Strategy adopted by research associations for success

This thesis presents results of a study of the strategy adopted by UK research associations which led to success. The success of research associations, being not for profit organisations, was measured in terms of sustainable growth. Research associations were established as a result of a government initiative to improve the performance of sectors of British industry. Initially they were financed by way of membership subscriptions and a related government grant. With the decline in the size ofthe manufacturing sectors they served and the removal of government grant, research associations have had to make the transition from publicly supported co-operative research associations to independent privately financed research institutes. The identification of the strategy was based on the analysis of documentary archival, interview and questionnaire data. A case study approach was adopted. The research associations were selected and evaluated in pairs to reduce the effect of the external environment, including the influence of the sector the research associations served. Pilot interviews indicated the importance of governance as well as strategy to these organisations. The study therefore included consideration of research associations' governance. The data collected and analysed for case study research associations enabled both their strategy and governance to be classified using the theoretical models of Whittington (2001) and Cornforth (2003) respectively. The more successful research associations were found to have adopted an evolutionary perspective on strategy and a partnership model of organisational governance. Size contributed to success, with the larger research associations exhibiting superior sustainable growth

Drinking water biofiltration: Removal of antibiotics and behaviour of antibiotic resistance genes

This research investigated the effectiveness of biofiltration systems for the attenuation of antibiotics and antibiotic resistance genes (ARGs) from drinking water. Five antibiotics, including amoxicillin, clarithromycin, oxytetracycline, sulfamethoxazole, and trimethoprim, and the relevant resistance genes (blaCTX-M, blaOXA-1, blaTEM, ermB, tetA, tetG, tetQ, tetW, tetX, sul 1, sul 2, dfrA1 and dfrA12) as well as integrase genes (intI 1 and intI 2) were targeted. In addition, the role the biofilm plays as a gene transfer site was also investigated. Both chemical (LC-MS/MS) and molecular biology (real-time qPCR, high-throughput qPCR and 16S rRNA amplicon sequencing) methodologies were used. A total of three biofiltration experiments using sand, granular activated carbon (GAC) and anthracite as filter media were set-up at bench-scale. Results showed that the target antibiotics were substantially removed (> 90%) by GAC-associated biofilters and partially removed (< 20%) by sand and anthracite-sand dual media biofilters. The position of GAC layer within the sand filter bed showed no effect on antibiotic removal. The absolute abundance of ARGs decreased (1.0-log reduction on average) after biofiltration, while ARGs’ normalised copy number remained unchanged or showed an increasing trend in the filtered water, especially when exposed to the target antibiotics, indicating that the biofilters did not contribute greatly to the elimination of ARG pollution from the feedwater despite the effective removal of antibiotics. Exposure to the target antibiotics affected the bacterial community in biofilm samples and the differences in bacterial community structure were correlated with the changes in the resistome. Plasmid conjugative transfer experiment based on biofiltration showed that the GAC media is more conducive to the horizontal transfer of ARGs in biofilms and the transfer occurred more frequently in biofilms than in the influents and effluents. Overall, the results of this study could enhance our understanding of the prevalence of ARGs during drinking water treatment

