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The first chapter incorporates imperfect substitution between two human-capital types and skill-specific technology to Bils and Klenow's (2000) model. Their model relies on the assumptions that (i) different types of workers are perfect substitutes, and (ii) technical changes are neutral. These premises contradict a vast literature showing that (i) the elasticity of substitution between skilled and unskilled workers is much less than infinity, and (ii) that recent technical changes have been favouring skilled rather than unskilled labour. The analysis of the chapter shows that altering the human capital specification leads to diverging conclusions regarding the effect of schooling on human capital and technology. The second chapter evaluates the impact of the A8 immigration into the UK on the output of its industries. An input-output general equilibrium model featuring three factors of production ---capital, low-skill and high-skill labour--- and industry-specific factor intensities is developed and calibrated for the country. I show that domestic commerce of intermediate inputs allows for a relay of the supply shock across industries. A model without this feature misestimates industrial output changes the most for industries more connected within the production network. The third chapter proposes an input-output model with international trade to evaluate the relevance of the production network in the effects on industry output of exogenous macroeconomic shocks. I compute the domestic connectivity of WIOD countries to select two distinct economies: one with a sparse production network ---Ireland--- and another with a dense one ---Korea. I calibrate the model for these countries and apply it to empirically assess the propagation of a labour supply shock and an import price shock through the economies. I find that ignoring input-output linkages results in misestimations of the industry output changes more than three times larger for the dense economy in comparison to the sparse one.

We conduct a theoretical study of a two-phase-fluid-structure interaction problem in which air is driven at constant volume flux into a liquid-filled Hele-Shaw channel whose upper boundary is an elastic sheet. A depth-averaged model in the frame of reference of the advancing air-liquid interface is used to investigate the steady and unsteady interface propagation modes via numerical simulation. In slightly collapsed channels at small propagation speeds, the steadily-propagating interface adopts a shape that is similar to the classic Saffman-Taylor finger in rigid Hele-Shaw cells. As the level of initial collapse or the propagation speed increases, the morphology of the finger varies in increasing complexity. The complex solution structure contains steady solutions present in the rigid channel, such as fingers with a curved front or asymmetric, as well as solutions that only emerge with the inclusion of the elastic membrane, such as fingers with high curvature at the tip. The unsteady calculations reveal: noise-driven tip-splitting instabilities, highly ordered small-scale fingering, and periodic oscillatory fingers. We report good quantitative agreement between our model and the experimental data from Ducloué et al. (J. Fluid Mech. vol. 819, 2017, p 121) and C. Cuttle (presented in chapter 4), provided that corrections to account for the presence of liquid films on the upper and lower walls of the channel are included in the model. Finally, we investigate the relative importance of elastic and viscous-capillary stresses as the driving force of the finger propagation.

Use of antibody-nanoparticle conjugates (ANCs) has emerged as a multi-disciplinary strategy for combating cancer - they combine the versatility of nanoparticles and the potential to deliver cargo to cancer cells with the high targeting specificity of surface antibodies to recognise specific biomarkers that are expressed in cancer cells. Several strategies have been employed to graft nanoparticles to antibodies, however, most of them rely on fragile non-covalent interactions or on methods that do not exert control on antibody paratope orientation (e.g. random modification of multiple lysine residues on antibodies). These issues greatly limit ANCs antigen binding capability, reproducibility and, thus, overall efficacy. In this thesis, alternatives strategies of generating ANCs are proposed, regarding antibody orientation on the nanoparticles' surface through the use of pyridazinedione-based linkers that site-selectively modify disulfide(s) on antibodies. The overall aim is to achieve highly-controlled ANC construction so that these next-generation ANCs can be employed in future cancer treatments. In Chapter 1, an introduction to current protein modification techniques is presented and, in a more biological context, the structure and use of full antibodies and antibody fragments is described. Additionally, an overview of the current biomedical applications of numerous different types of inorganic and organic nanoparticles is introduced. In Chapter 2, the creation of antibody fragment Fab targeted PEG-PLGA nanoparticles is reported. In particular, the generation of Trastuzumab Fab fragments via digestion techniques and a new approach for their attachment to PEG-PLGA nanoparticles and the consequent results of improved antigen binding are described. In Chapters 3 and 4, different proteins are employed for the generation of ANCs, namely Cetuximab Fab (in which cell studies are also performed) and considerably smaller proteins such as variable new antigen receptors (VNARs) via a similar methodology to that employed in Chapter 2. Concluding, an overview of achieved results and future work are covered.

