Bioinformatic analysis of genome-scale data reveals insights into host-pathogen interactions in farm animals

This thesis documents the contribution of my bioinformatics research activities, including novel software development, to a range of research projects aimed at investigating the interactions between bacterial and viral pathogens and their hosts. The focus is largely on farm animal species and their pathogens, although some of the research has a wider scientific impact. RNA interference (RNAi) refers to a variety of related regulatory pathways present in animals, plants and insects. The major pathways are microRNAs (miRNAs), small-interfering RNAs (siRNAs) and PIWI-interacting RNAs (piRNAs). Marek’s disease virus is an important pathogen of poultry, causing T-cell lymphoma. We identified the presence and expression patterns of several MDV-encoded microRNAs, including the identification of 5 novel microRNAs. We also showed that not only do virus-encoded microRNAs dominate the mirNome within chicken cells, but also that specific host-microRNAs are down-regulated. We also identify novel virus-encoded microRNAs in other Herpesviridae and provide the first evidence of miRNA evolution by duplication in viruses. In related work, we present a novel microRNA generated by the canonical miRNA biogenesis pathway in Avian Leukosis Virus, another avian oncogenic virus, and publish data showing the expression pattern of known chicken microRNAs across a range of important avian cells. Two of the other RNAi pathways (siRNA and piRNA) form an important part of the antiviral response in arthropods. We have published work demonstrating an siRNA antiviral response to bluetongue virus and Schmallenberg virus in cells from the Culicoides midge, an important insect vector, as well as work demonstrating the importance of the piRNA pathway in the antiviral response to Semliki forest virus (SFV). Further work on flaviviruses in ticks demonstrates the active suppression of the siRNA response by Langat Virus, as well as a key difference between the siRNA responses in Mosquitos compared to ticks. Salmonella is one of the most important zoonoses, with an estimated 1.4 million cases of human salmonellosis per annum in the USA alone. Salmonella infections of farm animals are an important route into the human food chain. This thesis presents work on the comparative structure and function of 13 fimbrial operons within Salmonella enterica serovar Enteritidis as well as a genomic comparison of that serovar with Salmonella enterica serovar Gallinarum, a chicken-specific serovar. We characterised the global expression profile of Salmonella enterica serovar Typhimurium during colonization of the chicken intestine, and we have published the genomes of four strains of Salmonella eneterica serovars of well-defined virulence in food-producing animals. Our work in this area led to us publishing an important and comprehensive review of the automatic annotation of bacterial genomes. Finally, I present work on novel software development. ProGenExpress, a software tool that allows the easy and accurate integration and visualisation of quantitative data with the genome annotation of bacteria; Meta4 is a web application that allows data sharing of bacterial genome annotations from metagenomes; CORNA, a software tool that allows scientists to link together microRNA targets, gene expression and functional annotation; viRome, a software tool for the analysis of siRNA and piRNA responses in virus-infection studies; DetectiV, a software tool for the analysis of pathogen-detection microarray data; and poRe, a software tool that enables users to organise and analyse nanopore sequencing dat

Systems Engineering Principles and the Challenges in Deriving Them

No abstract availabl

Engineering Elegant Systems: Postulates, Principles, and Hypotheses of Systems Engineering

No abstract availabl

Providing Feedback Following Leadership Walkrounds is Associated with Better Patient Safety Culture, Higher Employee Engagement and Lower Burnout

Background There is a poorly understood relationship between Leadership WalkRounds (WR) and domains such as safety culture, employee engagement, burnout and work-life balance. Methods This cross-sectional survey study evaluated associations between receiving feedback about actions taken as a result of WR and healthcare worker assessments of patient safety culture, employee engagement, burnout and work-life balance, across 829 work settings. Results 16 797 of 23 853 administered surveys were returned (70.4%). 5497 (32.7% of total) reported that they had participated in WR, and 4074 (24.3%) reported that they participated in WR with feedback. Work settings reporting more WR with feedback had substantially higher safety culture domain scores (first vs fourth quartile Cohen’s d range: 0.34–0.84; % increase range: 15–27) and significantly higher engagement scores for four of its six domains (first vs fourth quartile Cohen’s d range: 0.02–0.76; % increase range: 0.48–0.70). Conclusion This WR study of patient safety and organisational outcomes tested relationships with a comprehensive set of safety culture and engagement metrics in the largest sample of hospitals and respondents to date. Beyond measuring simply whether WRs occur, we examine WR with feedback, as WR being done well. We suggest that when WRs are conducted, acted on, and the results are fed back to those involved, the work setting is a better place to deliver and receive care as assessed across a broad range of metrics, including teamwork, safety, leadership, growth opportunities, participation in decision-making and the emotional exhaustion component of burnout. Whether WR with feedback is a manifestation of better norms, or a cause of these norms, is unknown, but the link is demonstrably potent

Pharmacological Inhibition of O-GlcNAcase (OGA) Prevents Cognitive Decline and Amyloid Plaque Formation in Bigenic Tau/APP Mutant Mice

Background Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer’s disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of amyloid plaques in the presence of tau pathology. Results We treated double transgenic TAPP mice, which express both mutant human tau and amyloid precursor protein (APP), with a highly selective orally bioavailable inhibitor of the enzyme responsible for removing O-GlcNAc (OGA) to increase O-GlcNAc in the brain. We find that increased O-GlcNAc levels block cognitive decline in the TAPP mice and this effect parallels decreased β-amyloid peptide levels and decreased levels of amyloid plaques. Conclusions This study indicates that increased O-GlcNAc can influence β-amyloid pathology in the presence of tau pathology. The findings provide good support for OGA as a promising therapeutic target to alter disease progression in Alzheimer disease

