Oligonucleotide-based drugs hold great promise for the treatment of many types of diseases, ranging from genetic disorders to viral infections and cancer. The problem is that efficient delivery across the cell membrane is required for oligonucleotides to have their desired effect. Cell-penetrating peptides (CPPs) provide a solution to this problem. CPPs are capable of transporting cargoes such as drugs or nucleic acids for gene therapy into the cell, either by covalent conjugation to the cargo or by non-covalent complex formation. This thesis is focused on the development of a class of peptides called PepFects, peptides with fatty acid modifications capable of forming nanoparticle-sized complexes with oligonucleotides. These complexes are efficiently internalized by many different cell types and are generally non-toxic and non-immunogenic. We have developed a number of novel PepFect peptides and a quantitative structure-activity model to predict the biological effect of our peptides. In addition, the involvement of scavenger receptors class A in the endocytic uptake of PepFect complexes as well as other CPPs and polymeric transfection agents was studied. Lastly, we have developed a series of PepFect peptides for delivery across the blood-brain barrier and a model system mimicking the blood-brain barrier in order to evaluate the passage of these peptides. The general aim of this thesis is to improve the understanding of intracellular delivery of oligonucleotides with PepFect peptides from both a chemical and a biological viewpoint, and further improve the efficacy of this delivery system with the long-term goal of making it useful in clinical settings.

As a very promising material of copper diffusion barrier for next generation microelectronics, Ru has already obtained a considerable attention recently. In this dissertation, we investigated ruthenium and ruthenium oxide electrochemical properties and the application as a copper diffusion barrier. Cu under potential deposition (UPD) on the RuOx formed electrochemically was first observed. Strong binding interaction, manifesting by the observed Cu UPD process, exists between Cu and Ru as well as its conductive ruthenium oxide. Since UPD can be conformally formed on the electrode surface, which enable Ru and RuOx has a potential application in the next generation anode. The [Cl-] and pH dependent experiment were conducted, both of them will affect UPD Cu on Ru oxide. We also found the Cu deposition is thermodynamically favored on RuOx formed electrochemically. We have studied the Ru thin film (5nm) as a copper diffusion barrier. It can successfully block Cu diffusion annealed at 300 oC for 10min under vacuum, and fail at 450 oC. We think the silicidation process at the interface between Ru and Si. PVD Cu/Ru/Si and ECP Cu/Ru/Si were compared each other during copper diffusion study. It was observed that ECP Cu is easy to diffuse through Ru barrier. The function of RuOx in diffusion study on Cu/Ru/Si stack was discussed. In pH 5 Cu2+ solution, Ru and Pt electrochemical behavior were investigated. A sharp difference was observed compared to low pH value. The mechanism in pH 5 Cu2+ solution was interpreted. An interesting compound (posnjakite) was obtained during the electrochemical process. An appropriate formation mechanism was proposed. Also Cu2O was formed in the process. We found oxygen reduction reaction is a key factor to cause this phenomenon.

The integration of copper (Cu) and dielectric materials has been outlined in the International Technology Roadmap for Semiconductors (ITRS) as a critical goal for future microelectronic devices. A necessity toward achieving this goal is the development of diffusion barriers that resolve the Cu and dielectric incompatibility. The focus of this research examines the potential use of tungsten nitride as a diffusion barrier by characterizing the interfacial properties with Cu and evaluating its process capability for industrial use. Tungsten nitride (β-W2N) development has been carried out using a plasma enhanced chemical vapor deposition (PECVD) technique that utilizes tungsten hexafluoride (WF6), nitrogen (N2), hydrogen (H2), and argon (Ar). Two design of experiments (DOE) were performed to optimize the process with respect to film stoichiometry, resistivity and uniformity across a 200 mm diameter Si wafer. Auger depth profiling showed a 2:1 W:N ratio. X-ray diffraction (XRD) showed a broad peak centered on the β-W2N phase. Film resistivity was 270 mohm-cm and film uniformity < 3 %. The step coverage (film thickness variance) across a structured etched dielectric (SiO2, 0.35 mm, 3:1 aspect ratio) was > 44 %. Secondary ion mass spectroscopy (SIMS) measurements showed good barrier performance for W2N between Cu and SiO2 with no intermixing of the Cu and silicon when annealed to 390o C for 3 hours. Cu nucleation behavior and thermal stability on clean and nitrided tungsten foil (WxN = δ-WN and β-W2N phases) have been characterized by Auger electron spectroscopy (AES) and thermal desorption spectroscopy (TDS) under controlled ultra high vacuum (UHV) conditions. At room temperature, the Auger intensity ratio vs. time plots demonstrates layer by layer Cu growth for the clean tungsten (W) surface and three-dimensional nucleation for the nitride overlayer. Auger intensity ratio vs. temperature measurements for the Cu/W system indicates a stable interface up to 1000 K. For the Cu /WxN/W system, initial Cu diffusion into the nitride overlayer is observed at 550 K.

