The budding yeast Saccharomyces cerevisiae has been an invaluable model organism in contributing to the current understanding of cellular biology, owing mainly to its highly tractable genetic system and the completion of its genome sequencing in 1996. Indeed, these bolstered the development of novel methods that have provided great insights into genetic and protein networks in human cells. With the large collection of datasets, S. cerevisiae also became an ideal platform for investigating the mechanism of action of novel compounds. The first part of my thesis uses a validated chemogenomic assay to investigate the mechanism of action of structurally related novel DNA-damaging agents, delineating valuable structure-activity relationship in the process. The second part describes the development of a method that uses drug-induced wild-type growth dynamic to characterize novel compounds, which, in combination with the chemogenomic assay, may complement existing high throughput screening experiments to improve the current drug development process.

The budding yeast Saccharomyces cerevisiae has been an invaluable model organism in contributing to the current understanding of cellular biology, owing mainly to its highly tractable genetic system and the completion of its genome sequencing in 1996. Indeed, these bolstered the development of novel methods that have provided great insights into genetic and protein networks in human cells. With the large collection of datasets, S. cerevisiae also became an ideal platform for investigating the mechanism of action of novel compounds. The first part of my thesis uses a validated chemogenomic assay to investigate the mechanism of action of structurally related novel DNA-damaging agents, delineating valuable structure-activity relationship in the process. The second part describes the development of a method that uses drug-induced wild-type growth dynamic to characterize novel compounds, which, in combination with the chemogenomic assay, may complement existing high throughput screening experiments to improve the current drug development process.

Industrial chemicals in European Union produced or imported in volumes above 1 tonne annually, necessitate a registration within REACH. A common problem, concerning these chemicals, is deficient information and lack of data for assessing the hazards posed to human health and the environment. Animal studies for the type of toxicological information needed are both expensive and time consuming, and to that an ethical aspect is added. Alternative methods to animal testing are thereby requested. REACH have called for an increased use of in silico tools for non-testing data as structure-activity relationships (SARs), quantitative structure-activity relationships (QSARs), and read-across. The main objective of the studies underlying this thesis is related to explore and refine the use of in silico tools in a risk assessment context of industrial chemicals. In particular, try to relate properties of the molecular structure to the toxic effect of the chemical substance, by using principles and methods of computational chemistry. The initial study was a survey of all industrial chemicals; the Industrial chemical map was created. A part of this map was identified including chemicals of potential concern. Secondly, the environmental pollutants, polychlorinated biphenyls (PCBs) were examined and in particular the non-dioxin-like PCBs (NDL-PCBs). A set of 20 NDL-PCBs was selected to represent the 178 PCB congeners with three to seven chlorine substituents. The selection procedure was a combined process including statistical molecular design for a representative selection and expert judgements to be able to include congeners of specific interest. The 20 selected congeners were tested in vitro in as much as 17 different assays. The data from the screening process was turned into interpretable toxicity profiles with multivariate methods, used for investigation of potential classes of NDL-PCBs. It was shown that NDL-PCBs cannot be treated as one group of substances with similar mechanisms of action. Two