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A combined theoretical and experimental study of the criteria governing the failure analysis of pressure vessels with defects has been performed. The fields of fracture mechanics (linear elastic and elastic-plastic behaviour), failure governed by large scale plastic deformation and energy balance methods are critically reviewed. All three approaches are shown to have relevance in the complete failure analysis of a structure with defects. An experimental study of the failure mechanisms of precracked polycarbonate and maraging steel plates and model polycarbonate vessels is presented. Room temperature, static loading tests are performed on 85 mm wide, 5 mm thick compact specimens of polycarbonate (0.013 andle; ^aandfrasl;_W andle; 0.810). For comparison, 51 mm wide maraging steel compact specimens are monotonically loaded at room temperature. The influence of through-thickness constraint on the fracture toughness and slow crack growth characteristics of the steel is investigated using plates of varying thickness (3.1 mm-25.4 mm) and initial crack length (0.386 andle; ^aandfrasl;_W andle; 0.766 for 3.1 mm thick sheet); various ancillary studies (scanning electron microscopy, surface deformation studies) complement the results. The crack growth behaviour of longitudinal through (0.704 ≤ c / andradic;‾DT/2</span> ≤ 1.434) and deep part-through (^dandfrasl;_T = 0.700 and 0.878) cracks in 50.8mm and 102mm diameter (5mm and 6mm wall thickness) polycarbonate cylinders is also studied. Bowling and Townley's two-criteria approach to failure i.e. LEFM on the one hand and limit analysis on the other, is shown to provide a useful method for assessing the relative importance of crack initiation, in the presence of limited crack tip plasticity and general yield as failure criteria for a given sized defect. Thus, for crack tip plasticity fully contained by an outer elastic field i.e. not general yield, the LEFM parameter, K_Ic (with the possibility of a plasticity correction factor for thin sheet) can be used to predict crack initiation. For the low strain-hardening maraging steel, Irwin's plane strain plasticity correction, ¹andfrasl;_6π (K_{Ic/σ_y})² is shown to be applicable to sheet thicknesses comparable to ¹andfrasl;_π (K_{Ic/σ_y})² i.e. twice Irwin's plane stress plastic zone radius.

Roundabout (Robo) receptors were first identified in neurons as guidance molecules, however growing evidence suggests that they also play a role in other cells. The aim of this thesis was to characterise the expression and function of a novel endothelial specific member of this family, Robo4. This study revealed that Robo4 is expressed primarily in vessels but also differentially expressed in tumour vessels. Interestingly Robo4 was primarily located within cytoplasmic vesicles coated with clathrin, suggesting that the presence of Robo4 on the cell surface is being tightly regulated. Overexpression of Robo4 induced filopodia and pseudopodia formation and actin re-organisation into stress fibres. It co-localised with actin and tubulin suggesting an important interaction between Robo4 and the cytoskeleton. Robo4's function in endothelial cells was directly investigated using two approaches, overexpression using adenovirus and knockdown using small interfering RNA. Functional cell-based assays revealed that disrupting Robo4's level of expression negatively affects endothelial cell functions that are required during angiogenesis, such as proliferation, migration and tubulogenesis. Overexpression of a truncated version of Robo4, which lacks the C-terminus, provided clues regarding Robo4's function. The intracellular domain is critical for Robo4's localisation and its association with the cytoskeleton. It is also required for pseudopodia formation. Other findings include possible cleavage of Robo4 and Robo4 homodimerisation and heterodimerisation with Robo1. Taken together, the findings presented in this study strongly suggest a role for Robo4 in endothelial cell guidance. Cell guidance during angiogenesis is poorly understood therefore the identification of a new molecule potentially involved in this mechanism will hopefully help elucidate the process.

Fibroblast growth factors (FGFs) are critical in many aspects of embryonic development and other cellular functions including apoptosis, cell adhesion, and proliferation. FGF8a, specifically, is known to initiate retinal ganglion cell (RGC) differentiation along with FGF3 early in retinal development (Martinez-Morales et al., 2005b). There has been little research into later roles for FGF8a in eye development. Here we show mRNA expression of fgf8a in the presumptive RGCs of 2 day-old zebrafish, past the time of RGC differentiation (28-48 hours)(Schmitt and Dowling, 1996). In addition, mRNA expression of putative receptor, FGFR1b, was localized outside the retina on the presumptive vasculature. Acerebellar (ace) mutants lacking FGF8a show mispatterned retinal vasculature and a lack of blood flow through the eye at 48 hpf. Further, we looked to see if this lack of blood flow had any effect on the developing neural retina. We found a significant reduction in the size of ace mutant eyes and also a reduction in total cell numbers in the retina starting at 48 hours post fertilization (hpf) suggesting a role for fgf8a in neurovascular signaling. The cause of the small eye phenotype was found to be due to a lack of proliferating cells and not an increase in cell death. We hypothesized if this phenotype was a result of a lack of blood flow to the retina. It has previously been reported that zebrafish survive and develop normally for 7 days without blood flow as the embryo receives nutrients by simple diffusion with its surroundings (Sehnert et al., 2002). To investigate the role that blood flow plays on the developing retina we utilized a silent heart mutant (sih) fish line, which lacks cardiac troponin t resulting in embryos without blood flow, as heart contractility does not initiate. To explore lack of blood flow to the retina as a cause for the observed ace mutant phenotype, sih mutant eye phenotypes were assessed. Retina cell counts from these embryos show a decreased eye diameter and a loss in total retina cell numbers due to lack of proliferation, phenocopying ace mutants. sih mutants also show a mis-patterning of their retinal vasculature with ectopic vessel branches similar to ace mutants. Our data support the small eye phenotype seen in both mutants is a result due to lack of proliferation. After morpholino knock down of the receptor, fgfr1b, we see mispatterend vasculature that phenocopies what we see in ace mutants. These finding led us to hypothesize that FGF8a, secreted by the RGCs, signals through its receptor, FGFR1b, on the retinal vasculature to promote cell growth and development. Further these data suggest that the retinal vasculature subsequently responds by secreting an unknown factor to support the proliferation and maintenance of the RGCs.