Dans cette thèse nous avons étudié quatre aspects fondamentaux de l’interaction ADN-protéine, notamment : l’affinité, la spécificité, l’accessibilité et la cinétique. En particulier, nous avons adressé les questions suivantes : comment un dimer du facteur de transcription NF-kB reconnait spécifiquement sa séquence d’ADN-cible, quelle est la rapidité de ces interactions, comment NF-kB interagit avec son site de fixation dans le contexte de la chromatine? Récemment, la spécificité de l’interaction NF-kB – ADN a reçu une attention particulière après l’observation que NF-kB peut se lier à des séquences qui n’entrent pas dans la classification de ses motifs « consensus ». Nous avons étudié la spécificité d’interaction de sept de ces motifs avec quatre dimers de NF-kB. Nos résultats montrent que le homo-dimer p50 sont les moins discriminatives et peuvent s’associer spécifiquement avec ces sept séquences. Par contre, les homo-dimers RelA se sont révélés hautement discriminatives ne pouvant pas s’associer spécifiquement avec ces séquences. Pour mesurer l’affinité de l’interaction nous avons utilisés deux méthodes distinctes : le traditionnel gel de retard (EMSA) et une nouvelle technique – « l’empreinte » au laser UV. Nos résultats montrent que le deuxième approche est plus approprié pour la mesure des constantes spécifiques de dissociation.Pour étudier la dynamique de l’interaction NF-kB – ADN, nous avons couplé l’empreinte au laser UV avec un appareil de mélange-rapide à façon. Cette combinaison nous a permis d’atteindre une résolution spatiale d’un nucléotide et temporaire de quelques millisecondes. Nous avons montré que l’homo-dimer p50 s’associe avec sa séquence-cible (MHC) H2 en suivant une cinétique à 2 pas. Le premier, de durée ~100 ms, reflète une reconnaissance initiale rapide, tandis que le deuxième, de durée ~1s, reflète une stabilisation lente du complexe. Nos expériences suggèrent aussi que les séquences voisines du site de reconnaissance jouent aussi un rôle dans la stabilisation du complexe.Finalement, nous avons étudié aussi l’accessibilité du nucléosome pour le NF-kB. Nos données in vitro montre que l’invasion spécifique de l’ADN à l’intérieure du nucléosome par NF-kB nécessite une perturbation majeure de la structure du nucléosome telle que l’éviction d’au moins un dimer d’histones H2A-H2B. / In this thesis we have attempted to study four basic aspects of DNA-protein interactions: Affinity, specificity, accessibility and kinetics. With NF-kB as our model transcription factor, we wanted to investigate how a particular dimer recognizes a specific binding sequence? How fast are these interactions? And finally, how does the NF-kB interact with it binding site in the chromatin context? Specificity of NF-kB-DNA interactions has recently come into focus after it was shown that these dimers can bind to the sequences which do not fall into the NF-kB general consensus motif. We studied seven such sequences for their specificity for four NF-kB dimers. Our results show that p50 homodimers are least discriminative and can bind specifically to all these sequences. While as, RelA homodimers were highly discriminative and did not bind to most of these nontraditional sequences. We used two different methods to measure binding affinities: traditional gel mobility shift assay (EMSA) and a novel technique called as UV laser footprinting. Our results show that UV laser footprinting is the better method to determine the binding constants.For studying the dynamics of NF-kB-DNA binding, we combined UV laser footprinting with stopped flow device. This combination, not only give us one base pair resolution but also milli-second time resolution. Using p50 homodimers as a model transcription factor, we showed that the binding of this factor follows a two-step mechanism. First step involves the fast recognition of the sequence and second step follows a slower kinetics most likely for the stabilization of the complex. Our experiments suggest that flanking sequences play a role in the recognition and stabilization process of the complex formation.Finally, we also studied the accessibility of nucleosomes to NF-kB. Our in vitro data sheds light on the in vivo requirements for the alterations in chromatin structure necessary for the productive binding of NF-kB. These include either a removal of H2A-H2B dimers from the nucleosome and/or chromatin remodeler induced relocation of the histone octamer.Our data sheds light on the in vivo requirements for the alterations in chromatin structure necessary for the productive binding of NF-kB. We hypothesize that some factors like PU.1 might be able to target the chromatin remodeling/dimer eviction machinery to particular nucleosomes and lead to productive binding of NF-kB.

