Les léiomyosarcomes sont des tumeurs malignes mésenchymateuses composées de cellules à différentiation musculaire lisse. Elles présentent des altérations génétiques complexes avec pertes et gains de chromosomes variables selon les tumeurs, sans anomalies moléculaires récurrentes permettant de définir une entité nosologique contrairement aux sarcomes associés à des translocations (sarcome d'Ewing), ou à des mutations (GIST). Les évènements moléculaires pilotant la tumeur restent inconnus et donc aucune thérapie ciblée n'est encore identifiée. L'objectif de ce travail était d'identifier par protéomique de nouvelles cibles potentielles dans les LMS. Nous avons identifié des kinases activées en analysant le profil d'expression et de phosphorylation des protéines de signalisation, sur une série de 13 tumeurs congelées. Parmi celles-ci, une surexpression de Tyro-3, PKCq, et MSH2 et une perte de phosphorylation de FAK Y397 ont été détectées dans les tumeurs comparées au tissu sain. Une classification hiérarchique non supervisée a montré deux groupes de LMS ayant des profils d'expression protéique distincts. Nous nous sommes intéressés à Tyro-3 dont la co-expression avec son ligand Gas6 a été exclusivement associée à la phosphorylation d'Akt dans 8 des 13 LMS. Ces corrélations ont été retrouvées dans les deux lignées SK-LMS-1 et CNIO AA. La déphosphorylation de FAK Y397 a été observée uniquement dans CNIO AA qui exprime fortement Gas6. L'ajout de Gas6 exogène à SK-LMS-1 induit la phospho-Akt, et la déphosphorylation de FAK Y397. La double extinction de l'expression des gènes de Tyro-3 et Axl dans CNIO AA réduit la viabilité des cellules, suggérant un rôle crucial de cette voie dans les LMS

Le mode de coordination parmi les différentes molécules qui régulent la migration reste très peu connu. Ce travail traite de deux voies de transduction régulant la migration: la voie Rac1/WRC (Wave Regulatory Complex) qui contrôle la formation du réseau d'actine au front des cellules migrantes, et la voie RalB/exocyst, dont les mécanismes moléculaires de son implication dans la motilité cellulaire étaient inconnus au début de cette thèse. Rac1 et RalB sont des petites protéines G des familles Rho et Ras, respectivement. Les complexes WRC et exocyst sont leurs effecteurs directs.Au cours de la recherche de connexions entre l'exocyst et des régulateurs de la migration, nous avons trouvé que deux sous-unités de l'exocyst, Exo70 et Sec6, interagissent directement in vitro avec Abi et Cyfip, respectivement, deux sous unités du WRC. De plus, nous avons trouvé que les sous-unités de l'exocyst peuvent interagir in vitro avec le WRC entier. Nous avons également montré que ces deux complexes s'associent in vivo. Sur le plan fonctionnel, l'exocyst est requis pour le positionnement du complexe WRC au front des cellules migrantes. D'autre part, nous avons également trouvé que deux autres sous- unités de l'exocyst Sec8 et Exo84, interagissent avec SH3BP1 (une RhoGAP) en double hybride et en co-immunoprécipitation. SH3BP1 se localise au front des cellules migrantes, et cette localisation dépend de l'exocyst. De façon intéressante, in vivo, la voie RalB/exocyst/SH3BP1 cible spécifiquement Rac1, et non Cdc42. Grâce à plusieurs approches, nous concluons que SH3BP1 est requis pour inactiver Rac1 au front. Dans notre modèle nous proposons que RalB/exocyst règulerait la migration cellulaire en véhiculant au front de migration deux éléments majeurs de la signalisation de Rac1 : son complexe effecteur WRC, qui stimule la nucléation de filaments d'actine et son régulateur négatif SH3BP1, une GAP qui promeut l'inactivation et le cycle GDP/GTP de Rac1. En conclusion, ce travail fournit de nouvelles connexions moléculaires et fonctionnelles entre l'exocytose polarisée et la dynamique de l'actine au cours de la motilité cellulaire.

