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Sulfur-containing compounds such as thiamin, biotin, molybdopterin, lipoic acid, and [Fe-S] clusters are essential for life. Sulfurtransferases are present in eukaryotes, eubacteria, and archaea and are believed to play important roles in mobilizing sulfur necessary for biosynthesis of these compounds and for normal cellular functions. The rhodanese homology domain is a ubiquitous structural module containing a characteristic active site cysteine residue. Some proteins containing a rhodanese domain display thiosulfate:cyanide sulfurtransferase activity in vitro. However, the physiological functions of rhodaneses remain largely unknown. YrkF, the first rhodanese to be characterized from Bacillus subtilis, is a unique protein containing two domains, an N-terminal Ccd1 domain and a C-terminal rhodanese domain. Ccd1 (conserved cysteine domain 1) is a ubiquitous structural module characterized by a Cys-Pro-X-Pro sequence motif. Thus, YrkF contains two cysteine residues (Cys¹⁵ and Cys¹⁴⁹), one in each domain. Biochemical, genetic, and bioinformatic approaches were used in order to characterize YrkF. First, YrkF was overexpressed and assayed for rhodanese activity to show that the protein is a functional rhodanese. A variant protein, YrkF^C15A, containing a cysteine to alanine substitution in the Ccd1 domain was created to determine if the Ccd1 cysteine is essential for rhodanese activity. The variant protein was overexpressed and rhodanese assays showed that YrkF^C15A is also a functional rhodanese. Inherent structural and catalytic differences were observed when comparing YrkF and YrkF^C15A, which may reflect the importance of the Ccd1 cysteine residue to normal enzymatic function and structural stability. Initial kinetic studies identified differences in activity between YrkF and YrkF^C15A. Cross-linking experiments showed a propensity for the formation of inter- and intramolecular disulfide bonds between the two cysteine residues and indicated that Cys¹⁵ and Cys¹⁴⁹ are located near one another in the 3-dimensional structure of the protein. Analysis of the proteins by mass spectrometry suggested YrkF contains a stable persulfide sulfur, whereas YrkF^C15A showed no evidence of a stable persulfide sulfur and was prone to oxidation and other active site modifications. A homology model of YrkF was created using structures of a rhodanese homolog and a Ccd1 homolog as templates. The model was used to predict the structure of YrkF based on the results of the cross-linking experiments. A strain containing a yrkF chromosomal deletion could be constructed, indicating YrkF is not essential for survival. Phenotypic analysis of the yrkF mutant revealed that YrkF is not needed for biosynthesis of sulfur-containing cofactors (thiamin, biotin, molybdopterin, or lipoic acid) or amino acids. The characterization of YrkF could lead to the discovery of novel physiological roles for rhodaneses and may give insight into possible roles for the Ccd1 module. / Master of Science

No / SJG-136 is a synthetic pyrrolobenzodiazepine (PBD) dimer in which two DNA-alkylating subunits are linked through an inert propanedioxy tether. Biophysical and biochemical studies of SJG-136 have shown a remarkable affinity for DNA and potent cytotoxicity in vitro. On this basis, together with its unique sequence selectivity and interstrand DNA cross-linking activity, SJG-136 has been selected for clinical trials. This study examines the pharmacological characteristics of SJG-136 and provides the first report of pharmacokinetic properties for this agent. A sensitive, selective and reproducible reversed-phase gradient LC/MS assay has been developed for detection and analysis, where a molecular ion ( m / z 557.2) is detectable for the SJG-136 parent imine. Fluorescence detection (260 nm excitation, 420 nm emission) gives a limit of sensitivity of 5 nM (2.5 ng ml(-1)) for analysis of SJG-136 in mouse plasma. Extraction efficiencies from plasma were >65% across a range of concentrations (5-1000 nM). Following administration to mice at the MTD (i.p., 0.2 mg kg(-1)), high peak plasma concentrations of SJG-136 were seen ( C (max) = 336 nM) at 30 min after dosing. A calculated terminal t (1/2) of 0.98 h and AUC of 0.34 microM.h resulted in a clearance rate of 17.7 ml min(-1) kg(-1). The PBD dimer binds only moderately to proteins (65-75%), and in vitro cytotoxicity studies confirmed IC(50) values of 4-30 nM with a panel of human cell lines. This finding demonstrates that plasma concentrations achieved in the mouse are substantially higher than those required to elicit an anti tumour response in vitro. This report forms an important phase in the pre-clinical characterization of the compound.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2014-08-29T19:24:13Z No. of bitstreams: 2 Dissertação Corrigida e Finalisada.pdf: 2280692 bytes, checksum: fa3c7d92b5ed8a39139ceeb3abb80551 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2014-08-29T19:24:13Z (GMT). No. of bitstreams: 2 Dissertação Corrigida e Finalisada.pdf: 2280692 bytes, checksum: fa3c7d92b5ed8a39139ceeb3abb80551 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2013-12-13 / Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq / In this dissertation we analyze questions of existence of a weak solution for a class of superlineares elliptic Dirichlet problems. Here we do not consider the Ambrosseti Rabinovitz condition , which restricts some nonlinearities. We obtain main results of this dissertation via Variational Methods, such as Mountain Pass Theorem and Linking Theorem. Furthermore, weusePalais-Smalecondition(P.S.) or Cerami condition(Ce) / Nesta dissertação analisamos questões de existência de uma solução fraca para uma classe de problemas de Dirichlet elípticos superlineares. Aqui não consideramos a condição deAmbrosetti-Rabinowitz,a qual restringealgumasfunçõesnão lineares. Obtemos os principais resultados desta dissertação via Métodos variacionais, tais como o Teorema do Passo da Montanha e um Teorema de Linking. Além disso, utilizamos a TeoriaEspectral e ascondições dePalais-Smale(P.S.) eCerami(Ce).