Alagille’s syndrome (ALGS) is a rare multisystemic disorder that usually presents in the first year of life with progressive and debilitating liver failure symptoms. Approximately 20 to 30% of ALGS children require liver transplantation in early infancy for end-stage liver disease. When compared to other paediatric indications for liver transplantation, ALGS patients have worst post-operative outcomes. These have been ascribed to concomitant congenital heart disease (CHD) and in particularly to peripheral pulmonary artery stenosis (PPS), which is present in the majority of patients. PPS, particularly if not treated appropriately and in a timely fashion, results in persistent right ventricular (RV) hypertension and progressive maladaptive ventricular as well as vascular remodelling (i.e. initially RV hypertrophy, and later RV dilation and systolic impairment as well as increased pulmonary stiffness). In turn, this may place these patients at high risk of RV ischaemia and pump failure particularly during the critical stage of the liver graft reperfusion, which is often accompanied with a marked systemic hypotension and corresponding coronary perfusion pressure drop. Currently, an hybrid X-ray/magnetic resonance guided catheterisation study (XMR) with dobutamine stress is used, pre-operatively, to identify those ALGS patients that are deemed to be at high risk of right heart failure (RHF). By measuring the systemic/pulmonary pressures and resistance, as well as the cardiac output response to dobutamine, clinicians hope to replicate some of the haemodynamics events of liver transplantation, such as the expected increase in heart rate and myocardial metabolic demand. While the adequate response do dobutamine stress has been described to be an increase in cardiac output of at least 40%, a key limitation of this workup is a failure to account for the systemic hypotension and corresponding coronary perfusion pressure drop that occurs during liver transplantation. By neglecting this, the risk of RV ischaemia leading to RHF might not be adequately predicted. However, studying the coronary responses in AGLS children to identify those deemed to be at high risk of RV ischaemia during liver transplantation presents several ethical and methodological challenges. In this PhD research we have designed an innovative experimental setup using recently developed imaging and computational modelling techniques that could be used to reproduce in silico some of the haemodynamic events of liver transplantation and investigate coronary autoregulation in ALGS patients. Two main computational methods were used: (1) the coupled multidomain momentum method to combine a three-dimensional (3D) portion of the vascular anatomy (i.e. the aorta, coronaries and proximal pulmonary arteries branches) segmented from the XMR, to zero-dimensional (0D) lumped parameter networks (LPNs) representing the heart chambers and the non-segmented systemic and pulmonary vasculature; and (2) a coronary autoregulation control method that adjusted the coronary microcirculation resistance to increase the coronary blood flow (CBF) and thus matched the left and right ventricular metabolic demands, which in turn were computed from the patient-specific ventricular pressure-volume (PV) loops extracted from the XMR data. As highly detailed images of the small coronaries of an ALGS child were to be segmented to create the 3D systemic domain of the patient-specific computational model (PSCM), several studies were concomitantly conducted aiming to improve the conventional one-dimensional (1D) respiratory-navigated (NAV) T2-prepared coronary magnetic resonance angiography (CMRA) sequence. We first tested the feasibility of a recently developed two-dimensional (2D) image-navigated (iNAV) CMRA sequence (Study 1) in healthy volunteers and in an adult patient cohort with CHD. We showed that the novel navigation scheme resulted in faster scan acquisitions and improved coronary image quality compared to the conventional 1D NAV. This was followed by a validation of the technique against gold standard invasive X-ray coronary angiography for screening significant coronary artery disease in an adult patient cohort (Study 2). We then replaced the conventional T2 preparation magnetisation scheme by an inversion recovery (IR) approach to improved blood-background differentiation, and acquired the 2D iNAV CMRA in a paediatric CHD cohort following the injection of gadobenate dimeglumine (Study 3). This is a high-relaxivity contrast agent, with a long half-life thus providing higher and longer intravascular signal ideal for CMRA. We showed that our methodology improved significantly image quality in small children with high heart rates. Finally, this sequence design was incorporated in Study 6 to provide the high resolution radiation-free anatomic data of the coronaries and proximal systemic and pulmonary arteries of a six year-old ALGS child with associated pulmonary vascular disease (i.e. increased pulmonary arterial pressure despite treated PPS) undergoing pre-liver transplantation risk assessment. This data was segmented using a custom-made software developed by our team (CRIMSON) to produce the 3D domains of the closed-loop 0D-3D multi-domain PSCM. Two separate studies were carried out in parallel, one in a sample of hypertrophic cardiomyopathy (HCM) patients (Study 4), and another in a mixed cohort of middle-aged twins and aortic coarctation patients (Study 5), both involving the evaluation of CMRderived methodologies to provide parameters such as left atrial volumes/elastance and vascular stiffness, respectively, that were used in the parametrisation of the PSCM. In Study 4, we studied the different components of left atrial (LA) function (the reservoir, conduit and booster pump function) using phasic volume changes and tissue-tracking, and showed that this robust methodology could improve disease staging. In Study 5, we developed and evaluated a novel tool for automated extraction of the thoracic aorta length from different CMR sequences to streamline pulse wave velocity calculation. The aforementioned measures together with other imaging and invasive data obtained during the clinical XMR study (e.g. intraventricular volumes and pressure, aortic and pulmonary flow, pressure and resistance) were used to calibrate the different components of the PSCM (e.g the LPNs resistance and capacitance) and replicated the rest and dobutamine stress haemodynamics (Study 6). We demonstrated that at rest, due to abnormally high RV afterload, CBF in the right coronary artery (RCA) territory occurred mainly in diastole, akin to the left coronary artery. This abnormal profile was even more pronounced during dobutamine stress. We then modelled a generalised vasodilation, similar to that occurring immediately post-transplant (post-reperfusion syndrome, PRS) by imposing a 31% drop in the mean arterial pressure through manual adjustment of the resistor components in the systemic arterial bed LPNs. Our computational model predicted that the heart would be unable to maintain adequate RCA perfusion in the face of such reduced aortic perfusion pressure, despite a major reduction in coronary resistance. This study provided a mechanistic 6 insight into how abnormal ventricular-vascular coupling (high RV afterload resulting in extravascular compressive resistance) could translate into RV ischaemia during the critical stage of liver reperfusion, eventually leading to pump failure, a resulted not expected given the adequate cardiac output increase (> 40%) during the clinical XMR dobutamine stress study. We hypothesise that this impaired coronary autoregulation and RV myocardial oxygen demand-supply imbalance could be related to the unfavourable ALGS post-transplant outcomes described in the literature when compared to other paediatric liver transplantation indications. This research shows great promise not only for the application of the novel 2D iNAV IR-CMRA sequence in paediatric CHD imaging but also for the use of the different imaging and computational methods to study CBF autoregulation in ALGS patients with pulmonary vascular disease. The PSCM presented could be an appealing option to refine pre-transplant risk assessment of these patients. On the one hand, there is a scarcity of strong medical evidence due to the low prevalence of the disease and the constrains of studying the coronary circulation in children. On the other hand, there is a great need to personalise medical management given the limitations of current pre-operative diagnostic workup. As the ethical and methodological constrains preclude direct invasive validation of these results, obtaining PSCM in other ALGS patients and correlating them to transplantation outcomes could enable clinical translation.

Anaerobic digestion is a widespread technology that is used to treat sewage sludge from wastewater. Mixing has been proven to be a key element for a well-performed digester but it is a power-intensive operation whose quantitative contributions to the system's energy-efficient balance in different designs is not well understood. In order to cut costs, operators try to keep mixing to minimum levels where biogas production is not adversely affected. However, sewage sludge inherently contains inert dense particles, such as grit, that cannot be biodegraded and tend to accumulate at the bottom of the digester. For the first time, the impact of inert particle suspensions on biogas production was evaluated at a range of mixing speeds and particle loadings in mechanically-mixed, laboratory-scale digesters. Five digesters were operated for a total period of five months at different speeds and particle loadings whilst digestion stability, biogas production and treatment quality were monitored. Digesters were fed with real sewage sludge samples six days a week. Computational fluid dynamics models were used to assess the liquid-solid flow characteristics. It has been shown that inert particles in suspension at highly-intensive mixing detrimentally affects anaerobic digestion performance and biogas yields. Low-speed mixing does not suspend inert particles but the digesters are not affected by their presence. Short-term, highly-intensive intermittent mixing, along with continuous low intensive mixing, resulted in particle suspension, stable digestion and biogas production; this being the best energy-efficient mixing regime. Computational fluid dynamics has successfully simulated sedimentation behaviour as well as particle solid distribution and cloud height within the liquid column. The liquid flow patterns change with increased particle loadings.

