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‣ Computational methods for multi-omic models of cell metabolism and their importance for theoretical computer science

Angione, Claudio
Fonte: University of Cambridge; Faculty of Computer Science and Technology; Computer Laboratory Publicador: University of Cambridge; Faculty of Computer Science and Technology; Computer Laboratory
Tipo: Thesis; doctoral; PhD
Português
Relevância na Pesquisa
70.83936%
To paraphrase Stan Ulam, a Polish mathematician who became a leading figure in the Manhattan Project, in this dissertation I focus not only on how computer science can help biologists, but also on how biology can inspire computer scientists. On one hand, computer science provides powerful abstraction tools for metabolic networks. Cell metabolism is the set of chemical reactions taking place in a cell, with the aim of maintaining the living state of the cell. Due to the intrinsic complexity of metabolic networks, predicting the phenotypic traits resulting from a given genotype and metabolic structure is a challenging task. To this end, mathematical models of metabolic networks, called genome-scale metabolic models, contain all known metabolic reactions in an organism and can be analyzed with computational methods. In this dissertation, I propose a set of methods to investigate models of metabolic networks. These include multi-objective optimization, sensitivity, robustness and identifiability analysis, and are applied to a set of genome-scale models. Then, I augment the framework to predict metabolic adaptation to a changing environment. The adaptation of a microorganism to new environmental conditions involves shifts in its biochemical network and in the gene expression level. However...

‣ Genome-wide microscopy screening identifies links across processes including a conserved connection between DNA damage control and the microtubule cytoskeleton

Lawson, Jonathan Luke Done
Fonte: University of Cambridge; Department of Genetics Publicador: University of Cambridge; Department of Genetics
Tipo: Thesis; doctoral; PhD
Português
Relevância na Pesquisa
129.90257%
Previous PhD students in the lab created a method for large-scale, high-content microscopy screening of a cell library consisting of over 3000 single mutant strains of the fission yeast, Schizosaccharomyces pombe. Each strain has one nonessential gene knocked-out, allowing investigation of the resulting phenotypes. I report the implementation and completion of this screen; developing methods to ensure reliable and accurate results through inclusion of many controls across multiple screening repeats. In total, over 4.5 million images from approximately 19 000 biologically independent cell populations were imaged and analysed. All strains screened contained GFP-labelled tubulin (GFP-Atb2) allowing visualisation of the microtubule polymer network and its organisation in cells, a feature that is conserved across eukaryotes and simplified in S. pombe, making it easy to study. Examination of cell outlines and microtubule patterns was used to study three cell processes: the shape of cells, the organisational pattern of interphase microtubules and the cell cycle stage of cells, as judged by microtubule pattern. Comparison with extensive data from wild-type cells led to the identification of 262 factors that influence one or more of these cell processes. I go on to biologically validate some of the outcomes from the screen...

‣ The Role of IGF-1 and TRPV4 in Regulation of [Ca2+]i and Actin Organization in ATDC5 Chondrocytes

Lam, Andy
Fonte: University of Delaware Publicador: University of Delaware
Tipo: Tese de Doutorado
Português
Relevância na Pesquisa
70.842715%
Randall Duncan; Cartilage is a thin layer of tissue composed of mainly water, collagen, and proteoglycans that forms a sliding area so that diarthrodial joints can easily function. Chondrocytes are the cells of this tissue that produces and maintains the cartilage of matrix and the phenotype and function of these cells is regulated by the organization of actin cytoskeleton. Two dimensional culture studies have shown that Insulin-like Growth Factor-1 (IGF-1) increased cell stiffness through regulation of actin cytoskeleton, which suppressed the activation of TRPV4. TRPV4, a Ca2+ channel, is an important regulator of intracellular Ca2+ and is an anabolic factor in chondrocytes for matrix synthesis. I hypothesize that IGF-1 has differential effects on the actin cytoskeletal organization and TRPV4 channel activity in ATDC5 chondrocyte cells in 2D/3D culture environments. ATDC5 chondrocytes were cultured in sodium alginate beads and treated with 4 different treatments: control, IGF-1 treatment, Rac-1 Inhibitor treatment, IGF-1+Rac-1 inhibitor treatment (n=10) and [Ca2+]i levels were measured with PTI and FURA-2AM protocol. ATDC5 chondrocytes were also grown in 2D culture environment (collagen II coated coverslips) and in 3D (collagen/agar matrix)...