Cutaneous squamous cell carcinoma (cSCC) is a type of non-melanoma skin cancer that is the 4th most common cancer registration in Scotland after BCC, lung and breast cancer. Over 30,000 cSCC incidences are reported each year in the United Kingdom. In addition, around 1 in 4 skin cancer deaths in the UK are due to cSCCs. Amongst those highly prone to developing cSCCs include organ transplant recipient, immunosuppressed, recessive dystrophic epidermolysis bullosa (RDEB) and Xeroderma Pigmentosum (XP) patients. cSCC patients that display regional metastasis have a 5-year survival rate of 25-50%, whilst this rate is close to 0% in RDEB patients with multiple cSCCs. Wild-type p53 (wt-p53) has been shown to prevent cSCC development and induce tanning and sunburn responses in skin cells. However, TP53 mutations are found in over half of all human cancers and cSCC is no exception as TP53 mutational frequency in cSCCs is around 64-87.5% (Durinck et al, 2011; South et al, 2014). The majority of TP53 mutations in cSCCs are UV-signature missense mutations, highlighting UV-radiation as one of the main risk factors for cSCC development. Mutant p53 proteins can lose wt-p53 functions, have dominant-negative effects against wt-p53 and acquire gain of function (GOF) activities. Mutant p53 GOF activity is induced by the accumulation of mutant p53 in tumour cells. Mutant p53 accumulation is not due to intrinsic properties of the mutants but requires other cellular events, possibly those known to stabilise wt-p53 under cellular stress. It is known that the TP53 mutations and mutant p53 accumulation are early steps in cSCC development. This makes skin an excellent system to investigate the early changes to p53. We have investigated the potential of targeting mutant p53 for cSCC therapy and mechanisms that promote mutant p53 accumulation in cSCCs. We selected low-passage cSCC cell lines that express hotspot mutant p53 proteins, in cSCCs and in general, by analysing TP53 mutational data from the IARC database and next generation sequencing studies performed on cSCC primary tumours by Dr South at Ninewells Hospital, Dundee. cSCC cell lines were generated from immunocompetent, transplant and RDEB patients by Dr South’s group at Ninewells Hospital, Dundee. We found that: 1. PRIMA-1MET, a small molecule reported to restore wt-p53 activity, lacked tumour selectivity as it is able to reduce cell viability in both normal skin and cSCC cells with similar potency. cSCC cell lines are relatively resistant to PRIMA-1MET compared to cell lines derived from other tumour types. 2. Mutant p53 knockdown studies performed on cSCC cell lines suggest that some p53 mutants play a pro-proliferative role. However, there is no evidence for a pro-migratory role of mutant p53 in cSCC. 3. There are no clear alterations in DNA-damage response pathways or the general ubiquitin proteasome system that could contribute to mutant p53 stabilisation in cSCC. 4. Heat shock factor 1 (HSF-1) is upregulated in cSCC compared to normal human keratinocytes (NHK). HSP90 inhibitors, 17-AAG and 17-DMAG, reduce mutant p53 protein levels suggesting that HSP90 plays a role in stabilising mutant p53 in cSCCs. 5. PR-619, a broad range deubiquitinating enzyme (DUB) inhibitor, reduces mutant p53 protein levels in a range of cSCC cell lines. This is rescued by the addition of bortezomib suggesting that DUBs can play a role in protecting mutant p53 from proteasomal degradation. Expression of HAUSP and USP10, which have been shown to stabilise wild-type p53, is generally elevated in cSCC compared to NHK. However, knockdown of these DUBs does not reduce protein levels of mutant p53 in cSCC cell lines. 6. A potential isoform of MDMX (51 kDa) is strongly upregulated in all cSCC cell lines examined. There is an association between the ability of MDMX siRNAs to deplete the 51 kDa protein and reduce mutant p53 protein levels and stability. Furthermore we show that the protein can form complexes with MDM2 in vitro and in cSCC cells. We propose that the MDMX isoform is able to stabilise mutant p53 in cSCC cells through this interaction with MDM2.