The success of captive breeding programmes demands planning and communication among zoos, national parks, conservation organizations and political institutions. To avoid inbreeding and enhance the likelihood of finding suitable partners, target individuals may need to be transported from one institution to another to allow biological (genetic) matching. The collaboration among institutions involved with the reproduction and reintroduction of threatened species in their natural environment can be mapped and analysed by social network analyses using studbook data. The cheetah (Acinonyx jubatus), considered as vulnerable by the IUCN Red List of Threatened Species, is a species which has been participating in captive breeding programmes for relative considerable time and can be a good model of study. Although this species has a low wild population density, it has been managed for many years and still has a significant sample of individuals for population and conservation studies, both in the wild or captivity. A general bibliometric review was first conducted with the intention of examining the nature of studbook studies published from 1988 to 2016 on different animal species. Furthermore, International Cheetah Studbooks were used to extract historical data, which was then processed and analysed to investigate the relationship between the transfers of individuals and the position of captive breeding institutions in social networks. Using UCINET software, measures of centralities, density and reciprocity from the collaborative network of institutions were calculated and several maps expressing the transfers between institutions were created using Netdraw to evaluate their patterns in relation to geographical, economic and biological factors. Lastly, longevity and reproductive success were also investigated using statistical analysis such as generalized linear models (GLM) in R software (R Core Team). Results showed that groups of institutions were formed regarding the exchange of animals, and some were highly connected as geographical regions of the world (America, Europe and Africa). Longevity of cheetahs can be partially explained by factors including many transfer-related variables. Reproductive success was not significantly affected by GDP per capita or climate category from the facility location. Breeding recommendations need to be followed by institutions to maximise the conservation value of the species; this will generate genetic improvement for future reintroductions in the wild and the avoidance of extinction. In conclusion, although there is some effort in protecting and managing zoo species through studbooks, conservationists should make maximum use of such datasets to inspire the creation of new tools for the best conservation management of species which need more care and attention such as the cheetah.

Feature Selection is central to modern data science, from exploratory data analysis to predictive model-building. The "stability"of a feature selection algorithm refers to the robustness of its feature preferences, with respect to data sampling and to its stochastic nature. An algorithm is "unstable" if a small change in data leads to large changes in the chosen feature subset. Whilst the idea is simple, quantifying this has proven more challenging---we note numerous proposals in the literature, each with different motivation and justification. We present a rigorous statistical and axiomatic treatment for this issue. In particular, with this work we consolidate the literature and provide (1) a deeper understanding of existing work based on a small set of properties, and (2) a clearly justified statistical approach with several novel benefits. This approach serves to identify a stability measure obeying all desirable properties, and (for the first time in the literature) allowing confidence intervals and hypothesis tests on the stability of an approach, enabling rigorous comparison of feature selection algorithms.

The rst chapter uses a unique dataset on Brazilian party members and variation from mayoral elections to examine the determinants of party membership in Brazil. It starts by examining the effect of winning office on the membership of political parties at the local level. The effect of interest is identi ed using a differences-indifferences approach that compares changes in membership of parties that assume office with changes in membership of all other political parties registered in a municipality. The results indicate that winning office increases the membership of the party of the mayor by 0:5%. In addition, political alignment with higher levels of government has a signifi cant effect on the membership of the mayoral candidate party. Finally, the paper documents that party switching is one of the drivers of the estimated increase in membership. The paper offers evidence in favor of the hypothesis that party membership is driven by opportunistic motives in addition to ideology. The second chapter combines data on the universe of recipients of the Bolsa Famlia program from 2005 to 2015 with data on party membership to investigate the returns to political loyalty. Speci cally, it uses variation from mayoral elections to investigate whether members of political parties that assume office at the local level are more likely to receive social transfers. Regression results from an IV estimation show that indeed members of the party that gained access to municipal government are signifi cantly more likely to receive the benefi t. Additionally, it finds no evidence that members of parties that did not win office are more likely to lose the benefi t as a result of the electoral defeat. This chapter offers direct evidence of material rewards to party membership. The last chapter focuses on the impact of pay transparency on earnings inequality in the Brazilian public sector. Differences-in-differences estimates show that the disclosure of wages reduced the 90/50 decile wage gap across municipalities located in states that adopted wage transparency in comparison to those located in states that did not adopt the policy. There is also no evidence that earnings decile gaps below the median were affected by the salary transparency policy, which indicates that the effect of disclosure in the public sector was mainly concentrated at the upper tail of the log earnings distribution. Finally, evidence presented suggests that the effect on inequality compression is the result of lower returns to top paid occupations rather than changes in employment. The paper suggests that at the margin, top paid public sector employees are insensitive to changes in their earnings, indicating that there are rents that accrue to holding these positions.

The main focus of this thesis is the development of high specific energy alkali metal-oxygen batteries. Chapter 1 provides a general point of view of the energy storage field and the specific background knowledge of each alkali metaloxygen system. Chapter 2 discusses the experimental methods and techniques applied for the investigation of these battery devices. Chapter 3 investigates specific approaches for the development of the nonaqueous lithium-oxygen battery. An attempt to fabricate more suitable positive electrodes is made by utilising hypercrosslinked polymer carbons. The effect of nitrogen heteroatom doping and pore volume on the performance of lithium-oxygen cell is discussed. The effect of integrating a tertiary amine acting as a singlet oxygen quencher on the performance of the cell is evaluated. Analysis of the chemical nature and morphology of discharge products helped elucidate the processes occurring during galvanostatic cycling. Chapter 4 sets out an investigation into several aspects of the non-aqueous sodium-oxygen battery. The stability of various cells components, such as carbon, polymeric binder and electrolyte solvent, against superoxide radical attack is evaluated. The conditions in which the discharge of the cell undergoes different solution or surface mechanisms is determined as well as the conditions in which different reaction products are obtained. The stability of sodium superoxide, the desired discharge product, in the battery environment is discussed. Chapter 5 presents a comprehensive study into the non-aqueous potassiumoxygen battery. In ether based electrolytes, faster kinetics for the formation and decomposition of potassium superoxide are obtained. Electrolyte degradation products are detected to a lesser extent compared to other alkali metal-oxygen cells. The main factor hindering long cycling are instabilities associated with the metal anode. The condition in which a protective surface layer or a passivating surface layer are formed on the metal anode are determined. Attempts to enhance the stability of the protective surface layer are performed by utilising highly concentrated electrolytes and ionic liquid based electrolytes. An alternative antimony based anode material is investigated and stable cycling with capacities close to the theoretical value are obtained. Finally, the oxygen reduction/evolution reactions occurring at the positive electrode are analysed by looking into the stability of polymer binders, the performance of carbon cathodes and the stability of potassium superoxide in the cell environment.

