As funções abrangentes e complexas de carboidratos nos sistemas biológicos oferecem muitas possibilidades para explorar essas estruturas no desenvolvimento de estratégias terapêuticas. Como consequência de sua estrutura e função, algumas glicosidases e glicosiltransferases envolvidas em patologias significativas como diabetes e doença de Chagas são alvos interessantes na busca por inibidores enzimáticos baseados em carboidratos. Assim, o conhecimento de características estruturais e mecanismo de ação de ?- e ?-glucosidases e trans-sialidases e as sólidas evidências de que glicosidases são sensíveis a efeito de multivalência sustentaram o planejamento de glycoclusters potencialmente inibidores dessas enzimas contendo três, quatro ou seis unidades correlatas aos seus substratos naturais (glicose e galactose/ácido siálico). Adicionalmente foram propostos glycoclusters baseados na estrutura do glicoaminoácido ?-GalNAc-O-Thr. Empregando reações de cicloadição CuAAC, treze dos dezesseis glycoclusters tetra- e hexavalentes inicialmente propostos foram obtidos em bons rendimentos, sendo 8 derivados de glicose, 4 de galactose e o derivado tetravalente de ácido siálico 7. Dez desses compostos são inéditos na literatura. Com a finalidade de gerar diversidade estrutural o derivado trivalente 29 foi preparado e permitiu o acoplamento de um imino-açúcar D-gluco ou L-gulo DNJ a estruturas trivalentes de glicose. A mesma estratégia levou à obtenção do glycocluster 85, contendo unidades de galactose e um resíduo de ácido siálico. Ensaios de cinética em ?-glucosidases de arroz e Saccharomyces cerevisiae e ?-glucosidase de amêndoas com os glycoclusters derivados de glicose 1-4, 9-12 e 63-66 mostraram atividade interessante apenas para os compostos mistos, evidenciando a importância do imino-açúcar para a interação com essas enzimas. No que diz respeito aos derivados multivalentes de galactose e/ou ácido siálico 5-7, 13, 14 e 85, inibição expressiva da enzima TcTS foi alcançada pelo derivado 7 (IC50 450 ?M). Ensaios de atividade tripanocida, bloqueio de invasão e citotoxicidade sobre fibroblastos de mamífero não-infectados cultivados in vitro evidenciaram atividade de todos esses compostos contra a forma amastigota e bloqueio de invasão celular por T. cruzi (diminuindo a infecção em concentrações de até 25?M). / The comprehensive and elaborate functions of carbohydrates in biological systems offer countless possibilities to apply these structures in the development of therapeutic strategies. Because of their structure and function, some glycosidases and glycosyltransferases involved in pathological conditions such as diabetes and Chagas disease are interesting targets in the search for carbohydrate-based enzyme inhibitors. Thus, the knowledge of structural features and the mechanism of action of ?- and ?-glucosidases and trans-sialidases, combined with strong evidences that glycosidases are sensitive to multivalent effect, have supported the design of substrate-based glycoclusters with potential glycosidases inhibitory properties. In addition, glycoclusters based on the structure of the ?-GalNAc-O-Thr glycoamino acid have been planned. Using CuAAC cycloaddition reactions, thirteen of the sixteen tetra- and hexavalent glycoclusters were obtained in good yields, being 8 glucose derivatives, 4 galactose, and the tetravalent sialic acid derivative 7. Ten of these compounds are unpublished. In order to generate structural diversity, the trivalent block 29 was prepared and allowed the coupling of trivalent glucose clusters to iminosugars D-gluco or L-gulo DNJ isomers. The same strategy afforded glycocluster 85, containing galactose units and a sialic acid residue. Kinetic assays in ? and ?-glucosidases with the glucose-derived glycoclusters 1-4, 9-12 and 63-66 showed interesting activity only for the heteroclusters compounds, evidencing the relevance of iminosugars for the interaction with these enzymes. Regarding galactose and/or sialic acid cluster 5-7, 13, 14 and 85, significant inhibition of the TcTS enzyme was achieved by derivative 7 (IC50 450 ?M). In vitro assays for trypanocidal activity and cytotoxicity showed good results for of all these compounds. They appear to block host cell invasion by T. cruzi (reducing infection index in concentrations up to 25?M).