Depuis plusieurs décennies, la fonctionnalisation directe de liens C-H représente une approche très étudiée par les chimistes puisque ces liaisons sont omniprésentes dans les substances organiques. Ainsi, en considérant la liaison C-H comme une fonctionnalité, une nouvelle ère a débuté dans le domaine de la synthèse organique avec de nouvelles opportunités intéressantes. Elles évitent la manipulation de groupements fonctionnels et permettent ainsi de développer de nouvelles voies de synthèse économiques en atomes et comportant le minimum d’étapes. Dans cette perspective, notre groupe de recherche a développé, il y a quelques années, une nouvelle méthodologie d’amination intramoléculaire de liaisons C-H qui utilisent les N-sulfonyloxycarbamates comme précurseurs de nitrènes métalliques. Ces derniers, en présence d’une base et d’un dimère de rhodium (II) tétracarboxylate sont capables de réaliser l’insertion efficace dans les liens de type C(sp3)-H pour former des carbamates cycliques à cinq chaînons, les oxazolidin-2-ones. Les travaux de cette thèse se sont, tout d’abord, attachés à l’élargissement de l’étendue réactionnelle de la méthodologie de C-H amination intramoléculaire, développée par Laura Mamani Laparra, une ancienne membre de notre groupe, à partir des N-mésyloxycarbamates dérivés d’alcools primaires. De nouvelles conditions réactionnelles ont pu être développées pour les substrats capricieux et qui ont mis en lumière une nouvelle base organique soluble, l’éthylhexanoate de sodium. Par la suite, une version diastéréosélective de la réaction d’amination intramoléculaire à partir des N-mésyloxycarbamates secondaires et tertiaires a pu être développée. Les oxazolidin-2-ones 4,5-disbustituées ont été obtenues avec des rendements allant de bons à excellents et des sélectivités variables. Puis, des efforts ont été déployés pour le développement d’une version énantiosélective de la réaction étudiée. Une optimisation a permis d’atteindre de bonnes réactivité et sélectivité. Enfin, l’auteure de cette thèse a tenté de déterminer les mécanismes réactionnels impliqués lors de ce processus catalytique. Elle a ainsi pu montrer que l’espèce réactive du système catalytique était une espèce nitrène métallique. Des études cinétiques ont montré que l’étape cinétiquement déterminante était l’étape d’insertion du nitrène de rhodium dans le lien C-H. De plus, une courte étude des réactions secondaires parallèles à l’amination de lien C-H a été aussi réalisée ce qui a permis de postuler des mécanismes pour la formation de sous-produits ainsi que la dégradation des catalyseurs. / The direct functionalization of C-H bonds is a very promising synthetic approach since these bonds are ubiquitous in organic substances. Thus, considering the C-H bond as a functional group, a new era began in the field of organic synthesis with new interesting opportunities, which avoid the manipulation of functional groups and thus making it possible to develop new atom and steps economic synthetic routes. In this perspective, our research group has developed, several years ago, a new methodology of intramolecular C-H amination using the N-sulfonyloxycarbamates as novel nitrene precursors. The latter, in the presence of a base and a rhodium dimer (II) tetracarboxylate are able to achieve the effective insertion into an C(sp3)-H bond to form oxazolidin-2-ones as a 5-membered carbamate heterocycles. The present work was, first, attached to the enlargement of the scope of the intramolecular C-H amination methodology, developed by Laura Laparra Mamani, a former member of our group starting from N-mésyloxycarbamates derived from primary alcohols. New reaction conditions have been developed for capricious substrates and highlighted a new soluble organic base, sodium ethylhexanoate. Subsequently, an intramolecular diastereoselective C-H amination reaction starting from secondary and tertiary N-mésyloxycarbamates have been developed. The 4,5-disbustituted oxazolidin-2-ones were obtained with yields ranging from good to excellent and variable selectivities. Furthermore, efforts have been made to the development of an enantioselective version of the reaction. Oriented optimization has led to good reactivity and selectivity. Finally, the author of this thesis has attempted to determine the mechanisms involved in this catalytic process. She was able to show that the catalytically reactive specie was a metal nitrène and that the rate-determining step was the insertion step of rhodium nitrene into the C-H bond. In addition, a brief study of secondary parallel reactions to the C-H amination was also performed which allowed proposing mechanisms for the formation of byproducts and catalyst degradation.

