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Nanomedicine is based primarily on the concept of drug formulation through nanotechnology. The main idea is based on the encapsulation of an active ingredient by a nanoparticle (NP) to allow it to accumulate in tumors, to penetrate a biological barrier or to target a biological component. However, the performance of these formulations is disappointing, and, in recent years, it has been noticed that their effectiveness has not improved in the last decade. Some recent hypotheses highlight our lack of knowledge about the interactions of nanotechnologies with living organism and more particularly the lack of techniques to quantify these interactions. We therefore explore in this thesis the development and adaptation of a new microscopy technique, dynamic differential microscopy (DDM), to study the interactions of nanotechnologies with biological matrices. Two subjects are discussed, the first on the interactions of NPs with the proteins of biological fluids and, the second one, on the capacity of NPs to diffuse in interstitial tissues. First, we reviewed quantification techniques that were allowing the measurement of protein adsorption at the surface of NPs. We then identified fundamental questions of this adsorption, namely, if it was generally structured in monolayers or in multilayers and if it was reversible or irreversible. A meta-analysis, based on these questions, could therefore guide the development of the DDM technique to measure protein adsorption and therefore answer these questions. The methodology proposed for the quantification of protein adsorption is based on the measurement of the fluorescence signal which comes from fluorescently tagged proteins adsorbed on non-fluorescent NPs. This methodology was successfully applied for the quantification of the adsorption of lysozyme, albumin and serum proteins. The technique demonstrated that all the proteins studied adsorbed in monolayers and that their adsorption was reversible. An atypical adsorption mechanism which was also hypothesized in our meta-analysis was evidenced by DDM as well. Next, we applied DDM to study the diffusion of NPs in extracellular matrices. The contribution of deformability has been a parameter studied in terms of its relation to improve their diffusion within these confined environments. The diffusion of "soft" NPs was compared to that of "hard" NPs in an agarose gel, mimicking the extracellular matrix. Soft NPs have been observed to diffuse up to 100 times faster than hard NPs of the same size. Evaluation of the hydrodynamic and electrostatic contributions determined that the soft NPs shrinks in the gel, boosting their diffusion in comparison to hard NPs. In summary, this work highlights the important contribution of analytical techniques to the field of nanotechnologies applied to pharmacy and to our understanding of their interactions with living organisms. It is clear that the contribution of these techniques to our detailed understanding of nanomedicine properties has a direct relation with their clinical translation potential. / La nanomédecine repose essentiellement sur le développement de nouvelles formulations pour délivrer les médicaments à partir de nanotechnologies. L’idée principale est que l’encapsulation d’un principe actif par une nanoparticule (NP) pourrait lui permettre de s’accumuler dans des tumeurs, de pénétrer une barrière biologique ou bien pour cibler une composante biologique. Or, les performances de ces « nano-formulations » sont décevantes et, depuis quelques années, il a été remarqué que leur efficacité ne semble pas avoir évoluée dans le temps. De récentes hypothèses mettent de l’avant notre manque de connaissances vis-à-vis les interactions des nanotechnologies avec les éléments du vivant, et plus particulièrement, le manque de techniques robustes permettant de quantifier ces interactions. Nous proposons donc dans cette thèse le développement et l’adaptation d’une nouvelle technique de microscopie, la microscopie différentielle dynamique (DDM), pour étudier les interactions entre les nanotechnologies et les matrices biologiques. Deux thématiques seront abordées, la première, les interactions des NPs avec les protéines des fluides biologiques et, la seconde, la capacité des NPs à diffuser dans des tissus interstitiels. D’abord, nous avons revus les techniques de quantification permettant la mesure de l’adsorption de protéines à la surface des NPs. Nous avons ensuite identifié les questions fondamentales en lien avec cette adsorption. Deux phénomènes sont largement débattus dans la littérature, il s’agit de la formation de multicouches et de la réversibilité de l’adsorption. Une méta-analyse a donc permis d’orienter le développement de la technique par DDM pour mesurer l’adsorption de protéines, dans le but de répondre à ces interrogations. La méthodologie proposée pour la quantification de l’adsorption de protéines à la surface des NPs repose sur la mesure du signal de fluorescence de protéines fluorescentes adsorbées à la surface des NPs non fluorescentes. Cette méthodologie a été