Segundo o teorema da indefinibilidade de Tarski-Gödel, não existe fórmula da linguagem da aritmética que defina o conjunto dos números de Gödel das sentenças verdadeiras da aritmética. No entanto, para cada número natural n, podemos definir o conjunto dos números de Gödel das sentenças verdadeiras da aritmética de grau menor que n. Essas definições produzem uma hierarquia V0(x), V1(x),..., Vn(x),... tal que, para todo x, se Vn(x), então Vn+1(x). Nesse estudo, ensairemos algumas aplicações desses predicados, chamados definições parciais de verdade, e outros predicados relacionados a eles na construção de sistemas formais para as verdades da aritmética. A ideia subjacente aos nossos sistemas é muito simples, devemos acumular de alguma maneira as definições parciais de verdade. Grosso modo, mostrar como fazê-lo é o objetivo desse estudo. / According to Tarski-Gödels undefinability theorem, there is no formula in the language of arithmetic which defines the set of Gödel numbers of arithmetical true sentences. Nevertheless, for each n, we can define the set of Gödel numbers of all arithmetical true sentences of degree n or less. These definitions yield a hierarchy of predicates V0(x), V1(x),..., Vn(x),... such that, for all x, if Vn(x), then Vn+1(x). In this study, we will ensay some aplications of these predicates, called partial truth definitions, and others related ones in building of formal systems for arithmetical truth. The underlying idea of our systems is very simple, we should accumulate in some way the partial truth definitions. Roughly speaking, showing how we can do that is the aim of this study.

The fate of any lineage is contingent on the rate at which its genome changes over time. Genome dynamics are influenced by patterns of mutation and recombination. Mutations as the raw force of variation can be acted on independently during exchanges of homologous genetic regions via meiotic recombination. While molecular evolution in sexual lineages is impacted by both mutation and recombination, asexual lineage fate is primarily influenced by the mutation rate; recombination is often altered or absent in asexuals. Although multiple studies show accelerated mutation accumulation in asexual lineages that have lost recombination, virtually nothing is known about rate patterns when meiosis is retained. Here, I use parasitic wasps in genus Diachasma to investigate genome evolution in a recently-derived asexual lineage. I provide evidence that asexual Diachasma possess a canonical set of meiosis genes as well as high levels of genomic homozygosity. Taken together, these observations support an active, albeit modified, form of meiosis in this asexual lineage. In addition, I present the first documentation of accelerated mutation accumulation in the nuclear genome of a naturally-occurring, meiotically- reproducing organism. If harmful, these mutations could impede asexual lineage persistence and contribute strong support for the long-term benefits of sex.

The purpose of this study is to evaluate the causal effects of malaria and poor health in general on economic outcome in Sub-Saharan Africa. This study uses panel data from the Living Standard Measurement Survey (LSMS) for Tanzania from 1991 to 2004. Three main hypotheses are tested. First, the study evaluates the effect of malaria and other chronic illnesses on labor supply using the number of hours worked per week as a measure of outcome. Second, it determines the impact of poor health on human capital accumulation by measuring the number of weekly school hours lost to illness. The third objective deals with the question of whether changes in preconditioning factors such as income levels and healthcare accessibility have improved the disease environment in Sub-Saharan Africa over time. The study uses several identification strategies in the empirical estimation process. The first estimation strategy applies the standard Ordinary Least Squares (OLS) and Fixed Effects (FE) estimators to the schooling and labor supply models. In addition to OLS and FE, the preferred methods of estimating the causal effects of malaria on schooling and labor supply outcomes are Two Stage Least Squares (2SLS) and Limited Information Maximum Likelihood (LIML). Findings in this study suggest that malaria significantly increases school absenteeism. In particular, 2SLS and LIML estimates of the number of school hours lost to malaria suggests that children sick with malaria are absent from school for approximately 24 hours a week. However, the results show the effect of malaria on work hours is inconclusive. Furthermore, difference in difference estimates of the disease environment show slight improvements in the disease environment resulting from changes in income levels. The study finds no statistically significant improvements in the disease environment due to increases in the number of health facilities over time.

Why some countries are so much richer than others is a question of central interest in economics. Low aggregate income per worker in poor countries is mostly accounted for by low labor productivity and high employment in agriculture. This thesis attempts to understand cross-country income difference through examining productivity differences at the sector level - in agriculture and in non-agriculture. Between rich and poor countries, there is a 45-fold difference in agricultural output per worker and a 34-fold difference in mean farm size. In the first chapter, I argue farmer's skill as a plausible explanation for these differences. The model features heterogeneity in innate agricultural skill, on-the-job skill accumulation, and span-of-control in agricultural production. I show that low total factor productivity (TFP) in poor countries not only induces more individuals with low innate skill to choose farming, but also reduces the incentive to accumulate skill. Between rich and poor countries, the model generates substantial difference in farmer's skill, which translates into differences in agricultural productivity and farm size distribution. Quantitatively, the calibrated model explains half of the cross-country differences in agricultural output per worker, and successfully replicates the size distribution of farms in both rich and poor countries. Cross-country productivity differences are asymmetric across sectors. The labor productivity gap between rich and poor countries in agriculture is twice as large as that in the aggregate, and ten times larger than that in non-agriculture. The second chapter shows that these sectoral productivity differences can arise solely from difference in aggregate TFP. I extend the framework in the first chapter to allow for different skill in non-agricultural production as well. Low TFP distorts the allocation of skills across sectors and discourages skill accumulation on the job. To discipline the initial skill distribution and skill accumulation, the model is calibrated to match earnings distribution and age-earnings profiles in both agriculture and non-agriculture in the U.S. The model's implications are then examined using a sample of 70 countries that covers a wide range of development. Between rich and poor countries, the model accounts for most of the productivity differences at the sector level - productivity difference in agriculture in the model is 1.8 times larger than those in the aggregate and 6 times larger than those in non-agriculture. As in the data, the share of farmer in the labor force in the model declines from 85 percent in the poorest countries to less than 2 percent in the richest countries. These results suggest that policy aiming at improving overall efficiency should be prioritized.