groups of congeners were identified. A group including in general lower chlorinated congeners with a higher degree of ortho substitution showed a higher potency in more assays (including all neurotoxic assays). A second group included abundant congeners with a similar toxic profile that might contribute to a common toxic burden. To investigate the structure-activity pattern of PCBs effect on DAT in rat striatal synaptosomes, ten additional congeners were selected and tested in vitro. NDL-PCBs were shown to be potent inhibitors of DAT binding. The congeners with highest DAT inhibiting potency were tetra- and penta-chlorinated with 2-3 chlorine atoms in ortho-position. The model was not able to distinguish the congeners with activities in the lower μM range, which could be explained by a relatively unspecific response for the lower ortho chlorinated PCBs. / Den europeiska kemikalielagstiftningen REACH har fastställt att kemikalier som produceras eller importeras i en mängd över 1 ton per år, måste registreras och riskbedömmas. En uppskattad siffra är att detta gäller för 30 000 kemikalier. Problemet är dock att data och information ofta är otillräcklig för en riskbedömning. Till stor del har djurförsök använts för effektdata, men djurförsök är både kostsamt och tidskrävande, dessutom kommer den etiska aspekten in. REACH har därför efterfrågat en undersökning av möjligheten att använda in silico verktyg för att bidra med efterfrågad data och information. In silico har en ungefärlig betydelse av i datorn, och innebär beräkningsmodeller och metoder som används för att få information om kemikaliers egenskaper och toxicitet. Avhandlingens syfte är att utforska möjligheten och förfina användningen av in silico verktyg för att skapa information för riskbedömning av industrikemikalier. Avhandlingen beskriver kvantitativa modeller framtagna med kemometriska metoder för att prediktera, dvs förutsäga specifika kemikaliers toxiska effekt. I den första studien (I) undersöktes 56 072 organiska industrikemikalier. Med multivariata metoder skapades en karta över industrikemikalierna som beskrev dess kemiska och fysikaliska egenskaper. Kartan användes för jämförelser med kända och potentiella miljöfarliga kemikalier. De mest kända miljöföroreningarna visade sig ha liknande principal egenskaper och grupperade i kartan. Genom att specialstudera den delen av kartan skulle man kunna identifiera fler potentiellt farliga kemiska substanser. I studie två till fyra (II-IV) specialstuderades miljögiftet PCB. Tjugo PCBs valdes ut så att de strukturellt och fysiokemiskt representerade de 178 PCB kongenerna med tre till sju klorsubstituenter. Den toxikologiska effekten hos dessa 20 PCBs undersöktes i 17 olika in vitro assays. De toxikologiska profilerna för de 20 testade kongenerna fastställdes, dvs vilka som har liknande skadliga effekter och vilka som skiljer sig åt. De toxicologiska profilerna användes för klassificering av PCBs. Kvantitativa modeller utvecklades för prediktioner, dvs att förutbestämma effekter hos ännu icke testade PCBs, och för att få ytterligare kunskap om strukturella egenskaper som ger icke önskvärda effekter i människa och natur. Information som kan användas vid en framtida riskbedömning av icke-dioxinlika PCBs. Den sista studien (IV) är en struktur-aktivitets studie som undersöker de icke-dioxinlika PCBernas hämmande effekt av signalsubstansen dopamin i hjärnan.

Chapter 1 gives background information on proteases and discusses the concept of protease inhibition as a therapeutic strategy for humans. It introduces the key concept that conformation defines biological activity. It also outlines how proteases almost universally bind their substrate/inhibitors in an extended β-strand conformation. The use of calpain as a prototype protease for the testing of β-strand mimics synthesised later in the thesis is also discussed. Chapter 2 describes how molecular modeling was used to rationalise the structure based activity relationships (SAR) of known calpain inhibitors. Molecular modeling was then used to successfully design a number of acyclic β-strand mimics. The