A bioinformatic analysis of Mycobacterium tuberculosis and host genomic data

Human tuberculosis disease (TB) is caused by bacteria within the Mycobacterium tuberculosis complex, including M. tuberculosis (Mtb). Genetic variation within the pathogen can lead to drug resistance, affect virulence and transmissibility. I have analysed Mtb whole genome sequence data to improve the understanding of global genetic variation, and the resulting insights could ultimately assist the development of TB control measures. Whole genome sequencing platforms are being used to infer drug resistance profiles, and thereby could assist clinical management. I investigated the reproducibility of sequence data from two platforms (Illumina MiSeq, Ion Torrent PGM™) and two rapid analytic pipelines (TBProfiler, Mykrobe predictor). DNA replicates from the reference strain (H37Rv) and 10 drug-resistant strains were sequenced, and inferred drug resistance genotypes were compared to drug susceptibility testing phenotypes. Genome-wide association study (GWAS) can be used to detect mutations associated with Mtb drug resistance. A first GWAS (n=127) attempted to identify mutations associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. A second GWAS was applied to a large global set (n>6400) to identify mutations associated with first- and secondline drug resistance. M. aurum is an environmental mycobacteria that has been proposed as a model for the development of anti-TB drugs. I have assembled and annotated its draft genome, and identified copy number variants in known drug resistance targets. Approximately 10% of the Mtb genome consists of two gene families (pe/ppe) that are poorly characterised, and are hypothesised to be important virulence factors. Using a de novo assembly approach, I characterised these genes and their diversity across a global collection of clinical isolates with high depth short-read sequence data (n=518). A follow-up study using a long-read sequence technology (n=18, diverse stain types) confirmed the findings. This work also generated new annotated reference genomes and characterised methylation sites, which may affect transmissibility, pathogenicity and virulence. A future direction of the TB genomics field is to identify genetic check points in host-pathogen interactions using both human and Mtb genotypes. I analysed the genomes of ~720 TB case–Mtb pairs and identified susceptibility markers, which are promising targets for future control measures

Genetic Evaluation of ESBL E. coli Urinary Isolates in Otago

The incidence of infections with extended spectrum beta-lactamase (ESBL)-producing E. coli in New Zealand is increasing. ESBL E. coli most commonly cause urinary tract infections and are seen in both community and hospital patients. The reason for the increasing incidence of ESBL E. coli infections is unknown. In this study, 66 urinary ESBL E. coli isolates from Otago in 2015 were fully genetically characterised to understand the mechanisms of transmission. The ESBL gene, E. coli sequence types, plasmid types, and genetic context (e.g. insertion sequences) of ESBL genes were determined by a combination of whole genome and plasmid sequencing. A bioinformatic pipeline was constructed for the hybrid assembly of Illumina short reads and MinION long reads of ESBL-encoding plasmids. Significant diversity of E. coli strains, plasmids, and the genetic context of ESBL genes was seen. This suggests multiple introductions of ESBL resistance genes or resistant bacterial strains accounts for the increased incidence of ESBL E. coli in this low prevalence area. Future studies should investigate modes of transmission of ESBL E. coli and the genes they encode in Otago

Robust hybrid central/self-organising multi-agent systems in intersections without traffic lights

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Mobile mercury resistance transposons: surveillance and resistance gene cassette variation in wastewater

In a wastewater environment, mercury resistance and other antimicrobial metal resistance genes have been observed despite their lack of use clinically. The hypotheses explored whether the change in populations to a rural wastewater treatment plant affects the abundance of Tn21 and similarly identify potential co–occurrence antimicrobial resistance genes carried within or alongside Tn21 and Tn21-like transposable elements. Finally, Tn21 is known to be carried by a wide range of Gram-negative bacteria, however without being able to cross-link Tn21 to the host it is not possible to identify in large scale samples which organisms may in fact carry the mobile element within an environmental sample. Results showed that large-scale population changes impacted the abundance of Tn21 and the carriage of co-occurrent resistance genes. Wastewater treatment processing was also shown to reduce diversity of Tn21 gene cassette arrays of the class I integron and therefore not remove the presence of antimicrobial resistance genes disseminating into the environment. The studies highlight the need for intervention within the wastewater treatment process

Mobile mercury resistance transposons: surveillance and resistance gene cassette variation in wastewater

In a wastewater environment, mercury resistance and other antimicrobial metal resistance genes have been observed despite their lack of use clinically. The hypotheses explored whether the change in populations to a rural wastewater treatment plant affects the abundance of Tn21 and similarly identify potential co–occurrence antimicrobial resistance genes carried within or alongside Tn21 and Tn21-like transposable elements. Finally, Tn21 is known to be carried by a wide range of Gram-negative bacteria, however without being able to cross-link Tn21 to the host it is not possible to identify in large scale samples which organisms may in fact carry the mobile element within an environmental sample. Results showed that large-scale population changes impacted the abundance of Tn21 and the carriage of co-occurrent resistance genes. Wastewater treatment processing was also shown to reduce diversity of Tn21 gene cassette arrays of the class I integron and therefore not remove the presence of antimicrobial resistance genes disseminating into the environment. The studies highlight the need for intervention within the wastewater treatment process