Tumour suppressors are the brakes of the cell that prevent abnormal cell division in our bodies. Loss of the tumour suppressor Merlin leads to tumours in multiple cell types within our nervous systems. We have two copies of a tumour suppressor (one on each chromosome we inherit from our parents), and Merlin deficient tumours can commonly arise either by sporadic loss of both copies in a single cell, or in familial cases of cancer (eg. Neurofibromatosis type 2, NF2) by inheriting one abnormal copy and the second copy been lost in a cell during our lifetime. As would be predicted in patients with NF2, the onset of disease is much earlier and patients have multiple tumours. Tumours can arise from the Schwann cells that wrap and myelinate axons (schwannomas), meningeal cells that form the membrane around the brain and spinal cord (meningiomas), and ependymal cells that line the ventricles of the brain (ependymomas). These tumours grow slowly, are resistant to chemotherapy, and require multiple difficult surgical operations to remove the tumour tissue. In NF2 patients this means multiple tumours and surgeries, starting in their teenage years and continuing through their lifetime. Patients with NF2 typically present with hearing loss and balance problems due to schwannoma tumours on the vestibulocochlear nerve which carries hearing and balance information to the brain. We use primary human schwannoma cells from patients as an in vitro model of the disease, and study interactions between Merlin and other proteins, specifically transcription factors, which bind DNA and regulate other genes, control the normal stop of proliferation and promote differentiation of Schwann cells in our peripheral nervous system. Analysis of human schwannoma tumours, both in vitro and in vivo, shows that the level of a transcription factor called Sox-10 is reduced or absent in all schwannoma tumours analysed (n=14). Sox-10 is important not only in the control of Schwann cell-axon interaction, but also in stopping Schwann cells from proliferating and drives the induction and maintenance of these cells to a differentiated, quiescent state. Re-introduction of Sox-10 alone into Merlin null human schwannoma cells allows them to induce a differentiated quiescent state. In humans, Merlin and Sox-10 lie close together on chromosome 22 and, in at least 60% of tumours, the two genes are lost together in the second 'hit' that occurs in NF2. We believe that this is one mechanism by which tumours lose Sox-10 function, but there may be others involving the regulation of the Sox-10 gene itself. We plan to comprehensively study the role of Sox-10 in the pathogenesis of Merlin null tumours in both human primary schwannoma cells and a transgenic knockout approach in mice. For the work with primary human schwannoma cells, we will study both the regulation of Sox-10 and the effects of Sox-10 re-introduction into these cells. In the transgenic mice, these offer a unique way to study the interaction between Merlin and Sox-10 proteins. Previous attempts to model NF2 in mice have shown that loss of Merlin alone induces a very different spectrum of tumours compared to the human disease; we think that the untested role of Sox-10 in these tumours may lie behind these differences. Because Sox-10 and Merlin are on different mouse chromosomes, we can remove Merlin in Schwann cells on a Sox-10 wild-type, hemizygous (only 1 copy of the gene) or Sox-10 null background both in vitro and in vivo, and truly study the effects of Sox-10 function on the pathology of these tumours. We can then correlate these findings in the mouse with our findings in primary human schwannoma cells. The endpoint of these experiments will be twofold: Firstly, to understand how loss of Merlin and Sox-10 co-operate to cause schwannoma tumours. Secondly, and more importantly, to create a new more accurate model of disease for NF2 in mice to allow in vivo testing of new compounds for treatment of these tumours.

To establish and deliver a business development and diversification strategy for the Port of Fowey pro actively managing resources for commercial and societal benefits.

The aims of this AAKTP are to establish platform-based technologies and cost-effective biopesticides/biostimulant products using innovative and novel bioprocesses for adoption by growers and smallholder farmers of all sizes within the Agricultural and Horticultural sectors.

Water wave impact on coastal structures such as sea walls, dikes and breakwaters, can lead to water overtopping the structure. This can cause difficulties in the area the structure was built to protect, and possibly damage the structure. Most previous studies of overtopping have examined the total flow of water for a given sea state, and many fewer studies consider individual wave events. These latter have focussed on collecting data on the overtopping event rather than relating it directly to the behaviour of the incident wave, which is the focus of the proposed work. Many types of disturbance and damage are more closely related to individual overtopping events than to the total flow over a longer period. Our recent substantial experimental and numerical modelling work on wave impact on walls, shows the likely importance of relatively rare very violent impacts, and provides a basis for quantitative modelling of wave overtopping, of both violent and more ordinary waves. Greater understanding of these infrequent events will be valuable for both coastal engineering researchers and practitioners alike.The present investigation will again capitalise on the advantages of interactive physical and numerical model studies as a means of gaining new insights into complex wave phenomena. Thus, it is proposed to concentrate in detail on situations of particular scientific interest rather than engage in extensive parametric testing. We note, for example, that there has been little study of the transition between breaking and non-breaking waves on steep beaches / gently sloping structures and expect to find significant differences in swash and overtopping between collapsing and surging breakers on a steep slope. Effects of the structure's geometry, such as different slopes and crest width, will also be examined. The approaching waves will either come over a plane sloping bed or meet a mound at the base of the structure that can trigger plunging or spilling breakers. Experimental measurements of water height, flow rate and pressure will be made. The flow will be numerically modelled by modifying existing programs, one of which includes the compressibility that can be important when air is trapped or entrained by the water. Scaling of results from laboratory measurements to prototype scale can be improved by including such effects. We expect the flow over a structure to depend significantly on its surface roughness, and many protective structures are made of units which are very rough. The study will consider simple roughness elements; for example circular cylinders projecting from the surface. Flow around and over a single roughness element will be related to their overall effect. In the case of the most violent wave impacts we expect that the roughness may also diminish the maximum pressure, by its disturbing effect on the flow.Theoretical work will include analytical study as well as making use of existing numerical programs. Analytical study is a 'blue skies' element of this proposal in that it is rather challenging. It will build on models of swash, since there are very few previous results for overtopping. However, analytical results can be of great value in comprehending different flow regimes.Overall, results from all aspects of this study are to be used to develop improved models of overtopping events that are expected to be useful for designers of coastal structures such as breakwaters and seawalls.

As agreed with AHRC please see the Case for Support attachment for the full application information