<p>The focus of this work has been on hybrid insulation in inhomogeneous electric fields under lightning impulse voltage stress. The principal idea behind hybrid insulation is the intentional use of surface charges to re-distribute the electric field within an insulation system. This allows a significant part of the electric stress to be transferred from the dielectric weaker gas to the dielectric stronger solid insulation thus increasing the total electric strength of the insulation system.</p><p>The concept has been theoretically and experimentally addressed by means of a hemispheric rod covered with a layer of solid insulation. Discharge activity and surface charge accumulation have been studied in an air gap by measuring the voltage and discharge current and recording the discharge activity using a high-speed digital camera. New methods have been introduced and evaluated for the evaluation of surface charge measurements.</p><p>The experiments found that the increase in positive inception voltage was considerable compared to uncovered rods. This increase varied from 35% up to 100% depending on the electrode distance. The increase in breakdown strength is higher than the increase in inception voltage and dependent on the covered length of the rod. During the application of a lightning impulse, the discharge activity spreads upwards along the rod and out into the air gap. Positive discharges form numerous branches and bridge the air gap in most cases. Negative discharges are more diffuse, less light intensive and only form a few branches around the tip of the rod where the electric field is the strongest. Discharge activity along the insulating surface has been observed where the background field is lower than the critical electric field strength. Visible discharge activity is observed where the background field is higher than 2.3 kV/mm and 2.5 kV/mm for positive and negative impulses respectively.</p><p>During the application of lightning impulses, discharge activity starts in the air gap around the tip where the electric field is highest and spreads upwards along the rod. As expected, negative charges accumulate on the surface in the case of positive impulse voltage and vice versa. However, after more powerful discharges during negative impulse voltage application, surface charges of both polarities have been observed.</p><p>Accumulated surface charges decay exponentially with a time constant τ varying from micro-seconds to hours depending on the material properties of the solid insulation. The dominating relaxation mechanism is found to be conduction through the solid insulation.</p><p>Improved methods to calculate surface charges based on probe response for a 2D axial symmetric case have been developed and evaluated. The method that is best suited for this purpose is the λ-method with truncated singular value decomposition (TSVD) as regularization.</p><p>Surface charge calculations show that the accumulated surface charges for the used configuration typically have a maximum value of 0.6 to 1.5 µC/m² and 0.4 to 1 µC/m² after positive and negative impulses respectively. The surface charge density in the areas with the highest discharge activity is relatively uniform. Further upwards along the rod, the surface charge density is reduced relatively fast towards zero, and in some cases, it changes polarity before approaching zero.</p>

Many large terrestrial ecosystems have patterned landscapes as a result of a positive feedback system between vegetation communities and environmental factors. One example is tree island habitats in the Florida Everglades. Although they only occupy a small portion of the Everglades landscape, tree islands are important features as the focus of nutrient accumulation and wildlife biodiversity in the Everglades ecosystem. The hardwood hammock community on the elevated head of tree island habitats can accumulate high phosphorus concentration in the otherwise P-limited Everglades ecosystem. In this dissertation, I examined two hypotheses derived from the chemohydrodynamic nutrient accumulation model, which suggests that high transpiration of tree island hammock plants is the driving force for nutrient accumulation in tree island soil. According to this model, I hypothesized that tree islands with lower dry season transpiration should have less phosphorus accumulated than the tree islands with higher dry season transpiration. By examining the water use and nutrient status from 18 tree islands in both slough (perennially wet) and prairie (seasonally wet) locations, I was able to compare water availability and nutrient accumulation in slough and prairie tree islands with different marsh hydroperiods. Chapter 1 uses elemental and stable isotope analysis to look at water stress and nutrient concentration in tree island plants. I showed that the prairie tree island plants suffer from drought stress during the dry season, when the marshes in the prairies dry out. Prairie tree islands also have lower soil and plant P concentration than the slough tree islands. Moreover, I showed that foliar N isotope ratio serves as a stable proxy for community level P availability for tree island plants, and prairie tree island plants have less P available than slough tree island plants. In Chapter 2, I showed that the satellite imagery derived normalized difference water index (NDWI) provides a robust indicator of community level canopy water content of these tree islands. NDWI, used as a proxy for water status, was positively related to foliar N isotope ratio, which suggests that water availability is linked to nutrient availability in the tree island hardwood hammock plant communities. These findings are consistent to the chemohydrodynamic nutrient accumulation model. In Chapter 3, I used sap flow sensors on individual trees to provide a real-time measurement of plant transpiration. I showed that tree island plant transpiration is affected by multiple factors including weather fluctuations, marsh water depth regulated by local water management, and canopy structure of different tree islands. Overall, my dissertation establishes a link between tree island plant water use and nutrient accumulation. It could be potentially important for future restoration plan of tree islands and Everglades hydrological management.

