the methodology for the research, using semi-structured interviews. The findings were interpreted in the light of the reports of commissions of inquiry and psychological research. The findings supported the view that abuse by clerics is a complex phenomenon that involves personal, situational, organisational, and environmental factors. The results are consistent with the findings from published qualitative research with priests and brothers, and the data from commissions of inquiry, including the importance of opportunity as a significant factor in the abuse of children by clerics. This is the first research project where the participants were all members of the same Roman Catholic religious order of brothers, and from the same country. The results were explored from the perspective of the vocation of brotherhood and, in particular, Marist brotherhood. St Marcellin Champagnat, the founder of the Marist Brothers, was opposed to physical, sexual, and emotional abuse and neglect, and established rules to prevent the abuse of children and to protect the brothers from the temptations of inappropriate behaviour. The regulations regarding relations with pupils and how to live a life of chastity from the time of the Founder until the mid-20th century were explored, especially the changes that took place at the time of Vatican II (1963–65) that led to significant developments in the theology and vocation of brothers in the Church. These developments enabled the Marist Brothers to respond to the abuse crisis by benefiting from insights from psychology and counselling, and from developments in theology, as well as by extending the mission and spirituality of the Marist Brothers to lay men and women. The themes of guilt, shame, redemption, membership, identity, loss, and belonging were explored from the perspective of psychology. Moral injury was proposed as a concept that could be applied to victims, secondary victims, perpetrators, and bystanders, as all felt betrayed and lost trust in individuals in leadership and in the Church as an institution. One of the implications of this research is that clerical status is not a significant variable regarding the abuse of children by priests and brothers. The research also showed that individuals are able to build new lives and identities and live meaningful lives after discovery and imprisonment. Brotherhood as a value and (for some) an identity, continues to have validity whether they continue to live as Marist brothers, leave, or are dismissed from the Order

Three essays on financial analysts

This thesis comprises three chapters in related to the financial analysts. The first chapter focuses on the textual information in analyst reports. The second chapter examines the impact of analyst coverage. The third chapter investigates analysts’ forecasting behavior in relation to the cultural characteristics of covered companies. The first study in Chapter one examines the determinants and the impacts of analysts’ tendency to provide similar textual information in their reports. To implement the tests, I collect a large sample of analyst report transcripts for the S&P 500 companies from 2015 to 2020. I introduce four factors to investigate the possible determinants of analyst report similarity, which include analysts’ herding behavior, analysts’ lack of ability, analysts’ learning behavior, and the significant firm-related news. The regression results indicate that these four factors are positively associated with the analyst report similarity, which suggests that the four factors are likely to be the determinants of analyst report similarity. Next, I examine whether this textual similarity among analyst reports has implications for the market. The results indicate a negative association between the analyst report similarity and the short-term investor reactions, suggesting that market investors consider an analyst report as less informative if the report contains the textual information that is more similar to that in other prior analysts’ reports. In the additional analysis, I find that this similarity likely hinders investors’ understanding of analysts’ quantitative outputs, including the earnings forecasts, stock recommendations, and price target forecasts. In addition, I find that the observed negative investor reaction to the analyst report similarity is stronger when firm managers have more incentives to withhold relevant information, but it is alleviated if the analysts are from larger brokers. The second study in Chapter two investigates the influence of analysts on corporate governance in the context of corporate culture. I first examine the association between the analyst coverage of a firm and the score of the firm’s culture. The baseline results show that the firm with higher level of analyst coverage is associated with a lower score of corporate culture. This is consistent with the argument that analysts can impose short-term pressure on firms, resulting in a weak corporate culture. In further tests, I find that this negative association is stronger for the long-term oriented cultural values than other cultural values. Furthermore, to deal with the potential endogeneity problems, I first employ the two-stage least squares model based on a commonly used instrumental variable in this field, the expected coverage. The results suggest that the analyst coverage has a negative impact on the corporate culture. Moreover, I implement a quasi-natural experiment based on two exogenous shocks to analyst coverage, the brokerage closures and mergers. Consistent with the above findings, the results of the Difference-in-Difference model indicate that the analyst coverage could negatively influence the covered firm’s culture. Taken together, these results are mostly consistent with the pressure effect that analysts impose short-term pressure on firms, increasing management myopia and resulting in a weak corporate culture. In additional tests, I find that analysts’ negative effect on the corporate culture is alleviated when firms are covered by more experienced analysts, when firms are more likely to reach analysts’ earnings forecasts, and when firms tend to have better corporate governance as captured by a higher competitive market. The third study in Chapter three examines whether analysts’ forecasting behavior is affected by the covered firm’s information environment that is characterized by a strong integrity culture. I first investigate the association between analyst forecast boldness and the covered firms’ scores of integrity culture. The baseline results indicate a positive relationship between the two variables, suggesting that analysts tend to issue bolder earnings forecasts when covering the firm with a stronger integrity culture. In further analysis, the results show that analysts’ bolder forecasts for firms with a strong integrity culture are associated with decreased market reactions, indicating that analysts’ bold opinions for these firms are regarded as less informative by market investors. Moreover, I find that the firm with a higher score of integrity culture is negatively associated with the number of analysts following the firm, suggesting that the analyst’s service is less demanded for the firm with a stronger integrity culture. Additionally, other results show that analysts tend to issue less accurate earnings forecasts for firms with higher scores of integrity culture. Furthermore, I mitigate the potential endogeneity issue by conducting the two-stage least squares regression based on two instrumental variables: the average score of corporate integrity culture in an industry and the CEO age of the firm. Consistently, the regression results support the positive association between the firm’s integrity culture and analyst forecast boldness. Finally, I introduce an alternative measure of the score of corporate integrity culture based on the analyst report transcripts. Consistent with the main findings, the regression results show that the corporate integrity culture is positively associated with analysts’ forecast boldness. However, the association is not statistically significant, possibly due to the limited sample of analyst report transcripts

A novel privacy-preserving data sharing system based on attributed-based encryption and zero knowledge proof

The exponential growth of digital data across various sectors, such as healthcare, finance, and e-commerce, has underscored critical concerns regarding data privacy, security, and ownership. Centralised data storage systems are inherently vulnerable to cyber-attacks, raising significant privacy risks and compliance challenges, despite regulatory frameworks like the General Data Protection Regulation (GDPR). This research introduces a decentralised, privacy-preserving data-sharing framework leveraging blockchain technology, Ciphertext-Policy Attribute-Based Encryption (CP-ABE), and Zero-Knowledge Proofs (ZKP). By employing CP-ABE, the proposed system enables fine-grained access control, ensuring that only authorised entities can access sensitive data based on specified attributes. The integration of Zero-Knowledge Proofs preserves user privacy by allowing verification of access rights without revealing the underlying attributes. The system architecture is underpinned by decentralised storage, with smart contracts managing secure access verification. Performance evaluations demonstrate that the system effectively handles dynamic policies and attribute sets, demonstrating its adaptability to real-world applications. This framework represents a significant advancement in privacy-preserving data-sharing technologies, offering a scalable and secure solution for safeguarding sensitive users’ attributes in decentralised environments

Investigating cognitive-motor function in younger and older adults, using multimodal MRI

Abstract not currently available