Adsorption of cations by clays has been a subject of investigation for many years. Many proposals have been advanced to explain this process of adsorption. Two proposals have been prominent in recent years. The Marshall "charged lattice" theory attributes adsorption of cations by clays to an electrostatic attration of the clay particles for cations. This charge on the clay particles is attributed to various isomorphic substitutions in the lattice of the clay which result in an unbalanced charge on the particle. This isomorphic substitution can take place either in the silicon-oxygen tetrahedra of the silicate structure or with the aluminum layer of the particle. The Cook "ion-pair" theory make the assumption that the charge on the clay particle is caused by the neutral clay chemisorbing hydroxyl molecules in the compact double layer thus giving the particle its negative charge. Cations are then attracted electrostatically to the diffuse outer layer. Experimental adsorption data is used to evaluate the validity of these two theories. Equations are set up representing mathematically the two mechanisms of adsorption and are tested graphically with the experimental data. These various graphs, in every case, show that the Marshall "charged lattice" mechanism is inconsistent with the experimental data. The Cook theory adequately represents a consistent agreement with this rather complete set of experimental data.

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Thèse présentée en cotutelle : Doctorat en Bioingénierie (Politecnico di Milano) et Doctorat en génie des matériaux et de la métallurgie (Université Laval) / Les stratégies de livraison de gènes non viraux ont suscité un intérêt manifeste pour le développement de nouvelles approches thérapeutiques ainsi que pour la recherche fondamentale et appliquée in vitro. Par rapport aux vecteurs viraux populaires, la classe des vecteurs non- viraux, comme les lipides (CLs) et les polymères (CPs) cationiques, capables de réagir spontanément avec des acides nucléiques (NAs) chargés négativement pour former des nanoparticules appelées complexes, connaît actuellement un regain d'intérêt au sein de la communauté scientifique. En effet, en plus d'être relativement sécuritaires, rentables, ils peuvent être facilement produits et fonctionnalisés, même à grande échelle. Cependant, leur efficacité est encore trop faible pour surpasser leurs homologues viraux. L'efficacité des vecteurs non viraux est un équilibre entre leur capacité à introduire des NAs dans les cellules, permettant ou inhibant ainsi leur expression, leur toxicité inhérente et leur capacité à délivrer des gènes aux cellules cibles. Ces dernières années, des efforts considérables en recherche ont donc été déployés pour développer de nouveaux moyens d'améliorer l'efficacité de cette classe de systèmes de livraison. Cette thèse de doctorat avait ainsi pour but de développer des stratégies innovantes pour améliorer l'efficacité des vecteurs non viraux. Dans ce contexte, nous avons considéré la problématique de la livraison sous deux perspectives différentes : d'une part, la modulation de la chimie du vecteur a été évaluée comme moyen de développer des transporteurs multifonctionnels avec une meilleure efficacité ; d'autre part, une stratégie de stimuler les interactions cellules-nanoparticules par modulation mécanique du comportement cellulaire sur la capacité de livraison de vecteurs non viraux a été étudiée. La première partie de cette thèse visait donc à mettre en évidence l'importance de la chimie de ces vecteurs, plus particulièrement ceux à base de lipides, sur la relation structure-fonction de ces matériaux et l'impact de la chimie du vecteur sur leur capacité ultime à livrer des gènes. Cette thèse a ensuite exploré de nouvelles façons d'améliorer les performances de la polyéthylèneimine (PEI), à savoir le vecteur polymère de référence, en configuration linéaire (lPEI) et ramifiée (bPEI). Tout d'abord, une étude approfondie de toutes les variables expérimentales qui peuvent influencer les performances des polyplexes à base de PEI, a été réalisée afin de déterminer les meilleures conditions de fonctionnement des vecteurs à base de PEI et d'améliorer la standardisation des protocoles de criblage in vitro. Ensuite, le focus a été fait sur le développement d'une approche vectorielle pour fonctionnaliser le bPEI avec des entités fonctionnelles ciblées afin d'améliorer la sélectivité du vecteur envers un type de cellule spécifique. Ainsi, il a été synthétisé une gamme de bPEI conjugués incorporant des peptides de ciblage pour délivrer sélectivement des gènes aux cellules musculaires lisses vasculaires (vSMCs). De plus, ces vecteurs de ciblage spécifique ont été incorporés dans une matrice afin de permettre leur libération locale et contrôlée pour des approches liées au domaine cardiovasculaire. Grâce à la conjugaison d'une séquence peptidique dérivée de l'élastine à la structure de la bPEI, l'efficacité du polymère sur les vSMCs a été améliorée tout en laissant les cellules non ciblées intactes. Ceci est particulièrement important pour la translation des approches non virales de livraison de gènes vers le in vivo. D'autre part, une nouvelle approche basée sur la régulation de la réponse cellulaire à l'administration de la nanoparticule a été élaborée. En effet, les cellules in vivo sont constamment exposées à différents facteurs environnementaux qui gouvernent certaines fonctions cellulaires essentielles. L'application d'un stimulus mécanique exogène en termes de sollicitation vibratoire sur des cellules en cours de transfection (processus de livraison de NAs par vecteurs non-viraux) a donc été évaluée avec des polyplexes à base de lPEI et bPEI. Étonnamment, l'efficacité des polyplexes à base d'lPEI a été grandement améliorée grâce à l'activation de certaines réponses cellulaires clés. Plus