TRAIL (TNF-Related Apoptosis Inducing Ligand) et CD40 Ligand, membre de la superfamille (SF) du TNF (Tumor Necrosis Factor) apparaissent comme des cibles attractives pour la thérapie ciblée du cancer. Une caractéristique commune des membres de la SF-TNF est la structure homotrimérique du ligand qui oligomérise les récepteurs pour induire la signalisation cellulaire. Cette interaction multivalente entre ligands et récepteurs est déterminante dans l’induction de la réponse cellulaire. L’objectif de cette thèse est de i) développer des ligands multivalents de TRAIL-R2 et CD40 afin d’améliorer leur efficacité anti-tumorale puis de les associer dans des stratégies anti-tumorales innovantes et ii) de caractériser les interactions entre ces ligands et les récepteurs à la surface de la cellule pour comprendre l’impact de l’oligomerisation sur l’initiation de l’apoptose au niveau membranaire.Ainsi nous avons utilisé des peptides cycliques spécifiques du récepteur de TRAIL-R2 (TRAILmim/DR5) que nous avons multimérisés sur des plateformes chimiques innovantes. Nous nous sommes également intéressés à l’état d’oligomérisation des récepteurs avant leur contact avec le ligand dans le but de mieux comprendre les interactions multivalentes. Enfin, nous avons caractérisé à l’aide de la technique de résonance plasmonique de surface et d’un biocapteur basé sur la fluorescence les interactions entre ces ligands multivalents et le récepteur TRAIL-R2. Ces travaux nous ont donc montré la nécessité d’analyser les interactions entre ligands et récepteurs directement à la surface de la cellule pour améliorer le développement de ligands pro apoptotiques efficaces. / TRAIL (TNF- Related Apoptosis Inducing Ligand) and CD40Ligand, members of the superfamily (SF) of TNF (Tumor Necrosis Factor), appear as attractive targets for cancer therapy. A common feature of members of the TNF-SF is the homotrimeric structure that oligomerized their receptors to induce cell signaling. This multivalent interaction between ligands and receptors is crucial for apoptosis induction.The aims of this thesis is to i) develop multivalent ligands of TRAIL -R2 and CD40 to enhance their antitumor efficacy and to associate them in innovative strategies and ii) to characterize the interactions between ligands and receptors at cell surface to understand the impact of oligomerization on the initiation of apoptosis at membrane level.We used cyclic peptides specific of TRAIL-R2 (TRAILmim/DR5) that we multimerized on innovative chemical scaffolds. We also interested in the state of receptor oligomerization before their contact with the ligand in order to better understand the multivalent interactions. Finally, we characterized using the technique of surface plasmon resonance and biosensor based fluorescence interactions between multivalent ligands and TRAIL- R2.In this work we showed the need to analyze the interactions between ligands and receptors directly on the surface of the cell to improve the development of effective pro -apoptotic ligands.

A型インフルエンザウイルス（IAV）は毎年流行を繰り返すインフルエンザの主要な原因ウイルスである。本研究ではIAVを構成するタンパク質の1種、ヘマグルチニン（HA）を標的とする抗IAV薬の創製し、その効果を細胞・個体レベルで検討した。また、抗IAV薬の作用機序の解析を通じて、IAV感染を制御する液胞状オルガネラを見出しており、本論文では本オルガネラの生化学的・形態的性状についても詳細に解析している。 / 博士(理学) / Doctor of Philosophy in Science / 同志社大学 / Doshisha University

No description available.