appliqué avec succès pour la quantification de l’adsorption des protéines du sérum, du lysozyme et de l’albumine. La technique a d’ailleurs permis de montrer que toutes les protéines étudiées s’adsorbaient en monocouches et que leur adsorption était réversible. Un mécanisme d’adsorption atypique a été mis en évidence dans le cadre de nos expériences et un parallèle a pu être fait avec certaines hypothèses émises avec notre méta-analyse. Ensuite, nous avons appliqué la DDM pour l’étude de la diffusion des NPs dans des matrices extracellulaires. La déformabilité des NPs a été étudiée afin de définir plus précisément sa contribution dans la diffusion à l’intérieur de milieux confinés. La diffusion des NPs « molles » a été comparée à celle des NPs « dures » dans un gel d’agarose, mimant la matrice extracellulaire. Les NPs molles ont été en mesure de diffuser jusqu’à 100 fois plus rapidement que les NPs dures de même taille. L’évaluation des contributions hydrodynamiques et électrostatiques a permis de déterminer que la taille des NPs molles, réduisant dans le gel, leur accordant un avantage diffusif par rapport aux NPs dures. En sommes, ces travaux ont permis de mettre en évidence l’importance des techniques analytiques pour l’étude des nanotechnologies appliquées à la médecine et pour affiner notre compréhension de leurs interactions avec le vivant. Il est clair que la contribution de ces techniques à l’avancement de nos connaissances théoriques relatives aux nanotechnologies aura un impact direct sur leurs chances d’effectuer une transition vers la clinique.

Dans ce mémoire, nous étudions le problème centre-foyer sur un système polynomial. Nous développons ainsi deux mécanismes permettant de conclure qu’un point singulier monodromique dans ce système non-linéaire polynomial est un centre. Le premier mécanisme est la méthode de Darboux. Cette méthode utilise des courbes algébriques invariantes dans la construction d’une intégrale première. La deuxième méthode analyse la réversibilité algébrique ou analytique du système. Un système possédant une singularité monodromique et étant algébriquement ou analytiquement réversible à ce point sera nécessairement un centre. Comme application, dans le dernier chapitre, nous considérons le modèle de Gauss généralisé avec récolte de proies. / In this thesis, we study the center-focus problem in a polynomial system. We describe two mechanisms to conclude that a monodromic singular point in this polynomial system is a center. The first one is the method of Darboux. In this method, one uses invariant algebraic curves to build a first integral. The second method is the algebraic (and analytic) reversibility. A monodromic singularity, which is algebraically or analytically reversible at the singular point, is necessarily a center. As an application, in the last chapter, we consider the generalized Gause model with prey harvesting and a generalized Holling response function of type III.

Um conjunto de modelos compostos de redes de filas em grades finitas servindo como ambientes aleatorios para um ou mais passeios aleatorios, que por sua vez podem afetar o comportamento das filas, e desenvolvido. Duas formas de interacao entre os passeios aleatorios sao consideradas. Para cada modelo, e provado que o processo Markoviano correspondente e recorrente positivo e reversivel. As equacoes de balanceamento detalhado sao analisadas para obter a forma funcional da medida invariante de cada modelo. Em todos os modelos analisados neste trabalho, a medida invariante em uma grade finita tem forma produto. Modelos de redes de filas como ambientes para multiplos passeios aleatorios sao estendidos a grades infinitas. Para cada modelo estendido, sao especificadas as condicoes para a existencia do processo estocastico na grade infinita. Alem disso, e provado que existe uma unica medida invariante na rede infinita cuja projecao em uma subgrade finita e dada pela medida correspondente de uma rede finita. Finalmente, e provado que essa medida invariante na rede infinita e reversivel. / A set of models composed of queueing networks serving as random environments for one or more random walks, which themselves can affect the behavior of the queues, is developed. Two forms of interaction between the random walkers are considered. For each model, it is proved that the corresponding Markov process is positive recurrent and reversible. The detailed balance equa- tions are analyzed to obtain the functional form of the invariant measure of each model. In all the models analyzed in the present work, the invariant measure on a finite lattice has product form. Models of queueing networks as environments for multiple random walks are extended to infinite lattices. For each model extended, the conditions for the existence of the stochastic process on the infinite lattice are specified. In addition, it is proved that there exists a unique invariant measure on the infinite network whose projection on a finite sublattice is given by the corresponding finite- network measure. Finally, it is proved that that invariant measure on the infinite lattice is reversible.