In the dedicated pursuit of dedicated capital: restoring an indigenous investment ethic to British capitalism

Tony Blair’s landslide electoral victory on May 1 (New Labour Day?) presents the party in power with a rare, perhaps even unprecedented, opportunity to revitalise and modernise Britain’s ailing and antiquated manufacturing economy.* If it is to do so, it must remain true to its long-standing (indeed, historic) commitment to restore an indigenous investment ethic to British capitalism. In this paper we argue that this in turn requires that the party reject the very neo-liberal orthodoxies which it offered to the electorate as evidence of its competence, moderation and ‘modernisation’, which is has internalised, and which it apparently now views as circumscribing the parameters of the politically and economically possible

Alliance Foundation Trial 09: A randomized, multicenter, phase 2 trial evaluating two sequences of pembrolizumab and standard platinum-based chemotherapy in patients with metastatic NSCLC

INTRODUCTION: The sequence of chemotherapy and pembrolizumab may affect antitumor immune response and efficacy of immunotherapy. METHODS: This multicenter, randomized, phase 2 trial was designed to evaluate the efficacy of two sequences of chemotherapy and pembrolizumab in patients with stage 4 NSCLC. Both arms were considered investigational, and the study used a pick a winner design. The primary end point was objective response rate by independent radiologic review after eight cycles (24 wk). Patients were randomized 1:1 to arm A (chemotherapy for four cycles followed by pembrolizumab for four cycles) or arm B (pembrolizumab for four cycles followed by chemotherapy for four cycles). Patients in both arms without disease progression after the initial eight cycles continued pembrolizumab until disease progression, unacceptable toxicity, or a maximum of 2 years. RESULTS: From March 2016 to July 2018, a total of 90 eligible patients were randomized (43 patients to arm A and 47 patients to arm B). The objective response rate at 24 weeks in arms A and B was 39.5 % (95 % confidence interval [CI]: 24.9%-54.1 %) and 40.4 % (95 % CI: 26.4%-54.5 %), respectively ( CONCLUSIONS: Additional evaluation of either sequence in a phase 3 trial is not warranted

Journal of Microelectronic Research - May 2003

https://scholarworks.rit.edu/meec_archive/1012/thumbnail.jp

Christianity as Public Religion::A Justification for using a Christian Sociological Approach for Studying the Social Scientific Aspects of Sport

The vast majority of social scientific studies of sport have been secular in nature and/or have tended to ignore the importance of studying the religious aspects of sport. In light of this, Shilling and Mellor (2014) have sought to encourage sociologists of sport not to divorce the ‘religious’ and the ‘sacred’ from their studies. In response to this call, the goal of the current essay is to explore how the conception of Christianity as ‘public religion’ can be utilised to help justify the use of a Christian sociological approach for studying the social scientific aspects of sport. After making a case for Christianity as public religion, we conclude that many of the sociological issues inherent in modern sport are an indirect result of its increasing secularisation and argue that this justifies the need for a Christian sociological approach. We encourage researchers to use the Bible, the tools of Christian theology and sociological concepts together, so to inform analyses of modern sport from a Christian perspective

Nitrite circumvents platelet resistance to nitric oxide in patients with heart failure preserved ejection fraction and chronic atrial fibrillation

Aims: Heart failure (HF) is a pro-thrombotic state. Both platelet and vascular responses to nitric oxide (NO) donors are impaired in HF patients with reduced ejection fraction (HFrEF) compared to healthy volunteers (HV) due to scavenging of NO, and possibly also reduced activity of the principal NO sensor, soluble guanylate cyclase (sGC), limiting the therapeutic potential of NO donors as anti-aggregatory agents. Previous studies have shown that nitrite inhibits platelet activation presumptively after its reduction to NO, but the mechanism(s) involved remain poorly characterized. Our aim was to compare the effects of nitrite on platelet function in HV vs. HF patients with preserved ejection fraction (HFpEF) and chronic atrial fibrillation (HFpEF-AF), vs. patients with chronic AF without HF, and to assess whether these effects occur independent of the interaction with other formed elements of blood. Methods and Results: Platelet responses to nitrite and the NO donor sodium nitroprusside (SNP) were compared in age-matched HV controls (n = 12), HFpEF-AF patients (n = 29) and chronic AF patients (n = 8). Anti-aggregatory effects of nitrite in the presence of NO scavengers/sGC inhibitor were determined and vasodilator-stimulated phosphoprotein (VASP) phosphorylation was assessed using Western blotting. In HV and chronic AF, both nitrite and SNP inhibited platelet aggregation in a concentration-dependent manner. Inhibition of platelet aggregation by the NO donor SNP was impaired in HFpEF-AF patients compared to healthy and chronic AF individuals, but there was no impairment of the anti-aggregatory effects of nitrite. Nitrite circumvented platelet NO resistance independently of other blood cells by directly activating sGC and phosphorylating VASP. Conclusion: We here show for the first time that HFpEF-AF (but not chronic AF without HF) is associated with marked impairment of platelet NO responses due to sGC dysfunction and nitrite circumvents the “platelet NO resistance” phenomenon in human HFpEF, at least partly, by acting as a direct sGC activator independent of NO