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Head direction (HD) cells in the rodent brain can use visual information about surrounding landmarks to 'reset' their represented orientation, to keep it aligned with the world (a process called landmark anchoring). This implies HD cells receive input from the visual system about the surrounding panorama and its landmarks. Which features in a panorama are used by the HD system? Can HD cells integrate raw luminance input from across the panorama, as might be subserved by subcortical visual processing? Alternatively, do HD cells need discretised landmarks with features, requiring more elaborate visual landmark processing and recognition? I present work addressing how visual information reaches the HD circuit in rats. In the first experiment, we ask whether HD cells require discrete landmarks to anchor to visual panoramas. We record HD cells in a landmark anchoring paradigm using a visual panorama containing a single gradient shifting gradually from black to grey to black. Although there was evidence HD cells could integrate information from this scene, cue control was weak and less reliable than anchoring to visual landmarks with edges. In the second experiment, I present HD cell recordings in rats with lesions of the lateral geniculate nucleus, the thalamic relay of the cortical visual pathway, to test whether subcortical vision is sufficient for landmark-anchoring. HD cells in these animals showed impaired anchoring to cue cards, and lesion extent correlated with the severity of the impairment. Together, these findings indicate that the cortical visual pathway is necessary for intact and stable landmark anchoring to visual cues. Although this process can use entire visual panoramas, it may be more precise if distinct features are available in the scene. Landmark processing in the brain may be complex, and further work could probe whether direct projections from visual cortex provide this information to the HD circuit.

Uranium carbide is a candidate fuel for Generation IV nuclear fission reactors due to its higher thermal conductivity and metal atom density than its oxide fuel counterpart. However, in order for carbide fuels to be implemented, a reprocessing method must be devised to increase fuel efficiency and limit the volume of nuclear waste produced. Currently, nuclear fuel is reprocessed by first dissolving it in nitric acid. However, when carbide fuel is dissolved in this way, organic compounds are formed in the resulting solution. These organics have been observed to complex the plutonium (IV) and uranium (VI) ions in the solution making their extraction from the solution for further processing significantly more difficult. Therefore, a method of removing the organic compounds, or preventing their formation, must be found. Mathematical models have been constructed that simulate both the dissolution of a UC/(U, Pu)C pellet in nitric acid, and a pre-oxidative process that implements a conversion into UO2 removing the possibility of organic formation. Models have been built by mathematically describing the physical processes, particularly heat and mass transfer, involved followed by a numerical solution generated using finite difference methods. Available literature was consulted for reaction coefficients and information on reaction products initially, with experimental data then used where possible to derive new coefficients and compare to the literature values. Further models were then produced through the modification of commercial code that uses the Lattice Boltzmann Method to calculate fluid flow around the pellet and consider batch processes. The completed models assist in characterising the proposed reprocessing method for carbide fuels by predicting reaction completion times under various initial conditions and therefore suggest the optimal oxidation and dissolution conditions. The result is a powerful tool for use by the nuclear industry in assessing the most feasible reprocessing method.