Um conjunto de modelos compostos de redes de filas em grades finitas servindo como ambientes aleatorios para um ou mais passeios aleatorios, que por sua vez podem afetar o comportamento das filas, e desenvolvido. Duas formas de interacao entre os passeios aleatorios sao consideradas. Para cada modelo, e provado que o processo Markoviano correspondente e recorrente positivo e reversivel. As equacoes de balanceamento detalhado sao analisadas para obter a forma funcional da medida invariante de cada modelo. Em todos os modelos analisados neste trabalho, a medida invariante em uma grade finita tem forma produto. Modelos de redes de filas como ambientes para multiplos passeios aleatorios sao estendidos a grades infinitas. Para cada modelo estendido, sao especificadas as condicoes para a existencia do processo estocastico na grade infinita. Alem disso, e provado que existe uma unica medida invariante na rede infinita cuja projecao em uma subgrade finita e dada pela medida correspondente de uma rede finita. Finalmente, e provado que essa medida invariante na rede infinita e reversivel. / A set of models composed of queueing networks serving as random environments for one or more random walks, which themselves can affect the behavior of the queues, is developed. Two forms of interaction between the random walkers are considered. For each model, it is proved that the corresponding Markov process is positive recurrent and reversible. The detailed balance equa- tions are analyzed to obtain the functional form of the invariant measure of each model. In all the models analyzed in the present work, the invariant measure on a finite lattice has product form. Models of queueing networks as environments for multiple random walks are extended to infinite lattices. For each model extended, the conditions for the existence of the stochastic process on the infinite lattice are specified. In addition, it is proved that there exists a unique invariant measure on the infinite network whose projection on a finite sublattice is given by the corresponding finite- network measure. Finally, it is proved that that invariant measure on the infinite lattice is reversible.

Dans ce mémoire, nous étudions le problème centre-foyer sur un système polynomial. Nous développons ainsi deux mécanismes permettant de conclure qu’un point singulier monodromique dans ce système non-linéaire polynomial est un centre. Le premier mécanisme est la méthode de Darboux. Cette méthode utilise des courbes algébriques invariantes dans la construction d’une intégrale première. La deuxième méthode analyse la réversibilité algébrique ou analytique du système. Un système possédant une singularité monodromique et étant algébriquement ou analytiquement réversible à ce point sera nécessairement un centre. Comme application, dans le dernier chapitre, nous considérons le modèle de Gauss généralisé avec récolte de proies. / In this thesis, we study the center-focus problem in a polynomial system. We describe two mechanisms to conclude that a monodromic singular point in this polynomial system is a center. The first one is the method of Darboux. In this method, one uses invariant algebraic curves to build a first integral. The second method is the algebraic (and analytic) reversibility. A monodromic singularity, which is algebraically or analytically reversible at the singular point, is necessarily a center. As an application, in the last chapter, we consider the generalized Gause model with prey harvesting and a generalized Holling response function of type III.