Applications of computational quantum chemistry are presented, including an analysis of the photophysics of cyclic trinuclear coinage metal pyrazolates, an investigation into a potential catalytic cycle utilizing transition metal scorpionates to activate arene C-H bonds, and a presentation of the benchmarking of a new composite model chemistry (the correlation consistent composite approach, ccCA) for the prediction of classical barrier heights. Modeling the pyrazolate photophysics indicates a significant geometric distortion upon excitation and the impact of both metal identity and substituents on the pyrazolates, pointing to ways in which these systems may be used to produce rationally-tuned phosphors. Similarly, thermodynamic and structural investigations into the catalyst system points to promising candidates for clean catalytic activation of arenes. The ccCA was found to reproduce classical reaction barriers with chemical accuracy, outperforming all DFT, ab initio, and composite methods benchmarked.

Orientador: José Alexandre Diniz / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Engenharia Elétrica e de Computação / Made available in DSpace on 2018-08-18T16:42:08Z (GMT). No. of bitstreams: 1 Lima_LucasPetersenBarbosa_M.pdf: 10518299 bytes, checksum: abe557fa5f682bd296c9fb416948d523 (MD5) Previous issue date: 2011 / Resumo: Filmes de nitreto de titânio (TiN) e nitreto de tântalo (TaN) foram depositados sobre substratos de Si (100) utilizando um sistema de sputtering reativo, com diferentes fluxos de N2 (10-80 sccm) e potência (500-1500W), em ambiente de N2/Ar. Foram analisadas as influências da mistura gasosa N2/Ar e potência nas propriedades estruturais e elétricas dos filmes de TiN e TaN, utilizando as técnicas de perfilometria, microscopia de força atômica, 4 pontas, espectroscopia Raman, difração de raios-x e espectroscopia de fotoelétron. As análises físicas e elétricas dos filmes de TiN e TaN demonstram que os filmes são policristalinos, com as orientações preferenciais (311)-( 111) e (200)-( 111), respectivamente. Os valores das taxas de deposições, resistividades elétricas e tamanho de grão para os filmes de TiN e TaN estão entre 4 e 78 nm/min, 150 e 7500 ??.cm e 0,001 e 0,027 ?m2, respectivamente. Foram fabricados capacitores MOS e diodos Schottky com eletrodos superiores de TiN e TaN com dielétricos de SiOxNy ou SiO2, e extraídas curvas CV e IV destes dispositivos, para extração de parâmetros como tensão de flatband (VFB), densidade de carga efetiva (Q0/q) e função trabalho do eletrodo superior (WF). As curvas CV dos capacitores MOS com dielétrico de SiOxNy e eletrodo superior de TiN apresentaram valores extraídos de Q0/q, VFB e WF de 1010 cm2, 0,29 V e 4,65 eV, respectivamente, que são compatíveis com a tecnologia CMOS. As curvas CV dos capacitores MOS com dielétrico de SiOxNy e eletrodo superior de TaN apresentaram valores extraídos de Q0/q, VFB e WF de 1010 cm2, 1,36 V e 3,81 eV, respectivamente, que não são compatíveis com a tecnologia CMOS. As curvas CV dos capacitores MOS com dielétrico de SiO2 e eletrodo superior de TiN apresentaram valores extraídos de Q0/q, VFB e WF de 1010 e 1012 cm2, de 0,12 V e 0,36 V, e, 4,15 eV e 4,43 eV, respectivamente, que são compatíveis com a tecnologia CMOS. As curvas CV dos capacitores MOS com dielétrico de SiO2 e eletrodo superior de TaN apresentaram valores extraídos de Q0/q, VFB e WF de 1010 e 1012 cm2, 0,29 V e 0,20 V, e, 4,41 eV e 4,44 eV, respectivamente, que são compatíveis com a tecnologia CMOS. Estes resultados indicam que os filmes de TiN e TaN são compatíveis para serem utilizados em dispositivos da tecnologia MOS / Abstract: Tantalum nitride (TaN) and titanium nitride (TiN) films have been obtained by DC sputtering, using different nitrogen flow (10 - 80 sccm) and power (500 - 1500 W), in a nitrogen (N2)/argon (Ar) ambient on Si (100) substrates. The N2/Ar ratio in gas mixture and power effects on structural and electrical properties of TaN and TiN films were investigated by scan profiler (film thickness and deposition rate), atomic force microscopy (rms roughness and grain size), fourprobe