Exposure to ultraviolet radiation (UV) results in both damaging and beneficial health outcomes. Excessive UV exposure has been linked to many skin and eye problems, but moderate exposure induces vitamin D production. It has been reported that humans receive 90-95% of their vitamin D from production that starts after UV exposure. Although it is possible to acquire vitamin D through dietary supplementation, the average person receives very little in this manner. Therefore, since most people acquire their vitamin D from synthesis after exposure to UV from sunlight, it is very important to understand the different environments in which people encounter UV. This project measured UV radiation and in-vitro vitamin D production in the urban canyon and at a nearby suburban location. The urban canyon is an environment consisting of tall buildings and tropospheric air pollution, which have an attenuating effect on UV. Typically, UV measurements are collected in areas outside the urban canyon, meaning that at times studies and public recommendations do not accurately represent the amount of UV reaching street-level in highly urbanized areas. Understanding of UV exposure in urban canyons becomes increasingly important as the number of people working and living in large cities steadily increases worldwide. This study was conducted in the central business district (CBD) of Brisbane, Australia, which models the urban canyons of large cities around the world in that it boasts a great number of tall buildings, including many skyscrapers, meaning that most areas only see a small amount of direct sunlight each day. During the winter of 2007 measurements of UV radiation and in-vitro vitamin D production were collected in the CBD and at a suburban site approximately 2.5km outside the CBD. Air pollution data was obtained from a central CBD measurement site. Data analysis showed that urban canyon measurements of both UV radiation and in-vitro vitamin D production were significantly lower than those collected at the suburban site. These results will aid both future researchers and policy makers in better understanding human UV exposure in Brisbane’s CBD and other urban canyons around the world.

The role of natural environments, especially ‘green space’, in promoting human health and well-being is well-researched. However, less is known about the benefits of ‘blue space’ (e.g. the coast) or ‘managed’ nature (e.g. zoos). In this thesis, six studies investigated the restorative potential of sub-aquatic settings, specifically public aquariums and the biological diversity within them. Studies 1 and 2 investigated preferences for, affective responses to, and the restorative potential of, five built and natural settings (i.e. built, green space, blue space, natural underwater and public aquariums). Using the same measures, Study 3 focused solely on people’s responses to aquarium exhibits, sub-categorised by geographic region, level of species richness and abundance, and taxonomic group. Study 4 examined behavioural, physiological and psychological responses to one aquarium exhibit during three stages of restocking. Finally, to establish how perceptions of species richness and abundance influenced well-being outcomes, people viewed and evaluated either one (Study 5) or two (Study 6) large aquarium exhibits. These studies found that natural sub-aquatic and aquarium settings were as preferred, and perceived as potentially restorative, as green space environments, and different exhibits elicited different responses: ratings were higher for tropical exhibits (vs. temperate), high abundance (vs. low) and vertebrates (vs. invertebrates), although findings for species richness were mixed. Within one exhibit, higher stocking levels resulted in increased attention and interest, greater improvements in mood, and some physiological evidence of relaxation (e.g. decreased heart rate). Broad levels of marine life could be distinguished but estimates of actual numbers were poor. Viewing one or two exhibits tended to improve mood, decrease arousal and be perceived as restorative; any differences between the two exhibits were more evident when both had been viewed. Overall, findings suggest that engaging with different types of managed nature may provide valuable perceived human health and well-being benefits.

The objective of this paper is to provide a robust understanding of the magnitude and direction of effect of urban green space on human health outcomes. This relationship has been studied using a variety of health and green space measures and multiple approaches to collect health data. Due to the various approaches used to study the relationship between green space and health, it is difficult to clearly understand the general relationship. In order to have a robust and clear understanding of the relationship between green space and human health, it is necessary to do a meta-analysis that considers all the approaches to assessing green space, health, and health data. Overall, the average estimated effect shows that surrounding urban green space improves human health by 1.14 fold (~u=0.13 (95% CI: (0.07-0.19)). The magnitude of effect increased when accounting for perceived health and when using greenness as the urban green space measure (~u=0.29 (95% CI: (-0.06-0.63)). In conclusion we can now objectively imply that health can be improved with increased surrounding green space. Further, that the magnitude depends on how studies assess green space and health measures, as well as how health data is collected.