précisément, les stimulations mécaniques appliquées aux cellules ont amélioré l'internalisation des polyplexes en déclenchant l'activation de l'endocytose médiée par la clathrine (CME). Cette stratégie a mis en évidence l'importance des réponses cellulaires aux signaux exogènes sur l'internalisation et l'expression finales d'un gène d'intérêt et a ouvert la voie à une nouvelle façon de traiter la question de la livraison non virale. En conclusion, ce projet de doctorat a clairement mis en évidence la pertinence de ces approches chimiques et cellulaires comme moyens efficaces d'améliorer l'efficacité des vecteurs non viraux. En combinant les stratégies conçues dans le cadre de ce projet, il serait possible de franchir une autre étape en ce qui concerne la recherche sur l'administration de gènes non viraux. En effet, le développement d'approches multidisciplinaires tenant en compte à la fois du vecteur d'administration, de l'environnement dans lequel l'administration des gènes a lieu et de la réponse cellulaire, pourrait ouvrir la voie à des stratégies encore plus efficaces et accélérer le passage du laboratoire au patient pour cette catégorie de matériaux. / Non-viral gene delivery strategies have attracted significant interest in the development of novel therapeutic approaches as well as for basic and applied research in vitro. Compared to popular viral vectors, the class of non-viral carriers, namely cationic lipids (CLs) and polymers (CPs) able to spontaneously interact with negatively charged nucleic acids (NAs) to give nanoparticles called complexes, is now witnessing a surge of interest within the scientific community because they are relatively safe, cost-effective, and they can be easily produced and functionalized even at large scale. However, their efficiency in achieving the delivery tasks is still too low to outperform their viral counterparts. The efficacy of non-viral vectors is a tradeoff between their ability to drive NAs into cells, thus allowing/inhibiting their expression, their inherent toxicity, and their ability to deliver genes to target cells. Extensive research effort has thus been put into developing novel ways to improve the efficiency of such a class of delivery systems. In this context, my Ph.D. aimed at developing innovative strategies to improve non-viral vector effectiveness. To this purpose, we dealt with the delivery issue from two different perspectives: on one hand, the modulation of the vector chemistry was disclosed as a way to develop multifunctional carriers with improved effectiveness; on the other hand, we sought to improve cell-(nano)particles' interactions through the mechanical modulation of the cell behavior in response to the delivery of non-viral vectors. The first part of this thesis was thus aimed at highlighting the importance of vector chemistry on the structure-function relationship of such kinds of materials, with a focus on lipid-based carriers. Furthermore, I dealt with the characterization of a novel class of lipid-based vectors to investigate the interconnection between their structure and ultimate gene transfer ability. This thesis next explored novel ways to improve the performances of polyethyleneimine (PEI), namely the gold standard polymer vector, both in linear (lPEI) and branched (bPEI) topography. First, a thorough investigation of all the experimental variables affecting the performances of PEI-based polyplexes was carried out to disclose the best working conditions of PEI-based carriers and improve the standardization of in vitro screening protocols. Next, I focused on the development of a vector-based approach to functionalize bPEI with targeting moieties to improve the vector's selectivity towards a specific cell type. We thus synthesized a series of bPEI conjugates incorporating targeting peptides to selectively deliver genes to vascular smooth muscle cells (vSMCs). Moreover, the targeting vectors were incorporated into a polyplex releasing matrix to enable their local and controlled release for cardiovascular-related approaches. Through the conjugation of an elastin-derived peptide sequence to the bPEI structure, we were able to improve the polymer's effectiveness on target vSMCs while leaving off-target cells unaffected, a fact that is especially relevant for the translation of non-viral gene delivery approaches in vivo. On the other side, a novel strategy based on the regulation of cell response to the delivery of nanoparticles was devised. Indeed, cells in vivo are constantly subjected to different environmental cues that govern some key cell functions. We thus investigated the application of an exogenous mechanical stimulus in terms of vibrational loading to cells undergoing transfection (i.e., the delivery of NAs utilizing non-viral vectors) using lPEI and bPEI-based polyplexes. Interestingly, mechanical stimuli applied to cells improved polyplex internalization by triggering the activation of clathrin-mediated endocytosis (CME), thus leading to greater transfection outcomes. This strategy outlined the importance of cell responses to exogenous cues on the ultimate internalization and expression of a gene of interest and set the stage for a novel way to deal with the non-viral delivery issue. Overall, the big picture drawn by this Ph.D. project highlighted the suitability of chemical-based approaches and cell-based approaches as promising ways to improve non-viral vector effectiveness. Further improvement in non-viral gene delivery research might be achieved by combining the strategies devised in this project. The development of multidisciplinary approaches taking into account both the delivery vector, the environment in which the delivery of genes takes place, and the cell response may thus pave the way to ever more effective strategies, and expedite the translation from the bench to the bedside of these materials.