The provision of clean drinking water typically involves treatment processes to remove contaminants. The conventional process involves coagulation with hydrolysing metal salts, typically of aluminium (‘alum’) or trivalent iron (‘ferric’). Along with the product water this also produces a waste by-product, or sludge. The fact of increasing sludge production — due to higher levels of treatment and greater volume of water supply — conflicts with modern demands for environmental best practice, leading to higher financial costs. A further issue is the significant quantity of water that is held up in the sludge, and wasted. / One means of dealing with these problems is to dewater the sludge further. This reduces the volume of waste to be disposed of. The consistency is also improved (e.g. for the purpose of landfilling). And a significant amount of water can be recovered. The efficiency, and efficacy, of this process depends on the dewaterability of the sludge.In fact, good dewaterability is vital to the operation of conventional drinking water treatment plants (WTP’s). The usual process of separating the particulates, formed from a blend of contaminants and coagulated precipitate, relies on ‘clarification’ and ‘thickening’, which are essentially settling operations of solid–liquid separation.WTP operators — and researchers — do attempt to measure sludge dewaterability, but usually rely on empirical characterisation techniques that do not tell the full story and can even mislead. Understanding of the physical and chemical nature of the sludge is also surprisingly rudimentary, considering the long history of these processes. / The present work begins by reviewing the current state of knowledge on raw water and sludge composition, with special focus on solid aluminium and iron phases and on fractal aggregate structure. Next the theory of dewatering is examined, with the adopted phenomenological theory contrasted with empirical techniques and other theories.The foundation for subsequent analyses is laid by experimental work which establishes the solid phase density of WTP sludges. Additionally, alum sludges are found to contain pseudoböhmite, while 2-line ferrihydrite and goethite are identified in ferric sludges. / A key hypothesis is that dewaterability is partly determined by the treatment conditions. To investigate this, numerous WTP sludges were studied that had been generated under diverse conditions: some plant samples were obtained, and the remainder were generated in the laboratory (results were consistent). Dewaterability was characterised for each sludge in concentration ranges relevant to settling, centrifugation and filtration using models developed by LANDMAN and WHITE inter alia; it is expressed in terms of both equilibrium and kinetic parameters, py(φ) and R(φ) respectively.This work confirmed that dewaterability is significantly influenced by treatment conditions.The strongest correlations were observed when varying coagulation pH and coagulant dose. At high doses precipitated coagulant controls the sludge behaviour, and dewaterability is poor. Dewaterability deteriorates as pH is increased for high-dose alum sludges; other sludges are less sensitive to pH. These findings can be linked to the faster coagulation dynamics prevailing at high coagulant and alkali dose.Alum and ferric sludges in general had comparable dewaterabilities, and the characteristics of a magnesium sludge were similar too.Small effects on dewaterability were observed in response to variations in raw water organic content and shearing. Polymer flocculation and conditioning appeared mainly to affect dewaterability at low sludge concentrations. Ageing did not produce clear changes in dewaterability.Dense, compact particles are known to dewater better than ‘fluffy’ aggregates or flocs usually encountered in drinking water treatment. This explains the superior dewaterability of a sludge containing powdered activated carbon (PAC). Even greater improvements were observed following a cycle of sludge freezing and thawing for a wide range of WTP sludges. / Further aspects considered in the present work include deviations from simplifying assumptions that are usually made. Specifically: investigation of long-time dewatering behaviour, wall effects, non-isotropic stresses, and reversibility of dewatering (or ‘elasticity’).Several other results and conclusions, of both theoretical and experimental nature, are presented on topics of subsidiary or peripheral interest that are nonetheless important for establishing a reliable basis for research in this area. / This work has proposed links between industrial drinking water coagulation conditions, sludge dewaterability from settling to filtration, and the microstructure of the aggregates making up that sludge. This information can be used when considering the operation or design of a WTP in order to optimise sludge dewaterability, within the constraints of producing drinking water of acceptable quality.

This dissertation is an empirically responsive philosophical exploration into the incorporation of technological tools within a framework comprising the structures of experience laid out in the early phenomenological tradition and an analysis of agency drawing from the analytical tradition. Technological tools have become so deeply integrated in our lives that they function like a part of us, transforming what we feel we can do and even who we are. Although new spaces of autonomous agency have been opened up, since the inner workings of technological tools can remain invisible, we risk diminishing our own capacities. Since we are fundamentally embedded in the world, we cannot understand ourselves without reference to the world and we cannot understand the world without reference to the way we are. The uniqueness involved in our use of technological tools grows out of a more primordial uniqueness that makes technological tool use possible and sets us apart from our closest evolutionary relatives. Several animals extend their physical influence on the environment by means of tools. We humans, however, use tools to extend our cognitive abilities as well. And since the computer is the most universal human tool, which can be put to sensorimotor and cognitive purposes alike, we take the computer to be...