technique (electrical resistivity), Raman spectroscopy, x-ray diffraction (crystal orientation) and X-ray photoelectron spectroscopy (film composition). The physical and structural analyses of TiN and TaN films show that TiN and TaN films were polycrystalline, with (311)-( 111) and (200)-( 111) preferred orientation, respectively. The deposition rates, electrical resistivities and grain size values of TiN and TaN films were between 4 and 78 nm/min, 150 and 7500 ??.cm and 0,001-0,027 ?m2, respectively. MOS capacitors and Schottky diodes were fabricated with TiN and TaN as upper electrodes and dielectrics with SiOxNy or SiO2. CV and IV measurements were carried out on these devices and flatband voltage (VFB), effective charge density (Q0/q) and metal gate work function (WF) were extracted from these measurements. The extracted values of Q0/q, VFB e WF 1010 cm2, 0,29 V e 4,65 eV, and these values were extracted from CV curves of MOS capacitors with TiN as gate electrode and SiOxNy as gate dielectric. The extracted values of Q0/q, VFB e WF 1010 cm2, 1,36 V e 3,81 eV, and these values were extracted from CV curves of MOS capacitors with TiN as gate electrode and SiOxNy as gate dielectric. The extracted values of Q0/q, VFB and WF were about 1010 and 1012 cm2, 0,12 V and 0,36V, and 4,15 eV and 4,43 eV, and these values were extracted from CV curves of MOS capacitors with TiN as gate electrode and SiO2 as gate dielectric. The extracted values of Q0/q, VFB and WF were about 1010 and 1012 cm2, 0,29 V and 0,20V, and 4,41 eV and 4,44 eV, and these values were extracted from CV curves of MOS capacitors with TaN as gate electrode and SiO2 as gate dielectric. These extracted values for VFB and WF indicates that the TiN and TaN films are suitable for MOS technology / Mestrado / Eletrônica, Microeletrônica e Optoeletrônica / Mestre em Engenharia Elétrica

Orientador: Vital Paulino Costa / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T05:19:20Z (GMT). No. of bitstreams: 1 Santana_AlanaMendonca_M.pdf: 2805390 bytes, checksum: 9512111e988de78a1ffde9d9f877658b (MD5) Previous issue date: 2014 / Resumo: O objetivo deste trabalho foi investigar os efeitos das combinações fixas dos análogos de prostaglandinas com timolol sobre a barreira hematoaquosa, a espessura macular central e a pressão intraocular (PIO), em pacientes pseudofácicos com glaucoma primário de ângulo aberto. Neste ensaio clínico randomizado, com observador mascarado e duração de 6 meses, os pacientes foram tratados uma vez por dia (20:00 horas) com lubrificante (grupo controle) ou com a combinação fixa de maleato de timolol 0,5% e latanoprosta 0,005% (CFLT), maleato de timolol 0,5% e bimatoprosta 0,03% (CFBT) ou maleato de timolol 0,5% e travoprosta 0,004% (CFTT). Foi incluído no estudo apenas um olho de 61 pacientes: CFLT (n=16), CFBT (n=15), CFTT (n=15) e grupo controle (n=15). A barreira hematoaquosa foi avaliada por meio do &quot;laser flare meter¿ antes do início do uso das medicações e após 15 dias, 1,2,3,4,5 e 6 meses de tratamento. A PIO foi medida sempre às 9:00 horas, nas mesmas ocasiões. A espessura macular central foi avaliada por meio da tomografia de coerência óptica antes do uso das medicações, após 1 e 6 meses de tratamento ou na hipótese de piora da acuidade visual. Não houve aumento estatisticamente significante nos valores médios de &quot;flare¿ em comparação aos valores iniciais em todos os grupos (p>0,05) em todas as visitas, exceto no grupo CFTT no primeiro mês (p=0,0476) e no grupo CFLT (p=0,0129) no terceiro mês de seguimento. Não houve diferença estatisticamente significativante entre os valores médios de &quot;flare¿ entre os grupos durante o estudo (p>0,05). A média dos valores da espessura macular central aumentou significativamente nos grupos CFLT (p=0,012) e CFTT (p=0,0419) no primeiro mês de tratamento em relação aos valores iniciais. Não houve aumento estatisticamente significante nos valores médios da espessura macular central em relação aos valores iniciais em todos os grupos após 6 meses de tratamento (p>0,05) e não ocorreu diferença estatisticamente significante entre os grupos