Faecal pollution regularly contaminates surface waters, introducing microorganisms, including bacteria and bacteria resistant to antibiotics, to coastal waters. People can come into contact with these potentially harmful microbes when they enjoy recreational activities in the sea. Understanding the risk to bathers of acquiring infections from the sea is important for developing effective intervention strategies to protect human health. This thesis consists of four original studies which aim to answer the question ‘are bacteria in the coastal zone a threat to human health’? First, we describe a systematic review on the risk of acquiring infections from recreational use of coastal waters. Synthesising risk estimates of reporting various symptoms of ill health, we quantify this risk as well as appraise the evidence that these infections are acquired from bathing in coastal waters. The results of the second study - a large online survey - corroborate these findings and provide updated estimates of risk for UK bathers. Third, we assess the risk of ingesting antibiotic resistant bacteria among UK coastal water users. In the final study, we measured the prevalence of faecal carriage of antibiotic resistant bacteria among a highly exposed group – surfers, and in an unexposed group (non-surfers). We conclude that despite improvements made to the collection, treatment and discharge of sewage, and initiatives to communicate water quality to members of the public in recent years, people who bathe in coastal waters are still at an increased risk of adverse health outcomes, whether this is experiencing symptoms of ill health, or exposure to and colonisation by antibiotic resistant bacteria.

Increased salinization of inland freshwater resources is present on a global scale, but is pro- gressing rapidly in the densely populated Mid-Atlantic United States. This phenomenon threatens aquatic health, ecosystem services and functionality, and can alter the percep- tion of potable drinking water. The Occoquan watershed, located in Northern Virginia has experienced rapid urbanization across recent decades and is now confronted with rising salinization. Various stakeholders in the area have focused efforts to quantify the drivers of salinization in order to take corrective action to preserve this resource. To aid these efforts, urbanization's relationship with in-stream salinity was analyzed, where its exerted influence was found to be dependent upon overland hydrologic flowpaths which connect urban areas to stream networks. The analysis was then broadened to Multiple Linear Regression models of urban and climatological drivers to statistically quantify each driver's relative influence on in-stream salinity. The models demonstrated that urbanization is the primary driver, where rainfall and roadway deicer application were also found to be significant. The model was then used to predict the magnitude of salinization in the Occoquan watershed to a time horizon of 2040 based on expected population growth as well as two anticipated climate scenarios. Finally, the analytical framework produced in this research was generated with scalability in mind, such that it can potentially be utilized as a watershed-scale screening tool accross the Mid-Atlantic, to inform proactive, regionally appropriate management decisions. / Master of Science / Increased salinization of inland freshwater resources is present on a global scale, but is progressing rapidly in the densely populated Mid-Atlantic United States. Driven by the engineered systems that define our modern world, this phenomenon threatens aquatic health, ecosystem services and functionality, and can alter the perception of potable drinking water. The Occoquan watershed, located in Northern Virginia has experienced rapid urbanization across recent decades and is now confronted with rising salinization. Various stakeholders in the area have focused efforts to quantify the drivers of salinization in order to take corrective action to preserve this resource. The analyses completed in this body of work act to model and statistically analyze the drivers which foster salinization in the Occoquan. The analyses demonstrated that while climatological factors drive salinity in the Occoquan, urbanization is the primary driver, where its exerted influence is dependent upon overland hydrologic flowpaths which connect urban areas to stream networks. Further analyses were completed to project salinization to a time horizon of 2040 based on expected population growth as well as two anticipated climate scenarios to predict the magnitude of salinization in the Occoquan watershed in decades to come. These results indicated that anticipated levels of in-stream salinity will increase across most sampling stations in coming years. Finally, the analytical framework produced in this research was generated with scalability in mind, such that it can potentially be utilized as a watershed-scale screening tool accross the Mid-Atlantic, to inform proactive, regionally appropriate management decisions.