This article explains the particular conformation and dynamic of the integrativeelements of the relationship between the tangible and intangible aspects in the processof local development  of San Juan  Nuevo  de Parangaricutiro (Michoacán, México). On one hand, the historical characteristics and their connection to the way thecommunity faces natural adversity; on the other, the creation of a participative and democratic leading style and the role of selection in the constitution of social capital and the local endogenous nucleus. In the same way, the decisive role played by the intangible aspects, in specific, the role of the meta local forces, in this dynamic is emphasized. The author supports the idea that local development is the result of a dynamic of feedback and mutual  growth among the tangible and intangible aspects, in a sequence that starts with the maturation and accumulation of one of these aspects in the community, widening the possibilities of development. In this dynamic, the role played by the meta local forces operating in the backings of the collective memory, long term linking the different moments of the process and serving as factors of re­ impulse within the feedback, is decisive. The author also explores the importance of the public policies in the successive moments of the dynamic between tangibles and intangibles in the local development and the concept of reversibility in the construction of this dynamic. / El artículo explica la particular conformación y dinámica de los elementos constitu­tivos de la relación entre los aspectos tangibles e intangibles en el proceso de desarrollo local de San Juan Nuevo de Parangaricutiro (Michoacán, México). Por un lado, los aglutinantes históricos y su vinculación con la forma en que la comunidad encara las adversidades naturales; por otro, la generación de un liderazgo de participación incipientemente democrático, así como el papel de la selección en la constitución de capital social y del núcleo endógeno local. Asimismo, se subraya el papel decisivo jugado por los aspectos intangibles y, especialmente, por lasfuerzas meta locales den­ tro de esta dinámica. Se sostiene que el desarrollo local es el resultado de una dinámi­ ca de retroalimentación y escalamiento mutuo entre los aspectos tangibles e intangibles, en una secuencia que se inicia con la maduración y acumulación de alguno de estos dos aspectos en la localidad, lo que abre las posibilidades de desarrollo. En esta diná­ mica, es decisivo el papel cumplido por las fuerzas meta locales que operan en el trasfondo de la memoria colectiva vinculando a largo plazo los distintos momentos del proceso y sirviendo de factores de reimpulso dentro de la retroalimentación. Se plantea también la importancia de las políticas públicas en los sucesivos momentos de la dinámica entre tangibles e intangibles en el desarrollo local, así como el concep­to de reversibilidad en la construcción de esta dinámica.

<p>Ako je<em> L </em>relacijski jezik, kondenzacioni pretporedak na skupu<em> Int</em>_L <em>(X)</em> svih <em>L-</em>interpretacija nad domenom <em>X,</em> dat je sa: &rho;≼_c <em>&sigma;</em> ako postoji bijektivni homomorfizam (kondenzacija)<em> f:〈X,&rho;</em>〉&rarr;<em>〈X,&sigma;〉.</em> Odgovarajući antisimetrični količnik <em>〈Int_L</em> (X)/~_c,&le;_c〉 ~naziva se kondenzacioni poredak. Za proizvoljnu<em> L-</em>interpretaciju &rho;, klasa [&rho;]~_c&nbsp; je konveksno zatvorenje klase [&rho;]_&cong; u Booleovoj mreži 〈<em>IntL (X</em>),&sube;〉. Za <em>L</em>-interpretaciju &rho; reći ćemo da je jako reverzibilna (redom, reverzibilna, slabo reverzibilna) akko je klasa [&rho;]_&cong;&nbsp; (ili, ekvivalentno, klasa [&rho;]~_c)) singlton (redom, antilanac, konveksan skup) u Booleovoj mreži 〈<em>IntL (X)</em>,&sube;〉. U cilju ispitivanja poseta 〈<em>Int(_Lb</em>) (X)/~c,&le;c〉, za &rho;&isin;<em>Irrefl_X</em> uveden je skup D_&rho;:={[&rho;&cup;&Delta;_A ](~_c ):<em>A&sube;X</em>} i pokazano je kako je poduređenje 〈D_&rho;,&le;_c 〉 izomorfno određenom količniku partitivnog skupa<em> P(X)</em>. Fenomen reverzibilnosti relacijskih struktura igra istaknutu ulogu u istraživanju tog poduređenja.