durante o estudo (p>0,05). A PIO média inicial foi significativamente menor no grupo controle (p=0,0000). Todas as combinações fixas reduziram significativamente a PIO em todas as visitas (P<0,0001), com efeito hipotensor semelhante entre si (p=0,816). Estes resultados indicam que o uso das combinações fixas de análogos de prostaglandinas com timolol não aumentou significativamente a média dos valores de &quot;flare¿ ou a média da espessura macular após 6 meses de tratamento nesta população / Abstract: The aim of this study was to investigate the effects of prostaglandin analogues and timolol fixed-combinations on the blood-aqueous barrier, central macular thickness and intraocular pressure (IOP) in pseudophakic patients with primary open angle glaucoma. In this randomized, masked-observer, 6-month clinical trial, patients were treated once daily (8 pm) with lubricant eye drops (control group), 0,5% timolol and 0,005% latanoprost fixed-combination (LTFC), 0,5% timolol and 0,03% bimatoprost fixed-combination (BTFC) or 0,5% timolol and 0,004% travoprost fixed-combination (TTFC). One eye of 61 patients were included in the study: LTFC (n=16), BTFC (n=15), TTFC (n=15) and control group (n=15). The blood-aqueous barrier status was assessed using the laser flare meter before the medications were started and after 15 days, 1, 2, 3, 4, 5 and 6 months of treatment. The IOP was measured always at 9 am, at the same intervals. The central macular thickness was evaluated with optical coherence tomography before medications were started, after 1 and 6 months of follow-up or if a patient showed decreased visual acuity at any time during follow-up. There was no significant increase in mean flare measurements from baseline in all groups (p>0.05) in all visits, except TTFC group at 1 month (p=0,0476) and LTFC group at 3 months (p=0,0129). There were no significant differences in mean flare values among the groups (p>0.05). Mean central macular thickness values were significantly higher in LTFC (p=0,012) and TTFC groups (p=0,0419) at 1 month of follow-up. There was no significant increase in mean central macular thickness values from baseline in all groups (p>0.05) after 6 months and no significant differences among the groups (p>0.05) during follow-up. At baseline, mean IOP was significantly lower in control group (p=0,0000). All fixed-combinations significantly reduced IOP in all follow-up visits, with similar lowering effect (p=0,816). These findings indicate that the use of prostaglandin analogues and timolol fixed-combinations didn't significantly increased mean flare values or mean central macular thicknes measurements after 6 months of follow-up in this population / Mestrado / Oftalmologia / Mestra em Ciências Médicas

Cadmium telluride (CdTe) is a leading thin film photovoltaic (PV) material due to its near ideal band gap of 1.45 eV, its high optical absorption coefficient and availability of various device fabrication methods. Superstrate CdTe solar cells fabricated on glass have to-date exhibited efficiencies of 16.5%. Work on substrate devices has been limited due to difficulties associated with the formation of an ohmic back contact with CdTe. The most promising approach used to-date is based on the use of an interlayer between the CdTe and a metal electrode, an approach that is believed to yield a pseudo-ohmic contact. This research investigates the use of ZnTe and Sb2Te3 as the interlayer, in the development of efficient back contacts. Excellent adhesion and minimum stress are also required of a CdTe thin film solar cell device on a flexible stainless steel (SS) foil substrate. Foil substrate curvature, flaking, delamination and adhesion as a result of compressive strain due to the coefficient of thermal expansion (CTE) mismatch between the flexible SS foil substrate and the solar cell films have been studied. A potential problem with the use of a SS foil as the substrate is the diffusion of iron (Fe), chromium (Cr) and other elemental impurities into the layers of the solar cell device structure during high temperature processing. A diffusion barrier limiting the out