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Les ADAMTS (a desintegrin and metalloprotease with thrombospondin type 1 repeat) sont des métallopeptidases sécrétées dans le milieu extracellulaire ayant comme fonction le clivage de différents substrats de la matrice extracellulaire tel le propeptide en N-terminal du collagène, l'aggrécan, ainsi que le von Willebrand factor retrouvé dans le plasma. Une mutation ou un dérèglement d'ADAMTS2, 5 et 13 sont directement responsable du syndrome de Ehlers-Danlos de type VII C, l'arthrose et la purpura thrombotique thrombocytopénique respectivement. De plus, ADAMTS1 et 8 sont reconnues pour avoir des propriétés anti-angiogéniques qui s'avèrent d'un potentiel thérapeutique contre la progression des tumeurs. La biosynthèse et les mécanismes menant à la pleine activité biologique de ces peptidases sont peu connus et ont été étudiés dans cet ouvrage. Nous avons démontré que les ADAMTS sont initialement synthétisées sous forme de zymogènes qui subissent un clivage protéolytique à la jonction de leur prodomaine et de leur domaine catalytique par différentes sérines peptidases de la famille des pro-protéines convertases de type subtilisine. Des études de marquages métaboliques des différents ADAMTS transfectées dans la lignée cellulaire CHO RPE.40 déficiente en furine ont dévoilé que ADAMTS1, 5, 7 et 9 sont toutes clivées par la furine. D'autres convertases clivent de façon moins efficace que la furine les prodomaines des ADAMTS (PACE4 et PC6B clivent ADAMTS1, PC6B et PC7 clivent ADAMTS7, PC5A Clive ADAMTS9 et PC7 Clive ADAMTS5). Malgré la présence de plusieurs sites consensus de clivage par la furine dans les prodomaines des ADAMTS, des études de mutagenèse dirigée abolissant les différents sites ont démontré que le site plus près du domaine catalytique est préférentiellement clivé par la furine. Le clivage du prodomaine d'ADAMTS1 et 7 s'effectue au réseau du trans -Golgi. Toutefois, des études de marquage à la biotine des protéines de la surface cellulaire démontrent que ADAMTS7 semble aussi être clivée à la surface de la cellule. ADAMTS5 est strictement maturée dans l'espace extracellulaire, soit à la surface cellulaire ou dans le milieu extracellulaire, ce qui révèle un nouveau mécanisme d'activation par la furine pour des substrats endogènes. En outre, ADAMTS9 est clivée à la surface de la cellule par la furine, mais contrairement à la presque totalité des substrats de la furine, celle-ci inactive ADAMTS9. En somme, il existe plusieurs mécanismes d'activation des ADAMTS : activation intracellulaire ou extracellulaire et inactivation extracellulaire par les convertases. La présence, dans les prodomaines des ADAMTS, d'acides aminés conservés à travers les membres de cette famille d'enzyme nous amène à penser qu'ils pourraient jouer un rôle important dans leur maturation. La mutation des acides aminés conservés des motifs CXYXG et YFIXPL d'ADAMTS1 et 9 ainsi que des sites de N-glycosylation d'ADAMTS9 ont grandement affecté la sécrétion de l'enzyme mature. Cette observation permet de conclure qu'outre le site consensus de clivage par la furine, des motifs conservés ainsi que la glycosylation des prodomaines sont impliqués dans la biosynthése des ADAMTS. La découverte de nouveaux mécanismes d'activation par la furine a une signification importante dans le domaine d'activation de précurseurs. L'activation extracellulaire d'ADAMTS5, l'enzyme responsable de la dégradation du cartilage, génère une cible thérapeutique potentielle pour un traitement futur de l'arthrose.

Poland's political fate and the plight of her exiles during the nineteenth century evoked a mixed response from various sectors of the British population. Five separate aspects of pro-Polish sympathy have been analyzed. The Literary Association's efforts to raise money for the relief of refugees resident in Great Britain were severly hampered and finally crippled by public opinion hostile to charity for foreigners in the midst of domestic distress. Agitation designed to place pressure on the Government to intervene by force in order to re-establish the independence of Poland was never sufficiently strong between 1832 and 1867 to deflect the Government from pursuing a course dictated by national interests. This has been illustrated by a study of public opinion and official policy towards the restoration of Poland during the Crimean War. The attitude of several of the more important religious denominations to the Polish question was not uniform. Roman Catholics feared the destruction of Papal possessions in the event of Polish revolutionary fervour reaching Italy; Anglo-Jewry tended to be absorbed in the problem of its own disabilities while it was difficult for the Poles as a predominantly Catholic nation to avoid giving offence to the Established Church and dissenting sects. Anglo-Polish masonic contacts produced a new form of passive Polonophilism quite distinct from the conventional pattern of demonstrative sympathy for Poland but equally futile from the political point of view. Polish experience of foreign oppression was far more relevant for Irish nationalists than for the English. A backward agrarian economy and the Roman Catholic religion also drew the two nations together. Ireland, however, could offer nothing more substantial to the Poles than moral support and in return was able to profit from sophisticated Polish theories of insurrection.

