Planarian flatworms are gaining popularity in regenerative medicine research due to the fact that they have unparalleled regeneration capacity. Their tissue recovery abilities are dependent on a pool of adult stem cells (neoblasts). Studies in the recent years have shown that epigenetic mechanisms have an important role in neoblasts’ self-renewal and differentiation properties. This thesis focuses on the study of trithorax-related genes and their function in neoblast regulation. Despite the fact that mammalian trithorax-related genes Mll3 and Mll4 are among the most frequently mutated genes in cancer, trithorax-related genes are the least well-studies members of the trithorax gene group (TrxG) of histone modifiers. The current study traced the evolutionary history of trithorax-related genes and concluded that they have undergone a number of independent gene fission events across phyla. In planarians, there are three partial orthologue of the mammalian Mll3 and Mll4 genes – Smed-LPT (corresponding to the N-terminus of Mll3/4), Smed-trr-1 and Smed-trr-2 (both corresponding to the C-terminus of Mll3/4). The three planarian trithorax-related genes are expressed in stem cells and control neoblast differentiation down certain lineages (brain, gut, eyes, pharynx, epidermis). Down-regulation of Smed-LPT results in hyperproliferation of stem cells, leading to tumour-like outgrowth formation. It was shown that trithorax-related genes’ function in stem cell regulation correlates with histone modification changes, specifically alterations in H3K4me1, H3K4me3 and H3K27me3. Future studies will focus on examining this correlation further via Next-Generation sequencing techniques.

Accelerated carbohydrate utilisation and suppressed lipid oxidative metabolism are hallmarks of heart failure (HF). Hypoxia mimics failing heart metabolic reprogramming and has been suggested to play a role in cardiac metabolic switch. One aspect of the regulation of cardiac energy metabolism is the pyruvate dehydrogenase complex (PDC). Hypoxia inducible factor (HIF) signalling is thought regulate hypoxia-induced adaptations. HIF transcriptional activity is controlled by prolyl hydroxylase domain (PHD) protein and factor inhibiting HIF (FIH-1). In chapter 3 revealed that relative to baseline, acute hypoxia increased cardiac lactate efflux and suppressed fatty acid oxidation (FAO) rates in non-treated isolated mouse hearts with final cardiac recovery being 63% of baseline values. Hypoxic and post-hypoxic PDC activation, via dichloroacetate (DCA), decreased cardiac lactate release and FAO during reoxygenation, but failed to improve cardiac recovery relative to control hearts. Chapter 4 sought to establish how chronic hypoxia (11%) upregulates cardiac glycolytic flux, determined via 3H-glucose. Findings of this chapter indicate that of four enzymes considered to set the pace of glycolysis, upregulated pyruvate kinase (PK) flux, appears to explain accelerated hypoxia-induced cardiac glycolytic flux. Western blotting analysis revealed increased PK M2 protein isoform. Sustained hypoxia increased pentose phosphate pathway (PPP) flux, but left lactate accumulation unaltered. Chapter 5 examined the role of sustained in vivo hypoxia in modulating cardiac tolerance to subsequent acute H/R injury and chronic PDC activation in modifying hypoxic heart tolerance to acute injury. Chronic hypoxia reduced cardiac tolerance to H/R injury accompanied by increased glycolytic flux and lactate efflux during reoxygenation injury. Chronic PDC activation improved hypoxic heart tolerance to the acute injury and normalized cardiac metabolic flux and reduced tissue lactate accumulation during reoxygenation, indicative of increased carbohydrate oxidation. Collectively, the data appear to imply that forced carbohydrate oxidation normalizes hypoxic heart recovery from acute injury. In chapter 6 we demonstrated that global FIH-1 deletion increased isolated heart glycolytic flux at baseline and during reoxygenated. FIH-1 KO hearts displayed increased reoxygenated hexokinase (HK) and PK activities, but no changes in PK protein isoforms. Functional analysis revealed that FIH-1 deficiency does not affect isolated heart function at baseline and in response to acute injury. Acute PDC activation does not appear to improve cardiac function during acute hypoxic stress. Conversely, chronic PDC activation normalized, via restored metabolic flux, cardiac tolerance to acute injury following sustained in vivo hypoxia. Furthermore, the present thesis revealed increased PPP flux following sustained in vivo hypoxia, and proposed a pivotal role PKM2 may play in the regulation of hypoxic heart carbohydrate metabolism. In addition, we identified FIH-1 as a novel regulator of cardiac carbohydrate metabolism at baseline and following acute hypoxic injury.

