In dieser Arbeit sollte das neuartige Zahnpflegeprodukt Tooth Mousse, das als Wirkstoff den CPP-ACP- Komplex (Caseinphosphopeptid-amorphes Calciumphosphat) enthält, experimentell auf seine Remineralisationsfähigkeit hin untersucht und diesbezüglich mit anderen Zahnpasten verglichen werden. Für die Vergleiche wurden eine 1400 ppm-fluoridhaltige Zahnpasta (Elmex rot), eine Placebozahncreme ohne Wirkstoff (Elmex Placebo) sowie eine weitere Neuentwicklung auf der Basis unterkühlter, amorpher Salzhydratschmelze mit hohem Calciumgehalt, herangezogen. Hierzu wurden Probekörper aus künstlichem Zahnschmelz in Form von Hydroxylapatitkörpern mit einer Dichte, wie sie bei porösem, demineralisierten humanen Schmelz üblich ist, hergestellt. Diese wurden mit allen genannten Zahnpasten behandelt und vor, während und nach Ablauf der Versuche gravimetrisch und radiographisch vermessen. Zwischen den in-vitro Behandlungen wurden die Hydroxylapatit-Tabletten in künstlichem Speichel aufbewahrt. Die Versuche ergaben, dass Tooth Mousse wie auch die schmelzehaltige Zahnpasta in-vitro geringere Remineralisation erzielten als Elmex Placebo. In-situ erreichte Elmex rot die höchsten Remineralisationswerte, dicht darauf folgte die schmelzehaltige Zahnpasta. Tooth Mousse lag als Schlusslicht noch hinter der Placebozahnpasta. / This thesis was to compare experimentally the novel dental care product “Tooth Mousse” containing CPP- ACP (Casein Phosphopeptide- amorphous Calcium Phosphate) as active agent, with other dentifrices concerning their remineralization qualities. The subject was compared with a 1400 ppm F – toothpaste (Elmex rot), a toothpaste without any active agents (Elmex Placebo) and a newly developed paste based on an calcium-containing salthydratic melt. Therefore artificial enamel discs were produced providing the same density as caries lesions in human enamel. They were treated with all products mentioned above and measured radiographically and gravimetrically before, while and after the experiments. Between the treatments discs were stored in artificial saliva. Examinations led to the conclusion that Tooth Mousse as well as the calcium-containing salthydratic melt paste achieved less remineralization values than Elmex Placebo. In situ Elmex rot reached highest remineralization, closely followed by the calcium-containing salthydratic melt paste. Tooth Mousse was last behind the Placebo group.

Cellular internalization is a highly regulated process controlled by proteins in the plasma membrane. Large and hydrophilic compounds, in particular, face difficulties conquering the plasma membrane barrier in order to gain access to intracellular environment. This puts serious constrains on the drug industry since many drugs are hydrophilic. Several methods aiming at aiding the cellular internalization of otherwise impermeable compounds have therefore been developed. One such class, so-called cell-penetrating peptides (CPPs), emerged around twenty years ago. This group constitutes hundreds of peptides that have shown a remarkable ability in translocating diverse molecules, ranging from small molecules to large proteins, over the cell membrane. The internalization mechanism of CPPs has been questioned ever since the first peptides were discovered. Initially, the consensus in the field was direct translocation but endocytosis has gradually gained ground. The confusion and the disunity within this research field through the years proceeds from divergent results between research groups that hamper comparison of the peptides. This thesis aims at characterizing several well-established CPPs with comprehensive studies on cellular toxicity, secondary structure and cellular internalization kinetics. The results demonstrate that CPPs act in general in a low or non-toxic way, but the apparent toxicity is both peptide- and cell line-dependent. Structural studies show that the CPPs have a diverse polymorphic behavior ranging from random coil to structured β-sheet or α-helix, depending on the environment. The ability to change secondary structure could be the key to the internalization property of the CPPs. Internalization kinetic studies of CPP conjugates reveal two sorts of internalization profiles, either fast curves that cease in few minutes or slow curves that peak in tens of minutes. Furthermore, improved synthesis of CPP conjugates is demonstrated. In conclusion, the studies in this thesis provide useful information about cytotoxicity and structural diversity of CPPs, and emphasize the importance of kinetic measurements over end-point studies in order to give better insights into the internalization mechanisms of CPPs. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Submitted.</p>

Porous constructs of calcium polyphosphate (CPP) are under investigation as a substrate for tissue engineering of cartilage for repair of osteochondral defects. Previous studies have shown that CPP has the required features to satisfy these requirements. However, its degradation rate is lower than desired. This study investigated the effect of doping with MgCO3, MgCl2, K2CO3 or KCl at a molar ratio of M/Ca = 0.02 on sintering and in vitro degradation behavior of CPP. Doping with magnesium or potassium improved the tensile and compressive strengths of CPP at similar porosities. After 15 days of aging in phosphate buffer saline, the rate of tensile strength loss was faster for the doped CPP groups than undoped CPP. The chemical degradation rate of Mg-doped CPP groups was the fastest among CPP groups. The chemical degradation rate of K-doped CPP groups was slower than undoped CPP.