This study investigated the influence of cations on biopolymer characteristics and sludge properties. Settling and dewatering properties of sludges were measured and correlated to the biopolymer characteristics. In addition, effects of cations on sludge conditioning with polymer were studied. Experiment mainly consisted of two parts, reactor study and batch study. In re- actor study continuous-flow reactors were operated. Variables used included varying types of substrate, addition of magnesium or sodium, and changes in pH. The batch study included conditioning tests on the sludges with combinations of cationic polymer and salts. Biopolymers were extracted using alkali extraction followed by gel filtration and subsequent carbohydrate and protein analysis. The sludge settling and dewatering were measured in terms of SVI and specific resistance, respectively. Sludge filtering rate (TIF) was used to measure the conditioning efficiency. The results indicated that the influence of cations depended on the type and concentration of salt. An optimal concentration of Mg was found to improve biopolymer binding. The organic composition of feed also affected biopolymer characteristics. A higher pH combined with a high amount of sodium released biopolymer and resulted in sludge deflocculation. A relationship between unbound biopolymer and soluble effluent COD was observed but no discernible relation between biopolymer binding and sludge settling and dewatering properties was found. Cations were found to reduce polymer requirement during sludge conditioning. In addition, the amount of extractable biopolymers by alkali extraction was greatly influenced by salt. Magnesium inhibited the release of biopolymer, but sodium im- proved the efficiency of biopolymer extraction. / Master of Science

Two soils from the Fernow Experimental Forest near Parsons, West Virginia were characterized and evaluated in terms of their susceptibility to enhanced soil acidification via acidic atmospheric inputs. After initial physical, chemical, and mineralogical characterization, the soils were analyzed for their ability to adsorb and retain sulfate (SO₄²⁻) through a series of batch adsorption and desorption experiments. Reconstructed soil profiles were then subjected to water leaching as the preliminary step to a base release study in which each soil will be placed under simulated acid rain and evaluated for base cation release and subsequent changes in soil chemistry. Experiments with SO₄²⁻ adsorption and desorption divide the soils into two categories: (i) shallow surface horizons with high organic matter and little Fe oxide content which had little ability to adsorb additional SO₄²⁻ and low capacity to retain SO₄²⁻; and (ii) deeper subsurface soils with low organic matter and high Fe oxide content which could adsorb SO₄²⁻ at solution concentrations above 0.5 mmol/L. All soil horizons desorbed SO₄²⁻ and had no ability for additional adsorption at solution concentrations below 0.5 mmol/L, which implies that the site may be saturated with respect to natural conditions. Initial mass (IM) and Langmiur modeling were used to illustrate SO₄²⁻ dynamics and make correlations with soil physical, chemical, and mineralogical properties. Fe oxides and Al-saturated organic matter were shown to be the preferential sites for SO₄²⁻ adsorption but may be already saturated or very near saturation. Preliminary results from the base release study indicate that the two soils are dominated by different chemical processes and hence release ions into soil solution at different rates. Ion release is shown to be a function of both reactions on the exchange complex and the dissolution of mineral components. / Master of Science

Aim. The human organic cation transporter subtype 2 (OCT2) is highly expressed in the renal tubular epithelium and can play an important role in the renal clearance of many drugs and drug-drug interactions occurring in the kidney. The purposes of this study are: (1) to investigate the genetic polymorphisms of OCT2 in Chinese population; (2) to evaluate the potential genotype-phenotype relationship involving OCT2 polymorphism in human subjects; and (3) to identify the SNPs in proximal promoter/enhancer region and assess their functional significance. / Conclusion. The present study demonstrated the existence of genetic polymorphisms of OCT2 gene in the Chinese population and for the first time showed that a ncSNP 808G>T is associated with a reduced renal transport function and can significantly impact the magnitude of drug interactions. Our study also for the first time found that a promoter polymorphism (-1283 T>C) is associated with an altered promoter activity in vitro, but no such relationship was observed with this SNP in the in vivo metformin study. Thus, it was the ncSNP 808G>T but not the -1283T>C in promoter that was associated with variations in the metformin renal clearance. (Abstract shortened by UMI.) / Method. One hundred and twelve Hong Kong Chinese subjects