Fingerprints in blood indicate a threshold of violence has been surpassed in crime scenarios - making the crime resolution more urgent. There exist multiple processes that enhance a blood fingerprint in its original position, or in-situ, with reliability so that an image can be obtained. However, blood fingerprint evidence that cannot directly be transported to a laboratory for further analysis, due to the size or mobility of the substrate, calls for portability. In 2010 Zar-Pro Fluorescent Blood Lifting Strips were patented by Jessica Zarate as a "fluorogenic method for lifting, enhancing, and preserving blood impression evidence". The lifted prints are also inherently fluorescent to further increase enhancement and contrast of the print. There are currently no studies comparing Zar-Pro results with the results of other laboratory enhancement methods. This experiment compared Zar-Pro to other non-portable and frequently used alternatives - blood peak absorption and Hungarian Red enhancement to determine if Zar-Pro gives better blood fingerprint enhancement results than other non-portable alternatives - ALS visualization and Hungarian Red enhancement. In this study, Zar-Pro methods produced more reliable and reproducible results over the Hungarian Red and blood peak absorption methods on white and black ceramic tile. From this study, one can also conclude that ALS peak absorption is better suited for the location of blood prints on a light-colored item of evidence, rather than an enhancement method of blood prints.

Tackling climate change and other associated environmental problems has become a significant global issue. In order to tackle these challenges governments have introduced policy frameworks, legislation and laws to help mitigate their effects. The Scottish Government have invested in numerous programmes and initiatives to create and enhance a low carbon rural economy, and in order to do so successfully understanding behaviour is a vital component in achieving the aims of such policies and legislation. Rural businesses can play an important role in encouraging the uptake of pro-environmental behaviour and energy saving practices. However individuals within rural SME’s (small and medium sized enterprises) often encounter barriers which may prevent reductions in greenhouse gas (GHG) emissions and other environmental objectives from being achieved. Therefore it is important to understand the influences associated with pro-environmental behaviour within the workplace, specific to the rural economy. This thesis aims to investigate the role of the physical, social and individual context in influencing individuals’ workplace pro-environmental behaviour. The thesis also aims to research the barriers, facilitators and motivations individuals experience during decision-making and action taken relating to issues such as recycling, waste management, energy efficiency, transport and procurement. Different employee levels within a variety of rural tourism businesses have been studied (e.g. employees, management, and business owners) utilising a mixed methodology consisting of focus groups and a questionnaire survey in order to enhance and validate the research. By doing so this study has managed to increase understanding of the views of employees, managers and business owners, who are crucial to the uptake of pro-environmental behaviour within the rural economy. A range of antecedents were identified from existing literature as having potential effects on pro-environmental behaviour, therefore a variety of these were thoroughly investigated. The results of the studies carried out herein show the importance of understanding workplace pro-environmental behaviour from the perspective of different contexts (physical, social and individual). With respect to the physical context, antecedents influencing individuals’ workplace pro-environmental behaviours include building infrastructure, business size and building location. Individuals expressed their businesses inability to be energy efficient due to poor building infrastructure, e.g. operating from an old rural building with inefficient roof and wall insulation, to no double glazing due to being in a listed building, thus letting heat escape. Furthermore, individuals discussed renting premises for their business, therefore have no control over structural decisions which affect energy efficiency. Business size was also mentioned as an important influence of behaviour in relation to the physical context, e.g. smaller businesses produce less turnover, and therefore are not in a financial position to upgrade heating systems, or utilise clean efficient technologies and materials which are perceived to be more expensive. With regard to business location, a high proportion of participants highlighted this as a barrier to undertaking pro-environmental behaviour, e.g. lack of public transport, recycling facilities and pick-ups for particular business materials, as well as not being able to procure goods for the workplace locally due to lack of availability. In terms of the social context, antecedents influencing individuals’ workplace pro-environmental behaviour included social norms. Individuals cite being influenced by professional relationships, e.g. neighbouring businesses, colleagues, customers and higher management (industry compliance), in addition to personal social relationships e.g. friends and family. Many business owners stated feeling responsible to behave pro-environmentally and were motivated to try and set a good example to other members of their workforce in order to increase participation and awareness. The study also highlighted the importance to strengthen an individual’s identification with their workplace, as results illustrated the more an individual strongly identified with their work, the more likely they were to engage in pro-environmental behaviour. Lastly with respect to the individual context, this refers to one’s personal circumstances, outlooks and attitudes specific to them as an individual. The thesis provides support that environmental identity and level of environmental activity (contingent to the workplace) were both influences of workplace pro-environmental behaviour. The study’s findings highlighted the more an individual strongly identified with the environment, the more likely they were to engage in pro-environmental behaviour at work. With respect to the level of environmental activity as an influence of workplace behaviour, results provided evidence that the more an individual was active (e.g. in green marketing, joining green schemes, holding/attending environmental meetings etc.), the more likely they were to engage in pro-environmental behaviour at work, thus illustrating the value of these practices. In conclusion, results from this research demonstrate the relationship between the physical, social and individual context when investigating the influences of workplace pro-environmental behaviour, and furthermore identify individuals’ personal motivations, barriers and facilitators. By doing so the thesis has been able to highlight what actions and procedures could potentially be implemented to increase sustainable tourism business practices in the transition to a low carbon rural economy. It is important to recognise individuals will perceive different barriers and retain motivations personal to them, therefore when business owners apply new environmental initiatives and goals, employees’ individual needs must be acknowledged to facilitate greater engagement. Workplace pro-environmental behaviour is complex and fairly under researched in comparison to investigating home-based pro-environmental behaviours. Therefore this study has added to the body of literature by highlighting the importance of different contexts (physical, social and individual) and has increased the understanding of what influences workplace pro-environmental behaviour specific to the rural tourism industry, which is vital to Scotland’s economy.

