A national coastal erosion risk assessment for Scotland

The geography of Scotland, with a highly undulating hinterland, long and indented coastline, together with a large number of islands, means that much social and economic activity is largely located at the coast. The importance of the coast is further highlighted by the large number of ecosystem services derived from the coast. The threat posed by climate change, particularly current and future sea level rise, is of considerable concern and the associated coastal erosion and coastal flooding has the potential to have a substantial effect on the socioeconomic activity of the whole country. Currently, the knowledge base of coastal erosion is poor, which serves to hinder the current and future management of the coast. This research reported here aimed to establish four key aspects of coastal erosion within Scotland: the physical susceptibility of the coast to erosion; the assets exposed to coastal erosion; the vulnerability of communities to coastal erosion; and the coastal erosion risk to those communities. Coastal erosion susceptibility was modelled here within a GIS, using data for ground elevation, rockhead elevation, wave exposure and proximity to the open coast. Combining these data produced the Underlying Physical Susceptibility Model (UPSM), in the form of a 50 m2 raster of national coverage. The Coastal Erosion Susceptibility Model (CESM) was produced with the addition of sediment supply and coastal defence data, which then moderates the outputs of the UPSM. Asset data for dwellings, key assets, transport infrastructure, historic assets, and natural assets were used along with the UPSM and CESM to assess their degree of exposure to coastal erosion. A Coastal Erosion Vulnerability Model (CEVM) was produced using Experian Mosaic Scotland (a geodemographic classification which identifies 44 different social groups within Scotland) to classify populations based upon 11 vulnerability variables. Dwellings were assigned a CESM and CEVM score in order to establish their coastal erosion risk. This research demonstrated that the issue of coastal erosion will impact on a relatively low number of properties compared to those impacted by flooding (both coastal and fluvial) as many dwellings are already protected by coastal defences. There is therefore, a considerable future liability, and great pressure for coastal defences to be maintained and upgraded in their current form. The use of the CEVM is a novel inclusion within a coastal erosion assessment for Scotland. Use of the CEVM established that coastal erosion risk is not distributed equally amongst the Scottish coastal population and highlighted that risk can be reduced by either reducing exposure or reducing vulnerability. Thus far in Scotland, reducing exposure has been the primary management approach, which has a number of implications with regards social justice. This research identified the existing data gaps that should be addressed by future research in order to further improve coastal management in Scotland. Future research should focus on assessing historical coastal change rates on a national scale, improve modelling of national scale wave exposure, enhance the information held about current coastal defences and, determine the direct and indirect economic cost associated with the loss of different asset types. It is also necessary to clarify the social justice implications of using adaptation approaches to manage coastal erosion as well as establishing a method to communicate the susceptibility, exposure, vulnerability and risk aspects whilst minimising the potential negative impacts (e.g. property blight) of releasing such information.

TRIB2 in normal and malignant hematopoiesis - a transcription factor network

Hematopoiesis is the tightly controlled and complex process in which the entire blood system is formed and maintained by a rare pool of hematopoietic stem cells (HSCs), and its dysregulation results in the formation of leukaemia. TRIB2, a member of the Tribbles family of serine/threonine pseudokinases, has been implicated in a variety of cancers and is a potent murine oncogene that induces acute myeloid leukaemia (AML) in vivo via modulation of the essential myeloid transcription factor CCAAT-enhancer binding protein α (C/EBPα). C/EBPα, which is crucial for myeloid cell differentiation, is commonly dysregulated in a variety of cancers, including AML. Two isoforms of C/EBPα exist - the full-length p42 isoform, and the truncated oncogenic p30 isoform. TRIB2 has been shown to selectively degrade the p42 isoform of C/EBPα and induce p30 expression in AML. In this study, overexpression of the p30 isoform in a bone marrow transplant (BMT) leads to perturbation of myelopoiesis, and in the presence of physiological levels of p42, this oncogene exhibited weak transformative ability. It was also shown by BMT that despite their degradative relationship, expression of C/EBPα was essential for TRIB2 mediated leukaemia. A conditional mouse model was used to demonstrate that oncogenic p30 cooperates with TRIB2 to reduce disease latency, only in the presence of p42. At the molecular level, a ubiquitination assay was used to show that TRIB2 degrades p42 by K48-mediated proteasomal ubiquitination and was unable to ubiquitinate p30. Mutation of a critical lysine residue in the C-terminus of C/EBPα abrogated TRIB2 mediated C/EBPα ubiquitination suggesting that this site, which is frequently mutated in AML, is the site at which TRIB2 mediates its degradative effects. The TRIB2-C/EBPα axis was effectively targeted by proteasome inhibition. AML is a very difficult disease to target therapeutically due to the extensive array of chromosomal translocations and genetic aberrations that contribute to the disease. The cell from which a specific leukaemia arises, or leukaemia initiating cell (LIC), can affect the phenotype and chemotherapeutic response of the resultant disease. The LIC has been elucidated for some common oncogenes but it is unknown for TRIB2. The data presented in this thesis investigate the ability of the oncogene TRIB2 to transform hematopoietic stem and progenitor cells in vitro and in vivo. TRIB2 overexpression conferred in vitro serially replating ability to all stem and progenitor cells studied. Upon transplantation, only TRIB2 overexpressing HSCs and granulocyte/macrophage progenitors (GMPs) resulted in the generation of leukaemia in vivo. TRIB2 induced a mature myeloid leukaemia from the GMP, and a mixed lineage leukaemia from the HSC. As such the role of TRIB2 in steady state hematopoiesis was also explored using a Trib2-/- mouse and it was determined that loss of Trib2 had no effect on lineage distribution in the hematopoietic compartment under steady-state conditions. The process of hematopoiesis is controlled by a host of lineage restricted transcription factors. Recently members of the Nuclear Factor 1 family of transcription factors (NFIA, NFIB, NFIC and NFIX) have been implicated in hematopoiesis. Little is known about the role of NFIX in lineage determination. Here we describe a novel role for NFIX in lineage fate determination. In human and murine datasets the expression of Nfix was shown to decrease as cells differentiated along the lymphoid pathway. NFIX overexpression resulted in enhanced myelopoiesis in vivo and in vitro and a block in B cell development at the pre-pro-B cell stage. Loss of NFIX resulted in disruption of myeloid and lymphoid differentiation in vivo. These effects on stem and progenitor cell fate correlated with changes in the expression levels of key transcription factors involved in hematopoietic differentiation including a 15-fold increase in Cebpa expression in Nfix overexpressing cells. The data presented support a role for NFIX as an important transcription factor influencing hematopoietic lineage specification. The identification of NFIX as a novel transcription factor influencing lineage determination will lead to further study of its role in hematopoiesis, and contribute to a better understanding of the process of differentiation. Elucidating the relationship between TRIB2 and C/EBPα not only impacts on our understanding of the pathophysiology of AML but is also relevant in other cancer types including lung and liver cancer. Thus in summary, the data presented in this thesis provide important insights into key areas which will facilitate the development of future therapeutic approaches in cancer treatment.