Orientador: José Sílvio Govone / Resumo: As variáveis aleatórias no espaço estão definidas como funções aleatórias sujeitas à teoria das variáveis regionalizadas. Para assumir continuidade espacial com um número limitado de realizações da variável aleatória são necessárias as hipóteses de estacionariedade, as quais envolvem diferentes graus de homogeneidade espacial. Formalmente, uma variável regionalizada Z é estacionária se os momentos estatísticos de Z(s+h) forem os mesmos para qualquer vetor h. A hipótese de estacionariedade de primeira ordem é definida como a hipótese de que o momento de primeira ordem da distribuição da função aleatória Z(s) é constante em toda a área. A hipótese intrínseca é baseada no cálculo de médias globais das semivariancias, com a pressuposição de estacionariedade de 1a ordem e da estacionariedade da variância dos incrementos. Embora muitas variáveis sejam suscetível a dupla ou múltipla estacionariedade, estas estruturas espaciais não são levadas em consideração pelo semivariograma usual. Na perspectiva de solucionar o problema apontado, buscou-se identificar os locais dos pontos de mudança na média que definem mais de uma estrutura de semivariancia, com o objetivo de melhorar a qualidade dos mapas de Krigagem Ordinária. Para isso, foi utilizado o Método de Partição Produto (MPP), com enfoque espacial, denominado Método de Partição Produto Espacial (MPPs). Para separar os grupos, foi criada uma função de busca de ponto de mudança na média utilizando o modelo hierárquico bayesiano, denom... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The random variables in space are defined by random functions subject to regionalized variable theory. To assume spatial continuity with a limited number of realization of the random variable, we need to assume stationarity hypotheses, which involve different degrees of spatial homogeneity. Formally, a regionalized variable Z is stationary if statistical moments of Z(s + h) are the same for any vector h. The first order stationarity hypothesis is defined to be the hypothesis that first order moment of the distribution of the random function Z(s) is constant throughout the area. The intrinsic hypothesis is based on the computation of global means of semivariate models, with the assumption of 1st order stationarity and incremental variation stationarity. Although many variables are capable of double or multiple stationarity, these spatial structures are not taken into account by the usual semivariogram, and, consequently, cause acuracy problems in Kriging maps. In order xvii to solve the described problem, it was identify the points of change in the average with the objective of improving the quality and accuracy of the maps of Ordinary Kriging. To separate the groups, a mean change point search function was created using the Bayesian hierarchical model, called the Space Product Partition Model (MPPs). Two databases were used to test the model’s potential to separate spatially dependent groups, in which the former suspected a change in mean while in the latter. “ Data2 ”, there... (Complete abstract click electronic access below) / Doutor

The mitochondrion is an important therapeutic target due to its roles in energy metabolism, reactive oxygen species production, and activation of cell death. The connection of these cellular processes with diabetes, obesity, neurodegenerative disorders, and cancer makes this organelle a potential control point for treatment of these diseases. The advancement of mitochondrial medicine will be accelerated by the development of organelle-specific cellular transporters as well as by strategies to enhance the activity of mitochondrially-active drugs. Here, the discovery and development of a new class of mitochondria-specific agents, mitochondria-penetrating peptides (MPPs), is described. These peptides, exemplified by the sequences (FXY)3 and (FXY)4 where FX=cyclohexylalanine and Y=basic arginine or lysine residues, display hydrophobic and cationic residues critical for access to this organelle, and appear to accumulate within cells and mitochondria through membrane potential-dependent mechanisms. Subcellular localization of the peptides was determined by the interplay of hydrophobicity and positive charge, and necessary lipophilicity “thresholds” for access to the mitochondrion. MPPs can be engineered to have minimal mitochondrial disruptive activity and cytotoxicity through minimization of hydrophobicity and length. Furthermore, MPPs appear to accumulate predominantly in the mitochondrial matrix, a feature which places them within an exclusive class of mitochondria-specific transporters and may enable delivery applications for a number of therapeutically-relevant cargoes. Information gained from MPP studies on the physiochemical parameters that drive mitochondrial localization were applied to improve the activity of the anticancer peptide d-(KLAKLAK)2, an agent that activates apoptosis through mitochondrial disruption. Residue substitutions that increased peptide hydrophobicity, regardless of changes to secondary structure, enhanced mitochondrial localization, activity, and cytotoxicity induced by the peptide. In conclusion, these studies provide important guidelines for how to drive the subcellular localization and activity of peptides, and expand the possibilities for mitochondrially-targeted therapeutics.

The mitochondrion is an important therapeutic target due to its roles in energy metabolism, reactive oxygen species production, and activation of cell death. The connection of these cellular processes with diabetes, obesity, neurodegenerative disorders, and cancer makes this organelle a potential control point for treatment of these diseases. The advancement of mitochondrial medicine will be accelerated by the development of organelle-specific cellular transporters as well as by strategies to enhance the activity of mitochondrially-active drugs. Here, the discovery and development of a new class of mitochondria-specific agents, mitochondria-penetrating peptides (MPPs), is described. These peptides, exemplified by the sequences (FXY)3 and (FXY)4 where FX=cyclohexylalanine and Y=basic arginine or lysine residues, display hydrophobic and cationic residues critical for access to this organelle, and appear to accumulate within cells and mitochondria through membrane potential-dependent mechanisms. Subcellular localization of the peptides was determined by the interplay of hydrophobicity and positive charge, and necessary lipophilicity “thresholds” for access to the mitochondrion. MPPs can be engineered to have minimal mitochondrial disruptive activity and cytotoxicity through minimization of hydrophobicity and length. Furthermore, MPPs appear to accumulate predominantly in the mitochondrial matrix, a feature which places them within an exclusive class of mitochondria-specific transporters and may enable delivery applications for a number of therapeutically-relevant cargoes. Information gained from MPP studies on the physiochemical parameters that drive mitochondrial localization were applied to improve the activity of the anticancer peptide d-(KLAKLAK)2, an agent that activates apoptosis through mitochondrial disruption. Residue substitutions that increased peptide hydrophobicity, regardless of changes to secondary structure, enhanced mitochondrial localization, activity, and cytotoxicity induced by the peptide. In conclusion, these studies provide important guidelines for how to drive the subcellular localization and activity of peptides, and expand the possibilities for mitochondrially-targeted therapeutics.