This diploma thesis is focused on franchising and a practical application of a theory. The theoretical part describes basic principles of franchising, its advantages and disadvantages and franchise agreement. I put more emphasis on development and current state of franchising in the Czech Republic. I describe and evaluate franchising in the company Alpine Pro in the practical part of the thesis. I show that a purely Czech franchise concept is able to succeed in stiff competition - and not only in the Czech Republic. The aim is to evaluate franchisor - franchisee relationship (on the basis of the questionnaire research) and to suggest some measures and recommendations that would lead to improvement of the weak points of the franchise concept Alpine Pro.

Le mélanome est la forme la plus rare et la plus grave des cancers de la peau. Il présente un fort pouvoir métastatique et à l'heure d'aujourd’hui, il n'y a pas de traitement efficace contre le mélanome disséminé. Le travail présenté dans ce mémoire s'inscrit dans la continuité d'une stratégie de d'adressage spécifique de pro-drogues vers le mélanome initiée au sein de notre laboratoire. Notre concept repose sur la conjugaison d'ICF01012, vecteur à fort tropisme pour les mélanines, avec un principe actif modèle (IUdR) sous forme de pro-drogues à espaceurs clivables de type disulfure d'éthyle carbonate ou pnitrobenzylcarbonate pour une double spécificité (i.e. distribution tumorale et libération spécifique de la tumeur). Un premier travail de fonctionnalisation d'ICF01012 a abouti à la synthèse de sept nouveaux vecteurs qui ont été radio-marqués à l'iode 125 afin d'évaluer leur comportement in vivo chez des souris C57Bl/6J porteuses de mélanome B16F0 par scintigraphie plane gamma et biodistribution ex vivo. Le vecteur radio-iodé présentant le profil pharmacocinétique le plus favorable (fixation tumorale forte, spécifique et durable) a été ensuite sélectionné en vue d'une première validation de notre concept de prodrogues vectorisées. Les entités "IUdR-espaceurs clivables" et leurs analogues non clivables à base d'espaceurs de type mercaptoéthylcarbonate ou benzylcarbonate ont également été synthétisés. L'étude de leur comportement au contact de 2S,3S-dithiothreitol et d'hydrosulfite de sodium (mimant l'action du glutathion et de conditions hypoxiques, respectivement) a montré que la libération de l'IUdR est quasitotale et qu'elle est bien induite par la présence du pont disulfure et du groupement nitré. Sur la base de ces résultats, deux pro-drogues ainsi que leurs analogues non clivables ont été synthétisés par association de la partie vectrice avec l'IUdR et les espaceurs clivables ou non clivables. Les études de biodistribution in vivo de l'IUdR et de la pro-drogue à espaceur disulfure radio-marquées à l'iode 125 ont démontré une absence de vectorisation, imputable à une métabolisation très rapide de la pro-drogue par la suite d'un clivage extrêmement rapide de l'espaceur disulfure in vivo provoquant la libération instantanée de l'IUdR dès les premières minutes qui suivent l'injection de la pro-drogue. Néanmoins, des voies de synthèse et des méthodes de suivi de clivages chimiques transposables ont été mises au point et peuvent être utilisées dans les futures études s'inscrivant dans le cadre d'une chimiothérapie vectorisée du mélanome. / Melanoma is the rarest and the most serious form of skin cancer. It has a high metastatic potential and in today's time, there is no effective treatment against disseminated melanoma. The present work is a continuation of a melanoma targeted prodrug therapy approach initiated in our laboratory. Our concept is based on the combination of ICF01012, vector that displays a high tropism for melanin, with IUdR, a drug model, as cleavable prodrugs containing a disulfide ethyl carbonate or a pnitrobenzylcarbonatespacer type for a dual specificity (i.e. tumoral distribution and specific delivery to the tumor). Functionalization of ICF01012 led to the synthesis of seven new vectors that were 125Iradiolabeled in order to evaluate their behavior in vivo (planar gamma scintigraphy and ex vivo biodistribution) in B16F0 melanoma-bearing mice. The radioiodinated vector having the most favorable pharmacokinetic profile (high, specific and long lasting tumoural uptake) was then selected for a first validation of our targeted prodrugs concept. Entities "IUdR-cleavable spacers" and their analogs with noncleavable spacers (mercaptoéthylcarbonate or benzylcarbonate kind) were also synthesized. The study of their behavior in contact with 2S,3S-dithiothreitol and sodium hydrosulfite (mimicking glutathione and hypoxic conditions actions, respectively) showed that the release of IUdR is almost complete and it is induced by the presence of the disulfide bridge and the nitro group. Based on these results, two prodrugs and their non-cleavable analogs were synthesized by combining the vector part with IUdR and cleavable or non-cleavable spacers. The in vivo biodistribution studies of 125I-radiolabeled IUdR and disulfide spacer based-prodrug showed no vectorization due to a very rapid metabolism of the prodrug following extremely rapid cleavage of the disulfide spacer in vivo causing instantaneous IUdR release in the firstminutes after prodrug injection. However, transposable synthetic routes and cleavage studies have been developed and can be used in future studies within the framework of melanoma targeted prodrug therapy