synthesis and testing of eight such inhibitors is described. The most potent β-strand mimic prepared was 2.13. This was determined to have an IC₅₀ of 30 nM against calpain II. Chapter 3 outlines the history and application of ring closing metathesis (RCM) to the synthesis of cyclic compounds. The attempted synthesis of an eight membered cyclic nitrogen to nitrogen conformationally constrained dipeptide is described. The synthesis of a conformationally constrained β-amino acid calpain inhibitor (3.73) is also described. A novel calpain inhibitor motif was designed in Chapter 4. On the basis of this an in-silico combinatorial library of two hundred and eighty eight possible β-strand templates was prepared. Conformational analysis of this library was performed and from this a number of excellent β-strand templates were identified and selected for synthesis. The preparation of ten β-strand templates is described. New microwave irradiation methodology was developed to achieve this. vii The formation of a six-membered catalyst deactivating chelate is also proposed to explain why some dienes fail to undergo RCM. Two methods to circumvent the formation of such a chelate are outlined. The addition of Lewis acid chloro-dicyclohexyl borane to the RCM reaction mixture and chain length alteration are investigated. Chapter 5 describes the design of macrocyclic β-strand mimics using induced fit molecular modelling. The physicochemical properties of these were calculated in-silico. From this analysis a number of Tyr-XX-Gly based and Tyr-XX-Cys based macrocyclic calpain inhibitors were selected for synthesis. The preparation and testing of these are described. In the Tyr-XX-Gly macrocyclic system a number of variables were investigated and numerous SAR implications concluded. Aldehyde 5.14 was identified as the best electrophilic warhead macrocyclic calpain inhibitor with an IC₅₀ against calpain II of 27 nM. The best non-electrophilic warhead macrocycle (5.13) had an IC₅₀ against calpain II of 704 nM. Chapter 6 describes synthetic optimisation for the preparation of calpain inhibitors 2.13, 5.14 and 5.17. Multi-gram quantities of each were prepared. Aldehydes 2.13 and 5.14 were evaluated as anti-cataract agents using in-vivo cataract sheep model. Both of these β-strand mimics were demonstrated to retard cataract development. Macrocycle 5.14 was found to be the most effective, decreasing the rate of cataract development between forty four and forty nine per cent relative to control. Chapter 7 outlines the attempted development of RCM methodology for the chiral synthesis of α-α disubstituted amino acid lactams. In addition, methodology for the stereoselective incorporation of a C-N constrained β-amino acid carbocycle into a peptide or peptidomimetic is described.

Thesis (MSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: This research considered the automated remote sensing-based classification of wetland extent within the Nuwejaars and Heuningnes River systems on the Agulhas Plain. The classification process was based on meaningful image objects created through image segmentation rather than on single pixels. An expert system classifier was compared to a nearest-neighbour supervised classifier, and one multispectral (SPOT 5) image (dry season) and two C-band, VV-polarisation synthetic aperture radar (SAR: ERS-2) images (dry and wet season) were used separately and in combination. Classifications were performed within two subset areas. Final classes identified were Permanent waterbody, Other wetland and Non-wetland. Statistical accuracy assessment was performed. Validation data was derived from a combination of high-resolution aerial photographs, the SPOT 5 image, high-resolution imagery on Google Earth and observations during a field visit. Wetland extent was defined as the total extent of wetland-specific vegetation, unvegetated seasonal pans and waterbodies. More detailed classes were originally envisaged, but available validation data was not considered adequate for assessing their accuracy with any confidence. The supervised classifier was found to be more accurate