</p><p>U slučaju prebrojivog jezika <span id="cke_bm_1038S" style="display: none;">&nbsp;</span><em>L</em><span id="cke_bm_1038E" style="display: none;">&nbsp;</span> i prebrojivog domena <em>X</em>, pokazano je da su ~_c i [&rho;]~_canalitički skupovi u poljskim prostorima, redom, <em>Int_L(&omega;)&times;Int_L(&omega;) i Int_L (&omega;)</em>, i pomoću toga, pokazano ja da su, u slučaju prebrojivog jezika i domena, klase [&rho;]&cong;&nbsp; i [&rho;]~_c iste veličine, i da je to neki kardinal iz {1,&omega;,c}. Dalje je istražena hijerarhija između kondenzacione ekvivalencije, elementarne ekvivalencije, ekvimorfizma (bi-utopivosti) i drugih sličnosti <em>L-</em>struktura određenih nekim sličnostima njihovih monoida samoutapanja.</p><p>Naposletku, temeljno je istražen fenomen reverzibilnosti <em>L</em>-struktura. Data je karakterizacija jako reverzibilnih<em> L</em>-intepretacija kao onih čije su komponentne relacije definabilne formulama praznog jezika<em> L</em>_&empty;, bez kvantifikatora i parametara. Pokazano je kako su slabo reverzibilne interpretacije upravo one koje imaju svojstvo Cantor-Schrӧder-Bernstein (kraće, svojstvo CSB) za kondenzacije.</p><p>Poseban naglasak stavljen je na detektovanje relevantnih klasa reverzibilnih struktura. Pri tome, prvo su proučene strukture koje su ekstremni elementi L_{&infin;&omega;}-definabilnih klasa interpretacija, pri određenim sintaktičkim ograničenjima, a zatim su istražene nepovezane<em> L</em>_b-strukture, gde je dato nekoliko karakterizacija njihove reverzibilnosti.</p> / <p>If <em>L</em> is a relational language, the condensational preorder on the set <em>Int_L (X)</em> of all <em>L-</em>interpretations over the domain<em> X</em>, is given with: &rho;≼_c &sigma; iff there exists a bijective homomorphism (condensation) <em>f:〈X,&rho;〉&rarr;〈X,&sigma;〉. </em>The corresponding antisymmetric quotient 〈<em>Int_L (X)/</em>~_<em>c</em>,&le;__c〉 will be called the condensational order. For any <em>L</em>-interpretation &rho;, the class<em> [&rho;]~_c )</em> is the convex closure of the class [<em>&rho;</em>]&cong; in the Boolean lattice 〈<em>IntL (X</em>),&sube;〉. An <em>L</em>-interpretation &rho; is said to be strongly reversible&nbsp; (respectively, reversible, weakly reversible) iff the class <em>[&rho;]</em>&cong;&nbsp; (or, equivalently, the class<em> [&rho;]~c )</em>) is a singleton (respectively, an antichain, a convex set) in the poset 〈 <em>IntL</em> <em>(X)</em>,&sube;〉. In order to investigate the poset 〈<em>Int_(Lb ) (X)/~c,&le;_c</em>〉, for &rho;&isin;<em> IrreflX</em> the following set is defined <em>D_&rho;</em>:={[&rho;&cup;&Delta;_A ]_~c :A&sube;X}. It is shown that the suborder 〈<em>D_&rho;,</em>&le;_c 〉 is isomorphic to a certain quotient of the power set <em>P(X)</em>. The phenomenon of reversibility plays prominent role in the investigation of that suborder.<br />In the case of a countable language<em> L</em> and a countable domain&nbsp; <em>X</em>, it is shown that ~c&nbsp; and [<em>&rho;]__~c&nbsp;</em>are analytic sets in the Polish spaces, respectively,<em> IntL (&omega;)&times; IntL (&omega;)</em> and <em>Int_L (&omega;)</em>, and, using those results, in the case of a countable language and domain it is shown that the classes <em>[&rho;]_</em>&cong;&nbsp; and <em>[&rho;]~_c&nbsp;</em>are of the same size, and that it is a cardinals from _{{1,&omega;,c}. N}ext, the hierarchy between condensational equivalence, elementary equivalence, equimorphism (bi- embedability) and other similarities of <em>L</em>-structures, determined by some similarities of their self-embedding monoids, is investigated.<br />In the last part, the phenomenon of reversibility of<em> L</em>-structures is investigated. Strongly reversible <em>L</em>-intepretations are characterized as those whose component relations are definable by the formulae of the empty language<em> L_&empty;, </em>without quantifiers and parameters. It is shown that weakly reversible interpretations are exactly those having the property Cantor-Schrӧder-Bernstein (shorter, the property CSB) for condensations.<br />Particular emphasis is put on detecting relevant classes of reversible structures. First, the structures that are extreme elements of<em> L</em>_{&infin;&omega;}-definable classes of interpretations, under certain syntactical restrictions, are investigated. Following that, disconnected Lb-structures are investigated, where several equivalents of their reversibility are proven.</p>