Described herein are copper-catalysed N-C heteroarylations of benzimidazole, 1-methylbenzimidazolone, imidazole and pyrrole. The products of these reactions then undergo palladium-catalysed C-C cross-couplings with aryl or heteroarylboronic acids under Suzuki-Miyaura conditions to provide a rapid entry to tris(hetero)aryl scaffolds comprising two or three N-heterocyclic rings. The sequential N-C and C-C couplings can be performed in a one-pot process. 1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been synthesised in good yields starting from (2-fluoro-5-pyridyl)boronic acid. The sequence comprises three steps: (i) palladium-catalysed Suzuki-Miyaura reaction; (ii) basic hydrolysis; (iii) copper-catalysed C-N coupling. X-ray crystal structures are reported for selected pyridin-2(1H)-one derivatives. These compounds are of interest as new scaffolds for drug discovery. A one-pot synthesis of 2-chloro-3,4-diiodopyridine from 2-chloropyridine is described via a Directed ortho Metallation (DoM)/Halogen Dance (HD) mechanism in 26-28% yields. By performing sequential iterative Suzuki-Miyaura cross-couplings using a variety of functionalised heteroaryl and arylboronic acids, a series of novel 2,3,4-triheteroarylpyridine scaffolds have been accessed in synthetically viable yields, including sterically hindered derivatives. An iterative two-fold Sonogashira/Suzuki-Miyaura reaction sequence gave access to 5-[3,4-bis(2-phenylethynyl)pyridine-2-yl]-2-fluoropyridine in 48% overall yield. Disclosed is a novel route towards benzimidazolo[1,2-f]phenanthridines starting from 4-tert-butyl-N-(2-iodophenyl)benzamide via a intermolecular palladium-catalysed N-C bond formation and dehydration to form 2-(4-tert-butylphenyl)-1-(2-bromophenyl)-1H-benzo[d]imidazole. Performing an intramolecular C-H activation reaction on this provided 6-tert-butylbenzimidazolo[1,2-f]phenanthridine. This compound could be of interest to materials science or as a new scaffold for drug discovery. Synthesis of novel soluble, shielding auxiliary ligand 4-(4-(2-ethylhexyloxy)-2,6-dimethylphenyl)pyridine-2-carboxylic acid (G1pic) has been achieved via a five step synthesis from commercially available starting materials utilising the Suzuki-Miyaura reaction on demanding substrates. A route towards a more shielded auxiliary ligand have been explored eventually providing 3-(4-pyridyl)-1,5-bis(4-(2-ethylhexyloxy)phenyl)-2,4-dimethylbenzene as an intermediate for future work. Ir(III) complexes have been synthesised with G1pic and picolinic acid.

Empirical testing is centred on p-values. These summary statistics are used to assess the plausibility of a null hypothesis, and therein lies a flaw in their interpretation. Central to this research is accounting for the behaviour of p-values, through density functions, under the alternative hypothesis, H1. These densities are determined by a combination of the sample size and parametric specification of H1. Here, several new contributions are presented to reflect p-value behaviour. By considering the likelihood of both hypotheses in parallel, it is possible to optimise the decision-making process. A framework for simultaneously testing the null and alternative hypotheses is outlined for various testing scenarios. To facilitate efficient empirical conclusions, a new set of critical value tables is presented requiring only the conventional p-value, hence avoiding the need for additional computation in order to apply this joint testing in practice. Simple and composite forms of H1 are considered. Recognising the conflict between different schools of thought with respect to hypothesis testing, a unified approach at consolidating the advantages of each is offered. Again, exploiting p-value distributions under various forms of H1, a revised conditioning statistic for conditional frequentist testing is developed from which original p-value curves and surfaces are produced to further ease decision making. Finally, attention turns to multiple hypothesis testing. Estimation of multiple testing error rates is discussed and a new estimator for the proportion of true null hypotheses, when simultaneously testing several independent hypotheses, is presented. Under certain conditions it is shown that this estimator is superior to an established estimator.

The physical and electronic structural changes that occur during lithium intercalation into two vanadium oxides. V205 and V6013, and the mixed metal spinel materials, Li,CoyMn4,08, where y = 0.1,2, 4 and x = 0,1,2, have been studied using a combination of theoretical methods. These transition metal oxides are of great interest as are possible cathode materials in solid-state lithium-ion batteries. Both interatomic potential based static lattice or 'atomistic' modelling, and electronic structure calculations based on Density Functional Theory have been used in this study. An interatomic potential model for V6013 has been derived using empirical fitting methods. We use Mott-Littleton methods to find the lowest energy sites occupied by intercalated lithium ions in both V,05 and V6013. Electronic structure methods have been used to investigate the relative stability of a series of Li,V,05 phases, where 0 x 2, and Li,V6013 phases. where 0 x 4, which has allowed us to predict average discharge voltages for both materials that are in good agreement with experiment. Calculated electron density distributions show that the lithium insertion reaction is accompanied by the localised reduction of vanadium metal atoms in both Li,V,05 and LixV6013. Li+ has been shown to be mobile along the [0/01 direction in Vi05. Calculated average voltages for the spinel family. Li,CoyMn4_y08, are in good agreement with experiment. and clearly show that the presence of cobalt is fundamental to the generation of voltages over 5V. The oxygen atoms are also shown to accept electron density during lithium intercalation and may play a role in the generation of such high voltages.