Porous constructs of calcium polyphosphate (CPP) are under investigation as a substrate for tissue engineering of cartilage for repair of osteochondral defects. Previous studies have shown that CPP has the required features to satisfy these requirements. However, its degradation rate is lower than desired. This study investigated the effect of doping with MgCO3, MgCl2, K2CO3 or KCl at a molar ratio of M/Ca = 0.02 on sintering and in vitro degradation behavior of CPP. Doping with magnesium or potassium improved the tensile and compressive strengths of CPP at similar porosities. After 15 days of aging in phosphate buffer saline, the rate of tensile strength loss was faster for the doped CPP groups than undoped CPP. The chemical degradation rate of Mg-doped CPP groups was the fastest among CPP groups. The chemical degradation rate of K-doped CPP groups was slower than undoped CPP.

No description available.

This dissertation focuses on the Capital Purchase Program (CPP) of the Troubled Asset Relief Program (TARP) and consists of a historical overview of TARP and three empirical studies of the CPP. In the first empirical analysis, presented in chapter 2, I use an event study approach to examine the impact of firm announcements of CPP approval on their stock price. I find that the average firm in my sample enjoyed a 1.31% abnormal return on their stock price in the trading days surrounding this news event. In a multivariate regression that examines cross-firm variation in abnormal returns, I find evidence that legislative action in February 2009 to increase the restrictions on executive compensation at CPP-funded firms may have played an important role in dulling market enthusiasm for a firm qualifying for CPP capital. In chapter 3, I propose a model of TARP funding with numerous financial, structure, economic and regulatory explanatory variables to determine which factors were most influential in directing CPP capital to specific firms in the banking system. I find a clear pattern that CPP capital flowed most prominently to both larger, systematically important firms and firms that, while not on the verge of failure, were experiencing greater financial stress. In chapter 4, I study whether CPP funding altered bank behavior. Modifying established models from the economic literature on bank lending, loss recognition and CEO pay, I investigate whether CPP recipients behaved differently than non-recipient firms in lending activities, acknowledging portfolio losses or altering CEO compensation. Controlling for firm condition, I find that CPP recipients were significantly less likely to lend, but significantly more likely to acknowledge losses and curb CEO pay. Collectively, these results suggest that the government's decision to inject capital into the banking system primarily led to greater transparency about the health of recipient financial institutions. / Economics

O presente estudo teve como objetivo realizar uma revisão da literatura para verificar se os novos compostos bioativos presentes no mercado, como CPP-ACP, fosfosilicato de cálcio e sódio e o nitrato de potássio são eficazes na remineralização do esmalte dental clareado. As alterações ocorridas na superfície dental devido ao clareamento são diversas. Dentre elas, pode-se citar a rugosidade, dureza, perda de conteúdo mineral e alterações morfológicas como as mais estudadas. Muitas formas de análises tem sido utilizadas para essas avaliações, porém duas novas técnicas demonstram-se promissoras: o QLF e a nanoidentação. O QLF relaciona-se com a auto fluorescência dental, possuindo vantagens relacionadas a sua especificidade, simples manuseio e preservação do espécime. Já a nanoidentação é capaz de mensurar a dureza em sítios específicos, em uma escala nanométrica, permitindo uma criteriosa seleção da área a ser analisada. Os resultados obtidos não necessitam da mensuração visual da área demarcada pelo identador, o que se torna mais uma vantagem da técnica. Foi conclusivo que a literatura diverge quanto aos resultados apresentados até o momento relacionados aos efeitos do clareamento dental na superfície dental, e os estudos que avaliaram os diversos compostos bioativos apresentam diferentes metodologias que não permitem o estabelecimento de um protocolo de aplicação dos mesmos. Sendo assim, faz-se necessária a realização de novos estudos para avaliar os possíveis efeitos dos diferentes compostos quando da utilização destes como dentifrícios de uso terapêutico após o tratamento clareador. / This study aimed to review the literature and verify if the new bioactive compounds, like CPP-ACP, calcium sodium phosphosilicate and potassium nitrate are effective on the remineralization of the bleached dental enamel. There are several alterations occurred on the dental surface owing to the bleaching procedure. Among them: roughness, microhardness, mineral content loss and morphologic alterations are the most evaluated. Many different analysis have been used to assess the changes in the dental structure, however two of them have shown to be promising: the QLF and the nanoindentation. The QLF is related with the auto fluorescence of the teeth and has advantages related to its specificity, simple manipulation and it is not a destructive technique. On the other hand, the nanoindentation is capable to measure the surface hardness in very specific sites, in a nanometric scale, enabling a criterious selection of the area which will be analyzed. The results obtained by this equipment do not require the visual measure of the impressed area of the indentation, which is one advantage of the methodology. It was conclusive that the literature disagrees of the results presented about the effects of dental bleaching on the enamel surface and the researches that evaluated the bioactive compounds have demonstrated differences in their methodologies. These inconclusive findings interfere on the establishment of an application protocol to those new dentifrices. Thus, it is necessary to develop new researches to better understand the possible effects of the bioactive compounds when the use of these dentifrices are related to a therapeutic use after treatment with bleaching agents.