<p> <p>&nbsp / </p> </p> <p align="left">IP multicast is an efficient mechanism for simultaneously transmitting bulk data to multiple receivers. Many applications can benefit from multicast, such as audio and videoconferencing, multi-player games, multimedia broadcasting, distance education, and data replication. For either technical or policy reasons, IP multicast still has not yet been deployed in today&rsquo / s Internet. Congestion is one of the most important issues impeding the development and deployment of IP multicast and multicast applications.</p>

The focus of this work has been on hybrid insulation in inhomogeneous electric fields under lightning impulse voltage stress. The principal idea behind hybrid insulation is the intentional use of surface charges to re-distribute the electric field within an insulation system. This allows a significant part of the electric stress to be transferred from the dielectric weaker gas to the dielectric stronger solid insulation thus increasing the total electric strength of the insulation system. The concept has been theoretically and experimentally addressed by means of a hemispheric rod covered with a layer of solid insulation. Discharge activity and surface charge accumulation have been studied in an air gap by measuring the voltage and discharge current and recording the discharge activity using a high-speed digital camera. New methods have been introduced and evaluated for the evaluation of surface charge measurements. The experiments found that the increase in positive inception voltage was considerable compared to uncovered rods. This increase varied from 35% up to 100% depending on the electrode distance. The increase in breakdown strength is higher than the increase in inception voltage and dependent on the covered length of the rod. During the application of a lightning impulse, the discharge activity spreads upwards along the rod and out into the air gap. Positive discharges form numerous branches and bridge the air gap in most cases. Negative discharges are more diffuse, less light intensive and only form a few branches around the tip of the rod where the electric field is the strongest. Discharge activity along the insulating surface has been observed where the background field is lower than the critical electric field strength. Visible discharge activity is observed where the background field is higher than 2.3 kV/mm and 2.5 kV/mm for positive and negative impulses respectively. During the application of lightning impulses, discharge activity starts in the air gap around the tip where the electric field is highest and spreads upwards along the rod. As expected, negative charges accumulate on the surface in the case of positive impulse voltage and vice versa. However, after more powerful discharges during negative impulse voltage application, surface charges of both polarities have been observed. Accumulated surface charges decay exponentially with a time constant τ varying from micro-seconds to hours depending on the material properties of the solid insulation. The dominating relaxation mechanism is found to be conduction through the solid insulation. Improved methods to calculate surface charges based on probe response for a 2D axial symmetric case have been developed and evaluated. The method that is best suited for this purpose is the λ-method with truncated singular value decomposition (TSVD) as regularization. Surface charge calculations show that the accumulated surface charges for the used configuration typically have a maximum value of 0.6 to 1.5 µC/m² and 0.4 to 1 µC/m² after positive and negative impulses respectively. The surface charge density in the areas with the highest discharge activity is relatively uniform. Further upwards along the rod, the surface charge density is reduced relatively fast towards zero, and in some cases, it changes polarity before approaching zero.

L'objectif de ce mémoire est de construire une analyse abstraite des crises économiques propres au système capitaliste à l'aide de la théorie marxiste et de la théorie de la régulation. Nous cherchons à étudier les processus fondamentaux qui mènent à l'éclatement d'une crise majeure, ou crise structurelle, du capitalisme. Cette démarche comprend trois étapes principales. Premièrement, nous verrons, à l'aide des écrits de Marx, pourquoi et comment les phénomènes extrêmes que sont les crises économiques sont endogènes à l'accumulation de capital. Deuxièmement, nous verrons, à l'aide de la théorie de la régulation, comment il se développe dans le système capitaliste un régime d'accumulation, ensemble institutionnel chargé de réguler l'accumulation et d'enrayer les crises. Troisièmement, nous verrons comment la relation contradictoire entre l'accumulation de capital et l'ensemble institutionnel chargé de le réguler mène éventuellement à l'éclatement d'une crise structurelle qui annonce une époque de conflits ouverts et de profondes mutations pour le système. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Crises économiques, régulation, financiarisation, capitalisme, monnaie