The purpose of this study has been to investigate the absorption of iron in various kinds of liver disease and to determine the influence of some of the factors which might affect absorption. Especial attention has bean paid to the possible role of the pancreas in influencing the absorption of iron in these conditions. The absorption of iron was studied in a total of 39 patients with liver disease. Twenty patients with iron-deficiency anaemia went also given iron absorption tests. Data from 61 normal control subjects and 46 patients with iron-deficiency anaemia was used in defining a range of absorption in normal and iron-deficient subjects. The absorption of iron was studied using the radio-isotope balance technique introduced by Dubach, Callender and Moore (1948). The principle of the method is that a known amount of activity is administered by mouth sad the amount of activity appearing in the faeces is determined. The amount of iron retained can then be calculated and equated to the amount absorbed. Using this method the absorption of labelled inorganic iron and food iron as represented by labelled haemoglobin was determined. The doses of iron were prepared so that 5 mg. of elemental iron was present in each dose of labelled ferrous sulphate or haemoglobin. The amount of radioactivity in each dose was also comparable and varied from 3 to 5 microcuries. The percentage of the dose given by mouth which was used for haemoglobin formation was determined from a blood sample taken 11 to 15 days after administration of the dose. Haematological investigations and biochemical tests were done by standard procedures. The results of iron absorption studies in normal control subjects given labelled ferrous sulphate showed in 45 observations on 37 subjects a mean absorption of 30 per cent. with a range of 7 to 70 per cent. The mean percentage appearing in the blood was 23 per cent. and the range 1 to 58 per cent. Iron absorption studies using labelled haemoglobin in normal control subjects showed in 24 subjects a mean absorption of 11 per cent. with a range of 0 to 32 per cent. The mean percentage of the dose which appeared in the blood was 6 per cent. and the range 0 to 21 per cent. In iron-deficient subjects absorption was increased. In 19 iron-deficient subjects given labelled ferrous sulphate the moan absorption was 54 per cent. with a range of 14 to 54 per cent. the mean percentage of the dose appearing in the blood was 53 per cent. with a range of 8 to 90 per cent.