Dendrimers are hyperbranched macromolecules, with branches-upon-branches architectures, precise constitutions and molecular weights of several kiloDaltons (Figure 1). The dendritic structure remains to be an influential feature in the developments of dendrimer chemistry at large. Organometallic catalysis forms an active area, wherein the dendrimers find a defined importance. A number of dendrimer types have been utilized to study organometallic catalysis that combine the dendritic architectural principles. Chapter 1 of the Thesis summarizes the advances in the dendrimer-mediated catalyses, apart from an overview of the methods adopted to synthesize dendrimers. Chapter 2 describes the synthesis of newer types of larger generation poly(propyl ether imine) (PETIM) dendrimers. The molecular structure of a sixth generation PETIM dendrimer is shown in Figure 2. The PETIM series of dendrimers are synthesized by iterative synthetic cycles of two reductions and two Michael addition reactions. Modifications of the synthetic methods were identified, so as to facilitate the synthesis and purification of the higher generation dendrimers. Formation of the PETIM dendrimers, possessing a tertiary amine as the branch juncture and ether as the linker component, is assessed systematically by routine analytical techniques. The peripheries of these dendrimers possess either alcohols or amines or carboxylic acids or esters or nitriles, thereby opening up possibilities for varied studies. Architecturally-driven effects are searched constantly while integrating dendrimers in wide ranging studies. With knowledge that un-functionalized PAMAM and PPI dendrimers show fluorescence properties, we tested the PETIM dendrimers for their luminescence property. The photophysical properties of PETIM dendrimers presenting esters, alcohols, acid salts, nitriles and amines at their peripheries were studied. The anomalous fluorescence arising from alcohol terminated PETIM dendrimers (Figure 3) was established through a series of experiments. Various experimental parameters including pH, viscosity of the solvents, aging, temperature and concentration were used to assess the photochemical properties of the PETIM dendrimers. It was observed that generations 1 to 5 absorbed in the region of 260-340 nm, in MeOH and in aqueous solutions. Excitation of the OH-terminated dendrimer solutions at 330 nm led to an emission at ~390 nm (Figure 4). Dendrimers presenting esters, acid salts and amines at their peripheries also exhibited a similar excitation and emission wavelengths. An increase in the fluorescence intensity was observed at low pH and with more viscous solvents. Lifetime measurements showed at least two species (~2.5 and ~7.0 ns) were responsible for the emission. The quenching of the fluorescence originating from the PETIM dendrimers by inorganic anions was also established in the present study. The periodate, persulfate, perchlorate and nitrite anions quenched the fluorescence efficiently among several anions tested. An ‘oxygen-interacted moiety’, in addition to altered hydrogen bonding properties of the dendrimers, was presumed contribute to the anomalous fluorescence behavior. Chapter 3 of the Thesis elaborates photophysical studies of several PETIM dendrimers. Incorporation of catalytically active moieties at the peripheries of dendrimers was identified as an important avenue, in order to explore the effect of the dendritic architectures on the catalytic activities of chosen catalytic moieties. In order to assess the effect of the dendritic scaffold, in relation to both numbers and locations of the catalytic units, an effort was undertaken to study the catalytic activities of catalytic units, that are present in varying numbers within one generation. Partial and full phosphine-metal complex substituted three generations of dendritic catalysts were synthesized, by using a selective alkylation as a key step. The number of the primary amine groups led to define the number of phosphine groups at the peripheries. The primary amine groups were, in turn, prepared by a Michael addition of acrylonitrile and hydroxyl groups, followed by a reduction of the nitrile moieties to the corresponding amines. The first and the second generation PETIM dendrimers utilized in this study present up to four and eight hydroxyl groups at their peripheries. A partial etherification was exercised in order to mask few hydroxyl groups, useful to prepare the partially substituted phosphine groups. Subsequent Michael addition of acrylonitrile with remaining hydroxyl groups, to afford the nitrile terminated dendrimers, and a metal-mediated reduction