Made available in DSpace on 2015-04-17T14:49:20Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1613275 bytes, checksum: 00b0097dfdb9c99181e93e899c5d60df (MD5) Previous issue date: 2011-11-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Recent years have seen a significant increase in demand for starches with specific properties, leading to the modification of these properties in order to get ideal for your application. The objective of this study was to obtain information about the properties of starch from avocado seed cv. "Butter" and submit it to the modification by acetylation and cross-linking, to provide rheological characteristics applicable in obtaining food. The native starch showed starch content of 74.47 % in the physical-chemical analysis and performance of the extraction process used in 11.36%. The degree of substitution (GS) of native starch by acetylation was 0.007 and 0.006 for cross-linking. The native starch granules and had modified oval and circular, their dimensions ranging from 26 to 26.34 μm for the smaller diameter and 35.75 to 36.85 μm for the larger diameter. The pattern of crystallinity shown by X-ray diffraction was type C. The swelling power and solubility at temperatures 75, 85 and 95 °C was maximum for the native starch and modified by acetylation in relation to cross-linking. The changes reduced the ability of native starch hydrophilic and hydrophobic increased their capacity. The native starch gel showed an opaque folder, and with a tendency to retrogradation, modified with acetic anhydride showed no difference compared to the native whereas modification by cross-linking improved the clarity of the folder and decreased the tendency to retrogradation. Stability to freezing and thawing all samples released water in the first cycle, but with each passing day there was a decrease in syneresis. The acetylated starch did not differ from native in the analysis of viscosity has low viscosity and a greater tendency to retrogradation. The starch is modified by cross-linking showed efficacy by introducing cross-links in native starch granule and its peak viscosity was well below the value obtained in native, just had a lower tendency to retrogradation. In Differential Scanning Calorimetry (DSC) was an initial decrease in temperature for starch modified by cross-linking, and all samples did not differ significantly in peak temperature. / Nos últimos anos houve um aumento expressivo na procura por amidos com propriedades específicas, levando à modificação dos mesmos a fim de obter propriedades ideais para sua aplicação. O objetivo deste trabalho foi obter informações a respeito das propriedades do amido da semente de abacate cv. Manteiga e submetê-lo à modificação por acetilação e cross-linking, a fim de oferecer características reológicas aplicáveis na obtenção de produtos alimentares. O amido nativo apresentou teor de amido de 74,47 % na análise físico-química e rendimento para o processo de extração utilizado de 11,36 %. O grau de substituição (GS) do amido nativo por acetilação foi de 0,007 e por cross-linking de 0,006. Os grânulos de amido nativo e modificado apresentaram formato oval e circular, suas dimensões variam de 26 a 26,34 μm para o diâmetro menor e de 35,75 a 36,85 μm para o diâmetro maior. O padrão de cristalinidade mostrado por difratometria de raios-X foi do tipo C. O poder de intumescimento e a solubilidade nas temperaturas 75, 85 e 95 ºC foi máxima para o amido nativo e modificado por acetilação em relação ao cross-linking. As modificações reduziram a capacidade hidrofílica do amido nativo e aumentaram a sua capacidade hidrofóbica. O gel do amido nativo apresentou uma pasta opaca e com tendência a retrogradação, a modificação com anidrido acético não apresentou diferença em relação ao nativo enquanto que, a modificação por cross-linking melhorou a claridade da pasta e diminuiu a tendência a retrogradação. Na estabilidade ao congelamento e descongelamento todas as amostras liberaram água no primeiro ciclo, mas com o passar dos dias houve uma diminuição da sinérese. O amido acetilado não divergiu do nativo na análise de viscosidade apresentando baixa viscosidade e maior tendência a retrogradação. O amido modificado por cross-linking apresentou eficácia com a introdução de ligações cruzadas no grânulo de amido nativo e seu pico de viscosidade foi bem abaixo do valor obtido no nativo, logo teve menor tendência a retrogradação. Na Calorimetria Exploratória Diferencial (DSC) houve uma diminuição da temperatura inicial para o amido modificado por cross-linking, sendo que todas as amostras analisadas não diferiram significativamente na temperatura de pico.

