In the 21st century change is inevitable and management accounting has not been immune to the changing business environment. The morphogenic change, has been brought about because of three distinctly identifiable drivers of change namely rapidly advancing communications and information technology, the onslaught of globalisation and an increased emphasis on the knowledge worker in organisations. Questions have been raised by business leaders about management accountants ability to keep pace with the challenges, as well as higher education's ability to provide graduate management accountants with the required skills for the new business environment. A triangulation method was used to conduct an investigation into the perception of the skills required and acquired by South African management accountants to meet the challenges of the changing business environment. As the fundamental nature of the study implied performance measurement, a balanced scorecard was employed to report on and measure if academia is delivering what practice wants. The study found that tertiary management accounting education has been slow to adopt the changes of the business environment and that a gap does indeed exist between what practice want and educators teach. Information obtained from the customer, learning and growth, internal business process and financial perspectives of the balanced scorecard was used to develop a framework for curriculum design. Academics involved in curriculum design should take note of the recommendations listed in this research in order to ensure that qualifications remain relevant to an ever-changing business environment. / Financial Accounting / D.Comm.

In the 21st century change is inevitable and management accounting has not been immune to the changing business environment. The morphogenic change, has been brought about because of three distinctly identifiable drivers of change namely rapidly advancing communications and information technology, the onslaught of globalisation and an increased emphasis on the knowledge worker in organisations. Questions have been raised by business leaders about management accountants ability to keep pace with the challenges, as well as higher education's ability to provide graduate management accountants with the required skills for the new business environment. A triangulation method was used to conduct an investigation into the perception of the skills required and acquired by South African management accountants to meet the challenges of the changing business environment. As the fundamental nature of the study implied performance measurement, a balanced scorecard was employed to report on and measure if academia is delivering what practice wants. The study found that tertiary management accounting education has been slow to adopt the changes of the business environment and that a gap does indeed exist between what practice want and educators teach. Information obtained from the customer, learning and growth, internal business process and financial perspectives of the balanced scorecard was used to develop a framework for curriculum design. Academics involved in curriculum design should take note of the recommendations listed in this research in order to ensure that qualifications remain relevant to an ever-changing business environment. / Financial Accounting / D.Comm.

Made available in DSpace on 2014-12-17T15:32:33Z (GMT). No. of bitstreams: 1 CyntiaHPC_TESE.pdf: 1535929 bytes, checksum: 7d7c8298def3233365b9ad5eb617d015 (MD5) Previous issue date: 2014-02-27 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in the oral cavity and reach a large number of individuals, has become an important public health problem. Studies have demonstrated changes in pathway components BMP in various types of cancers as prostate, colon, breast, gastric and OSCCs. Is the current knowledge that these proteins may exert pro-tumor effect in more advanced stages of neoplastic development coming to favor progression and invasion tumor. The inhibition of the signaling pathway BMP-2 through its antagonists, have shown positive results of antitumor activity and use of Noggin may be a novel therapeutic target for cancer. Given this evidence and the few studies with BMP-2, Noggin and OSCC, the objective of this research was to evaluate the effect of BMP-2 and its antagonist Noggin on proliferation and migration cell in line of cell cultures of human tongue squamous cell carcinoma (SCC25). The study was divided in three groups, a control group, where SCC25 cells suffered no treatment, a BMP-2 group, in which cells were treated with 100ng/ml of BMP-2 and a group of cells that were treated with 100ng/ml of Noggin. For the proliferation assay and cell cycle were established three time intervals (24, 48 and 72 hours). Proliferative activity was investigated by trypan blue and cell cycle analysis by staining with propidium iodide flow cytometry. The potential for migration / invasion of SCC25 cells was performing by a cell invasion assay using Matrigel in a 48-hour interval. The proliferation curve showed a higher proliferation in cells treated with BMP-2 in 72 hours (p < 0.05), and lower overgrowth and cell viability in Noggin group. Recombinant proteins favored a greater percentage of cells in cell cycle phase Go/G1 with a statistically significant difference in the interval of 24 hours (p < 0.05). BMP- 2 produced a greater invasion of cells studied as well as its antagonist Noggin inhibits invasion of cells (p < 0.05). Thus, these results indicate that BMP-2 promotes malignant phenotype, dues stimulates proliferation and invasion of SCC25 cells and, its antagonist Noggin may be an alternative treatment, due to inhibit the tumor progression / O carcinoma epiderm?ide oral (CEO) representa a neoplasia maligna mais prevalente na cavidade oral e por atingir um grande n?mero de indiv?duos, acaba se tornado um relevante problema de sa?de p?blica. Muitos estudos demonstram altera??es nos componentes da via BMP em v?rios tipos de tumores, como os de pr?stata, c?lon, mama, g?stricos e CEOs. ? do conhecimento atual que essas prote?nas podem exercer efeito pr?-tumoral em est?gios mais avan?ados do desenvolvimento neopl?sico vindo a favorecer a progress?o e invas?o tumoral. A inibi??o da via de sinaliza??o da BMP-2, atrav?s dos seus antagonistas, tem mostrado resultados positivos de a??o antitumoral e que assim, o uso do Noggin pode ser um novo alvo terap?utico contra o c?ncer. Diante destas evid?ncias e dos escassos trabalhos com BMP-2, Noggin e CEO, o objetivo desta pesquisa foi avaliar o efeito da BMP-2 e seu antagonista Noggin sobre a prolifera??o e migra??o celulares em culturas de c?lulas de carcinoma epiderm?ide de l?ngua humana (SCC25). Foi feita a divis?o em tr?s grupos de estudo, um grupo controle, onde as c?lulas SCC25 n?o sofriam tratamento com subst?ncia alguma, um grupo BMP-2, no qual as c?lulas eram tratadas com 100ng/ml de BMP-2 e um grupo de c?lulas que eram tratadas com 100ng/ml de Noggin. Para o ensaio de prolifera??o e ciclo celular foram estabelecidos tr?s intervalos de tempo (24, 48 e 72 horas). A atividade proliferativa foi investigada por azul de tripan e a an?lise do ciclo celular atrav?s da marca??o por iodeto de prop?dio em Citometria de fluxo. O potencial de migra??o/invas?o das c?lulas SCC25 foi avaliado atrav?s da realiza??o de um ensaio de invas?o celular utilizando o matrigel em um intervalo de 48 horas. A curva de prolifera??o revelou maior crescimento celular nas c?lulas tratadas com BMP-2 no intervalo de 72 horas (p<0.05) e menor crecimento e viabilidade celular no grupo Noggin. As prote?nas recombinantes favoreceram a maior porcentagem das c?lulas na fase do ciclo celular Go/G1 com diferen?a estatisticamente significativa no intervalo de 24 horas (p<0,05). A BMP-2 promoveu uma maior invas?o das c?lulas estudadas, assim como o seu antagonista Noggin inibiu a invas?o das c?lulas estudadas (p<0,05). Dessa forma, os resultados indicam que a BMP-2 favorece o fen?tipo maligno, pois estimula a prolifera??o e invas?o das c?lulas SCC25 e seu antagonista Noggin pode ser uma alternativa terap?utica pois inibiu essas caracter?sticas pr?-tumorais