overall than the developed expert system. The difference between the two was however not always significant. The two SAR images alone did not contain sufficient information for the accurate classification of Agulhas wetlands’ extent, with recorded overall accuracies not exceeding 65% regardless of the classifier used. The SPOT image alone achieved accuracies higher than 80%; this was considered a good result. In comparison, combining the SAR and SPOT data did not improve the classification accuracy. The potential of the expert system to be applied with little modification to images acquired over other areas or over the same area in other years should be further investigated. However, several reservations are noted in this regard. Future research could potentially improve the results obtained from supervised classification by augmenting it with expert system rules to identify more complicated classes. KEYWORDS ERS-2, SPOT 5, SAR, wetlands, expert system classifier, nearest-neighbour supervised classifier / AFRIKAANSE OPSOMMING: Hierdie navorsing het die geoutomatiseerde afstandswaarneminggebaseerde klassifikasie van vleilandomvang binne die Nuwejaars- en Heuningnesrivier stelsels op die Agulhasvlakte ondersoek. Die klassifikasieproses was gebaseer op betekenisvolle beeldobjekte geskep deur middel van beeldsegmentasie eerder as op enkele beeldelemente. ‘n Deskundige stelsel klassifiseerder is vergelyk met ‘n naaste-naburige gerigte klassifiseerder. Een multispektrale (SPOT 5) beeld vir die droë seisoen, sowel as twee C-band, VV-polarisasie sintetiese diafragma radar (SAR, ERS2) beelde (vir die droë en nat seisoene) is afsonderlik en in kombinasie gebruik. Klassifikasies is uitgevoer binne twee sub-areas in die beelde. Finale klasse wat geïdentifiseer is was Permanente waterliggaam, Ander vleiland en Nie-vleiland. Statistiese akkuraatheidsassessering is uitgevoer. Verwysingsdata is geskep vanuit ‘n kombinasie van hoë- resolusie lugfoto’s, die SPOT 5 beeld, hoë-resolusie beelde op Google Earth en waarnemings tydens ‘n besoek aan die studiegebied. Vleiland omvang is gedefinieer as die totale omvang van vleiland-spesifieke plantegroei, onbegroeide seisoenale panne en waterliggame. Die gerigte klassifiseerder blyk om oor die algemeen meer akkuraat as die ontwikkelde deskundige stelsel te wees. Die verskil was egter nie altyd beduidend nie. Die twee SAR beelde alleen het nie genoegsame inligting bevat vir die akkurate klassifikasie van Agulhas-vleilande se omvang nie, met behaalde algehele akkuraatheidsvlakke wat nie 65% oorskry het nie, ongeag van die klassifiseerder. Die SPOT-beeld alleenlik het algehele akkuraathede van meer as 80% behaal; wat as ‘n goeie resultaat beskou kan word. In vergelyking hiermee kon die kombinering van SAR- en SPOT-data nie ‘n verbetering teweeg bring nie. Die potensiaal van die deskundige stelsel om met min aanpassing op beelde van ander gebiede of van dieselfde gebied in ander jare toegepas te word, verg verdere ondersoek. Verskeie voorbehoude word egter in hierdie verband gemeld. Toekomstige navorsing kan potensieel die resultate van gerigte klassifikasie verbeter deur dit aan te vul met deskundige stelsel reëls vir die klassifikasie van meer komplekse klasse. TREFWOORDE ERS-2, SPOT 5, SAR, vleilande, deskundige stelsel klassifiseerder, naaste-naburige gerigte klassifiseerder.

Submitted by Geyciane Santos (geyciane_thamires@hotmail.com) on 2015-07-27T15:15:30Z No. of bitstreams: 1 Dissertação - Jorge Alberto Lopes da Costa.pdf: 12254367 bytes, checksum: e92aa3fbce27b2b569e2f3aae45e851d (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-07-28T15:14:18Z (GMT) No. of bitstreams: 1 Dissertação - Jorge Alberto Lopes da Costa.pdf: 12254367 bytes, checksum: e92aa3fbce27b2b569e2f3aae45e851d (MD5) / Approved for entry into archive by Divisão de Documentação/BC Biblioteca Central (ddbc@ufam.edu.br) on 2015-07-28T15:19:49Z (GMT) No. of bitstreams: 1 Dissertação - Jorge Alberto Lopes da Costa.pdf: 12254367 bytes, checksum: e92aa3fbce27b2b569e2f3aae45e851d (MD5) / Made available in DSpace on 2015-07-28T15:19:50Z (GMT). No. of bitstreams: 1 Dissertação - Jorge Alberto Lopes da Costa.pdf: 12254367 bytes, checksum: e92aa3fbce27b2b569e2f3aae45e851d (MD5) Previous issue date: 2011-07-07 / Não informada / In recent decades the areas of rainforest in the Amazon region has been heavily impacted by a rapid process of conversion of vegetation cover in other types of use due to human action. In the context of global change, the use of mapping and monitoring land cover and provide information for the analysis and evaluation of environmental impacts due to accelerated changes in the landscape. Therefore, this study evaluated the potential of data from synthetic aperture radar for discriminating use and land cover in the region of Manaus, Amazonas state. We used a multipolarized image from sensor airborne SAR-R99B (L band), with 3 m spatial resolution. Were evaluated the MAXVER-ICM and SVM (Support Vector Machine) classifiers, where in all cases we used the images individually multipolarized amplitude (HH, HV and VV), in pairs (HH and HV), (HV and VV) and (HH and VV) and together (HH, HV and VV). The results were compared using as parameter the Kappa coefficient. The SVM classifier had higher accuracy compared to MAXVER-ICM classifier. The best classifications were obtained for the dual polarization (HH and VV) with MARVER-ICM classifier and (HH, HV and VV) with the SVM classifier both using the images with the filter. The accuracy was highest with SVM for classification and filter images (kappa = 0.7736). Were analyzed the influence of using GAMMA filter performance on the classifiers where it showed that filtered images have provided an increase in the results, on average, about 8%. Thus there was the analysis of the classification results, which found that the best result was provided by the dataset multipolarized (HH, HV and VV) classified by the SVM method. Thus, we concluded that the use of radar imagery in mapping thematic classes use and land cover in tropical regions, can be considered as a viable proposal. / Nas últimas décadas as áreas de floresta tropical na região Amazônica têm sido fortemente impactada por um rápido processo de conversão da cobertura vegetal em outros tipos de uso devido à ação antrópica. No contexto das mudanças globais, os mapeamentos e monitoramentos de uso e cobertura da terra fornecem subsídios para as análises e avaliações dos impactos ambientas em virtude de acelerados processos de mudança na paisagem. Neste contexto, este estudo avaliou o potencial dos dados de radar de abertura sintética para discriminação de uso e cobertura da terra na região de Manaus, estado do Amazonas. Foi utilizada uma imagem multipolarizada do sensor aerotransportado SAR-R99B (banda L), com 3 metros de resolução espacial. Realizaram-se classificações na imagem radar sem filtro e com filtro Gamma 3x3. Avaliou-se o classificador pontual MAXVER-ICM e o SVM (Support Vector Machine), onde em todos os casos utilizou-se das imagens multipolarizadas em amplitude individualmente (HH, HV e VV), aos pares (HH e HV), (HV e VV) e (HH e VV) e em conjunto (HH, HV e VV). Os resultados obtidos foram comparados utilizando-se como parâmetro o coeficiente de concordância Kappa. O classificador SVM apresentou acurácia superior em relação ao classificador MAXVER-ICM. As melhores classificações foram obtidas para a polarização dual HH e VV com o classificador MAXVER-ICM e (HH, HV e VV) com o classificador SVM ambos utilizando as imagens com filtro. A acurácia mais elevada foi para a classificação com SVM e imagens com filtro (kappa = 0,7736). Analisou-se a influência do uso de filtro GAMMA no desempenho dos classificadores onde se contatou que as imagens filtradas proporcionaram um incremento nos resultados, em média, na ordem de 8%. Deste modo realizou-se a análise dos resultados das classificações, onde se constatou que o melhor resultado foi proporcionado pelo conjunto de dados multipolarizados (HH, HV e VV)classificados através do método SVM. Assim, concluiu-se que o uso de imagens de radar no mapeamento de classes temáticas de uso e cobertura da terra, em regiões tropicais, pode ser considerado como uma proposta viável.