The thesis looks at three conflicts related to the 2014 World Cup preparation in Belo Horizonte, Brazil. In each of the cases, affected groups – informal workers, informal residents and middle-class citizens – engage with the state to claim rights over space. It examines how the entanglements between social class and legal/institutional developments engendered through “peripheral urbanisation” shape the capacities of those groups to affect formal/informal boundaries and have their demands legitimated. This research draws on the findings from a fieldwork in Belo Horizonte, which lasted eight months in total between 2014 and 2016 and involved archival research, participant observation and semi-structured interviews with relevant actors. Three cases are considered, which include: the Mineirão stadium redevelopment that displaced a group of informal workers while creating a conflict in a middle-class neighbourhood; the demolition of an informal settlement to make way for a transport infrastructure project; the construction of a hotel in a middle-class area against the will of local residents. The thesis presents three key findings. Firstly, the urban space production is affected by citizens’ capacity to engage with the state. While the state-society boundaries are blurry, citizens are unevenly empowered to have their demands validated and avoid displacement, i.e. the loss of place. Secondly, while informal residents have their rights partially recognised thanks to the “insurgent citizenship” struggles of the past, informal workers are not entitled to compensation because of the disassociation of work informality debates from spatial considerations. Finally, middle-class politics matter, as middle-class residents are better equipped to validate their claims and protect their place in the city. The research contributes to recent postcolonial debates on urban space production and informality. I show that both informal working and housing practices are interconnected through the place-making strategies of the urban poor as well as of the urban middle-class, all of which generate important implications for the reproduction of socio-spatial segregation and thinking of the Brazilian urban future.

Chlamydia trachomatis infection targets the mucosal epithelium, where squamous and columnar epithelia can be found. Research on Chlamydia trachomatis-epithelia interaction has predominantly focused on columnar epithelia, with very little known on how Chlamydia trachomatis interacts with the squamous epithelium. The stratification and differentiation processes found in the squamous epithelium might influence chlamydial growth and infection dissemination. For this reason, 3D stratified squamous epithelial cultures were adapted to mimic the stratified squamous epithelium, and chlamydial infection was characterized. Chlamydia trachomatis infection in monolayers and 3D cultures were monitored by immunofluorescence and transmission electron microscopy to characterize inclusion growth and chlamydial interconversion between elementary and reticulate body. We observed that the stratified epithelium varied in susceptibility to Chlamydia trachomatis infection. The undifferentiated basal cells were susceptible to infection, while the terminally differentiated upper layers were resistant. If given access to the basal layer Chlamydia trachomatis is able to disseminate and disrupt the epithelial. This disruption have clinical relevance, such as facilitating secondary infection by other STIs. The use of a punch biopsy in 3D cultures revealed that infected samples were unable to close the wound as efficiently as the mock-infected sample. A simplified 2D wound healing assay confirmed these observations. Additionally, this correlated with a reorganization of hemidesmosomes in Chlamydia trachomatis-infected cells but, most importantly, in bystander uninfected cells within the infected sample. The lack of motility and the hemidesmosomes reorganization was shown to be dependent on myosin II contractility and the chlamydial protein CTL0480. This chlamydial protein recruits MYPT1 to the inclusion membrane, which could potentially prevent the cell from controlling the actomyosin tension. In summary, this is the first study to use a 3D stratified epithelial to determine how Chlamydia interacts with this physiologically relevant tissue. Most importantly, this work demonstrates that Chlamydia trachomatis is able to alter the organization of hemidesmosomes which has never been reported for any other bacterial pathogen.

The number of disasters over the past fourteen years (2000-2014) has already exceeded the number of disasters that occurred over the entire decades of the 1970s, 1980s, 1990s. It is estimated that the number of deaths in disasters over the past ten years (2004-2014) has already exceeded the number of deaths that occurred over the previous twenty years (1984 -2004). The total economic damage of disasters over the past ten years (2004-2014) has also already exceeded the damage of disasters that occurred over the previous twenty years (1984 -2004). Transnational disasters may be even more complex because they involve various aspects such as number of countries affected, number of victims, socio-economic aspects, geo-political factors, legal jurisdiction, cultural differences, and the coordination of multiple agencies. In this arena, INTERPOL plays a crucial role since it is the world’s largest international police organisation and a leader in disaster management engaging its 190 member countries and developing a command and control role within the international disaster networks around the globe. Consequently, it becomes crucial to create frameworks to manage transnational disasters. However, up to now INTERPOL does not have a framework to manage transnational disasters under its auspices. Therefore, the main objective of this thesis is to fill this gap and build a crisis management framework for INTERPOL when working with transnational disasters. This thesis is based on case studies: tsunami in the Indian Ocean in 2004; Air France air crash in Brazil in 2009. It was carried out an analysis across cases to figure out similarities and differences in order to identify behaviour patterns (key factors) and use them as a common framework for analogous cases. The key factors affecting all phases of transnational disasters at INTERPOL are as follows: (1) Governance; (2) Service; (3) Resource; (4) Multi-agency Network; (5) Stakeholder; (6) Finance; (7) Barrier; (8) Facilitator. The studies of the cases also identified the main barriers to, and facilitators of effective multi-agency working and transnational cooperation at INTERPOL. 4 The main purpose of this thesis was not to produce a general theory about disasters, although one may emerge incidentally, but to create and use a crisis management framework (called CMF) for the understanding and management of transnational disasters under the auspices of INTERPOL. CMF was compared with other existing international frameworks developed in the research and international organisations. The result of this comparison proved that CMF was the most complete. The study of CMF’s impacts also revealed that it affects all levels of management at INTERPOL: individual, departmental and organisational. In order to ratify the practical use of CMF, this thesis created an information system called CRIMAFIS. It a business intelligence system based on Artificial Intelligence (AI) techniques that uses the themes and codes emerged from data analysis and provides relevant information upon transnational disasters. Ultimately, this thesis made forty-two recommendations for INTERPOL to increase and enhance its crisis and disaster management capability.

Fretting fatigue is the phenomenon of combined contact and fatigue loads which may accelerate crack initiation and reduce the operational life of components. One of the most relevant problems of fretting fatigue occurs in the blade to disc assemblies, particularly those in the hot stages of gas turbines. The 'fir-tree' blade to disc assemblies in gas turbines operate at extreme conditions of loading and temperature, and the presence of multiple frictional contact points, often interacting with other stress concentrators, makes it an extremely challenging problems in solid mechanics. This thesis focus on two aspects of the problem found in 'fir-tree' assemblies: i) what is the impact of using single-crystal blades on the contact tractions and fretting fatigue behaviour; and ii) what is the effect of edge rounding on the contact tractions between the blade and disc?