La nécessité d’une action mondiale pour limiter les émissions de gaz à effet de serre est reconnue par la majorité des pays, mais l’incapacité du régime climatique international à fournir une régulation globale des rejets de GES dans l’atmosphère a conduit à l’échec de l’approche top-down. Cet impossible consensus a conduit à un point de rupture dans la structure du régime climatique mondial dont témoignent notamment le développement, avant l’Accord de Paris d’une approche bottom-up, fondée sur une gouvernance climatique polycentrique et multiniveaux. C’est dans ce contexte qu’émergent et se développent, à différentes échelles administratives, les dix-neuf systèmes de permis d’émissions négociables aujourd’hui en fonctionnement dans le monde. De fait, aucune homogénéité n’est recherchée dans la conception de ces mécanismes de réglementation. Les choix structurels sont dépendants des caractéristiques et contraintes politiques et économiques de la zone géographique à laquelle ils appartiennent. Les configurations et les effets de l’élargissement des systèmes de permis négociables sont encore débattus et cette thèse apporte des recommandations sur la manière dont ces extensions et connexions pourraient avoir lieu.A partir d’analyses de la littérature empirique et de simulations à l’aide d’un modèle d’équilibre partiel pour le secteur énergétique (modèle POLES), nous préconisons la mise en place de mécanismes de cloisonnement sectoriel et de restrictions aux échanges de permis. En effet, dans un contexte caractérisé par des constructions hétérogènes de systèmes de permis d’émissions négociables, une diffusion non-universelle de ces marchés et une inclusion non-intégrale de tous les secteurs de l’économie, nous concluons que deux types d’ajustements sont essentiels. Premièrement, nous démontrons la nécessité d’une configuration et d’un cloisonnement sectoriel des marchés, cela afin d’impulser une dynamique d’innovations, de limiter les impacts sur la compétitivité internationale et de rendre conforme le système aux exigences des politiques connexes. Deuxièmement, nous justifions l’intérêt des mécanismes de restriction aux échanges internationaux de permis d’émissions négociables ; ils permettent en particulier une meilleure redistribution des gains liés à l’échange, tout en réduisant le coût total de la politique climatique et les quantités de GES émis par rapport à une pure segmentation des marchés.Finalement, l’existence de plusieurs prix du carbone apparaît incontournable dans le contexte actuel d’une gouvernance climatique mondiale hétérogène et d’une multiplicité d’objectifs politiques nationaux. Encourager le développement de prix différents par secteur et par pays permettrait, sous certaines conditions, de favoriser l’acceptabilité politique, de renforcer l’efficacité environnementale et d’améliorer l’efficience économique des systèmes de permis d’émission. / Most countries recognize that a coordinated worldwide action to limit greenhouse gas (GHG) emissions has to be implemented. However, the countries inability to coordinate their efforts led to the failure of the top-down climate architecture. Today, the international climate governance adopts a different direction, which based on bottom-up approach. This approach promotes polycentric and multi-level governances, that induce several independent policy-makers in different administrative scales (province, state and region). Therefore, the actual implemented Emission Trading Systems (ETS), as well as the emerging ones, grow in a domestic context. This context, in terms of economic development, political commitment and geographical coverage, determine the ETS design. Then, there is no harmonized design among ETS, no universal diffusion of these mechanisms in the world and a lack of integral inclusion of all sectors in these carbon markets. While researchers and policy-makers discuss the optimal features of such systems, this thesis examines different configuration options and coverage areas for the tradable permit schemes.Using a world energy-economy partial equilibrium simulation model (POLES) and drawing on experiences with real-world ETSs (based on empirical literature), we recommend two types of adjustments: the restrictions on trade permits between sectors, in one hand, and the control of international permit exchange between ETS, in the second hand. Indeed, we demonstrate firstly the necessity to separate ETS by sector and adapt them considering the specificities of each sector. This kind of policy will stimulate innovation in each sector. Also, it will limit the impacts on the international competitiveness and it will lead climate policy to other economic policies. Secondly, we develop a model to describe the effects of exchange permits emissions considering international linking among emissions trading systems. We prove that restriction exchange mechanisms are necessary to insure the redistribution of exchange gain compared to full linking. At the same time, these trade restriction mechanisms minimize the total cost and increase GHG emissions reductions compared to a segmented market.Considering the diversity of national political objectives and the bottom-up context of world climate framework, we concluded that the coexistence of several carbon prices is unavoidable and necessary. Encouraging the development of several carbon prices can promote political acceptability, strengthen environmental efficiency and improve economic efficiency.