Solar DEC (Desiccant and Evaporative Cooling) air-conditioning is a renewable technological approach to the future air-conditioning of buildings driven with solar-thermal heat. The principal acceptance of solar airconditioning has led to system prototypes mainly across Europe, however the diffusion of this innovative technology is proceeding slowly due to little field testing experience. In climates with coexisting heating demand particularly, a multivalent system approach that utilizes solar-heat not only for air-conditioning but also for hot water preparation and heating has potential as a feasible concept. However, previous research focused on systems using solar heat exclusively for the DEC-process. This research contributes to the advancement of the solar DEC-technology with multivalent use of solar thermal heat. The investigation consists of an initial detailed in-situ monitoring analysis of a system prototype operated in an industrial environment, followed by the development of optimised system concepts and a climate-specific analysis of the solar DEC-technology. The monitoring provided in-depth knowledge about the system operation, revealing the reasons for the insufficient refrigeration capacity achieved in practice. A detailed simulation model for an entire multivalent solar DEC-system including the heat sinks, DEC-system, heating and hot-water preparation was developed and a DEC-control strategy has been formulated. A new optimised control strategy for multivalent systems with simultaneous sink supply concept was devised. A sensitivity analysis was carried out to investigate the key design parameters for the dimensioning of multivalent solar DEC-systems. The research concluded that the auxiliary primary energy consumption of the optimised system was lower by one third compared to the initial system. Finally, a methodological zoning approach was developed, to systematically produce design-specific outline data for the application of the solar DEC-technology at climatically different sites.

The main object of this thesis is to obtain numerous applications of fractional derivative operator concerning analytic and ρ-valent (or multivalent) functions in the open unit disk by introducing new classes and deriving new properties. Our finding will provide interesting new results and indicate extensions of a number of known results. In this thesis we investigate a wide class of problems. First, by making use of certain fractional derivative operator, we define various new classes of ρ-valent functions with negative coefficients in the open unit disk such as classes of ρ-valent starlike functions involving results of (Owa, 1985a), classes of ρ-valent starlike and convex functions involving the Hadamard product (or convolution) and classes of κ-uniformly ρ-valent starlike and convex functions, in obtaining, coefficient estimates, distortion properties, extreme points, closure theorems, modified Hadmard products and inclusion properties. Also, we obtain radii of convexity, starlikeness and close-to-convexity for functions belonging to those classes. Moreover, we derive several new sufficient conditions for starlikeness and convexity of the fractional derivative operator by using certain results of (Owa, 1985a), convolution, Jack's lemma and Nunokakawa' Lemma. In addition, we obtain coefficient bounds for the functional |α_ρ+2-θα²_ρ+1| of functions belonging to certain classes of p-valent functions of complex order which generalized the concepts of starlike, Bazilevič and non-Bazilevič functions. We use the method of differential subordination and superordination for analytic functions in the open unit disk in order to derive various new subordination, superordination and sandwich results involving the fractional derivative operator. Finally, we obtain some new strong differential subordination, superordination, sandwich results for ρ-valent functions associated with the fractional derivative operator by investigating appropriate classes of admissible functions. First order linear strong differential subordination properties are studied. Further results including strong differential subordination and superordination based on the fact that the coefficients of the functions associated with the fractional derivative operator are not constants but complex-valued functions are also studied.