Ce travail de thèse consiste en la conception et l'analyse d’un système d'exposition des animaux in vivo avec les signaux Wi-Fi dans une chambre réverbérante. La nouvelle méthode d'excitation est appliquée avec 6 antennes qui fonctionnent aléatoirement pour avoir un champ plus homogène et des ondes venant de toutes les directions. Cette configuration permet d'éviter une grande taille du brasseur de la chambre réalisée. La répartition de puissance chez les rats est étudiée par la méthode hybride de simulation-mesure. La puissance incidente est enregistrée de même que le champ au centre de la chambre. Le rapport de la puissance incidente sur E carré moyenné est déterminé. La méthode FDTD est choisie pour la simulation et permet d’analyser la répartition de la puissance absorbée par les rats. La distribution du champ dans la chambre suit une statistique de Rayleigh comme il a été prouvé par les études et les mesures. Donc, la boîte de Huygens est utilisée pour émettre des ondes planes aléatoires (avec les paramètres suivant distribution Rayleigh) et exposer les rats. On peut alors obtenir le rapport de DAS pour le corps entier chez les rats sur E carré moyenné dans la chambre. Donc il est possible de relier le DAS corps entier chez les rats et la puissance d’entrée dans la chambre à E carré moyenné. Une autre méthode de simulation est aussi appliquée pour vérifier ce résultat. L’évaluation de la variabilité des résultats pour plusieurs paramètres à différents âges des rats est effectuée. En générale, les sources de variabilité sont classifiées selon trois parties : simulation, mesure, et interface entre les deux. Le DAS corps entier chez les rats pendant toute la période d’exposition avec le domaine de variabilité sont présentés dans ce travail. Cette étude pourra être utilisée afin d'évaluer des résultats d’une exposition à long terme des animaux. Elle pourra aussi servir à caractériser le champ dans des environnements domestiques et urbains / This thesis dedicates to design and analysis for the animal in vivo Wi-Fi exposure system by reverberation chamber. 6 random functioned antennas are deployed in the reverberation chamber to radiate the rats with homogenous field and Omni-direction waves. So, there is no significant size stirrer in the system. Power absorption by rats is studied by the simulation-measurement hybrid method. In this method, by measurement, incident power and the mean squared E in the system are recorded. The ratio these factors are obtained. For simulation, FDTD is chosen to analyse the power absorption by the rats. E distribution in reverberation chamber is proved as Rayleigh statistics by studies and measurements. One Huygens box is constructed to radiate the rats. There is no need to realise the wall, the antennas and the accessories of the system. So the whole body averaged SAR can be obtained with the mean squared E in the chamber. Then whole body averaged SAR is linked with the incident power. One other method has also been applied to verify the results. Evaluation of the result variability depending on different parameters of rats with different ages is performed. The variability comes from simulation, measurement and interface between these two parts. Whole body averaged SAR with the variability domain on function of the rat's age is presented in this thesis. This work can be used to evaluate the long term animal exposition. It can also serve to characterise the field in modern domestic and urban environments

In recent years, Polarimetric Synthetic Aperture Radar (PolSAR) has been one of the most important instruments for earth observation, and is increasingly used in various remote sensing applications. Statistical modelling and scattering analysis are two main ways for PolSAR data interpretation, and have been intensively investigated in the past two decades. Moreover, spatial analysis was applied in the analysis of PolSAR data and found to be beneficial to achieve more accurate interpretation results. This thesis focuses on extracting typical spatial information, i.e., edges and regions by exploring the statistical characteristics of PolSAR data. The existing spatial analysing methods are mainly based on the complex Wishart distribution, which well characterizes the inherent statistical features in homogeneous areas. However, the non-Gaussian models can give better representation of the PolSAR statistics, and therefore have the potential to improve the performance of spatial analysis, especially in heterogeneous areas. In addition, the traditional fixed-shape windows cannot accurately estimate the distribution parameter in some complicated areas, leading to the loss of the refined spatial details. Furthermore, many of the existing methods are not spatially adaptive so that the obtained results are promising in some areas whereas unsatisfactory in other areas. Therefore, this thesis is dedicated to extracting spatial information by applying the non-Gaussian statistical models and spatially adaptive strategies. The specific objectives of the thesis include: (1) to develop reliable edge detection method, (2) to develop spatially adaptive superpixel generation method, and (3) to investigate a new framework of region-based segmentation. Automatic edge detection plays a fundamental role in spatial analysis, whereas the performance of classical PolSAR edge detection methods is limited by the fixed-shape windows. Paper 1 investigates an enhanced edge detection