Submitted by Secretaria Pós de Produção (tpp@vm.uff.br) on 2017-07-27T19:24:17Z No. of bitstreams: 1 D2016 - Glauco Barbosa da Silva.pdf: 5776264 bytes, checksum: d50812d465487f52e8c02b7f636435ab (MD5) / Made available in DSpace on 2017-07-27T19:24:17Z (GMT). No. of bitstreams: 1 D2016 - Glauco Barbosa da Silva.pdf: 5776264 bytes, checksum: d50812d465487f52e8c02b7f636435ab (MD5) / Problem: From Modeling decision maker preferences, the Multicriteria Decision Aid (MCDA) is a field dedicated to the study of real-world decision-making problems that are, usually, too complex and not so well-structured to be considered through the examination of a single point of view (criteria). This feature of MCDA implies that a comprehensive model of a decision maker situation cannot be “created”, but instead, the model should be developed to meet the requirements of the Decision Maker (DM). In general, the development of such a model can only be achieved through an iterative and interactive process, until the preferences of the decision maker are consistently represented in the model. However, an interactive method is a procedure that consists of an alternation of calculation and discussion stages, which presumes that the decision maker is willing to answer a large number of relatively difficult questions. For instance, one of the main difficulties to be faced when interacting with a Decision Maker in order to build a decision aid procedure is the various parameters’ elicitation of the preference model. Methodology: In this thesis, as an alternative to interactive process, among the main streams of MCDA, a Preference Disaggregation Analysis method was used, which is considered to assess or to infer preference models from the given preferential structures and to address decision-aiding activities to elicit preferential information and to construct decision models from decision examples. Combining Composition Probabilistic of Preference with Data Mining techniques, a proposal of a three-step process is presented: attribute selection; clustering; and classification. The first and the second ones are data mining tasks and the last one is a multicriteria task. Purpose: This thesis aims to present a new approach with a Data Mining Layer (attribute selection and/or clustering) in Composition Probabilistic of Preferences in Trichotomic procedure (CPP-TRI), which combines data mining techniques with a Multicriteria Decision Aid method in classification (sorting) problems. Findings: The decision maker ability to comprehend without powerful tools has been exceeded. Therefore, important decisions are often made based not on the information-rich data stored in data repositories, but rather, on intuition of the decision maker. Involved in similar problems, the connections between disaggregation methods and data mining (identifying patterns, extracting knowledge from data, eliciting preferential information and constructing decision models from decision examples) are explored to combine and improve the CPP-TRI Method from Attribute Selection Techniques. / Problem: From Modeling decision maker preferences, the Multicriteria Decision Aid (MCDA) is a field dedicated to the study of real-world decision-making problems that are, usually, too complex and not so well-structured to be considered through the examination of a single point of view (criteria). This feature of MCDA implies that a comprehensive model of a decision maker situation cannot be “created”, but instead, the model should be developed to meet the requirements of the Decision Maker (DM). In general, the development of such a model can only be achieved through an iterative and interactive process, until the preferences of the decision maker are consistently represented in the model. However, an interactive method is a procedure that consists of an alternation of calculation and discussion stages, which presumes that the decision maker is willing to answer a large number of relatively difficult questions. For instance, one of the main difficulties to be faced when interacting with a Decision Maker in order to build a decision aid procedure is the various parameters’ elicitation of the preference model. Methodology: In this thesis, as an alternative to interactive process, among the main streams of MCDA, a Preference Disaggregation Analysis method was used, which is considered to assess or to infer preference models from the given preferential structures and to address decision-aiding activities to elicit preferential information and to construct decision models from decision examples. Combining Composition Probabilistic of Preference with Data Mining techniques, a proposal of a three-step process is presented: attribute selection; clustering; and classification. The first and the second ones are data mining tasks and the last one is a multicriteria task. Purpose: This thesis aims to present a new approach with a Data Mining Layer (attribute selection and/or clustering) in Composition Probabilistic of Preferences in Trichotomic procedure (CPP-TRI), which combines data mining techniques with a Multicriteria Decision Aid method in classification (sorting) problems. Findings: The decision maker ability to comprehend without powerful tools has been exceeded. Therefore, important decisions are often made based not on the information-rich data stored in data repositories, but rather, on intuition of the decision maker. Involved in similar problems, the connections between disaggregation methods and data mining (identifying patterns, extracting knowledge from data, eliciting preferential information and constructing decision models from decision examples) are explored to combine and improve the CPP-TRI Method from Attribute Selection Techniques.