Das Influenza A Virus (IAV) stellt weltweit eine ernstzunehmende Bedrohung für Gesundheit und Wirtschaft der Menschheit dar. Ein universeller und langanhaltender Impfstoff konnte noch nicht entwickelt werden und klinisch zugelassene Medikamente verlieren durch die rasante Entstehung von resistenten Stämmen zunehmend ihre Wirkung. Aus diesem Grund gewinnt die Erforschung neuer antiviraler Strategien zur Bekämpfung des Influenzavirus an Bedeutung zum Schutze unserer Gesellschaft. Eine vielversprechende Zielstruktur für die Entwicklung neuer antiviraler Medikamente stellt das virale Hämagglutinin (HA) dar. Das HA liegt in hoher Dichte auf Influenzaviren vor und ermöglicht die Bindung an Sialinsäuren (SA) auf Wirtszellen und die Verschmelzung mit deren Lipidmembran. HA-bindende Moleküle entfalten eine hemmende Wirkung bereits bei dem ersten Kontakt mit Zellen, sodass eine Infektion erst gar nicht stattfinden kann. Aufgrund einer hohen HA-Dichte auf der Virusoberfläche eignen sich besonders multivalente SA tragende Nanopartikel für die Hemmung einer viralen Infektion. Aufbauend auf diesen Erkenntnissen, wurden in der vorliegenden Arbeit neue multivalente Binder gegenüber dem viralen Hämagglutinin (HA) entwickelt und studiert. Im Gegensatz zu bereits bekannten multivalenten Sialosiden, die in einer undefinierten räumlichen Orientierung auf Polymergerüsten präsentiert wurden, konnten in der vorliegenden Arbeit strukturelle Aspekte identifiziert werden, um Gerüstsysteme mit optimaler Rezeptorpräsentation gegenüber der Influenza A Virusoberfläche zu generieren. Neben SA-basierten Polymersystemen wurde auch ein gegen HA gerichtetes Peptid aus einem Antikörper identifiziert, welches sich auch für eine multivalente Interaktion mit IAV eignet. Diese Arbeit ermöglicht neue Einblicke in die Auswahl geeigneter Trägersysteme, eines optimalen Rezeptorabstandes und der Verwendung alternativer Rezeptoren mit dem Ziel einer Infektionshemmung von IAV. / Influenza A virus (IAV) still poses a serious threat to global health and economy of mankind. So far, a universal, long-lasting vaccine could not be developed, and clinically approved drugs are prone to lose activity due to the fast development of resistant strains. Because of this, research on new antiviral compounds and strategies to combat influenza viruses is of great importance for the protection of our society. A promising candidate for the development of novel antiviral drugs is the viral hemagglutinin (HA) protein. HA is present at high density on the viral envelope, which allows binding to sialic acid (SA) molecules on host cells and fusion with their membrane. Following, HA binding molecules have an inhibitory effect at the very first step of the infection cycle, leading to the inability of an infection. Based on a high HA density on the viral surface, SA carrying nanoparticles qualify for the inhibition of a viral infection. Based on this knowledge the study at hand demonstrates the development of new multivalent binders against viral HA and discusses them critically. In contrast to published multivalent sialosides, which are displayed in an undefined fashion on polymer scaffolds, the results of this thesis support the identification of structural requirements for the design of new scaffold systems with an optimal match to the viral surface. Beside sialoside based polymer systems, completely new peptide based systems, based on an HA binding antibody, were developed. Similar to polyglycerolsialosides, such multivalent peptide-decorated polymers were able to achieve nanomolar binding inhibition constants, too. In summary, this thesis enables new insights into the choice of a suitable carrier system, the optimal receptor spacing, and the use of alternative receptors with the ultimate goal of virus neutralization.

Este trabalho aborda analiticamente o Trio em fá sustenido menor (1916) do compositor brasileiro Alberto Nepomuceno, com objetivo de constituir um estudo de caso que permita um melhor posicionamento da obra do compositor no período de transição entre o romantismo e o modernismo brasileiros. Ele levanta dados do contexto ideológico-musical no qual se insere a obra, em especial das noções francesas de progresso e suas consequências musicais no início do século XX. A pesquisa apresenta também os fundamentos teóricos de uma proposta analítica que visa incorporar à análise estrutural os desdobramentos do significado musical. Ela procura unir, por meio do conceito de multivalência, os estudos das tópicas, dos esquemas, da narratividade e da intertextualidade. O trabalho apresenta quatro análises multivalentes, uma para cada movimento da obra. Os resultados apontam para uma obra que se constitui em uma rede de símbolos musicais introversivos e extroversivos, que faz um equilíbrio entre a tradição formal e expressiva e o uso de novos materiais sonoros. / This work analyzes the Piano Trio in F sharp minor by the Brazilian composer Alberto Nepomuceno, aiming to constitute a case study that allows a better positioning of the composer\'s work in the period of transition between Brazilian romanticism and modernism. It raises data from the ideological-musical context in which the work is inserted, especially the French notions of progress and its musical consequences in the early twentieth century. The research also presents the theoretical foundations of an analytical proposal that aims to incorporate into the structural analysis the unfolding of musical meaning. It seeks to unite, through the concept of multivalence, the studies of topics, schemata, narrativity and intertextuality. The work presents four multivalent analysis, one for each movement of the work. The results point to a work that constitutes a network of introversive and extroversive musical symbols, which makes a balance between formal and expressive tradition and the use of new sound materials.