method using the proposed directional span-driven adaptive (DSDA) window. The DSDA window has variable sizes and flexible shapes, and can overcome the limitation of fixed-shape windows by adaptively selecting homogeneous samples. The spherically invariant random vector (SIRV) product model is adopted to characterize the PolSAR data, and a span ratio is combined with the SIRV distance to highlight the dissimilarity measure. The experimental results demonstrated that the proposed method can detect not only the obvious edges, but also the tiny and inconspicuous edges in heterogeneous areas. Edge detection and region segmentation are two important aspects of spatial analysis. As to the region segmentation, paper 2 presents an adaptive PolSAR superpixel generation method based on the simple linear iterative clustering (SLIC) framework. In the k-means clustering procedure, multiple cues including polarimetric, spatial, and texture information are considered to measure the distance. Since the constant weighting factor which balances the spectral similarity and spatial proximity may cause over- or under-superpixel segmentation in different areas, the proposed method sets the factor adaptively based on the homogeneity analysis. Then, in heterogeneous areas, the spectral similarity is more significant than the spatial constraint, generating superpixels which better preserved local details and refined structures. Paper 3 investigates another PolSAR superpixel generation method, which is achieved from the global optimization aspect, using the entropy rate method. The distance between neighbouring pixels is calculated based on their corresponding DSDA regions. In addition, the SIRV distance and the Wishart distance are combined together. Therefore, the proposed method makes good use of the entropy rate framework, and also incorporates the merits of the SIRV distance and the Wishart distance. The superpixels are generated in a homogeneity-adaptive manner, resulting in smooth representation of the land covers in homogeneous areas, and well preserved details in heterogeneous areas. / <p>QC 20171123</p>

La marge Ligure est une marge passive soumise à une déformation tectonique compressive associée à la tectonique salifère messinienne. La reprise en compression de la marge s’accompagne d’une sismicité modérée récurrente ponctuée d’évènements plus forts. La marge Ligure est le siège d’une sédimentation importante au Plio-Quaternaire. Elle constitue un environnement propice à l’étude des déstabilisations gravitaires. L’objectif principal de ce travail était de décrire et caractériser les principaux mouvements en masse ayant affecté la marge continentale Ligure au cours du Plio-Quaternaire, de localiser les principales zones sujettes aux déstabilisations et d’identifier les facteurs pré-conditionnant et déclenchant les ruptures dans le but de mieux évaluer l’aléa gravitaire. Une large couverture de données bathymétriques, géophysiques et des carottages acquis sur l’ensemble de la marge a permis de réaliser une étude multi-échelles des processus de ruptures gravitaires et des facteurs déclenchant associés. Près de 1500 glissements ont été identifiés. L’étude de leur répartition spatio-temporelle illustre que l’ensemble de la marge a toujours été affectée par des déstabilisations de pente mais que les principales zones de ruptures auraient migré vers l’ouest au cours du Plio-Quaternaire. Les grandes ruptures sous-marines sont préférentiellement associées aux zones de déformation maximale, cette dernière étant contrôlée par la tectonique crustale et/ou la tectonique salifère. Il apparaît que les ruptures résultent plus généralement d’une association de facteurs distincts qui ont participé à fragiliser la stabilité des dépôts de la pente et qui ont pu provoquer leur rupture. / The Ligurian margin is a passive margin characterized by high sedimentation rates during the Plio-Quaternary. It is affected by a compressive tectonic deformation leading to the inversion of the margin, together with a salt tectonic. The present-day moderate seismic activity is punctuated by stronger seismic events. Thus, this margin offers a good natural laboratory to study submarine landslides and their triggering factors. Although the Var Turbidite System has been well investigated over the last 20 years, the morphology and tectonics/sedimentary processes affecting the whole margin remained poorly known. This study aims to describe and to characterize the main types of mass movements, their preferential locations along the Ligurian margin during the Plio-Quaternary and their triggering factors to improve geohazards assessment related to landslides. A dataset including bathymetric and geophysical data and cores allowed to realize a multi-scale study of submarine failures and their associated triggering factors. About 1500 landslides were identified on the margin and in the basin. The study of their spatio-temporal distribution revealed that the margin has always been affected by mass-wasting processes and that the main zones of landsliding migrated westward during the Plio-Quaternary. The largest submarine landslides are preferentially associated with the highest deformation rates and their location is controlled by crustal tectonics and/or salt tectonics. The initiation of failures results from the combination of several factors including the margin deformation, earthquakes, salt tectonics and sediment under-consolidation.