O presente trabalho tem por objetivo avaliar &ldquo;in vitro&rdquo; diferentes tratamentos na remineralização do esmalte desmineralizado em situação de alto desafio cariogênico. Foram obtidos 55 blocos de esmalte de dentes bovinos com dimensões de 4x4x2mm, que tiveram sua superfície planificada e polida. Metade da superfície foi protegida com resina, antes da formação de lesão de mancha branca, mantendo-a íntegra. Para a formação da lesão de desmineralização os blocos foram imersos em solução tampão de acetato por 43h. Os espécimes foram divididos aleatoriamente em 5 grupos: controle (sem tratamento), Verniz Duraphat; Flúor gel; Mi Paste e Mi Paste Plus. Todas as superfícies desmineralizadas receberam tratamento, com os seus respectivos produtos, 1x/semana durante 3 semanas. Nos intervalos das aplicações os espécimes foram submetidos a ciclos de pH num total de 21 dias. Antes da desmineralização, após, em seguida à 1a aplicação e ao final dos 21 dias de ciclagem foram obtidas imagens da superfície e análise da rugosidade superficial, e morfologia por meio de Microscopia Confocal a Laser, ao final a resina que protegia a área controle foi removida e capturada uma nova imagem para análise do perfil de desgaste. Os dados foram analisados quanto a sua distribuição e verificada a normalidade e a homogeneidade da distribuição amostral, foi realizada Análise de Variância e teste de tukey (p<0,05). Pode-se observar que tanto para a rugosidade superficial como para o perfil de desgaste os grupos estudados apresentaram resultados similares entre si (p>0,05). Na rugosidade superficial observou-se que apenas no verniz ocorreu um aumento significante de rugosidade com o tempo (p<0,05). Na morfologia pode-se observar uma topografia irregular que foi mais evidenciada ao término da ciclagem, tendo o controle e os Mi Paste (convencional e plus) apresentado perda de estrutura mais evidente. Baseado nos resultados obtidos pode-se concluir que nenhum tratamento preventivo isolado foi efetivo para paralisação do desenvolvimento da lesão de cárie que foi agravado com o tempo de exposição ao processo DES-RE. / The aim of this study was to evaluate, in vitro, different treatments in previously demineralized enamel in a high cariogenic challenge. 55 enamel slabs of bovine teeth with dimensions of 4x4x2mm were planned and polished surface. Half the surface was protected with resin before the formation of white spot lesions, and half stay sound. For the formation of the demineralization challenge the blocks were immersed in acetate buffer solution for 43h. The specimens were randomly divided into 5 groups: control (no treatment), Duraphat; Fluoride gel; Mi Paste and Mi Paste Plus. All demineralized surfaces were treated with their respective products, 1x/week for 3 weeks. During intervals among applications specimens were subjected to pH cycles in a total of 21 days. Before demineralization, after the first application and after 21 days of cycling were obtained images of surface and it was analyzed for surface roughness and morphology by 3D Confocal Laser microscope, the end the resin protecting the control area was removed and a new image captured for analysis of the wear profile. Data were analyzed for distribution and checked for normality and homogeneity of the sampling distribution, it was performed analysis of variance and Tukey test (p <0.05). It can be seen that both the surface roughness and profile for the wear groups had similar results (p> 0.05). Surface roughness was observed only in the duraphat showed a significant increase in roughness with time (p <0.05) occurred. Morphology can be observed an irregular topography that was more evident at the end of cycling, it had been control and Mi Paste (conventional and plus) presented more evident loss of structure. Based on the results obtained in vitro can be concluded that no preventive treatment alone was effective in paralyzed the development of caries lesion. The integrity of enamel surface was deteriorated with time of exposure in DES-RE process.

