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Completed suicide in schizophrenia remains a significant unanswered challenge, requiring new perspectives and novel investigation. This thesis examines how previously under-investigated symptoms, including blunted affect and social withdrawal, may be associated with suicidal behaviour in people with schizophrenia. For this study, a multidisciplinary approach was used incorporating philosophy, psychiatry, and neuroimaging. I begin with Chapter 1, in which I give a philosophical consideration of why we should not regard suicide as an irrational action in schizophrenia. My arguments are based on the idea that overwhelming feelings and suffering such as isolation and of not belonging, which relate to negative symptoms including blunted affect, could be sufficient reasons for someone to end their life and therefore could be considered as rational acts. In chapter two, I present a systematic review on the negative symptom of blunted affect in suicide in schizophrenia, aiming to show the gaps in existing evidence and current knowledge. In summary, this highlights that blunted affect is likely to influence suicidal behaviour in the presence of depression, anxiety, or hopelessness. Following the systematic review's findings, a primary data chapter then focuses on quantitative examination of suicidal behaviour in first-episode psychosis (FEP) patients examining the associations between blunted affect, social withdrawal, and suicidal behaviour in FEP. Specifically, a mediational analysis demonstrated that blunted affect and social withdrawal are associated with suicidal behaviour when hopelessness acts as a mediator. To further enhance our understanding of suicidal behaviour in people with schizophrenia, I present a second data chapter conducting a functional Magnetic Resonance Imaging (fMRI) study, which compared brain function in patients with FEP and high vs low suicidal behaviour during an emotional face response task, aiming to explore whether there are any differences in brain function between the two groups. Findings demonstrate that patients with high suicidal behaviour reported reduced activation in the prefrontal cortex: specifically, the Medial Frontal Gyrus and Anterior Cingulate Gyrus, in response to presentation of emotional faces; areas related to decision making and executive function. The summary and discussion chapter includes implications such the mechanisms of blunted affect and social withdrawal and how high scores on such symptoms might impact patient's brain function, as well as early identification of suicide risk, and implications for treatment that focus on social connectedness and recovery. The novelty this thesis presents, focuses on the multidimensional examination of under-examined factors such as blunted affect and social withdrawal, that might play an indirect role to the development of suicidal behaviour. The symptoms of blunted affect and social withdrawal might lead to suicide when risk factors such as hopelessness act as mediator. Lastly, high scores on these symptoms might potentially be related to underlying brain dysfunction; however, this in itself does not automatically equate to suicide being irrational. Findings in this thesis could be seen as evidence which might lead to better identification of risk, and prevention of suicidal behaviour in people with schizophrenia.

This thesis focuses on the development of novel enzymatic approaches for chiral amine synthesis utilizing amine transaminases (ATAs) and 'smart' amine donors. Different strategies were combined for the expansion of the existing biocatalytic toolbox, paving the way towards green alternatives for the enantioselective production of valuable chemicals. In the first chapter, the wider application of the 'smart' amine donors is presented. Initially, a panel of 400 ketones/aldehydes was screened, using o-xylylenediamine as the amine donor, with a commercially available ATA. The colored precipitate was used as a positive indicator, to reveal a pattern for the carbonyl tolerance of the ATA. Subsequently, the commercial value of the corresponding chiral amines was evaluated with the assistance of the industrial partner Key Organics. The viable substrates were thoroughly investigated with different 'smart' diamine donors, in an effort to reduce the production costs. 1,5-Diaminopentane (cadaverine) was the most effective donor and was used for the preparation of five ketones on preparative scale, from which three became commercially available through Key Organics. In the second chapter, the development of a novel whole-cell system, mediating ATA reaction in a self-sufficient manner, is presented. A selection of (S)- and (R)-selective ATAs were screened against 'smart' amine donors utilizing a panel of carbonyl-containing compounds. Five (S)-selective ATAs were identified and transformed in Corynebacterium glutamicum cells, which have been engineered to produce cadaverine and 1,4- diaminobutane (putrescine). Due to endogenous side-reactions and complications with expression, three ATAs were successfully expressed and utilized for the whole-cell transamination of a model ketone substrate. New strains with enhanced ATA production were developed and the reaction conditions were optimized to afford an enantiomerically pure (>99%) (S)- pyrroline with 42% isolated yield.