of the nitrile to amine led to the required number of amine functionalized dendrimers. Functionalization of the peripheries with alkyldiphenyl phosphine moieties was conducted through a Mannich reaction of the amines with formaldehyde and diphenyl phosphine. The subsequent metal complexation with Pd(COD)Cl2 afforded a series of phosphine-Pd(II) complexes, for the zero, first and second generation PETIM dendrimers. Figure 5 shows the molecular structures of a partially and a fully substituted second generation dendrimer. Catalytic activities of the dendrimer-Pd(II) complexes were assessed in both Heck and Suzuki coupling reactions. A C-C bond forming reactions were studied, with the series of dendritic-Pd(II) catalysts, using Cs2CO3 as a base and at 40 oC. In an overall observation, it was found that an individual catalytic site showed a considerable increase in the catalytic activity when it was present in multiple numbers than as a single unit within the same generation (Figure 6). Figure 6. Bar diagrams of (a) Heck reaction and (b) Suzuki reaction, employing the dendritic catalysts 1 - 11. The Heck coupling reaction involved tert-butyl acrylate and iodobenzene, and the Suzuki coupling reaction involved phenyl boronic acid and iodobenzene. The observations revealed that: (i) the higher generation dendritic catalysts exhibited higher catalytic activities per catalytic site and (ii) the dendritic scaffold has a role in enhancing the activities of the individual catalytic sites. The catalysis study identified the catalytic activities that occurred when a series of catalysts within a given dendrimer generation was used. Such a study is hitherto unknown and the observations of this study address some of the pertinent queries relating to the efficiencies of multivalent dendritic catalysts. Chapter 4 of the Thesis describes the synthesis and characterization of series of organometallic PETIM dendrimer and studies of their catalytic activities. Studies on solid-supported catalysis present a significant importance in heterogeneous organometallic catalysis. Silica is a prominently utilized heterogeneous metal catalyst support. Functionalization of the solid supports with suitable chelating ligands is emerging as a viable strategy to circumvent not only the pertinent metal catalyst deterioration and leaching limitations, but also to stabilize the metal particles and to adjust their catalytic efficiencies. In exploring heterogeneous organometallic catalysis, functionalization of silica with a first generation phosphinated dendritic amine was undertaken. The synthetic scheme adopted to synthesize dendrimer functionalized silica is shown in Scheme 1. The reaction of the chloropropylated silica 4 with amine 3 was conducted in CHCl3. Complexation of the functionalized silica 5 with Pd(COD)Cl2 led to isolation of Pd(II)- impregnated silica. Scheme 1. Preparation of Pd nanoparticles stabilized by functionalized silica. It was anticipated that the ratio of phosphine to Pd(II) would be 1:0.5, resulting from a bidendate binding of the phosphine ligand to Pd metal. The observed ICP-OES result indicated that all phosphine ligands did not chelate the metal. With the desire to obtain the metal nanoparticles, the metal complex was subjected to a reduction, which was performed by conditioning 5-Pd(II) complex in EtOH. The Pd metal nanoparticle thus formed was characterized by physical methods, and the spherical nanoparticles were found to have >85 % size distribution between 2-4 nm (Figure 7). Analyses of the Pd(0) impregnated in dendrimer functionalized silica were performed using NMR, XPS spectroscopies, elemental analysis and microscopies. Figure 7. Transmission electron micrograph and histogram of 6, obtained after treatment with EtOH. The Pd-nanoparticle stabilized silica was used in the hydrogenation of several α, β-unsaturated olefins. The catalyst recycling experiments were conducted more than 10 times, and no loss in the catalytic activities were observed. Chapter 5 describes the functionalization of the silica support with diphenylphosphinomethyl-derivatized dendritic amine, palladium nanoparticle formation and the catalysis studies. Overall, the Thesis establishes the synthesis of larger generation PETIM dendrimers, studies of their anomalous fluorescence behavior, organometallic catalysis in solution, as well as, in heterogeneous conditions, pertaining to the C-C bond forming reactions and hydrogenation reactions. (For figure, graph and structural formula pl see the pdf file)