Le paludisme et la leishmaniose sont les deux plus importantes infections parasitaires au monde, en termes de mortalité. La recherche de nouvelles molécules actives contre les protozoaires responsables de ces « maladies tropicales négligées », Plasmodium sp et Leishmania sp, est un enjeu majeur de santé publique. Après une première partie dressant un état des lieux des connaissances disponibles en matière de chimiothérapie antiplasmodiale, une seconde partie s’est intéressée à l’étude des propriétés anti-infectieuses du noyau 2-trichlorométhyl-quinazoline, en introduisant en position 4 des motifs alcynyles par couplage de Sonogashira, optimisés par LC/MS. Une troisième partie a porté sur la pharmacomodulation en positions 2 et 4 du même noyau, notamment par réactions de SNAr. Une quatrième partie a consisté à rechercher le mécanisme d'action des meilleures quinazolines antiplasmodiales, via une approche de chromatographie d'affinité sur inhibiteur immobilisé. La fonctionnalisation multi-étapes des molécules les plus puissantes, par un bras espaceur, a été suivie de leur ancrage sur divers supports solides, pour constituer des matrices biocompatibles spécifiques. L’une d’entre-elles a permis la mise en évidence de 2 cibles plasmodiales protéiques originales : la GTPase Pfrab6 et la pyruvate-kinase PfpyrK1. Enfin, une cinquième partie relate la pharmacomodulation antileishmanienne du noyau 8-nitroquinoléin-2(1H)-one. Les travaux se sont intéressés à l'étude de la substitution de la position 4 de ce noyau par des réactions de SNAr, ainsi que des réactions de couplages pallado-catalysés optimisées à l’aide de la technologie micro-ondes. / Malaria and leishmaniasis are the two most important parasitic infections worldwide, in terms of mortality. Thus, the research for new molecules targeting the protozoa parasites responsible for these “neglected tropical diseases”, Plasmodium sp and Leishmania sp, constitute a major challenge in public health. Our work focused first on a current state of knowledge about antiplasmodial chemotherapy. In a view to develop the study of the anti-infective properties of the 2-trichloromethylquinazoline scaffold, a second part presented antiplasmodial pharmacomodulation at position 4 using Sonogashira cross-coupling reaction, optimized with the LC/MS technology. A third part concerned other pharmacomodulation reactions, especially at positions 2 and 4, using especially SNAR reactions. A fourth part consisted in the research of the mechanism of action of the best antiplasmodial quinazolines by using the affinity chromatography on immobilized inhibitor approach. The multi-step functionalization of the most potent derivatives by a spacer side chain was followed by their anchoring onto various solid supports, so as to generate different biocompatible specific matrices. One of them, put in contact with a parasitic lysate, allowed the identification of two original plasmodial targets: the GTPase Pfrab6 and the pyruvate-kinase PfpyrK1. Finally, a fifth part presented the antileishmanial pharmacomodulation of the 8-nitroquinolin-2(1H)-one scaffold, especially at position 4 of the quinoline ring, involving SNAr reactions (with amines, phenols or thiophenols) or pallado-catalyzed coupling reactions (in particular Suzuki-Miyaura), some of them being optimized under microwave irradiation.