The absorption of labelled haemoglobin in 27 patients showed a mean value of 20 per cent. with a range of 1 to 56 per cent. The mean percentage appearing in the blood was 18 per cent. with a range from 0 to 40 per cent. Eight patients with haemochromatosis were investigated. Seven were untreated. They were ail tested with labelled haemoglobin. One patient had completed a full course of venesection end was not iron-laden. In the seven iron-laden patients the mean absorption of labelled haemoglobin was 12 per cent. with a range of 5 to 20 per cent. The amount of the dose utilised for red-cell formation showed a mean of 4 per cent. with a range of 1.5 to 7 per cent. In the patient who had been venesected absorption was 47 per cent. and the patient utilised 13 per cent. of the dose for red-cell formation. The absorption of iron in these patients was comparable to that seen in normal control subjects, but iron overload usually reduces absorption. Therefore this in fact represents a high absorption when the state of the increased tissue iron is taken into consideration. Seventeen patients with cirrhosis of the liver were studied using either labelled ferrous sulphate or labelled haemoglobin iron. In seven patients with cirrhosis of the liver given labelled ferrous sulphate the mean absorption was 63 per cent. with a range of 17 to 100 per cent., an increase in absorption which is statistically significant when compared with a group of normal control subjects. In 10 patients with cirrhosis given labelled haemoglobin the mean absorption was 37 per cent. with a range of 3 to 64 per cent. This increase in absorption was also statistically significant. Examination of this group of cirrhotic patients shows that nine had anaemia or recent bleeding which might be expected to increase absorption. However in the eight others no such complicating factor was present and in addition the saturation of the iron-binding capacity was increased. This group is noteworthy in that it contained patients with cryptogenic cirrhosis and also patients in whom cirrhosis was associated with alcoholism. Previous workers have suggested that increased absorption is specifically associated with alcoholic cirrhosis, but this was not confirmed. The utilisation of the absorbed iron was remarkably low in nearly all patients with cirrhosis of the liver. The levels of absorption seen in the cirrhotic patients frequently exceeded the upper limits seen in patients who were iron-deficient. The only other group who showed such high levels of absorption in this study were two chronic alcoholic subjects with little or no evidence of liver damage who absorbed 46 and 50 per cent. respectively of a dose of labelled haemoglobin. The low levels of absorption found in general in patients with acute liver disease and transfusion siderosis are in marked contrast to the findings in cirrhosis. In eight patients with acute liver disease the absorption of labelled ferrous sulphate varied markedly during the course of the illness. It is not possible to state a range of absorption but with the exception of lupoid hepatitis other acute forms of liver disease tended to show a low absorption at the beginning of the disease which rose with clinical Improvement or administration of steroid hormones. The mean absorption in four patients with transfusion siderosis given labelled haemoglobin was 5 per cent. with a range of 1 to 11 per cent. Utilisation of the dose of iron in these patieatft was extremely low. The findings by previous workers (Davis and Badenoch, 1962) that patients with primary pancreatic disease show an increased absorption of iron and the high incidence of pancreatic fibrosis reported in post-mortem studies on patients with cirrhosis of the liver and haemochromatosis prompted an investigation into the effect of pancreatin on the absorption of iron. This was studied using sequential iron absorption tests. Either the first or second dose of radioactive iron was accompanied by pancreatin; the order was determined randomly. In eight patients with haemochromatosis the mean absorption of labelled haemoglobin was reduced by the pancreatin from 17 to 9.7 per cent. In one treated patient with haemochromatosis absorption was reduced from 47 to 16 per cent. Although the reduction in absorption in the group as a whole was not statistically significant a definite trend is evident and further investigation with patients whose haemochromatosis has been treated is warranted. In six patients with cirrhosis of the liver the absorption of labelled ferrous sulphate was reduced from a mean level of 60 per cent. to 26 per cent. by pancreatin. The absorption of labelled haemoglobin was reduced from 56 to 32 per cent. in four patients. Thus pancreatin was effective in reducing the absorption of iron in both haemochromatosis and in cirrhosis of the liver, conditions known to be associated with pancreatic fibrosis. When pancreatin was given to patients with acute liver disease, a condition in which pancreatic fibrosis would not be expected to occur, there was no effect. There was a remarkably variable effect when pancreatin was given to iron-deficient subjects and the results in this particular group are without explanation at the moment. The findings in patients with liver disease suggest that the pancreas is normally responsible for producing some agent that has an inhibitory effect on iron absorption. In preliminary studies it has been shown that this inhibitory factor in pancreatic extract is heat labile and partly resistant to an acid medium. One of the constituents of pancreatin, the enzyme trypsin, has been shown to have an effect, though less marked than pancreatin, in reducing the absorption of iron, which suggests that enzymes are probably involved at some stage in the inhibition of iron absorption. The increase in the absorption of iron in patients with cirrhosis of the liver affords an explanation for the siderosis sometimes seen in cirrhosis. Although no patients in the present study showed florid manifestations of secondary siderosis, eight showed increased saturation of their iron-binding protein and some excess stainable iron was seen either in liver biopsy of bone-marrow biopsy in some patients. If these patients survive it is likely that they will show the features of the patients with cirrhosis and secondary haemosiderosis described by Caroli et al. (1964). The implications of the finding of increased iron absorption in some patients with cirrhosis of the liver are discussed with particular reference to the treatment of these patients with iron. The present study lends no support to the 'mucosal block' theory of the control of iron absorption but emphasises the rôle of factors acting within the lumen of the intestine which enhance or inhibit the absorption of iron.

