Regulation of early steps of GPVI signal transduction by phosphatases: a systems biology approach

We present a data-driven mathematical model of a key initiating step in platelet activation, a central process in the prevention of bleeding following Injury. In vascular disease, this process is activated inappropriately and causes thrombosis, heart attacks and stroke. The collagen receptor GPVI is the primary trigger for platelet activation at sites of injury. Understanding the complex molecular mechanisms initiated by this receptor is important for development of more effective antithrombotic medicines. In this work we developed a series of nonlinear ordinary differential equation models that are direct representations of biological hypotheses surrounding the initial steps in GPVI-stimulated signal transduction. At each stage model simulations were compared to our own quantitative, high-temporal experimental data that guides further experimental design, data collection and model refinement. Much is known about the linear forward reactions within platelet signalling pathways but knowledge of the roles of putative reverse reactions are poorly understood. An initial model, that includes a simple constitutively active phosphatase, was unable to explain experimental data. Model revisions, incorporating a complex pathway of interactions (and specifically the phosphatase TULA-2), provided a good description of the experimental data both based on observations of phosphorylation in samples from one donor and in those of a wider population. Our model was used to investigate the levels of proteins involved in regulating the pathway and the effect of low GPVI levels that have been associated with disease. Results indicate a clear separation in healthy and GPVI deficient states in respect of the signalling cascade dynamics associated with Syk tyrosine phosphorylation and activation. Our approach reveals the central importance of this negative feedback pathway that results in the temporal regulation of a specific class of protein tyrosine phosphatases in controlling the rate, and therefore extent, of GPVI-stimulated platelet activation.

Optimising mirid control on cocoa farms through complementary monitoring systems

Mirids (Sahlbergella singularis and Distantiella theobroma) are the most important insect pests affecting cocoa production across West Africa. Understanding the population dynamics of mirids is key to their management, however, the current recommended hand-height assessment method is labour intensive. The objective of the study was to compare recently developed mirid sex pheromone trapping and visual hand-height assessment methods as monitoring tools on cocoa farms and to consider implications for a decision support system. Ten farms from the Eastern and Ashanti regions of Ghana were used for the study. Mirid numbers and damage were assessed fortnightly on twenty trees per farm, using both methods, from January 2012 to April 2013. The mirid population increased rapidly in June, reached a peak in September and began to decline in October. There was a significant linear relationship between numbers of mirids sampled to hand-height and mirid damage. High numbers of male mirids were recorded in pheromone traps between January and April 2012 after which there was a gradual decline. There was a significant inverse relationship between numbers of trapped adult mirids and mirids sampled to hand-height (predominantly nymphs). Higher temperatures and lower relative humidities in the first half of the year were associated with fewer mirids at hand-height but larger numbers of adult males were caught in pheromone traps. The study showed that relying solely on one method is not sufficient to provide accurate information on mirid population dynamics and a combination of the two methods is necessary.