Cells are in constant and dynamic interactions with the extracellular environment. They receive several inputs involved in the regulation of cell behaviour. Fibronectin, an abundant protein of the ECM, contains multiple binding domains and binds to cell receptors, growth factors and other ECM proteins. FN undergoes conformational changes through cell-generated contractile forces which consequently affects cell response. Tissue engineering aims at engineering biomaterials that recreate the in vivo ECM. In addition to biomaterials, stem cells have emerged as a promising source due to their inherent differentiation potential. In this work, the role of poly acrylates in controlling human mesenchymal stem cell behaviour (hMSCs) was explored. Particularly, a series of copolymers with specific ratio of ethyl(acrylate), EA, and methyl(acrylate), MA, were used. It is known that poly(ethyl)acrylate, PEA, triggers a network-like conformation of FN upon adsorption, whereas poly(methyl)acrylate, PMA, elicits a globular conformation. It was found that a different degree of FN organisation can be obtained dependent on the EA/MA ratio, with the network being more connected with increased EA ratio. This differential conformation was shown to affect the availability of critical binding sites. This system was further used to study hMSCs response in terms of adhesion and osteogenic differentiation. All surfaces support cell growth and focal adhesion formation. However, increased cell size and spreading was promoted on surfaces with higher EA concentration. Next, the potential of the surfaces after sequential adsorption of FN and the growth factor BMP-2 to drive osteogenic commitment was explored. Enhanced expression of the osteogenic markers RUNX2 and OCN was found with higher concentration of EA whereas the opposite was observed with ALP expression. Another part of this work involved investigating cell migration on PEA and PMA. Higher cell speed was found on PEA where FN adopts a more extended conformation. Moreover, the protein composition of focal adhesions was evaluated by proteomic analysis. The findings of this work give further insights into how the surface with well-defined chemical properties can modulate FN conformation and how these changes affect cellular processes.

This thesis deals with a new paradigm for Complex Systems of an evolving structure which is referred to as Structure Evolving Systems (SES). A wide range of challenging issues are concerned involving the evolution of structure and associated system properties through different forms of complexity and these are closely related to integrated system design. The thesis deals specifically with issues related to the representation of t.he different forms of structural evolut.ion. A number of new forms of evolution are introduced expressing differ- ent design problems, such as Design Time Evolution, Dimensional Graph Evolution, Life Cycle Structural Evolution, Cascade Design Evolution. The main objective is to develop a representation framework for the different types of structural evolution which will offer the proper set up for the study of evolution of structural characteristics and system prop- erties. The main part of the study is concerned with the development of representation of the System Structure Evolution in terms of a chain of models as a way to represent the different stages of Design Time Evolution which involves the modelling of a system from the very early stages up to the late stages when detailed descriptions are used for design. The development of nested representations for the case of Single-Input, Single-Output Systems is presented here based on the theory of continuous fraction expansion of rational functions and then examine property evolution within the naturally generated nests. A " natural" way for generating chains of models of variable complexity is introduced based on a frequency domain approach using the infinite Laurent expansion. This approach provides a natural link to the problem of partial realization, which in turn provides a useful set up for tpe study of evolution of system structure and properties. Within the framework of Cascade Design Evolution, we develop a generic representation describing the evolution from the aggregate system to the composite system. This involves the development of the new concept of COTY1- pleteness of composition. We also clarify the notion of deviations from completeness ,; , develop a representation of the noncomplete composite system in terms of standard control concepts and tools. This provides the fundamentals for the development of a control theory based approach for designing composite systems with desirable structural characteristics. Within this framework, completeness is expressed as output feedback and deviations from completeness as input and output decentralized squaring down. This representation pro- vides control concepts and tools which allow the structuring of linear composite systems to be addressed as a problem of generalised control design. The present work contributes to the development of the theory of the new system paradigm and studies the evolution of a number of system properties under different types of system structure evolution.

Health care now accounts for just under 10% of national income in most developed OEeD countries. Yet, despite its importance in the overall economy, the factors that drive health care expenditure remain only imperfectly understood. This thesis shows that the determinants of health care expenditures are simply too diverse amongst different countries to be brought within a common denominator such as GDP, as it has been argued for decades. It also shows that the assumption that health care is a homogeneous good across countries is over-simplistic and arbitrary, and finds ample evidence showing that health care is not a luxury good, as widely suggested. The contribution of the thesis is on methodological, theoretical and empirical grounds. In terms of methodology, the thesis shows that there are significant flaws in several areas that influence our thinking concerning the determinants of health care expenditures and offers alternative ways of analysis and appraisal. Flaws were shown in: the relationship between health expenditure and GDP; the importance of factors such as ageing; the macroeconomic context and the burden of disease; the measurement of key variables used in empirical analysis such as health spending, national income, technology, and health prices; the method of analysis that has been pursued; and the conversion factors used to translate prices and monetary variables across countries into a single and comparable denominator. The thesis makes a theoretical contribution of the analysis of health care expenditures, assuming that health care is at least a quasi-public good. The proposed conceptual framework explicitly links the determinants of health care expenditures to the theory of public finance and allows flexible adjustments by decision-makers to account for changes in technology, prices, and the macroeconomic environment. The impact of the macroeconomy on health spending is assessed by evaluating whether the rate of growth of income has any influence on the demand for health and whether the fiscal deficit impacts on health spending and to what extent. The proposed framework incorporates technology and this is an advance from the published literature, which has almost invariably considered technology to be a residual factor. Finally, the thesis recognises that the lag structure of the model, the availability of data, and knowledge of the relationship between disease and need for services are not sufficient to test for the impact of lifestyle and disease factors on health spending. The empirical investigation provides conclusive evidence of the non-importance of GOP in explaining health care spending trends over time. Consumption is shown to be a predictor of health expenditures; technology is an important cost-push factor across countries; the macroeconomy exerts, in general, significant pressure on health care expenditure; however, the impact of health care reforms does not show any significant impact on health care expenditures; and the number of doctors per capita has little or no association with health care expenditures.