diffusion of these substrate elements is being investigated in this study. Silicon nitride (Si3N4) films deposited on SS foils are being investigated as the barrier layer, to reduce or inhibit the diffusion of substrate impurities into the solar cell. Thin film CdTe solar cells have been fabricated and characterized by AFM, XRD, SEM, ASTM D3359-08 tape test, current-voltage (I-V) and spectral measurements. My individual contributions to this work include the Molybdenum (Mo) development, the adhesion studies, the silicon nitride (Si3N4) barrier studies, and EDS and SEM lines measurements and analysis of substrate out-diffused impurities. The rest of my colleagues focused on the development of CdTe, CdS, ZnTe, the CdCl2 heat treatment, and other back contact interlayer materials.

Solutes are often most efficiently deployed in discrete pulses, for example in the delivery of herbicides or drugs. Manual application of each pulse can be labor-intensive, automated application of each pulse can be capital intensive, and both are often costly and impractical. Barrier-Mediated Pulsatile Release (BMPR) systems offer a materials-based alternative for automated pulsatile drug delivery, without pumps, power supplies, or complex circuitry. While earlier materials-based approaches such as delayed-release microcapsules are limited to two or three pulses due to the independent nature of each pulse’s timing control, BMPR systems link the timing of each pulse to the previous pulse. Each dose of drug is sequestered in its own stimuli-sensitive depot, releasing only upon contact with the stimulant. These depots are stacked with sacrificial barriers in between, each of which block the stimulant for a predetermined time. For instance, layers of soluble drug may be separated by degradable polymer layers. Water, as the stimulant, will erode the polymer layer over a fixed period of time, followed by quick dissolution and release of the underlying drug and the start of degradation for the next polymer layer. This example, however, is quickly limited by irregular polymer erosion, a single stimulant (water), and difficulty in scaling delay times. The research work presented in this thesis reports the development of a generalized BMPR system which overcomes those limitations. Model drugs (methylene blue and methyl orange) were immobilized in a pH-sensitive polymer [poly(methyl methacrylate-co-dimethylaminoethyl methacrylate)] which released only at low pH. Zinc oxide (ZnO) nanoparticles immobilized in a pH-insensitive matrix [poly(vinyl alcohol)] served as the barrier layer. The time required for acid to penetrate the barrier layer scaled with the ZnO concentration and with the square of the polymer thickness, allowing wide scaling of the delay time with only minor changes to the barrier layer. Harnessing the swelling pressure of the acid-sensitive hydrogel, each barrier/depot bilayer can delaminate upon solute release, directly exposing the next bilayer to the stimulant source. This system has demonstrated tuned release using a citric acid stimulant to produce up to ten pulses of model drug (methylene blue) over various preset timescales. This system has also demonstrated the alternate release of multiple solutes (methylene blue and methyl orange) at regular time intervals up to five pulses from a single BMPR device. For non-delaminating BMPR systems, spent bilayers impede stimulant diffusion to the inner layers and solute diffusion from the inner layers, increasing the delay time and the pulse width. To predict these changes, a computational model was constructed in FORTRAN. This model was extensively explored over a wide range of parameter space to understand the release behavior of various kinds of non-delaminating BMPR systems. The computer model also validates the performances of experimental delaminating BMPR system. This model can be used to guide the physical modeling of BMPR systems. The model also allows to incorporate variety of stimulants other than just acid. BMPR technology introduces efforts to further generalize the delivery strategy by incorporating glucose as a stimulant.