Enzymes from filamentous fungi have a key role in degradation of the most abundant biopolymers found in nature, cellulose and hemicelluloses. For this reason, these enzymes are of great interest in the industrial conversion of lignocellulosic substrates into biofuels. The production of plant cell wall degrading enzymes is regulated mainly at the transcriptional level in filamentous fungi but little is known about the signalling pathways and transcription factors (TFs) involved in this regulation in Aspergillus niger. RNA-sequencing analysis has been previously carried out to investigate the transcriptional changes that occur when A. niger is transferred from the simple carbon source glucose onto the complex lignocellulosic biomass wheat straw. This has highlighted the up-regulation in transcript level of genes encoding some glycosyl hydrolase (GH) enzymes as well as hydrophobic surface interacting proteins (HSIPs) that may be involved in the interface between lignocellulosic biomass and A. niger. Genes encoding the key TFs XlnR, ClrA and ClrB were deleted from A. niger and the resulting strains were assessed for growth on glucose and wheat straw, transcription of genes encoding glycosyl hydrolases and saccharification activity. Growth of all mutant strains, based in straw on measurement of pH and assay of glucosamine, was impaired in relation to the wild-type (WT) strain although deletion of clrA had less effect than deletion of xlnR or clrB. Release of sugars from wheat straw was also lowered when culture filtrates from TF deletion strains were compared with WT culture filtrates. Transcript levels of cbhA, bglB, eglC and xynA were measured in all strains in glucose and wheat straw media in batch culture with and without pH control. Transcript levels from cbhA, bglB and eglC were lowered in all mutant strains compared to WT although the impact of deleting clrA was not pronounced with expression of eglC and had no effect on xynA. The impact on transcription was not related to changes in pH. In addition to impaired growth on wheat straw, the ΔxlnR strain was sensitive to oxidative stress and displayed cell wall defects in the glucose condition suggesting additional roles for XlnR. Phosphorylation is a key reversible modification that regulates protein function, subcellular localization, complex formation, activation of TFs and cell signalling pathways. A phosphoproteomic study was carried out on both the WT and the ΔxlnR deletion strains of A. niger in order to identify key regulators of the signalling pathways involved in the breakdown of a lignocellulosic substrate, wheat straw. The analysis consisted of comparing the phosphoproteome profiles of the strains when grown in glucose with the phosphoproteome profile of the same strains when exposed to wheat straw for 6h, 12h and 24h. The results suggested a difference in the phosphoproteome profiles of the two strains when exposed to both glucose and wheat straw. These data may provide new information on the importance of XlnR in the regulation of expression of GHs but also in controlling the environment to which A. niger is exposed depending on the nutrient availability. To investigate the role of HSIPs in the induction of A. niger response to wheat straw, single gene deletion strains for hfbD, hyp1 and hsbA as well as the double deletion strain for hfbD and hyp1 have been constructed. The expression of some genes encoding GH enzymes was then followed in these strains using qRT-PCR. The results showed that the transcript levels of the GH genes studied were lowered in the HSIPs deletion strains when compared to the wild-type strain, when the cultures were transferred from glucose medium to wheat straw. These results suggest that HSIPs may have a role in the utilisation of lignocellulosic biomass in A. niger. The precise nature of such a role as well as the characterisation of new TFs, such as ClrB, provides new areas of improvement for industrial processes for production of second generation biofuels.

