PhD Project

"A comprehensive systems approach to predict functionality of Duffy-Binding-Like (DBL) domains in malarial proteins".

Supervisors:

Richard Pleass, Molecular and Biochemical Parasitology Group, Liverpool School of Tropical Medicine.

Hugo van den Berg, Systems Biology Centre, University of Warwick.

The Duffy-Binding-Like (DBL) protein domains are essential to the function of malarial proteins involved in critical interactions with both the mosquito vector and human host. A new method for iterative domain prediction, called correlation function decomposition, will be used to define the structural features that define the propensity of a given DBL domain to engage a particular ligand (which in turn determines which physiological evasion mechanism is deployed by the parasite). Results of this analysis will be used to perform sequence alignment via adaptive dynamic programming, which is an improvement of the standard alignment algorithm, and to build Hidden Markov Chain models that incorporate functional propensities. Furthermore, at the system-wide level, infected-cell-immune cell interactions will be modelled to predict organism-level outcomes of possible mutations by determination of the effective propagation number.

MSc Experimental Project

"Establishing a dual colour live cell assay to observe multi-generational mitotic inheritance in human cells".

Supervised by Andrew McAinsh, Centre for Mechanochemical Cell Biology, University of Warwick.

Cells with the chromosomal instability phenotype show and increased probability of chromosome segregation errors linked with a genetic instability. This leads to the survival of aneuploid cells which are associated with cancer as well as other major human diseases. A bipolar mitotic spindle is known to promote amphitelic kinetochore-microtubule attachments - the only attachment associated with accurate chromosome segregation. Any other spindel geometry promotes erroneous attachments leading to chromosome segregation errors. However, it is unknown whether the geometry of the mitotic spindle and chromosome segregation errors are inherited.

The focus of this investigation, therefore, was the link between segregation errors and spindle geometry in order to further our understanding of how non-disjunction events occur. First, the two geometrically distinct pathways through mitosis - the prophase and prometaphase pathways - were studied. From this it was established that the rate of lagging chromosomes was increased in cells following the prometaphase pathway, where a monopolar intermediate stage in spindle formation is present. This confirms the link between mitotic spindle geometry and lagging chromosomes. It has also been shown here that mitotic timings are not an indicator of segregation errors. Finally, the first dual colour 72 assay has been developed to investigate inheritance of mitotic pathway and segregation errors over muliple generations in HeLa cells. Data from this experiment suggests that the mitotic pathway is not inherited, however, further work is needed to investigate patterns of segregation error inheritance over multiple generations.

MSc Theoretical Project

"Competition between light and temperature in the Arabidopsis thaliana circadian clock: A study of the Locke model".

Supervised by Mirela Domijan, Systems Biology Centre, University of Warwick.

The circadian clock is an endogenous timers that controls numerous metabolic, developmental and physiological processes across the plant and animal kingdoms. The clock can be entrained to light and temperature cycles, however the interaction with these external inputs, especially with temperature, is still poorly understood. Temperature sensitive parameters were identified in the Locke model of the Arabidopsis thaliana circadian clock using a variety of methods (Locke et al., 2006). This allowed different temperature sensitive models of the circadian clock to be created. The combined phase response of the parameters to a decrease in temperature was then calculated for each model using the theory of infinitesimal response curves. By fitting this to an experimental phase response curve (Salome and McClung, 2005) using linear regression, the effect of temperature on the temperature sensitive parameters was quantified. This enabled competition studies to be performed for each version of the temperature sensitive clock: subjecting the clock to in-phase or out-of-phase effects of light and temperature. The result of these simulations were compared, identifying differences in the network structure and the output observed. These results will form the basis for future experiments whose outcome might provide an insight into the molecular mechanisms behing the temperature response in the A. thaliana circadian clock.

BSc Dissertation

"Optimal strategies in bird migration".

Supervised by Nick Hill, Mathematics Department, University of Glasgow.