Herkömmliche Zytostatika greifen vornehmlich in den Zellzyklus ein und somit werden Zellen mit hoher Proliferationsrate geschädigt. Allerdings fallen hierunter nicht ausschließlich Krebszellen, sondern auch gesunde, schnell proliferierende Gewebearten. Auf Grund dessen verursacht eine klassische Chemotherapie schwerwiegende Nebenwirkungen. Neuere Therapieansätze greifen daher geno- sowie phänotypischer Unterschiede zwischen malignen und gesunden Zellpopulationen auf und können selektiv den zytotoxischen Wirkstoff in die Tumorpopulation einbringen. Dazu werden sogenannte Prodrug-Konzepte verfolgt, bei denen ein möglichst „untoxisches” Prodrug gezielt im entarteten Gewebe enzymatisch zum zytotoxischen Wirkstoff (Drug) aktiviert wird. In diesem Rahmen werden Substrate für die Antibody-Directed Enzyme Prodrug Therapy (ADEPT) hergestellt. Bei diesem Konzept wird eine hohe Tumorspezifität durch Konjugate aus Enzymen und Antikörpern erlangt, indem das Immunglobulin selektiv an tumorassoziierte Antigene bindet und durch das konjugierte Enzym die Drugfreisetzung ermöglicht wird. Die natürlichen zytotoxischen Antibiotika (+)-CC 1065 und (+)-Duocarmycin SA dienen hierbei als Leitstrukturen für die Synthese entsprechender Prodrugs. Im Rahmen der vorliegenden Arbeit wurden insgesamt zwei neue Duocarmycin-analoge Prodrugs sowie neun neue seco-Drugs synthetisiert, wobei vier Vertreter eine terminale Alkinfunktion aufweisen. Für die Darstellung der Prodrugs wurden auf die Galaktose als Glykosideinheit zurückgegriffen. Zudem wurde ein neuartiges dimeres seco Drug hergestellt, das aus zwei pharmakophoren Einheiten sowie einem verbrückenden Linker mit Alkineinheit besteht. Die jeweiligen Substanzen wurden auf ihre In-vitro-Zytotoxizitäten sowie die Eignung für eine Anwendung im ADEPT-Ansatz evaluiert. Neun der neuen Duocarmycin-Analoga wurden in Form von seco- und Prodrugs wurden im Rahmen des aktivitätsbasierten Protein-Profilings untersucht. Hierbei konnte die Aldehyddehydrogenase 1 als wichtiges Angriffsziel der Duocarmycin-Familie verifiziert werden.

Submitted by Pedro Silva Filho (pfsilva@ipen.br) on 2017-11-23T12:28:11Z No. of bitstreams: 0 / Made available in DSpace on 2017-11-23T12:28:12Z (GMT). No. of bitstreams: 0 / A Organização Mundial da Saúde (OMS) relata o câncer como uma das principais causas de morte no mundo. O câncer de próstata é o segundo tipo de câncer mais prevalente em homens, com cerca de 1,1 milhão de casos diagnosticados em 2012. Braquiterapia com iodo-125 é uma método de radioterapia que consiste na introdução de sementes com material radioativo no interior do órgão a ser tratado. As sementes de iodo-125 podem ser inseridas soltas ou em cordas poliméricas bioabsorvíveis, mais comumente o poli(ácido lático-co-ácido glicólico) (PLGA). A função do polímero é reduzir a possibilidade de migração das sementes, o que poderia ser prejudicial para órgãos e tecidos saudáveis. De modo a reduzir os custos do tratamento, a síntese dos dímeros L-lactídeo e glicolídeo, para posterior utilização para preparação do PLGA, por meio da polimerização por abertura de anel, é proposta neste trabalho. Adicionalmente, propõe-se a utilização do amino-alcóxido tris(fenolato) de zircônio (IV) como alternativa ao usual octanoato de estanho (SnOct2), uma vez que a toxicidade do estanho permanece como obstáculo na produção do PLGA para aplicações biomédicas. Embora o iniciador de zircônio seja mais lento do que o SnOct2, massas molares relativamente elevadas foram obtidas quando razões monômero/iniciador (M/I) de 1000/1 (24 h), e 5000/1 (48 h) foram utilizadas. Considerando que as unidades glicolila (GA) são mais reativas do que as unidades lactila (LA), tempos longos de reação são necessários para atingir uma razão LA/GA próxima do objetivo do trabalho (85/15). O grau de racemização também depende do iniciador utilizado. As reações de polimerização realizadas com o iniciador de zircônio mostraram um maior grau de racemização, quando comparadas com aquelas realizadas com o SnOct2. Também foi observado um ligeiro aumento na racemização com o tempo. Considerando os resultados obtidos na síntese e purificação dos dímeros, e na síntese do PLGA em condições semelhantes às industriais, foi possível preparar o polímero de alta massa molar com um custo dezenas de vezes inferior ao custo do PLGA no mercado internacional. Os efeitos da radiação gama no PLGA também foram estudados. Doses normalmente aplicadas para esterilizar materiais para aplicações biomédicas foram empregadas: 10, 18, 25 e 50 kGy. A massa molar de todas as amostras irradiadas diminuiu de uma forma proporcional à dose até 56% de perda para 10 kGy e 72% para 50 kGy porém, são menos pronunciadas para doses mais elevadas. Alterações nas propriedades térmicas, tais como temperatura de fusão, temperatura de transição vítrea e a entalpia de cristalização e fusão foram também observadas após a irradiação. / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP

Strong light matter interactions in metallic nanoparticles (NPs), especially those made of noble metals such as Gold and Silver is at the heart of much ongoing research in nanoplasmonics. Individual NPs can support collective excitations (Plasmon’s) of the electron plasma at certain wavelengths, known as the localized surface Plasmon resonance (LSPR) which provides a powerful platform for various sensing, imaging and therapeutic applications. For a collection of NPs their optical properties can be signify cannily different from isolated particles, an effect which originates in the electromagnetic interactions between the localised Plasmon modes. An interesting aspect of such interactions is their strong dependence on the geometry of NP collection and accordingly new optical properties can arise. While this problem has been well considered in one and two dimensions with periodic as well as with random arrays of NPs, three dimensional systems are yet to be fully explored. In particular, there are challenges in the successful de-sign and fabrication of three dimensional (3D) plasmonic metamaterials at optical frequencies. In the work presented in this thesis we present a detail investigation of the theoretical and experimental aspects of plasmonic interactions in two geometrically different three dimensional plasmonic nanostructured systems - a chiral system consisting of achiral plasmonic nanoparticles arranged in a helical geometry and an achiral system consisting of achiral plasmonic nanoparticle arrays stacked vertically into three dimensional geometry. The helical arrangement of achiral plasmonic nanoparticles were realised using a wafer scale technique known as Glancing Angle Deposition (GLAD). The measured chiro-optical response which arises solely from the interactions of the individual achiral plasmonic NPs was found to be one of the largest reported value in the visible. Semi analytical calculation based on couple dipole approximation was able to model the experimental chiro-optical response including all the variabilities present in the experimental system. Various strategies based on antiparticle spacing, oriented elliptical nanoparticles, dielectric constant value of the dielectric template were explored such as to engineer a strong and tunable chiro-optical response. A key point of the experimental system despite the presence of variabilities, was that the measured chiro-optical response showed less than 10 % variability along the sample surface. Additionally we could exploit the strong near held interactions of the plasmonic nanoparticles to achieve a strongly nonlinear circular differential response of two photon photoluminescent from the helically arranged nanoparticles. In addition to these plasmonic chiral systems, our study also includes investigation of light matter interactions in purely dielectric chiral systems of solid and core shell helical geometry. The chiro-optical response was found to be similar for both the systems and depend strongly on their helical geometry. A core-shell helical geometry provides an easy route for tuning the chiro-optical response over the entire visible and near IR range by simply changing the shell thickness as well as shell material. The measured response of the samples was found to be very large and very uniform over the sample surface. Since the material system is based entirely on dielectrics, losses are minimal and hence could possibly serve as an alternative to conventional plasmonic chiro-optical materials. Finally we demonstrated the used of an achiral three dimensional plasmonic nanostructure as a SERS (surface enhance Raman spectroscopy) substrate. The structure consisted of porous 3D metallic NP arrays that are held in place by dielectric rods. For practically important applications, the enhancement factor, as well as the spatial density of the metallic NPs within the laser illumination volume, arranged in a porous 3D array needs to be large, such that any molecule in the vicinity of the metal NP gives rise to an enhanced Raman signal. Having a large number of metallic NPs within the laser illumination volume, increases the probability of a target molecule to come in the vicinity of the metal NPs. This has been achieved in the structures reported here, where high enhancement factor (EF) in conjunction with large surface area available in a three dimensional structure, makes the 3D NP arrays attractive candidates as SERS substrates.