Survivin is an essential protein that is highly overexpressed in most human cancers and is known to be involved in many cellular processes by virtue of its different locations and interacting partners in the cell. At mitosis it is part of the chromosomal passenger complex, which ensures correct temporal and spatial regulation of chromosome movements and cytokinesis. Survivin also acts in apoptosis suppression via distinct mechanisms many of which have been ascribed to the mitochondrial pool of survivin. However, it is still unclear precisely how survivin gains access to this organelle, its other possible functions while there and its effect on mitochondrial morphology. Though mitochondria play an essential role in apoptosis induction and execution, they also provide phospholipids for incorporation into membranes. Of particular interest to this study, they synthesise phosphatidylethanolamine (PE), by decarboxylation of phosphatidylserine, which is catalysed by phosphatidylserine decarboxylase (PSD). The purpose of this thesis was to test the hypothesis that mitochondrial survivin regulates PSD-mediated conversion of PS to PE in the mitochondria. This thesis shows PSD is a novel partner of survivin which interacts with it both in vivo and in vitro. The interaction was mapped to the N-terminal BIR domain of survivin. Furthermore, only mature catalytically active PSD could interact with survivin, suggesting that survivin regulates PSD activity, and thereby could regulate PE availability to the cell. In addition to discovering that survivin is a novel regulator of PSD activity, this thesis also identified a second isoform of human PSD, and discovered that the NH2 terminal ten amino acids of survivin area non-canonical mitochondrial targeting sequence. As PE is an essential phospholipid which is required for maintenance of mitochondrial integrity, successful cytokinesis and lipidation of autophagosomes during autophagy, the identification of mitochondrial survivin as a regulator of PSD activity can be expected to have a significant impact on cellular health. Therefore, this thesis identified a completely novel mechanism by which mitochondrial survivin could be further fuelling tumorigenesis in vivo.

La dispersion des virus dans l'air est un phénomène encore mal compris. La transmission par contact direct avec une personne infectée ou indirecte via des surfaces contaminées a été largement documentée, mais la littérature sur les aérosols viraux reste pauvre. L’aérosolisation de virus pathogènes requérant d’importantes mesures de biosécurité, des modèles de virus non pathogènes constitueraient des outils précieux dans l’étude des aérosols viraux. Ce projet vise le développement de modèles standardisés pour l’étude des aérosols viraux. Ainsi, des phages ont été testés comme modèles de virus eucaryotes. Pour évaluer leur résistance aux stress environnementaux et aux différents temps d’exposition, ces phages ont été aérosolisés dans une chambre rotative où ils ont été exposés à diverses conditions environnementales (humidité relative [HR], température, UV) et temps. Les résultats obtenus suggèrent que les phages choisis pourraient être de bons modèles pour l’étude du comportement des virus dans l’air. / The spread of virus in the air is a poorly understood phenomenon. Transmission by direct contact with an infected person or by indirect contact via contaminated surfaces has been widely documented, but the literature on viral aerosols remains poor. Because the aerosolization of pathogenic viruses requiring significant biosecurity measures, the availability of non-pathogenic viral models would be a valuable tool in the study of viral aerosols. The aim of this project is to develop standardized models for the study of viral aerosols. Consequently, phages were tested as models for eukaryotic viruses. To evaluate their resistance to environmental stresses and to different exposure times, these phages were aerosolized in a rotating chamber where they were exposed to various environmental conditions (relative humidity [RH], temperature, UV) and time. The results suggest that the selected phages could be good models for studying the behavior of the virus in the air.