Made available in DSpace on 2015-05-15T11:46:18Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 899692 bytes, checksum: d08b5615c89c2ad179f1f6dda0a8c410 (MD5) Previous issue date: 2014-06-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / In this work, we study issues related the existence, nonexistence and regularity of solutions to semilinear Schrödinger equations of type u + a(x)u = jujp2u; u 2 H1(RN); where N 2, p > 2 if N = 2 and 2 < p < 2N=(N 2) if N 3 and the potential a(x) is a positive function that belongs to L1(RN). To obtain the results, we use a Linking Theorem and the Principle of Symmetric Criticality. / Neste trabalho, estudamos questões relacionadas a existência, não-existência e regularidade de soluções para equações de Schrödinger semilineares do tipo u + a(x)u = jujp2u; u 2 H1(RN); onde N 2, p > 2 se N = 2 e 2 < p < 2N=(N 2) se N 3 e o potencial a(x) é uma função positiva que pertence a L1(RN). Para obtenção dos resultados, usamos um Teorema de Linking e o Princípio da Criticalidade Simétrica.

Differenzielles Itemfunktionieren bedeutet für die Trendschätzung durch Linking in querschnittlich angelegten Large-Scale Assessments eine Voraussetzungsverletzung. Solche Voraussetzungsverletzungen können sich negativ auf die Eigenschaften von Trendschätzern auswirken, woraus sich Einschränkungen für die Interpretierbarkeit der Trendschätzung ergeben können. Die vorliegende Arbeit umfasst, eingebettet in einen Rahmungstext, drei Einzelbeiträge, die sich mit der Prüfung der Auswirkung differenziellen Itemfunktionierens unterschiedlicher Provenienz auseinandersetzen. Im ersten Einzelbeitrag wird die Interaktion von Linkingdesigns und Linkingmethoden mit zwischen Ländern und über die Zeit unsystematisch unterschiedlich funktionierenden Items untersucht. Dabei zeigte sich, dass die Wahl des Designs von großer Bedeutung sein kann, während der Performanzunterschied zwischen gängigen Linkingmethoden marginal war. Darüber hinaus führte der häufig praktizierte Ausschluss von differenziell funktionierenden Items zu einem Effizienzverlust. Im zweiten Einzelbeitrag wird die Unsicherheit der Trendschätzung, die entsteht, wenn Items zwischen Ländern und über die Zeit unsystematisch unterschiedlich funktionieren, quantifiziert und in die Berechnung der zugehörigen Standardfehler integriert. Im dritten Einzelbeitrag wird betrachtet, wie differenziellem Itemfunktionieren begegnet werden kann, das durch fehlende Werte und wechselnde Ausfallmechanismen zustande kommt. Wurden die fehlenden Werte inadäquat behandelt, verloren die Trendschätzer ihre Erwartungstreue und Konsistenz sowie an Effizienz. In der Summe wird in der vorliegenden Arbeit identifiziert und hervorgehoben, dass es in den untersuchten Bedingungen je nach Art des differenziellen Itemfunktionierens effektive Möglichkeiten des Umgangs mit diesem gibt, die potenziellen Einschränkungen bei der validen Interpretation der Trendschätzung zumindest teilweise entgegenwirken können. / Differential item functioning signifies a violation of the prerequisites required for trend estimation, which involves the linking of cross-sectional large-scale assessments. Such violations can negatively affect the properties of the trend estimators. Hence, the interpretability of trend estimates will be limited under such circumstances. Embedded within an overarching framework, three individual contributions that examine and deal with the effects of differential item functioning from different origins are presented in the current dissertation. The first article examines the interactions of linking designs and linking methods with items that show unsystematic and differential functioning between countries and across time. It showed that the choice of the design can be of great importance, whereas the difference in performance between common linking methods was marginal. In addition, the exclusion of differentially functioning items, an approach that is frequently used in practice, led to a loss of efficiency. In the second contribution, the uncertainty for the trend estimation resulting from items that show unsystematic and differential functioning between countries and across time is quantified and incorporated into the calculation of the trends' standard errors. The third article focuses on differential item functioning that is induced by missing values and nonresponse mechanisms that change over time. When the missing values were treated inappropriately, the trend estimators lost their unbiasedness, their consistency, and their efficiency. In sum, this dissertation identifies and emphasizes the ideas that, depending on the type of differential item functioning, there are effective ways to deal with it under the investigated conditions, and these can at least partially counteract potential limitations so that the trend estimates can still be interpreted validly.