The main aim of this project was to study Candida albicans cell wall biosynthesis in response to stress. The role of the MAPK, Ca2+/calcineurin and cAMP/PKA signal transduction pathways in regulating the C. albicans cell wall stress response was investigated. A library of mutants lacking receptors, signalling elements and transcription factors were screened for alterations in their ability to respond to a range of cell wall stressing agents, including CaCl2, Calcofluor White and caspofungin. Pretreatment of wild-type cells with CaCl2 and CFW, activates the Ca2+/calcineurin and PKC pathways, leading to an increase in chitin content, and reduced susceptibility to caspofungin. Although elevation of cell wall chitin content often resulted in decreased sensitivity to caspofungin, I show here that some strains with increased chitin levels remained sensitive to caspofungin. The results show that elevation of chitin is a common property of a range of mutants that are affected in coordinating cell wall stress pathways, but that multiple mechanisms are likely to operate in maintaining the robustness of the C. albicans cell wall. Some of the mutant strains of the MAPK, Ca2+/calcineurin and cAMP signalling pathways showed evidence of paradoxical growth, whereby less inhibition was achieved by higher concentrations of antifungal drug. The role of chitin-related genes and stress signalling pathways in regulating C. albicans paradoxical growth was also investigated. Based on these results, more detailed analyses were performed to investigate the correlations between sensitivity and resistance to caspofungin, in relation to paradoxical growth. The MAPK-Mkc1 and the calcineurin pathways played major roles in the paradoxical growth effect. There was a proportional relationship between echinocandin concentration and the chitin content of the cell wall although the chitin content did not continue to be upregulated by the highest echinocandin concentration. Different echinocandins, carbon source, cell morphology and medium composition influenced the extent of paradoxical growth effect. The existence of paradoxical growth in resistant strains such as Fks1 also highlights association of paradoxical growth with resistance mechanisms.

The academic and practitioner-based literatures often invoke notions such as "corporate sustainability" or 'sustainable firms' without questioning the processes through which these labels are acquired and become firmly established. By focusing on qualification processes, this thesis challenges the usage of these taken-for-granted definitions, aimed at producing stable qualities. This study endorses a relational view of strategy to investigate how sustainability qualities emerge and how different actors influence, and/or are influenced by a company's ability to develop and establish sustainability qualifications. This thesis is positioned at the intersection of the three theoretical frameworks: 1) studies of qualities and qualifications, 2) studies on developing sustainability strategies and creating sustainable firms, and 3) studies that adopt a relational view of strategy (namely Actor-Network Theory (ANT) and the Industrial Networks (IN) approach). Drawing on a relational ontology, four case studies were analysed and within these 23 practices contributing to build up sustainability qualities were selected and studied in-depth. The resulting findings led to the development of a framework to investigate the establishment of firms' sustainability qualifications. This framework comprises four types of strategising processes: framing, valuing, enrolling and stabilising. By opening up the discussion from the qualification of goods in consumer markets to the qualification of firms in industrial settings, and by taking a strategic approach to understand qualification-requalification processes, this framework extends previous work developed on qualification processes. This study also adds to the IN approach and to the strategic management literatures by providing an empirical study that describes the relational nature of the processes through which a qualification strategy emerges and the role of non-humans in the processes of strategising. Finally, the thesis contributes to the ongoing debates within IN and the 'greening the business' literature on what constitutes value. It suggests a redirection of focus to analyse processes of valuing, rather than assuming a linear relationship between strategies and value creation. Key words: qualification of firms; sustainability; value and valuation; relational approaches to strategy.

Carotenoids and ketocarotenoids are isoprenoid molecules, which represent one of the most widespread classes of natural pigments, found in animals, plants and microorganisms. Moreover, they have valuable antioxidant properties. Their health benefits and colorant aspects have led to attempts to elevate their level in foodstuffs. In the present study, several metabolic engineering strategies were tested in order to enhance the levels of high-value carotenoid and ketocarotenoid compounds, such as lycopene, -carotene, canthaxanthin and astaxanthin, in tomato and tobacco plants. Biosynthetic bacterial pathway genes have been overexpressed independently (GGPP synthase (CrtE), phytoene synthase (CrtB) and phytoene desaturase (CrtI)) and in combination (CrtE+B, CrtE+I, CrtB+I and -carotene hydroxylase and ketolase (CrtZ+W)), with different promoters (for CrtB, CrtI and CrtB+I) or in association with transcription factors (Phytochrome-interacting factor 5 (CrtZ+W+PIF5) and Arabidopsis Response Regulator 14 (CrtZ+W+ARR14)). The effects of these different strategies on the plant metabolism and especially on carotenoid formation, sequestration and the activation of regulation mechanisms were studied. The combination of the two genes CrtB and CrtI, in their hemizygous state, had a synergistic effect on the production of carotenoids and the expression of CrtZ+W+ARR14 increased the levels of ketocarotenoids in the plants. The important features for the design of metabolic engineering strategies were highlighted. Moreover, regulatory mechanisms that operate across multiple levels of cellular regulation, including transcription, protein localisation, metabolite levels, cell or tissue type, and organelle/sub-organelle structure and organisation were revealed. It was demonstrated how changes to chromoplast and sub-chromoplast structures, such as crystal formation, plastoglobule and membrane composition/structures can arise in response to changes in metabolites. A new carotenoid regulation mechanism at the sub-organellar level was discovered and a schematic model was proposed.

The purpose of this study is to provide innovative design criteria for urban playgrounds based on the principles of biophilic design. Derived from the biophilia hypothesis, biophilic design aims to provide humans with a positive contact with nature in a built environment. The biophilia hypothesis asserts that human's attachment with nature is a biological need, and it was used as a framework to demonstrate the crucial importance of a connection between humans and nature. The relationship between children and nature was explored through empirical studies, which reveal the importance of this connection for children's health. The analyses of empirical studies demonstrate children's preferences for spaces to play, which reinforces the idea that children like to play in natural environments. The playground's design overview was explored and it reveals that the design of many playgrounds today do not support children's overall development as they once did. Understanding that safety concerns became the primary driver for the design of the majority of contemporary playgrounds within the U.S., biophilic design is proposed as the basis for alternative guidelines to be applied to the design of playgrounds to benefit children. Based on the analysis of children's preferred spaces in which to play, sixteen biophilic design principles were selected as ideal to be applied to the overall playground site design and specific play elements of the playground. Due to the relative lack of available natural space in dense urban cities, private or public vacant lots were considered as available and a dense neighborhood in Honolulu was chosen for the application of this study. Through critical spatial analysis, vacant--or available--lots were identified as potential sites to apply this design. The spatial investigations of the biophilic design principles revealed opportunities to apply them to the overall playground site design and specific play elements of the playground. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