Les propriétés optiques et vibrationnelles de nanoparticules métalliques individuelles ont été étudiées par spectroscopie par modulation spatiale (SMS), avec une attention particulière aux effets de forme, composition, environnement local, ainsi que de couplage inter-particule. La réponse optique de nanoparticules (métalliques au cœur-couronne métal-diélectrique) allongées et des particules bimétalliques (hétérodimères or-argent) a été mesuré et en suite interprétée grâce à une corrélation avec la caractérisation morphologique de la même particule obtenue par microscopie à transmission électronique et avec des simulations par éléments finis prenants en compte la réelle géométrie du nano-objet et le substrat. Une technique pompe sonde résolue en temps a été en suite utilisée pour étudier le profil Fano dans l'absorption d'une particule d'or au sein d'un hétérodimères or-argent. Sur une échelle de temps des quelques dizaines de picosecondes, les vibrations acoustiques multimodales de nanobipyramides d'or individuelles ont été optiquement détectées et caractérisées par rapport à un modèle élastique classique / Optical and vibrational properties of individual metal-based nanoparticles have been investigated by spatial modulation spectroscopy (SMS), focusing on their dependence on nano-object shape, composition, environment and inter-particle coupling. Quantitative investigations of the optical response, and in particular, the surface plasmon resonance (extinction cross-section amplitude, spectral position and linewidth) of elongated metal or metal-dielectric (gold nanorods, nanobipyramids with or without silica coating) and bimetallic (gold-silver heterodimers) nanoparticles deposited on a substrate have first been performed. The same nanoparticles were characterized by electron microscopy permitting quantitative interpretation of their optical response using finite element numerical simulations, taking into account the influence of the substrate. Combining SMS microscopy with a high sensitivity femtosecond two-color pump-probe setup, the ultrafast dynamics of single nano-objects has been investigated. The Fano absorption profile of a gold nanoparticle within a single gold-silver heterodimer, a parameter not accessible by linear spectroscopy, was directly measured. On a picosecond time-scale, multimodal acoustic vibrations of single gold nanobipyramids were optically lunched and detected, and their features compared to a model based on continuum elasticity

L'étude systématique de l'hémostase post-thrombolytique a été peu étudiée. Chez 80 malades thrombolysés consécutifs, une étude prospective a comporté l'étude – aux heures 0, 2 et 24 – des facteurs de l'hémostase suivants: fibrinogène, plasminogène, PDF (produits de dégradation de la fibrine et du fibrinogène), D-dimères, alpha2-antiplasmine et facteur XIII, ainsi que l'hématocrite et la numération plaquettaire. Des calculs statistiques approfondis ont exploré les corrélations des variations des facteurs hémostatiques entre eux et avec 37 paramètres cliniques et étiologiques. Processus moléculaires post-thrombolytiques. Le rt-PA induit deux processus, indépendants statistiquement à la 2ème heure: d'une part une élévation des PDF et des D-dimères; d'autre part, une baisse du fibrinogène, corrélée à une baisse du plasminogène (r=0,48, p=0.01), de l'alpha2-antiplasmine (r=0.48, p =0.004) et du facteur XIII (r=0.44, p=0.01). La baisse du plasminogène est corrélée significativement avec celle de l'alpha2-antiplasmine (r=0.77, p<0.001), et du facteur XIII (r=0.47, p=0.02). La mise en jeu de facteurs anti-fibrinolytiques, qui n'avait jamais été décrite précédemment, peut jouer un rôle dans une limitation de la fibrinolyse et dans la rethrombose. Des corrélations sont notées entre la baisse précoce du plasminogène et l'étiologie cardioembolique (p=0.04), et un mauvais pronostic final (p=0.03), possiblement en rapport la thrombolyse intense de gros caillots. Les hématomes intra-cérébraux parenchymateux (HP) sont liés significativement à la baisse du fibrinogène (p=0.01) et à l'augmentation des PDF (p=0.01). Une baisse du fibrinogène au-dessous de 2g/L multiplie la probabilité de HP précoce par un facteur 12,82. Ainsi est confirmé le modèle d'une “coagulopathie précoce avec dégradation du fibrinogène”», prédictive de l'hématome, proposé par l'équipe lyonnaise de thrombolyse en 2004 / A systematic study of post-thrombolytic haemostasis has rarely been performed. In 80 consecutive patients, we have prospectively studied at hours 0, 2 and 24 the following parameters: fibrinogen, plasminogen, alpha2-antiplasmin, factor XIII, fibrin(ogen) Degradation Products (FDP), D-dimers, haematocrit and platelet count. Comprehensive statistical studies calculated correlations of the haemostatic values betwen themselves and with 38 etiological and clinical parameters. Molecular dynamics. Two changes between h0 and h2 were statistically independent: an increase in FDP and D-Dimers; a decrease in fibrinogen, plasminogen, alpha2-antiplasmin and factor XIII. At h2, the decrease in fibrinogen was significantly correlated with that of plasminogen (0.48, p = 0.01), alpha2-antiplasmin (0.48, p = 0.004), and factor XIII (0.44, p = 0.01). The decrease in plasminogen was significantly correlated with those of antifibrinolytic components, alpha2-antiplasmin (r=0.77, p<0.001) and factor XIII (0.47, p=0.02). To our knowledge, such an activation of antifibrinolytic components had not hitherto been mentioned. The h2 decrease of plasminogen was correlated with cardioembolic etiology (p=0.04) and final poor oucome (p=0.03), a fact possibly due to intense thrombolysis of large clots. Patients having early parenchymal hematomas (PH) showed h2 haemostasis disturbances: high FDP (p=0.01), and low fibrinogen (p=0.01). The decrease in fibrinogen less than 2g/L multiplies the odds of early PH by a factor 12.82. Thus, we confirm the model of an “early fibrinogen degradation coagulopathy” predictive of hematomas, which had been coined by the Lyon thrombolysis team in 2004