Le Norte-Chico constitue une zone tampon ayant enregistrée les fluctuations climatiques quaternaires. La fraîcheur des modelés et des formes présents dans la haute cordillère de l’Elqui, va nous permettre de tenter d’expliquer le calendrier de mise en place des éléments du relief. Les indices de terrain nous permettent de mettre en évidence un enchaînement de processus faisant intervenir la notion de relais et de zones tampons dans le transit sédimentaire. Les crises morphogéniques à l’origine des formations de versant et de fond de vallée actuellement visibles résultent d’une réponse plus ou moins directe de l’orogène Andin aux épisodes climatiques ; par conséquent, les résultats obtenus sont confrontés aux résultats d’autres études et dans des sites proches ou non de notre lieu d’étude afin d’apporter des exemples et des arguments aux hypothèses actuelles sur l’évolution des conditions climatiques quaternaires du Norte-Chico. La complexité de la mise en place des éléments du relief nécessite en premier lieu une explication des différentes phases orogéniques ainsi que des évolutions morphoclimatiques ayant abouti à la mise en place des conditions actuelles. Ensuite, la méthodologie nécessaire au travail de terrain et à l’obtention de résultats cohérents est définie et expliquée. Une dernière partie est consacrée à la synthèse de l’enchaînement de mise en place des formations de fond de vallée ; les résultats de cette étude sont également replacés dans un débat scientifique plus large permettant d’appréhender les potentialités apportées par la géomorphologie dans l’étude des paléoenvironnements quaternaires dans le Norte-Chico comme à l’échelle planétaire. / Norte Chico is a buffer zone having registered Quaternary climatic fluctuations. The preservation of landforms and relief present in the Elqui cordillera, make it a rich geomorphological study area, which may provide answers to many of the assumptions Quaternary calendar climate of the region. Freshness and modeled forms present in the high Andes of Elqui, coupled with the presence of datable organic matter, will allow us to to explain the timing of implementation of the elements of relief. Field indices surveys allow us to highlight a series of processes involving the notion of relay and buffer zones in the sediment transport. Morphogenic crises originally training slope and valley floor currently visible result of a more or less direct answer of the Andean orogen to climatic events, so the results are compared with the results of other studies and in sites close or not our place of study to provide examples and arguments to current hypotheses on the evolution of the Quaternary climatic Norte Chico and multiscale way. The complexity of the implementation of the relief units, requires firstly an explanation of the different orogenic phases and developments morphoclimatic leading to the gradual development of current conditions. Second, the methodology necessary fieldwork and consistent results is defined and explained. A final section presents the synthesis of the series of training implementation valley bottom; the results of this study are also viewed in a broader scientific debate to apprehend the potential provided by the geomorphology in the Quaternary paleoenvironmental study of the Norte Chico as globally.