Over the past 20 years, governments in many countries around the world have sought to implement governance mechanisms to measure and assess the performance of public service organisations. As a consequence, public service organisations, especially those considered as poorly-performing organisations, have been subjected to unprecedented pressure to improve their performance and sustain performance improvement as a continuous process. However, efforts of public managers to improve the performance of their organisations have been undertaken without “comprehensive theories and rigorous evidence on this issue” (Boyne, 2006: 366). This thesis takes up the challenge of providing robust evidence on the factors associated with the performance improvement of public organisations. We propose that the notion of organisational capabilities offers a promising way to meet this challenge. From this standpoint, this research sought to identify the organisational capabilities whose development and use explain a public service organisation’s ability to improve its performance and sustain good performance in the long run. The empirical analysis was conducted in a population of hospital trusts in England. We firstly applied longitudinal and comparative case studies method into two acute hospitals trusts: one case of a successful performance improvement and one case of less-successful performance improvement. The purpose was to examine how the development (or lack of) a set of capabilities over time accounted for the differences in the performance outcome and trajectory of the two cases. Our findings identified the following capabilities as advantageous for achieving a sustained performance: collective leadership; action-oriented culture; effective clinical-managerial relationship; supportive external context; performance / finance control capability; coordination capability of the key delivery process; sensing capability and learning capability. We then employed quantitative method over the population of acute hospital trusts in England to explore the relationship between complementarities of capabilities and performance. The results demonstrated that only when in combination does the presence of the capabilities yield positive and significant association with performance. In other words, the presence of the whole system of the capabilities increases the trusts’ performance, while partial presence of a set of capabilities is either not significantly associated with, or even detrimental to, the trusts’ performance.

This research develops a bio-economic modelling framework for the assessment of agricultural and water policy change implications for irrigated agriculture. It aims to contribute towards the implementation of the Water Framework Directive within the European Union, particularly in regard to the principles of cost recovery of water services and water demand management for irrigation. The bio-economic framework combines local agro-ecological with socio-economic elements, allowing for the introduction of biophysical relationships of irrigated agricultural production into the appraisal of policy instruments. This framework is used to investigate the comparative performance of water management policy instruments for irrigation, including volumetric pricing, flat pricing, a two-part tariff and water allotments. Implications of these water policy instruments are assessed in combination with agricultural market and policy scenarios, which are used to define the economic background in which water policies will operate. This operational framework is designed within a microeconomic context at the farm level that takes into account crop yield-water relationships, the revealed economic behaviour of farmers, as well as structural productive patterns of representative agricultural systems in two case study areas in the south of Portugal. This integrated approach provides a comprehensive understanding of the implications of agricultural and water policies on irrigated agriculture within the European Union, unravels conflicts and identifies synergies between these policies. Simulation of water policy instruments produced substantial differences in performance across farming systems, enforcement levels, and agricultural policy and market settings. Results suggest that water pricing, on its own, is not necessarily the most effective means for achieving the WFD water demand management and cost recovery objectives, and proposes that a policy mix combining economic with regulatory elements may be best designed to pursue these objectives with fewer detrimental consequences. This study highlights that conflicts between CAP and the WFD may result in losses of efficiency, policy efficacy and losses of welfare, that could be minimised by integrating both policy measures and objectives, in a coherent and combined approach, exploring synergies and coordinating efforts to overcome sources of conflict.

This research develops a bio-economic modelling framework for the assessment of agricultural and water policy change implications for irrigated agriculture. It aims to contribute towards the implementation of the Water Framework Directive within the European Union, particularly in regard to the principles of cost recovery of water services and water demand management for irrigation.

Nanoscale photonic functionalities based on light-induced structural transitions in nanoparticles have been investigated, and it hag been experimentally shown that nanoparticles can act as both low power nanoscale optical switches and as resonator-less optical memory elements. A system for in-situ growth and characterization of gallium nanoparticles, which combined technologies including atomic-beam deposition, ultra-high vacuum, cryogenics, and sophisticated fibre instrumentation including diode and ultra-fast laaers, has been developed. Optica,l switching has been observed in a gallium nanoparticle film on the end of a single mode optical fibre simultaneously in rejection and transmission, and under different regimes of excitation, for the first time. Measurements of the sub-microsecond dynamics of such light-by-light control allowed the first study of the fast kinetics of solid-solid and solid-hquid structural transformations in gallium nanoparticles to be performed. Single gallium nanoparticles have been grown from an atomic beam in the nanoaperture at the tip of a tapered optical fibre for the first time. Reversible light-induced reflectivity changes associated with a sequence of transformations between different structural forms (both solid-solid and solid-liquid) stimulated by optical excitation at nanowatt power levels, have been observed in such particles for the first time. The complex temperature hysteresis of the narioparticle's nonlinear response has been observed and it has been discovered that the extent of overcooling can be controlled by varying the optical pumping regime. The first demonstration of nanoscale all-optical resonator-less memory functionality baaed on phase transformations has been performed using a film of gallium nanoparticles. It has been shown that single 1 μs optical pulses of a few mW peak power can be used to 'write' information to the memory by converting the particles from a lower energy phase (logic state 0) to a higher energy phase (logic state 1). A high contrast method for 'reading' the state of the particle memory, based on measurements of the reflectivity change induced by a modulated pump beam, has been developed. Both volatile and non-volatile modes of memory operation have been demonstrated. For the 6rst time, an optical memory element based on a single particle has been demonstrated. It has been shown that an 80 nm gallium nanoparticle can act as a fourlevel nanoscale optical memory. Information is encoded on the particle by switching it between phases using single optical pulses with energies as low as 1.5 pJ, and by varying the pulse energy different states can be directly accessed from both ground and intermediate states, A closely packed array of such particles could provide a storage density of about 0.2Tb/in^. The experimental work has been underpinned by the development of appropriate qualitative physical models of the processes involved, so as to describe the relationships between excitation controlled phase coexistence in nanoparticles, their optical properties and the demonstrated functionalities.