The synthesis of five homoleptic transition metal complexes of bis-(phenyl)-diisoindol-aza-methene is described together with the optical, electrochemical and thermal properties of these compounds. Additionally, crystal structures for the Co and the Zn complex are reported. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The work discusses the development of molecular electronics based on the possibility of the usage of anorganic quantum dots and organic molecules as basis material. Of special interest are the properties of semiconductor quantum dots and their modification due to the coupling of quantum dots from different materials. Eventually these are proper candidates to avoid the fast recombination of excitons which is a problem in many organic photovoltaic materials, by local separation of charge carriers. Another materials class investigated are the so called charge transfer dimers. On the way to usable molecular building blocks switching and rectification behavior are important properties, therefore they were of special interest in the investigation. Especially the usage of charge transfer materials in rectification was already suggested in the 70’s, but could be realized till now only with a quiet limited success. Already around the millennium it was shown that a too strong coupling between the components leads to a resymmetrization of the I-V-characteristics. For all systems the electronic structure was investigated by means of density functional theory. Additional the charge transport in between gold leads was computed based on non equilibrium Greens functions. For the system of coupled quantum dots it is shown how the combination of several gates can be used to adjust the transport properties. This work shows that the rectification effect within weakly coupled charge transfer systems stays also small because also in this case a resymmetrization of the I-V-characteristics takes place.:1 Introduction 2 Molecular Electronics 3 Theoretical background 4 Computational details and software packages 5 Modeling 6 Results and Discussion 6.1 Quantum dots 6.2 Transport through coupled quantum dots 6.3 Charge transfer dimers 6.4 Transport through charge transfer dimers 7 Conclusion 8 Outlook Acknowledgement List of Figures List of Tables Bibliography List of own Publications / Die Arbeit befasst sich mit der Entwicklung der molekularen Elektronik und insbesondere mit der Prüfung der Verwendbarkeit von anorganischen Quantenpunkten und organischen Molekülen für diesen Bereich. Quantenpunkte aus Halbleitermaterialien besitzen eine grosse Bandbreite von Eigenschaften. Es wird untersucht, wie die Eigenschaften durch die Kopplung von Quantenpunkten unterschiedlicher Materialien modifiziert werden können. Eine Idee besteht in der lokalen Trennung von Ladungsträgern um die schnelle Rekombination von Exzitonen zu vermeiden, welche in organischen Solarzellen häufig ein Problem darstellt. Als weitere Materialklasse werden molekulare Ladungstransferdimere untersucht. Auf dem Weg zu nutzbaren Bauelementen sind das Schalt- und Gleichrichtverhalten wichtige Eigenschaften, daher sind sie von besonderem Interesse. Insbesondere die Frage des Ladungstransfers in Bezug auf das Gleichrichten wurde schon in den 1970ern vorgeschlagen, konnte aber bisher immer nur mit begrenztem Erfolg realisiert werden. Schon um die Jahrtausendwende wurde gezeigt, dass Systeme mit einer zu starken Kopplung zu einer Symmetrisierung der Strom-Spannungs-Kennlinie führen. Bei beiden Systemen wird jeweils die elektronische Struktur im Sinne der Dichtefunktionaltheorie berechnet. Zusätzlich wird jeweils der Ladungstransport zwischen Goldkontakten mittels Nichtgleichgewichts-Greenschen Funktionen berechnet. Für die Systeme gekoppelter Quantenpunkte wird gezeigt, wie die Transporteigenschaften mittels Gatespannungen eingestellt werden können. In der vorliegenden Arbeit wird gezeigt, dass es auch im Fall schwach gekoppelter Ladungstransferdimere zu weitgehend symmetrischen Strom-Spannungs-Kennlinien kommt und es auch für diese Systeme nur zu einem schwachen Gleichrichtverhalten kommt.:1 Introduction 2 Molecular Electronics 3 Theoretical background 4 Computational details and software packages 5 Modeling 6 Results and Discussion 6.1 Quantum dots 6.2 Transport through coupled quantum dots 6.3 Charge transfer dimers 6.4 Transport through charge transfer dimers 7 Conclusion 8 Outlook Acknowledgement List of Figures List of Tables Bibliography List of own Publications