were recruited and their DNA samples were obtained. / Results. A total of 13 SNPs were identified in the coding and surrounding non-coding regions of OCT2, with minor allele frequencies (MAF) ranged from 4.5% to 24.7%. From these SNP data sets, 28 haplotypes were inferred with 4 being the common ones (frequencies ranged from 5.4% to 50.4%). Only one non-synonymous coding region SNP (ncSNP), 808G>T in the exon 4, was observed among all the identified SNPs. Significant differences were observed in the renal clearance of metformin in subjects with different mutation status for this variant. The mean renal tubular clearance (CLt) values of metformin were 8.54 +/- 1.86, 7.72 +/- 0.64, and 6 36 +/- 0.98 ml/kg/min for subjects with GG (n = 6), GT (n = 5) and TT (n = 4) genotypes respectively (P = .043. 1-way ANOVA). After a 6-day cimetidine treatment, a mean decrease of 50.7%, 34.6% and 18.9% in metformin CLt was observed in the GG, GT and TT genotype groups (P =.013, P =.002 and P = .065 respectively compared to metformin alone). The decrease of CLt was significantly lower in the TT genotype group than that in the GG group (P = .027). Five SNPs were identified and 5 haplotypes inferred (frequencies ranged from 2.7% to 38.4%) in promoter/enhancer area. One haplotype, characterized by the presence of -1283 T>C, was associated with a significantly lower luciferase activity in vitro (26.7% decrease in comparison to wild-type, P = .016), but not with metformin CLt in Chinese Subjects. / Wang, Zhijun. / "Aug 2007." / Adviser: Moses Chow. / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0966. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 148-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Cette thèse, menée en collaboration avec Michelin dans le cadre de la fabrication de matériaux composites, porte sur la stabilité colloïdale du latex de caoutchouc naturel (NR). Ce latex est une dispersion colloïdale polydisperse d'un polymère naturel dans un sérum aqueux. Les particules sont stabilisées par une couche complexe de phospholipides et de protéines. Cette dispersion peut être coagulée de façon irréversible par voie physique (sous cisaillement) ou par voie physico-chimique (ajout de cations divalents ou de particules hydrophobes). Dans ce travail, nous avons étudié la coagulation du latex par les cations divalents. Pour cela nous avons utilisé des outils physico-chimiques : diagrammes de stabilité en présence de divers cations, suivi cinétique de l'agrégation des particules et mesures rhéologiques. Ensuite, nous avons sondé la surface de particules de NR, par électrophorèse, en présence de tensioactifs et aussi selon la taille des particules. Pour expliquer la coagulation, nous suggérons que l'augmentation de la force ionique écrante les interactions répulsives et que les cations forment des ponts ioniques entre les particules. Ces ponts les maintiennent au contact et l'irréversibilité du phénomène est assurée par l'adhésion entre les chaines de polymères proches de la surface. L'adsorption des tensioactifs modifie la surface des particules et la coagulation du latex. Une légère différence de charge de surface a été observée entre les particules de NR selon leur taille. Enfin, un phénomène de coagulation similaire a été obtenu avec un latex synthétique, ce qui ouvre la voie à l'exploitation industrielle de ce phénomène de coagulation. / This work, in collaboration with Michelin for the fabrication of composite materials, deals with the colloidal stability of the latex of natural rubber (NR). The NR latex is a polydisperse colloidal dispersion of a bio-polymer in an aqueous serum. The particles are stabilized by a complex layer of phospholipids and proteins. This dispersion can be coagulated by a physical way (under shearing), or by a physical-chemical way (addition of divalent cations or hydrophobic particles). In this thesis, we studied the coagulation of the NR latex by divalent cations with physical-chemical tools (stability diagrams with different cations, aggregation kinetic of particles, rheological measuremments). Then, the surface of NR particles has been characterized by electrophoresis, firstly in the presence surfactants and secondly depending on the particles size. From the results of the first part we suggest that the coagulation with divalent cations is due to a screening effect because of the increase of ionic strength and that divalent cations can bridge the particles together. This allows keeping them in contact. Adhesion between polymer chains near the surface ensures the irrversible cohesion. In a second time, we saw that the adsorption of surfactants changes the particles surface and the coagulation of NR latex with cations. A small difference of surface charge is observed between the biggest and the smallest NR particles. Finally, a similar behavior has been obtained with a synthetic latex in presence of divalent cations. Our results could be used to develop an industrial process based on this coagulation phenomenon.