No description available.

La barrière hémato-encéphalique (BHE) régule finement l’apport en oxygène et en nutriments du cerveau et le protège d’éventuels pathogènes, notamment en bloquant le passage des molécules de poids moléculaire supérieur à 400 Da. Malheureusement, cette barrière est un obstacle à la délivrance de nombreux médicaments. Les ultrasons focalisés de basse intensité, combinés avec des microbulles, représentent un outil de choix pour perméabiliser la BHE, de façon sûre et réversible, et ainsi permettre de délivrer efficacement des médicaments ou des agents de contraste dans le cerveau. Dans la première partie de ma thèse, j’ai développé de nouvelles stratégies ultrasonores de perméabilisation de la BHE chez le rongeur. J’ai mesuré l’atténuation du faisceau ultrasonore par le crâne et étudié l’influence des paramètres acoustiques sur l’intensité et la durée de la perméabilisation. Ces développements m’ont ensuite permis de délivrer des nanoparticules dans le cerveau de rongeurs et d’observer cette délivrance par imagerie par résonance magnétique (IRM), tomographie par émission de positrons, imagerie de contraste de phase par rayons-X, spectrométrie de masse ou encore histologie. La seconde partie de mon travail a porté sur l’application de cette technologie ultrasonore à la maladie d’Alzheimer (MA). J’ai tout d’abord optimisé un protocole IRM T2* à très haute résolution permettant l’imagerie ex vivo des plaques amyloïdes de souris modèles de la MA. J’ai développé un traitement semi-automatique des images pour détecter et quantifier la charge amyloïde dans le cortex. Enfin, j’ai évalué la perméabilisation répétée de la BHE en tant que thérapie pour la MA et démontré que des perméabilisations répétées de la BHE pouvaient avoir un effet bénéfique sur la mémoire de rongeurs modèles de la maladie. / The blood-brain barrier (BBB) plays a crucial role in maintaining the hemostasis of the brain and protects it from pathogens. The BBB prevents molecules with a molecular weight higher than 400 Da to enter the brain. Crucial, the BBB becomes a limit to deliver drugs to the brain. Low intensity focused ultrasound and microbubbles are a unique tool to open the BBB, in a safe and reversible way, to deliver drugs to the brain. The first part of the PhD was dedicated to developing new strategies for BBB opening. To do so, I measured the attenuation of the ultrasound beam by the skull and studied the dependency of the intensity and of the duration of the BBB opening on the acoustic parameters. Thanks to these developments, I was able to deliver many kinds of nanoparticles to rodent brains and I could observe their delivery with techniques such as magnetic resonance imaging (MRI), positron emission tomography, phase-contrast X-ray imaging, mass spectroscopy or histology. The second part of my PhD was focused on applying this technology to Alzheimer’s disease (AD). I optimized a T2* MRI protocol at very high resolution for ex vivo imaging of amyloid plaques in the cortex of mice modeling AD. I developed a semi-automatic image treatment to detect and quantify the amyloid load. Finally, I tested a repeated BBB opening as a therapy for AD and showed that repeated BBB openings could have a beneficial impact on the memory on rodents modeling AD.