The critical understanding of 'development' presented in this thesis has its focus on the Green Revolution and its effects. The general view that resulted from this analysis points to how development policies have worsened life for large sections of the world's population but favoured global trade in a scale unthinkable during colonial times. Different types of practices that are identified with the term Theatre for Development were classified into three categories. This helped to highlight the specific contributions of the Dialogical Theatre for Development' approach, which is based on Paulo Freire's principle of respect for the knowledge and culture of rural and urban community members. This category is presented as the one that could help to resist the injustices of market-oriented globalisation. Aside from an affirmation of the methods of the Dialogical Theatre for Development practices, this thesis presents a criticism of its discursive approach. The 'poetically correct' theatre I am advocating should search for a poetical expression, have the right to use fantasy and imagination, and to experiment with both form and content as part of its creative process, without losing touch with reality. How could the Dialogical Theatre for Development approach be 'poetically correct'? The suggestion presented is based on the expansion of Freire's concept of codification to include imaginary representations of reality. Three contemporary practices of Theatre for Development in Brazil, England and the Philippines, are presented, in order to identify current trends and to try to improve understanding about methods and form in the Dialogical Theatre for Development. The expected results of this thesis include the clarification of the meaning of Theatre for Development, an increased awareness in relation to the importance of methods of interaction with communities, and a challenge for those who support theatre practices within communities of the First and Third Worlds, to develop works in which the imagination is free to consider reality.

The formal specification community has produced many languages but few structured design methods. Those which exist tend to be abstract, providing little guidance in tackling problems in particular domains. One way of devising domain-specific design methods is by reconstructing an example in the domain using the target method; then generalising the design structures to cover a class of designs in the domain and finally building an environment in which these structures may more easily by re-applied to new problems. We demonstrate this approach using animal population dynamics models as the domain and Prolog techniques as the target method. We have identified domain-specific techniques which use a parameterisation method from techniques editing but which contain information specific to the population dynamics domain; we define a problem description language which uses concepts from population dynamics; an interface which allows these concepts to be supplied; and provide an automated system which bridges between population dynamics problem description and the domain-specific techniques needed for model generation. TeMS - Techniques-based Model Synthesiser, is the system constructed as the main instrument of our research. Because it is an embodiment of our views on the issues addressed, we submitted TeMS to user evaluation by ecological modelling experts, which produced material for a broad discussion of the system itself, its approach to modelling and its potential uses on the ecological modelling scenario.

A physiological model of an individual Daphnia was developed starting from first principles. The model was based on general life-cycle biology from which general allocation rules were developed. A simple feeding behaviour involving sensitivity to the presence of toxicants and no active food selection was implemented. The model addresses growth, survival, and reproduction under different environmental conditions, e.g. differing food levels and/or toxicant concentrations. Toxic effects are described on the basis of simple interactions with feeding and metabolic processes. Model parameterisation was performed using available literature data together with data generated within this thesis. Values for almost all parameters used could determined from experimental data. Furthermore, parameters which could not be directly or indirectly estimated revealed themselves as insensitive. Experimental work using pulsed food deprivation experiments on adolescent and adult instars was carried out to generate precise data on moulting, while generating information to test the allocation rules used in the model. Samples of individuals were collected at critical points during the experiments to judge if the biochemical composition of the samples was a good indicator of individual physiological state. A full sensitivity analysis was carried out with the model which it was validated using data from differing food conditions and from different non-lethal cadmium concentrations. During the validation process, the model revealed itself to be robust and able to simulate life-history performance under a range of environmental conditions. The model is well-posed and robust, capturing the basic and essential properties of an individual and addressing its development from egg to adult. The model behavior is consistent at both low and high food levels, whilst addressing the description of toxic effects in a realistic way. The model can be used as a valuable tool for teaching and experiment designing, by generating results for long term exposures to different environmental conditions within a short period of time.

The role of demand in the Ricardian system has been the subject of a great controversy. Initially, the idea that demand does not play any significant part in Ricardo's analysis predominated in the literature, especially with the rise and development of the Sraffian school. A reaction to this line of interpretation has already appeared in the literature, in particular, in the works of Samuel Hollander. This controversy, however, has been basically confined to the discussion of price determination and the mechanism of resource allocation. It is in the context of that debate that the present study of the role of demand in Ricardo within the broader perspective of accumulation and economic development is set. Ricardo's concern with the feed-back effect between the process of growth and changes in the structure of consumption of society is illustrated, as also its importance as a necessary condition for the development of the industrial sector.

We study various aspects of the dynamics of skew-products (Rand Z-extensions) over a subshift of finite type (ssft). In Chapter I we give the basic definitions and terminology. Conditions are given in Chapter II to ensure ergodicity of the skew-product defined by a function of summable variation with respect to an invariant measure u x ⋋ where u is an ergodic shift-invariant Borel probability measure which is quasi-invariant under finite coordinate changes in the shift space (or under finite block exchanges), and ⋋ denotes Lebesgue measure on R or Z (depending on whether the function is real or integer valued). In Chapter III we define a topological entropy concept for the skew-product (defined by a Holder continuous function f), which is given by the growth rate of periodic orbits of bounded f-weights, and we show that this is the minimum value of the pressure function of f. The asymptotics in the central limit theorem is studied in Chapter IV, for the class of Holder continuous functions defined on a subshift of finite type endowed with a stationary equilibrium state of another HOlder continuous function.

Historically, higher education has played an important role in the development of societies. Indeed, this has been the case in both Argentina and Brazil. The overall goal of this dissertation is to examine the historical development and the current situation of higher education in Argentina and Brazil. In relation to history, it discusses the creation and the development of higher education institutions; the changes in educational policies; and the varying opportunities to access higher education that were offered to the populations of these two countries. In relation to the current situation, the study discuss the main strengths and challenges of higher education in Argentina and Brazil; the diversification of institutions and courses; the process of granting access to higher education adopted by institutions in each country; and finally the main policies implemented by the federal governments of both countries to expand access to higher education and assure quality. The analysis of the history of higher education in Argentina and Brazil is based on relevant literature in the field, while the analysis of the current situation is based on interviews carried out with 19 key actors in the field of higher education in these countries. These key actors include government officials in charge of creating and implementing higher education policies in both countries, as well as academic specialists on the subject. Several different activities were conducted to achieve the goals of this dissertation. First, there is an attempt to clarify the theoretical foundations upon which the analysis of higher education in Argentina and Brazil is developed. There is a debate about the state and its role in relation to education, as well as the impact of globalization the state and on higher education. Then, higher education in Argentina and Brazil is put into the context of higher education in Latin America. The status of higher education in Argentina and in Brazil is first examined individually, with a subsequent comparative analysis of the main aspects. This dissertation discusses important aspects of the history of higher education in Argentina and Brazil, as well as some key features of these institutions in the present. It also helps to illuminate relevant trends and alternative paths for the future. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]

This thesis consists of two parts: In Part A we study the category of finitely presented functors and use it to determine the representation type of the Auslander Algebra of Aq = K-algebra , denoted Rq (K is a field). This is possible because the category of finitely generated modules over Rq, mod Rq , is equivalent to the category of finitely presented functors from (mod Aq)op to Mod k. Part A finishes with the construction of the Auslander-Reiten quiver of Rq in case q = 3. Part B deals with the construction of almost split sequences in the category mod° Δ of lattices over an R-order Δ , where R is a complete discrete rank 1 valuation ring. In the first chapter of part B we give a description of some unpublished work by J. A. Green who permitted me to include it in this thesis. This work contains a method to construct a short exact sequence 0-> N-> E-> S-> 0 in a way which gives an explicit expression for the subfunctor Im( ,g) of ( ,S) , and shows that the construction of almost split sequences can be viewed as a particular case of this problem. In the second chapter of part B we continue this work by deducing a "trace formula" which provides a practical way of dealing with a certain step of the construction of almost split sequences in mod° Δ. Then we consider the particular case where Δ is the group ring.