Les plasmides confèrent aux bactéries qui les possèdent diverses fonctions pouvant accroître leurs chances de survie dans des environnements défavorables. C’est le cas d’Aeromonas salmonicida ssp. salmonicida, bactérie à l’origine de la furonculose chez les salmonidés. Elle possède trois petits plasmides (pAsa1, pAsa2 et pAsa3) qui sont cryptiques c’est-à-dire sans fonction connue. Pour compléter son plasmidome standard, s’ajoutent aux précédents, deux autres plasmides fréquemment retrouvés, pAsal1 et pAsa5, porteurs de gènes codant pour le système de sécrétion de type III, important facteur de virulence pour ce microorganisme. Enfin, ce ne sont pas moins de 17 plasmides porteurs de gènes de résistance aux antibiotiques et quatre supportant des facteurs de virulence qui ont été mis en évidence au cours des 30 dernières années pour cette bactérie. La propagation des gènes de résistance aux antibiotiques pose un problème dans le contexte vétérinaire puisqu’elle constitue, pour le moment, un obstacle au traitement efficace et durable contre la bactérie et conséquemment contre la furonculose. L’étude des petits plasmides d’A. salmonicida ssp. salmonicida s’inscrit dans cette démarche d’une meilleure connaissance de leur plasticité et de leur diversité. Ce projet a donc permis de mettre en évidence la présence de trois nouveaux petits plasmides : pAsa10, pAsaXI et pAsaXII. pAsa10 est la preuve supplémentaire que la propagation des gènes de résistance aux antibiotiques se poursuit, notamment par l’entremise du transposon Tn1721. L’analyse des séquences de pAsaXI et pAsaXII a permis de mettre en évidence des plasmides porteurs de nouvelles fonctionnalités pour A. salmonicida ssp. salmonicida, et des dérivés respectifs des plasmides cryptiques pAsa3 et pAsa2, très présents dans la bactérie, mais sans utilité apparente. Enfin, la haute capacité de transfert de ce microorganisme est encore démontrée, car ces plasmides sont identiques à d’autres retrouvés dans Shewanella baltica et Aeromonas bivalvium, respectivement. / Plasmids confer to the bacteria that possess them various functions that increase their chances of survival in adverse environments. This is the case with Aeromonas salmonicida ssp. salmonicida, a bacterium which causes furunculosis in salmonids. It has three small plasmids (pAsa1, pAsa2 and pAsa3) that are cryptic that is to say without a known function. To supplement its standard plasmidome, two other frequently found plasmids, pAsal1 and pAsa5, which are carriers of genes coding for the type III secretion system, an important virulence factor of this microorganism. Finally, there are no less than 17 plasmids with genes coding for antibiotic resistance and 4 bearing virulence factors that have been demonstrated over the last 30 years for this bacterium. The spread of antibiotic resistance poses a problem in the veterinary context, since it is currently an obstacle to effective and sustainable treatment against the bacterium and consequently to furunculosis. The study of the small plasmids of A. salmonicida ssp. salmonicida is part of this process of a better knowledge of their plasticity and diversity. This project highlighted the presence of three new small plasmids: pAsa10, pAsaXI and pAsaXII. pAsa10 is a new evidence that propagation of antibiotic resistance genes continues, notably through the transposon Tn1721. The analysis of pAsaXI and pAsaXII sequences allowed to identify plasmids carrying new functionalities for A. salmonicida ssp. salmonicida, and derivatives of cryptic plasmids pAsa3 and pAsa2, respectively, very present in the bacterium but without apparent utility. Finally, the high transfer capacity of this microorganism is further demonstrated because these plasmids are identical to others found in Shewanella baltica and Aeromonas bivalvium, respectively.

Made available in DSpace on 2015-04-14T14:12:21Z (GMT). No. of bitstreams: 1 345671.pdf: 592577 bytes, checksum: 008fea4136e0eca4cd776e2c637ff6cf (MD5) Previous issue date: 2006-01-25 / Este estudo, desenvolvido em uma sala de aula de Qu?mica, tem por objetivo compreender como a constru??o de uma Unidade de Aprendizagem sobre Leis Ponderais pode contribuir para conhecimentos significativos desse componente curricular. Para tanto, a Unidade de Aprendizagem ? realizada por meio de atividades diversificadas, buscando atender ?s necessidades dos alunos. A partir da?, procura-se explorar as possibilidades metodol?gicas que uma Unidade de Aprendizagem propicia, dando ?nfase ao aprender a aprender. Os dados discutidos neste trabalho foram colhidos em uma turma de primeira s?rie do Ensino M?dio, com trinta e cinco alunos, de uma Escola T?cnica Estadual de Porto Alegre, ao longo do primeiro trimestre do ano letivo de 2004. O processo envolve observa??es, registros di?rios e question?rios. O trabalho ? elaborado levando em considera??o uma abordagem qualitativa, sendo a fenomenologia a op??o metodol?gica adotada. Sobre a an?lise dos dados resultantes emergem tr?s ess?ncias: a complexifica??o do conhecimento pelo sujeito, o aluno frente ao processo ensino-aprendizagem e o aluno frente aos conte?dos selecionados. Mostra ainda que as Unidades de Aprendizagens servem como um caminho poss?vel para os professores superarem as pr?ticas metodol?gicas tradicionais e avan?arem na compreens?o de sua pr?pria a??o docente. O processo de pesquisa viabiliza uma reflex?o sobre a concep??o de aprendizagem significativa. As considera??es finais apontam para a validade de utilizar-se essa proposta metodol?gica, em sala de aula, a fim de possibilitar a aprendizagem significativa em Qu?mica.

