The design and characterisation of miniature bioreactors for microbial fermentation process development.

This thesis focuses on the design and characterisation of miniature bioreactors and evaluates their potential as a scale-down device for microbial cultivation processes. Miniature bioreactors, such as the one detailed in this work, have been developed by many research groups and companies, and seek to increase throughput at the early stages of bioprocess development. Power input was measured in two prototype stirred-tank miniature bioreactors (10 ml and 25 ml) as a function of impeller speed and the vessels were characterised alongside a 7 L bioreactor. The results show that both miniature bioreactors used in this study were able to be characterised using the same methods developed for larger vessels and that the key engineering parameters of volumetric oxygen transfer coefficient and mixing time compared favourably with those of a conventionally-sized bioreactor when expressed as a function of specific power input. An Escherichia coli plasmid DNA cultivation was successfully scaled down to the 10 ml miniature bioreactor from a 7 L bioreactor on the basis of equal specific power input, and demonstrated equivalent performance under oxygen-rich and oxygen- limited conditions. An intermittently-fed process to produce a Fab' antibody fragment using E. coli and a batch cultivation of the filamentous bacterium Saccharopolyspora erythraea producing erythromycin were also evaluated in the 25 ml miniature bioreactor and three other small scale cell cultivation devices (i.e. microtitre plate, miniature bubble column reactor and shake flasks). Their relative performances in terms of growth and product formation were related to that of the 7 L bioreactor. The results obtained demonstrated the ability of the 25 ml miniature stirred tank bioreactor to perform both of these technically-demanding, industrially-relevant bioprocesses to a comparable degree as the 7 L vessel that was not achievable using the other miniature devices tested. The results shown in this thesis highlight the potential of miniature bioreactors to be used to deliver a fully-integrated, high-throughput solution for cell cultivation process development

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Item does not contain fulltex