Este trabalho aborda analiticamente o Trio em fá sustenido menor (1916) do compositor brasileiro Alberto Nepomuceno, com objetivo de constituir um estudo de caso que permita um melhor posicionamento da obra do compositor no período de transição entre o romantismo e o modernismo brasileiros. Ele levanta dados do contexto ideológico-musical no qual se insere a obra, em especial das noções francesas de progresso e suas consequências musicais no início do século XX. A pesquisa apresenta também os fundamentos teóricos de uma proposta analítica que visa incorporar à análise estrutural os desdobramentos do significado musical. Ela procura unir, por meio do conceito de multivalência, os estudos das tópicas, dos esquemas, da narratividade e da intertextualidade. O trabalho apresenta quatro análises multivalentes, uma para cada movimento da obra. Os resultados apontam para uma obra que se constitui em uma rede de símbolos musicais introversivos e extroversivos, que faz um equilíbrio entre a tradição formal e expressiva e o uso de novos materiais sonoros. / This work analyzes the Piano Trio in F sharp minor by the Brazilian composer Alberto Nepomuceno, aiming to constitute a case study that allows a better positioning of the composer\'s work in the period of transition between Brazilian romanticism and modernism. It raises data from the ideological-musical context in which the work is inserted, especially the French notions of progress and its musical consequences in the early twentieth century. The research also presents the theoretical foundations of an analytical proposal that aims to incorporate into the structural analysis the unfolding of musical meaning. It seeks to unite, through the concept of multivalence, the studies of topics, schemata, narrativity and intertextuality. The work presents four multivalent analysis, one for each movement of the work. The results point to a work that constitutes a network of introversive and extroversive musical symbols, which makes a balance between formal and expressive tradition and the use of new sound materials.

This thesis focuses on the design, synthesis and development of dynamic multivalent nanostructures such as supramolecular dendrimers, liposomes and gold-functionalized nanostructures. These structures can be used for drug delivery and molecular sensing applications. This thesis is divided into three parts: In part one, a general introduction to self-assembly, dynamic systems, metalligand exchange, nanostructured dendritic scaffolds, liposomes and gold nanostructures is given. In part two, a microwave approach is presented as an efficient method for the regioselective deuteration of bipyridine scaffolds. Dynamic systems based on transition metal-bipyridine coordination complexes were investigated. The compositional self-adaptation and kinetics of these dynamic systems were successfully assessed by ESI-MS. Based on this amphiphilic dendrimers/metallodendrimers were also designed and synthesized via  a convergent strategy. Their ability to self-assemble into supramolecular assemblies and their controlled disassembly was effectively demonstrated. In part three, two types of drug delivery systems based on dynamic multivalent nanostructures of glycodendrimers/metalloglycodendrimers and drugpresenting liposomes were developed. The dynamic self-assembly of these architectures into supramolecular nanostructures with site-specific functionality through interacting carbohydrate or cholesterol moieties was assessed. The host-guest interaction/encapsulation and controlled release with external stimuli were studied using a fluorescent probe, as well as selected drug molecules. The antibacterial property of the drug delivery systems was also evaluated, demonstrating an enhanced bactericidal activity. A new, rapid and simple approach for the functionalization of plasmonic gold nanostructured surfaces was also developed. The optical performance and light-specific sensitivity of the fluorescent probe on the resulting nanostructures were also presented. / <p>QC 20151119</p>