<p>Oxygen consumption and carbon dioxide production are usual measurements within the sports and training physiology. The same measurements are also common when it comes to establish the amount of energy that is used during work and to establish the intensity of work. The volume of oxygen that is consumed contra the volume of carbon dioxide that is produced can be used to calculate the metabolic rate within the human body. This calculation shows the percent relationship between carbohydrates and fat in the metabolism. </p><p>The first accurate method to measure the breathing gases for use in metabolic calculation was established in the early twenty century when the Douglas bag method was introduced. The expired air is collected in sealed bags and the volume of expired air is then analyzed when it comes to its content of oxygen and carbon dioxide. In our days several methods have been developed for automatic analysis of the breathing gases where the expired air is analyzed immediately by electronic instruments. </p><p>When it comes to the modern automatic instruments there are few scientific investigations about their reliability and that has raised questions about how accurate measurements they produce. One instrument is the Oxycon Stationary Pro which is used by Gymnastik- och Idrottshögskolan in Stockholm Sweden and several of the Swedish university hospital. In this report there has been done a practical comparison between the Douglas bag method and the automatic instrument Oxycon Stationary Pro. The comparison showed a great similarity when it come to the metabolic rate. When it comes to the respiratory gases however, the Oxycon Stationary Pro shows values up to five percent higher than the Douglas bag.</p>

Oxygen consumption and carbon dioxide production are usual measurements within the sports and training physiology. The same measurements are also common when it comes to establish the amount of energy that is used during work and to establish the intensity of work. The volume of oxygen that is consumed contra the volume of carbon dioxide that is produced can be used to calculate the metabolic rate within the human body. This calculation shows the percent relationship between carbohydrates and fat in the metabolism. The first accurate method to measure the breathing gases for use in metabolic calculation was established in the early twenty century when the Douglas bag method was introduced. The expired air is collected in sealed bags and the volume of expired air is then analyzed when it comes to its content of oxygen and carbon dioxide. In our days several methods have been developed for automatic analysis of the breathing gases where the expired air is analyzed immediately by electronic instruments. When it comes to the modern automatic instruments there are few scientific investigations about their reliability and that has raised questions about how accurate measurements they produce. One instrument is the Oxycon Stationary Pro which is used by Gymnastik- och Idrottshögskolan in Stockholm Sweden and several of the Swedish university hospital. In this report there has been done a practical comparison between the Douglas bag method and the automatic instrument Oxycon Stationary Pro. The comparison showed a great similarity when it come to the metabolic rate. When it comes to the respiratory gases however, the Oxycon Stationary Pro shows values up to five percent higher than the Douglas bag.