Duchenne muscular dystrophy is a severe childhood-onset striated muscle disease that has no cure. The current treatment for skeletal muscle weakness has substantial side-effects. We have previously shown that treatment with drugs that inactivate the mineralocorticoid receptor (MR) improves skeletal muscle function in muscular dystrophy mice. To determine if these MR antagonists work through direct mechanisms in the skeletal muscle, we conditionally knocked out the myofiber MR in muscular dystrophy mice. Genetic ablation of MR improved skeletal muscle force and reduced fibrosis in muscular dystrophy mice similar to that observed with MR antagonist drugs. Additionally, MR antagonists stabilize fragile dystrophic skeletal muscle membranes in a MR independent manner, suggesting that these drugs have many benefits for skeletal muscle in muscular dystrophy. We then evaluated previously identified candidate MR responsive genes for their role in muscular dystrophy. None of the evaluated genes appeared to be direct myofiber specific MR targets. To investigate the role of the myofiber MR in normal muscle biology, we acutely injured the skeletal muscle of myofiber MR conditional knockout mice on a wild-type background. We found for the first time that acutely injured skeletal muscle has MR hormonal regulation and genetic ablation of the MR temporarily stabilized damaged myofibers at four days after acute muscle injury. Pharmacological inhibition of the MR with MR antagonist treatment delayed normal muscle repair in acute injury, suggesting additional roles for MR in other cell types in skeletal muscle contribute to regeneration after acute injury. These results have implications for MR modulation after acute and chronic skeletal muscle injuries.

This work is an original novel.

Beliefs that are not the result of science-based interpretation of evidence (e.g., belief in ghosts or belief that prayer is effective) are extremely common. Science enthusiasts have expressed interest in automatic detection of non-science-based claims. This thesis intends to provide some first steps toward a solution, specifically aimed at detecting Twitter users who are likely or unlikely to take a science-based perspective on all topics. As part of this thesis, a set a Twitter users was labeled as being either "pro-science" (i.e. as having the view that beliefs are rational if and only if they are in accord with science-based reasoning) or "non-pro-science" (i.e. as having the view that beliefs may be reasonable even if they are not in accord with science-based reasoning). Word frequency ratios relative to a neutral dataset, and a simple topic alignment technique, suggest considerable linguistic divergence between the pro-science and non-pro-science users. High accuracy logistic regression classification using linguistic features of users' recent tweets support that idea. Supervised classification experiments suggest that the pro-science and non-pro-science perspectives are not only detectable from linguistic features, but that they can be abstracted away from particular topics (i.e. that the pro-science and non-pro-science perspectives are not inherently topic-specific). Results from distantly supervised classification suggest that using easily acquired, weakly labeled data may be preferable to the much slower process of individually labeling data for some applications, despite the pronounced inferiority to the fully supervised approach in terms of accuracy. The best classifier obtained in this thesis has an accuracy of 93.9%.

Stand dynamics and disturbance histories of five eastern, oak-dominated old-growth stands were investigated using ecological field sampling techniques, dendrochronologogical methods, and a review of historical resources of original forest composition and patterns of human and natural disturbance. Witness tree tallies from 18th century land surveys show that presettlement forests in the study areas were oak-dominated forests. Quercus alba was, at minimum, twice as abundant as Q. velutina, the second ranked species. Acer saccharum and Fagus grandifolia were among the top ten ranked species at each site; however their importance value was consistently less than one-third the value for Q. alba. Querus rubra, Q. prinus, Castanea dentata, and Acer rubrum were relatively minor components of presettlement forests, rarely ranked among the ten most abundant tree species.;On average, at least one canopy disturbance occurred on these study sites every three years; larger multiple-tree disturbances occurred every 17 years. Although there was some variation by site and by historical period, there has been little significant change in canopy disturbance rates for the 300-year period reviewed. A review of tree-ring chronologies yielded three growth strategies. For these oaks, the likelihood of originating in a large opening and achieving overstory status before canopy closure is about the same as the probability of requiring a major release, either from the understory or from a smaller gap that closed. Half of the cored trees established individually, and 30% attained overstory status individually, members of no identifiable cohort. The majority of multiple-tree events occurred in gaps