Les multicouches de polyélectrolytes, systèmes auto-assemblés par adsorptions successives de polycations et polyanions, peinent à trouver des applications concrètes en raison de leur fragilité mécanique et du temps nécessaire à leur assemblage. Pour améliorer leur tenue mécanique, nous avons développé une méthode d'assemblage couche-par-couche par liaisons covalentes de films polymères. Des films formés de polymères portant des groupements alcynes et azides ont ainsi été réticulés par une réaction click catalysée par les ions Cu+ obtenus par voie électrochimique. Pour améliorer le mode d'assemblage, l'auto-construction en une seule étape de films par approche morphogénique, a été développée. Cette approche, confinée à la surface et caractérisée par la présence en solution de l'ensemble des constituants, marque une rupture. Elle permet ainsi un contrôle spatial de l'assemblage des films et la combinaison de plusieurs modes d'interactions pendant leur assemblage. Des films dont la cohésion repose sur des interactions covalentes, hôtes-invités et supramoléculaires, ont ainsi été assemblés. L'introduction de nanoparticules métalliques dans les films (multicouches et auto-construits) a également été effectuée dans le but de développer des électrodes de grande surface spécifique. / Polyelectrolyte multilayer films, built by alternated adsorption of polycations and polyanions, face two main challenges: their construction process is tedious and their mechanical stability is poor. We developped a layer-by-layer strategy to improve the film stability by covalent reticulation of the polymers chains by click chemistry. Polymers bearing alkyne and azide functions were reticulated by triggering electrochemically the production of Cu+ catalyst ions. A one pot morphogen driven self-construction strategy was also developped to improve the buildup process of the films.In this case, all the constituants are simultaneously present in solution while the film grows up only at the electrode. Films based on covalent, host-guest and supramolecular interactions were obtained and the possibility of combining different interactions was also demonstrated. Nanoparticles were also included in layer-by-layer and self-constructed films in order to improve the electrode specific area.

Au fil des siècles, de nombreux cours d’eau ont été régulés par des barrages pour assurer différents besoins tels que la gestion des inondations, la production d’énergie hydro-électrique, l’irrigation, l’approvisionnement en eau potable, etc. Aujourd’hui, dans le tiers nord de la planète, 77% des cours d’eau sont concernés par la présence de ces ouvrages et de très nombreux ouvrages sont en cours de construction ou prévus dans les prochaines décennies. Les impacts des barrages, notamment ceux dont les réservoirs sont les plus volumineux, sont aujourd’hui bien connus. Leur influence, plus ou moins prononcée, peut notamment affecter les crues (débits, fréquence, pointe et durée), ce qui entraine de facto une modification de l’occurrence du « débit morphogène » naturel dans les tronçons situés en aval. Il en résulte une morphologie et une dynamique fluviales modifiées, avec des Incidences sur la biologie et les usages. Afin d’améliorer, voire de restaurer le bon fonctionnement des milieux aquatiques et rivulaires, il est de plus en plus souvent demandé aux gestionnaires de barrages de générer des débits élevés, dits « morphogènes », depuis leurs ouvrages. Ce travail de thèse s’est attaché dans un premier temps à clarifier les concepts de débits, lâchers et écoulements « morphogènes ». Il a été proposé une nouvelle terminologie s’intégrant dans le contexte plus large des débits environnementaux et des débits écologiques (environmental et ecological flows). Dans un second temps, les précédents travaux et les expérimentations menées sur la Durance, la Selves et l’Isère, ont fourni des éléments pour construire une méthodologie de mise en œuvre de lâchers morphogènes dans le cadre d’une gestion adaptative. Cette méthodologie opérationnelle repose sur une série d’étapes successives découlant d’un diagnostic préalable. Elle permet de déterminer les paramètres nécessaires au dimensionnement, d’identifier les contraintes et de définir les résultats attendus (compartiments visés, ordres de grandeurs des processus, etc.) pour évaluer l’efficience de l’opération. Enfin, grâce à la mise en œuvre d’indicateurs de déclenchement, elle fournit des éléments d’évaluation pour décider de renouveler, d’améliorer ou non le lâcher. / Over the centuries, many rivers have been regulated by dams to meet various needs such as flood management, hydropower production, irrigation, drinking water supply, etc. Today, in the northern third of the planet, 77% of watercourses are affected by dams and a very large number are under construction or planned in the coming decades. The impacts of dams, particularly those with the largest reservoirs, are now well-known. Their influence, more or less pronounced, can affect floods (flow, frequency, peak and duration), which results in a change of the occurrence of the natural "channel morphing discharge" in the downstream reaches. The result is a modified river morphology and dynamics, with impacts on biological communities and uses. In order to improve/restore aquatic and riparian environments, dam managers are increasingly being asked to generate high flows, known as "flushing flows” or “ecomorphogenic flows”, from their dams.This thesis focuses initially on clarifying the concepts of discharge, water release, and "ecomorphogenic flows”. A new terminology has been proposed that fits into the broader context of “environmental flows” and “ecological flows”. In a second step, previous works and experiments carried out on the Durance River, the Selves River and the Isère River provided elements to build a methodology for implementing ecomorphogenic flow releases as part of adaptive management. This operational methodology is based on a series of successive steps resulting from a preliminary diagnosis. It makes it possible to determine the parameters necessary for designing releases, identifying constraints and defining expected results (target compartments, orders of magnitude of process, etc.) to evaluate the efficiency of the operation. Finally, through the implementation of trigger indicators, it provides evaluation information to decide whether to renew, or improve releases or to replace them with other management actions.