Biofloc technology (BFT) is an aquaculture production system that has gained popularity with tilapia producers. Probiotics provide benefits for the host and/or the environment. Probiotics have been reported in some cases to enhance growth performance, improve water quality, and prevent infections. One of the administration routes for probiotics is to apply them through the feed. When a probiotic is combined with a biofloc system, the production yield may be improved through better fish growth, disease resistance, or enhanced survival. This research aimed to evaluate the growth performance of Nile tilapia Oreochromis niloticus fed commercial top-coated probiotics. Two growth trials were conducted, Trial A had fish with a mean initial weight of 71.4 ± 4.4g, and fish in Trial B had a mean initial weight of 5.34 ± 0.42g. Tilapia were offered commercial feed (38 % protein floating tilapia feed, Optimal Aquafeed, Omaha, NE) in both trials, in the first fish feed was top coated with two probiotics, AP193 (Bacillus spp.; provided by Dr Mark Liles, Auburn University) final concentration of 1 x 107 CFU g-1, and BiOWISH® Feedbuilder Syn3 (BiOWISH Technologies ® Cincinnati, OH, USA) in a final concentration of 3.6 x 104 CFU g-1. In Trial B, feed was top coated with two different concentrations of BiOWISH® Feedbuilder Syn3 (BiOWISH Technologies, Cincinnati, OH, USA) at the final concentrations of 3.6 x 104 CFU g-1 and 7.2 x 104 CFU g-1. The same commercial feed was used as a reference, resulting in 3 experimental treatments with three tank replicates each. The results of both growth trials indicated no significant differences in growth performance (except FCR (feed conversion rate) that showed significant differences in Trial B, where both concentrations of BiOWISH® Feedbuilder Syn3 showed improvement), survival, water quality, solids management, and bacterial composition of water and fecal matter. Even though growth performance results presented no significant differences, results could differ based on the concentration and the route of the probiotic administration, but most importantly, their impact on the microbial community of the culture water developed in the biofloc system. According to the data collected, testing on a larger scale with different probiotic doses is necessary to achieve an effective dosage to improve tilapia culture.

Low back pain is the leading cause of years lived with disability and is associated with personal suffering and societal and economic burden. The burden of low back pain has not improved since 1990, partially because most current interventions are ineffective, and patients do not have access to many adequate treatments. The findings of this thesis have provided new evidence on the effects of a promising pharmacological intervention, the effects of contemporary nonpharmacological interventions, and the mechanisms and acceptability of novel interventions with new treatment targets for low back pain. This thesis has six chapters. Chapter One introduced problems and evidence gaps in the literature on low back pain addressed in the following thesis chapters. Chapter Two provided evidence that the most promising and advanced pharmacological intervention in the development pipeline for chronic pain, anti-NGF, does not provide clinically meaningful improvements in pain and function and is associated with an increased risk of experiencing an adverse event in adults with low back pain. Chapter Three summarised the findings from all Cochrane systematic reviews that investigated the effects of nonpharmacological interventions for low back pain, providing an accessible synthesis for consumers of the high-quality evidence of current treatments for low back pain. Chapter Four investigated the importance of targeting pain catastrophising to reduce pain intensity for chronic low back pain. Chapter Five presented the facilitators and barriers for the acceptability of an effective nonpharmacological intervention involving new treatment targets to treat chronic low back pain. Chapter Six summarised the main findings and provided the clinical and research implications for the management of low back pain. This doctoral thesis provides new evidence to optimise the management of low back pain. It is unlikely that a new and effective pharmacological intervention will be available for the management of low back pain in the following years. There are nonpharmacological options that probably provide benefits for chronic low back pain. Higher-quality randomised controlled trials are necessary to clarify the effects of nonpharmacological interventions on acute low back pain. Treatment optimisation for chronic low back pain depends on identifying new treatment targets and interventions. The identification of effective treatment targets requires high-quality mediation studies. The successful implementation of interventions with new treatment targets will depend on strategies to address common barriers to the acceptability of the treatment.

Cancer is considered the single most critical barrier to improving life expectancy in every country. More specifically, the high prevalence of breast cancer is a global health concern, but there are no safe or effective treatments for it at its advanced stages. Those facts urge the development of novel treatment strategies. Annexin A5 (ANXA5) is a natural human protein that binds with high specificity to phosphatidylserine, a phospholipid tightly maintained in the inner leaflet of the cell membrane on most healthy cells but externalized in tumor cells, tumor vasculature, and metastatic cells. We have linked annexin A5 to single-walled carbon nanotubes (SWCNT) and gold nanoparticles (AuNP) in this work. First, we have developed a targeted photosensitizer for photothermal therapy (PTT) of solid tumors through the functionalization of SWCNT to ANXA5: the SWCNT-ANXA5 conjugate. The ablation of tumors through the SWCNT-ANXA5-mediated PTT synergizes with checkpoint inhibition creating a systemic anti-cancer immune response. This treatment strategy was tested in two murine breast cancer tumor models, EMT6 and 4T1. Although EMT6 tumors are aggressive and metastatic, 4T1 tumors are considered even more threatening and less immunogenic than EMT6. For both tumors, enhanced therapeutic effects were achieved. While EMT6 tumors were treated with lower temperatures in the PTT, 4T1 required higher temperatures and the addition of an immune adjuvant to induce curative effects. For both studies, evidence of immune system activation strengthens the hypothesis of an abscopal effect. SWCNT-ANXA5 was also studied as a responsive material for radiofrequency ablation (RFA), showing an impressive heating rate and potential for carbon nanotube-mediated RFA of tumors. Lastly, a multi-modal conjugate for the detection and therapy of cancer was developed linking ANXA5 to a chemotherapeutic drug, mertansine (DM1), and gold nanoparticles (AuNP) for drug delivery and contrasting agent in microCT scans in the diagnosis of breast cancer. Those linkages created the conjugate AuNP-ANXA5-DM1. This novel agent was able to induce cytotoxic effects and has the potential to increase the effectiveness of chemotherapeutic delivery to solid tumors.