La protoporphyrie érythropoïétique (PPE) est une maladie héréditaire rare caractérisée par un déficit en activité FECH responsable d’une accumulation de PPIX. Elle se manifeste par une photosensibilité très invalidante. Il n’existe pas de traitement efficace pour la PPE. 95 % des malades présentent un allèle FECH hypomorphe (c.315-48C) en trans d'une mutation FECH délétère, ce qui entraine une diminution de l'activité FECH résiduelle dans les érythroblastes en dessous d'un seuil critique d'environ 35 % de l'activité normale. L’allèle hypomorphe (c.315-48C) favorise l'utilisation d'un site cryptique d'épissage situé en -63 de l’intron 3 générant un ARNm FECH incluant une partie de l’intron 3 et possédant un codon stop prématuré. L’ARN est alors dégradé par NMD pendant sa maturation. Nous avons déjà identifié un oligonucléotide antisens (ASO-V1) qui redirige l'épissage vers le site accepteur physiologique de l’intron 3 et augmente la production d’ARN FECH WT. Nous avons développé par ce travail une nouvelle stratégie d’adressage d’ASO-V1 en utilisant des peptides ciblant le récepteur de la transferrine (RTf1) qui est exprimé à un niveau très élevé dans les progéniteurs érythroïdes en différenciation concomitamment à la FECH. Nous avons développé des peptides bifonctionnels à partir des séquences peptidiques ciblant le RTf1 tout en les couplant à des séquences Cell Penetrating Peptide (CPP) qui facilitent la sortie de l’ASO-V1 de la vésicule endosomale. Après la transfection des lignées lymphoblastoïdes de malades PPE par différents nanocomplexes RTf1-CPP/ASO-V1, nous avons pu montrer que plusieurs des peptides bifonctionnels utilisés permettaient une redirection efficace et prolongée de l’épissage cryptique vers l’épissage physiologique exon3-exon4 et que cela permettait une correction des taux d’ARN FECH WT. Nous avons ensuite testé l’effet des nanocomplexes RTf1-CPP/ASO-V1, ex vivo, dans les progéniteurs érythroïdes en différenciation de différents sujets atteints de PPE et nous sommes arrivés à augmenter l’ARN FECH WT et diminuer significativement l’accumulation de la PPIX dans ces cellules par rapport à celles transfectées par des nanocomplexes RTf1-CPP/ASO-Mock. La prochaine étape de notre étude serait d’apporter la preuve de concept, in vivo, dans un modèle murin humanisé de PPE après l'administration de nanocomplexes RTf1-CPP/ASOV1 / Erythropoietic protoporphyria (EPP) is a rare hereditary disease characterized by a deficiency in FECH activity responsible for the accumulation of PPIX. EPP is manifested by a very disabling photosensitivity. There is no effective treatment for EPP. 95% of the patients present a hypomorphic FECH allele (c.315-48C) in trans of a deleterious FECH mutation, resulting in a decrease in residual FECH activity in erythroblasts below a critical threshold of about 35% of normal activity. The hypomorphic allele (c.315-48C) promotes the use of a cryptic splicing site located at -63 of the intron 3 generating a FECH mRNA including a part of the intron 3 and possessing a premature stop codon. The RNA is then degraded by NMD during its maturation. We have previously identified an antisense oligonucleotide (ASO-V1) that redirects splicing to the physiological acceptor site of intron 3 and increases the production of WT FECH mRNA. Here, we developed a new ASO-V1 addressing strategy using transferrin receptor (TRf1) targeted peptides. TfR1 is expressed at a very high level in differentiating erythroid progenitors concomitantly with FECH. We developed bifunctional peptides from peptide sequences targeting TfR1 while coupling them to Cell Penetrating Peptide (CPP) sequences that facilitate the release of ASO-V1 from the endosomal vesicle. We transfected the lymphoblastoid cell lines from EPP patients by different TfR1-CPP/ASO-V1 nanocomplexes and we demonstated that several of the bifunctional peptides allowed an efficient and prolonged redirection of the cryptic splicing towards the exon3-exon4 physiological splicing and the correction of the WT FECH mRNA levels. Then, we tested the effect of TfR1-CPP/ASO-V1 nanocomplexes, ex vivo, in differentiating erythroid progenitors of different EPP subjects and we were able to increase WT FECH mRNA and decrease significantly the accumulation of the PPIX in these cells compared to those transfected by TfR1-CPP/ASO-Scr nanocomplexes. The next step of our study would be to provide a proof of concept, in vivo, in a humanized murine model of EPP after the administration of TfR1-CPP/ASOV-1 nanocomplexes