Recombinant human bone morphogenic proteins (rhBMPs) are extensively studied and employed clinically for treatment of various bone defects. Current clinical delivery vehicles suffer wasteful burst releases that mandate supra-physiological dosing driving concerns over safety and cost. It was therefore investigated whether a unique drug delivery vehicle sequestered within a composite scaffold could lower the burst release of rhBMP-2. PLGA-calcium phosphate tri-phasic composite scaffolds delivered model protein BSA with burst release of ~13% and sustained kinetics of 0.5-1.5% BSA/day up to 45 days. rhBMP-2 was delivered with zero burst release however at much lower levels, totaling 0.09% to 0.9 % release over 10 days, but had up to 6.3-fold greater bioactivity than fresh rhBMP-2 (p<0.05). In conclusion, the three-phase composite scaffold can deliver bioactive proteins with a reduced burst release and sustained secondary kinetics.

Recombinant human bone morphogenic proteins (rhBMPs) are extensively studied and employed clinically for treatment of various bone defects. Current clinical delivery vehicles suffer wasteful burst releases that mandate supra-physiological dosing driving concerns over safety and cost. It was therefore investigated whether a unique drug delivery vehicle sequestered within a composite scaffold could lower the burst release of rhBMP-2. PLGA-calcium phosphate tri-phasic composite scaffolds delivered model protein BSA with burst release of ~13% and sustained kinetics of 0.5-1.5% BSA/day up to 45 days. rhBMP-2 was delivered with zero burst release however at much lower levels, totaling 0.09% to 0.9 % release over 10 days, but had up to 6.3-fold greater bioactivity than fresh rhBMP-2 (p<0.05). In conclusion, the three-phase composite scaffold can deliver bioactive proteins with a reduced burst release and sustained secondary kinetics.

<strong>Chapter 1</strong> Provides an overview of drug discovery with particular emphasis on library selection and hit identification methods using virtual based approaches. <strong>Chapter 2</strong> Gives an outline of the bone morphogenetic protein (BMP) signalling pathway and literature BMP pathway modulators. The association between the regulation of BMP pathway and cardiomyogenesis is also described. <strong>Chapter 3</strong> Describes the use of ligand based virtual screening to discover small molecule activators of the BMP signalling pathway. A robust cell based BMP responsive gene activity reporter assay was developed to test the libraries of small molecules selected. Hit molecules from the screen were synthesised to validate activity. It was found that a group of known histone deacetylase (HDAC) inhibitors displayed most promising activity. These were evaluated in a secondary assay measuring the expression of two BMP pathway regulated genes, hepcidin and Id1, using reverse transcription polymerase chain reaction (RT-PCR). 188 was discovered to increase expression of both BMP-responsive genes. <strong>Chapter 4</strong> Provides an overview of existing cannabinoid receptor (CBR) modulating molecules and their connection to progression of atherosclerosis. <strong>Chapter 5</strong> Outlines the identification and optimisation of selective small molecule agonists acting at the cannabinoid 2 receptor (CB₂R). Ligand based virtual screen was undertaken and promising hits were synthesised to allow structure activity relationship (SAR) to be developed around the hit molecule providing further information of the functional groups tolerated at the active site. Subsequent studies led to the investigation and optimisation of physicochemical properties around 236 leading to the development of a suitable compound for in vivo testing. Finally, a CB₂R selective compound with favourable physicochemical properties was evaluated in vivo in a murine inflammation model and displayed reduced recruitment of monocytes to the site of inflammation.