The electrochemical enzymatic electrodes dominate the world market for blood glucose monitoring devices for controlling, as well as reducing the detrimental effects of diabetes. However, the enzymatic electrodes exhibit constraints restricting their reliance on the enzyme’s activity which can be influenced by the external, and the environmental factors such as temperature, pH, and humidity etc. However, the greater thickness of the enzyme layer hinders the performance of the glucose biosensors resulting in signal dampening or loss. In addition, the selectivity of the electrodes is affected by the interferents present in blood. Moreover, the invasive nature of the electrodes is a major problem considering the patient’s perspective. In contrast, recent research activities demonstrated that the electrochemical non-enzymatic electrodes possess huge potential for inexpensive and highly sensitive glucose monitoring devices, yet these electrodes are invasive in nature. Therefore, the purpose of this research was to fabricate electrochemical non-enzymatic non-invasive electrodes for sweat glucose monitoring devices. A very simple low-cost fabrication technique has been shown to make the facile, flexible, and inexpensive electrodes to detect sugar in sweat bio-analyte for a non-invasive glucose monitoring system using the native stable Cu oxides (CuNOx), Cu2O, layers grown on 35 µm thin Cu foils keeping under ambient conditions (25℃- and 760-mm Hg) for more than 2 years so that the oxide layers are full-grown, and fully stable. Moreover, the foils also annealed at various temperatures such as 160, 230, and 280℃ with new temperature profile for reducing the required time of growing stable oxides and producing oxides with larger crystallized structures with higher surface – to – volume ratio. The X-ray photoelectron spectroscopy (XPS) and high-resolution transmission electron microscopy (HRTEM) results supported that at 280℃ annealing temperature the surface, mostly, transformed into highly electrocatalytic CuO with larger grain sizes, crystallized structures, and the uniform layer of ~ 140 nm. The electrochemical characterization, and sensing performance of the electrodes have been done by cyclic voltammetry (CV), one of the excellent and well accepted electrochemical methods, with the 3 – electrode configuration of the potentiostat. The CuNOx sensors of having ~10 nm layer of stable Cu2O exhibited a sensitivity of 603.42 μA mM−1 cm−2, a linear range beyond the desired limit of 7.00 mM with excellent linearity (R2 = 0.9983) and a low limit of detection of 94.21 μM. In contrast, the new annealing profile has. the CuNOx sensors annealed at 280 ºC using new temperature profile provided twin calibration curves of linear ranges of 0.05 – 1.00 mM and 1.00 – 7.00 mM, that applicable for sweat and blood glucose sensing, respectively, and exhibited a sensitivity of 1795 μA mM−1 cm−2, a linear range up to the desired limit of 1.00 mM for sweat glucose sensing with excellent linearity (R2 = 0.9844), and a lower limit of detection of 135.39 μM. In addition, it has been shown that the peak electro-oxidation current of glucose sensing is linearly related with the squire root of the annealing temperature, √T. This can help to figure out the required applied annealing temperature for getting desired peak electro-oxidation current of glucose in a human health monitoring system. / Dissertation / Doctor of Philosophy (PhD)

In low-income, rural, and indigenous communities, metal mining is associated with numerous negative social, political, economic, human, and environmental health impacts. A number of studies from around the world have looked at specific aspects of human and environmental health related to various contaminants from mining and the landscape alterations associated with the processes, along with the growing community resistance and opposition to mining operations. The individual impacts of each of these components are understood, but a deeper understanding of the syndemic effects of a mine operating in a community, particularly in an indigenous community, was needed, especially as the industry is expected to grow around the world. Using a community-based participatory research (CBPR) approach, we utilized a combination of participatory mapping, interviews, and community mapping workshops to examine the underlying patterns and perceptions of environmental risk and healthy and unhealthy spaces in the Ch'orti' communities of Olopa, Guatemala that have been impacted by the Cantera Los Manantiales antimony mine. Results suggest that, since mining operations began, residents have experienced an increase in violence and community divisions surrounding the mine, a higher incidence of a variety of diseases, and an extensive loss of crops and domesticated animals. Furthermore, participants were concerned about both water and air contamination, all of which they attributed to the mine. The results of the study will be useful for local activist leaders and allied NGOs to effectively assess and improve health in indigenous communities impacted by the Cantera Los Manantiales mine in Olopa. The approach, particularly the use of participatory mapping methods, could be implemented in future studies attempting to understand syndemics and other environmental health risks and outcomes. / Master of Science / In low-income, rural, and indigenous populations, metal mining is associated with numerous negative social, political, economic, human, and environmental health impacts. A number of studies from around the world have looked at the specific ways that human and environmental health are impacted by mining processes, along with how and why communities protest mining operations. Each effect is well understood, but a deeper understanding of how those effects of a mine operating in a community interact was needed, especially as the mining industry is predicted to grow. Involving the community throughout the study, we used interviews and maps made by members of the Ch'orti' communities of Olopa, Guatemala that are impacted by the Cantera Los Manantiales antimony mine to understand patterns and perceptions of environmental risk and healthy and unhealthy places. Results suggest that, since mining operations began, residents have experienced an increase in violence and community divisions surrounding the mine, an increase in disease and illness, and an extensive loss of crops and domesticated animals. Furthermore, participants were concerned about both water and air contamination, all of which they attributed to the mine. The results of the study will be useful for local activist leaders and allied organizations to understand and improve health in the communities impacted by the Cantera Los Manantiales mine in Olopa, and the mapping methods that were employed will be useful for future studies that are mapping interacting health threats and outcomes.

