L’objectif de ce projet est d’étudier une nouvelle voie de thérapie basée sur l’échographie de contraste. Les agents de contraste utilisés sont capables de vectoriser différentes molécules chimiques et de les libérer lorsqu’ils sont détruits par le biais des ultrasons. Cette méthode permet donc un traitement ciblé et contrôlé ce qui a pour avantages de réduire la quantité de principe actif (donc des effets de secondaires). De plus, les microbulles augmentent la perméabilité cellulaire ou tissulaire donc améliore leur incorporation cellulaire. Cependant le mécanisme n’est pas connu. In vitro, nous avons utilisé un ensemble de techniques dont le patch clamp pour visualiser les échanges trans-membranaires et la TEER pour les modifications de la perméabilité trans-endothéliales. In vivo, nous avons effectué des ECG pour observer et comprendre les effets secondaires afin de mieux les prévenir. Le but de la thèse est d’aboutir à la connaissance du phénomène d’augmentation de la perméabilité induite par les ultrasons et les microbulles afin de pouvoir l’optimiser. / The aim of this work is to study a new way of therapy based on the contrast ultrasonography. The used contrast agents are able of transport different chemical molecules and to liberate them when they are destroyed by means of ultrasounds. This method allows a controlled and targeted treatment therefore what has as advantages to reduce drugs quantity (therefore side effects). Moreover, microbubbles augment cell or tissue permeability therefore ameliorates their cell uptake. However, the mechanism is not known. In vitro, we used the whole technology of which the patch clamp to show exchanges through the cell membrane and TEER for modification of trans-endothelial permeability. In vivo, we have performed ECG to notice and understand side effects to their apparition. The purpose of PhD work is to succeed to the knowledge of the phenomenon of increase of the permeability led by ultrasounds and microbubbles to be able to optimise it.

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Ca2+ entry through voltage-gated calcium channels (CaVs) triggers a range of physiological events, including synaptic neurotransmission and muscular excito-contraction coupling. CaVs are often localised to discrete membrane microdomains and are required to be targeted to such fine structures in order to perform their cellular functions. CaVs are multi-subunit protein complexes that consist of a core, pore-forming α1 subunit and auxiliary β and α2/δ subunits. The α2/δ subunit is required for the optimal cell surface expression and function of CaVs and is itself localised to cholesterol-rich membrane microdomains called lipid rafts. What is unclear is whether the α2/δ subunit is required for whole CaV complexes to be localised to lipid rafts and what effects lipid raft association has on the cell surface distribution and function of CaVs. By a combination of cellular imaging, biochemistry and electrophysiology, this project shows that the auxiliary α2/δ-1 subunit is both necessary and sufficient to target CaV2.2 to lipid rafts in the COS-7 cell heterologous expression system (Robinson et al, 2010). In addition, α2/δ is localised at the cell surface in discrete puncta and co-localises with two endogenous lipid raft resident proteins, caveolin and flotillin-1. While the punctate cell surface distribution of α2/δ is co-incident with that of caveolin and flotillin-1, its distribution is not dependent on cellular cholesterol, but rather the integrity of the actin cytoskeleton. Additional structure-function analysis by employment of the pIN-α2/δ series of deletion and substitution mutants has shown that the association of α2/δ with lipid rafts is bestowed by an extracellular region of the delta peptide, contrary to other evidence supporting the notion that α2/δ may be a GPI-anchored protein. The exact physiological and functional significance of α2/δ and CaV association with lipid rafts remains poorly understood, but the fact that CaVs are enriched within these fine structures provides a potential mechanism for targeting and access to lipid raft associated signalling pathways.

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<p> This is the first study of the karst features found at Moira River karst. This study intends to investigate a number of different karst features of the area rather than concentrating on one highly specific problem. Hopefully this will enable the reader to appreciate the wide diversity of karst able to form within a small area such as Moira karst.</p> <p> The variation in karst features encountered at Moira River ranged from a relatively rare form of karst, called a draped karst, to dissolution patterns (scallops), found within a cave. The draped karst dominates much of the area and is formed by the preferential removal of thin, recessive limestone beds. The overlying, massive bedded unit remains and is "draped" over an underlying massive unit.</p> <p> The river plays a dominant role in the formation of karst features at Moira Karst. It floods quite frequently as evidenced by the number of runoff channels found in the area. The caves at Moira River karst have developed as a short cut across a bend in the river and are fully inundated when the river reaches high flow rates. Karst development does not extend much beyond a range of 300 m from either bank of the river and is concentrated on the east side of the river.</p> / Thesis / Bachelor of Science (BSc)

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No / The determination of velocity profiles in turbulent narrow open channels is a difficult task due to the significant effects of the anisotropic turbulence that drives the Prandtl’s second kind of secondary flow in the cross section. Due to these currents the maximum velocity appears below the free surface. This is called the dip phenomenon. The classical log law describes the velocity distribution in the inner region of the turbulent boundary layer. The Coles law and its wake function are not able to predict the velocity profile in the outer region of narrow channels. This paper relies on an analysis of the Navier-Stokes equations and yields a new formulation of the vertical velocity profile in the outer region of the boundary layer in the central cross section area of steady, fully developed turbulent flows in open channels. This formulation is able to predict primary velocity profiles for both narrow and wide open channels. This new law is a modification of the classical one, it involves an additional parameter CAr that is a function of the position of the maximum velocity ξdip and roughness height (kS).ξdip may be derived either from measurements or from an empirical equation given in this paper. A wide range of longitudinal velocity profile data for narrow open channel has been used for validating the new law. The agreement between the experimental data and the profile given by the law is very good, despite the simplification used.

KirBac channels are prokaryotic homologs of eukaryotic inwardly-rectifying potassium channels, which have served as models for gaining insight into the structure of eukaryotic channels. This thesis focuses on the structure-function relationship in these channels. The first part of this study concerns a novel KirBac channel, KirBac9.2, which contains a unique amino acid sequence in the place of the canonical GYG selectivity filter. Although expressed and purified in a stable and functional form, the protein did not form well-diffracting crystals. Functional studies suggest that KirBac9.2 is non-selective for monovalent cations and a random mutagenesis screen identified a number of activatory mutants in the cytoplasmic domains of the channel. A full electrophysiological investigation of KirBac9.2 channel function is beyond the scope of this study. However, initial studies suggest that it is possible to record currents from KirBac9.2 channels reconstituted into lipid bilayers. The second part of this thesis investigates KirBac3.1, which is a classical KirBac channel containing the consensus GYG sequence for potassium selectivity. Five high resolution structures of a mutant channel are reported, which suggest a new feature in the gating mechanism of KirBac3.1 where a rotation of the cytoplasmic domains is linked to a change in the electrostatic environment of the cytoplasmic cavity. In addition, a functional study of the KirBac3.1 showed that the channel is highly pH sensitive.