Passive solar strategies have been present in architectural design for a long time. Basic concepts such as south facing openings to capture winter sunlight had been understood since ancient times and came about as a necessity to heat and cool a building with modern day mechanical systems. Over time, architects began to recognize the importance of sunlight and fresh air as primary concerns of design. Much of this understanding began to take place through practices originally implemented as a means for aiding in human recovery from disease. Sanatoriums began to emerge in the early 1900's, providing groundbreaking design strategies that incorporated natural sunlight and exposure to fresh air as means for recovery. At the time, these design strategies were not fully recognized for their ability to aid in a building's energy usage but were primarily focused on human health. These early projects still functioned exceptionally well for their time and many still function today. Unfortunately, while these projects were starting to break ground in solar design practices, the invention of forced air heating and cooling was starting to work its way into buildings. Petrochemical heating and cooling quickly became the standard for how buildings would operate. Over time, the primary focus of design began to stray away from traditional methods of passive design in favor of the simpler implementation of mechanical HVAC systems. Over the past decade, there has been a shift in architectural design with a much stronger focus on sustainability. As research is being done into climate change and the negative affects it has had on our planet, architects have come to understand how important the role of the building plays in the world ecosystem. Buildings account for roughly 40% of human energy consumption, with the major share of this energy use being focused on heating and cooling. Passive designs are so important because they can begin to cut into this energy usage, and in some case even reduce it entirely through net zero projects. The architect has near complete control over the passive design of a building because the passive solar strategies are inherently "built in" to the building through its site orientation, formal strategies, and shading. It is the responsibility of the architect to consider these factors. It is important, however, that passive strategies do not overlook human health and productivity. Human sensitivity to thermal and lighting conditions is equally as important as the building's energy performance. Humans are very sensitive to light conditions, an idea expressed early on in the sanatorium movement. Access to natural light aids in human health, benefiting a multitude of anatomical systems. It also aids in mental health, aiding in creativity, emotional well-being, and focus. The lighting conditions of a building affect our natural circadian rhythm on a daily basis. Combining ideas of passive solar design in terms of energy use and human health, this thesis hopes to create ideal conditions for the building and its inhabitants by optimizing building and human performance. / Master of Architecture / Passive design strategies are those that are inherent to the design of the building. Window shades, building orientation, materialliity, are just some of the examples of factors that go into passive design. Passive design is where architects can have the greatest control, simply due to the fact the design of the building is performative in itself. These strategies use the sun to aid with natural heating, cooling, and lighting, which is a much more sustainable practice than traditional mechanical systems. Passive design has been used dating back to ancient times. Greek towns were typically planned with large courtyards oriented to the south to capture sunlight. Ancient adobes were carved into the side of south facing cliffs to capture the warmth of the sun. This thesis expands upon these traditional strategies with the use of modern knowledge and technologies. This thesis takes concepts of passive solar design a step further by introducing concepts that can promote human health and productivity. Humans have evolved to live in cooperation with the sun. We have natural rhythms that allow our bodies and minds to be in tune with the rising and setting sun. In addition to natural cycles over the course of the day, we are uniquely in tune with qualities of light. We interpret light as intensity and temperature, both which combine to produce a "quality" to the light. These different qualities are better suited for different activity, whether that be relaxing, focused work, or gathering. With a passive design project that is focused so heavily on the sun, it was important to consider how this would affect the inhabitants of the building. By combining sustainable passive design strategies with concepts surround human health and productivity, this project outlines a method for design that can inspire public works to pay attention to detail when planning spaces. Through careful consideration of site specific climate data and its connection to not only building performance but human well-being, this thesis project provides a new form of thinking for solar design.