Submitted by Caroline Xavier (caroline.xavier@pucrs.br) on 2017-06-30T18:25:05Z No. of bitstreams: 1 DIS_CRISTIANO_CENTENO_SPECHT_COMPLETO.pdf: 1860927 bytes, checksum: 08252d5fbed6487955580648a6527a8a (MD5) / Made available in DSpace on 2017-06-30T18:25:05Z (GMT). No. of bitstreams: 1 DIS_CRISTIANO_CENTENO_SPECHT_COMPLETO.pdf: 1860927 bytes, checksum: 08252d5fbed6487955580648a6527a8a (MD5) Previous issue date: 2017-01-18 / This research seeks to answer the following research question. How are questions asked and what are the consequences for learning the questions asked by four teachers and 455 high school students during chemistry classes in schools in an inner city of Rio Grande do Sul? During the research, 1,178 questions were annotated in 18 high school classes of public and private schools in the sweet coast of the state of Rio Grande do Sul. After observations made in 40 chemistry classes. The questions were analyzed under the focus of their demand and their profile, having been classified and analyzed according to Roca, M?rquez and Sanmart? (2013). The questions were classified according to the content Coll et al. (1998). The conduct of the teachers in front of the questions in the chemistry classes were treated through the Textual Analysis Discusive - ATD emerging five categories of analysis. We also analyzed the questions according to the management of the classroom emerging nine categories that were analyzed according to the ATD. The semi-structured interviews with the investigated teachers were established "a priori" categories that were also analyzed by the ATD. The results of the interviews reinforce the results of the other analyzes. The result of the analysis of the collected information can be perceived that these questions are, for the most part, informative profile. Besides the questions asked in the majority by the teachers, it is intended to lead the reproduction of the disciplinary content endorsed in the textbooks. There are few questions asked in chemistry classes to provide an investigation. Therefore the didactic model of the investigated teachers that prevails in this research is to transmit the knowledge to the students. / Esta disserta??o apresenta os resultados de uma investiga??o realizada sobre as perguntas de professores e estudantes presentes em aulas de Qu?mica. Buscou responder ? seguinte quest?o de pesquisa: De que modo as perguntas s?o valorizadas por professores e a que condutas docentes elas levam em aulas de Qu?mica em escolas de uma cidade interior do Rio Grande do Sul? Para a investiga??o, foram coletadas 1.178 perguntas obtidas da observa??o de 40 aulas de Qu?mica, de quatro professores e 455 estudantes, em 18 turmas de ensino m?dio de escolas p?blicas e privadas da regi?o da Costa Doce do Estado do Rio Grande do Sul. As perguntas foram analisadas sob o enfoque de sua demanda e de seu perfil, tendo sido classificadas e analisadas de acordo com Roca, M?rquez e Sanmart? (2013). Ainda foram classificadas as perguntas conforme o conte?do na perspectiva de Coll et al (1998). A conduta dos professores diante as perguntas nas aulas de qu?mica foram tratadas por meio da An?lise Textual Discusiva ? ATD, emergindo cinco categorias de an?lise. Tamb?m foram analisadas as perguntas na perspectiva da gest?o da sala de aula, emergindo nove categorias que foram analisadas. Foram tamb?m realizadas entrevistas semiestruturadas com os professores participantes da pesquisa, sendo, neste caso, produzidas categorias ?a priori?. Os resultados das entrevistas refor?am o resultado das outras an?lises, que permite observar que a maioria das perguntas prov?m dos professores, o que remete a um ensino transmissivo e reprodutivo, muito comum nos livros did?ticos. Possibilita concluir tamb?m que as perguntas de estudantes e professores s?o, em sua maioria, de perfil informativo, pois ? muito pequeno o n?mero de perguntas manifestas nas aulas observadas com potencial para investiga??o, o que caracteriza um modelo did?tico em que prevalece a transmiss?o do conhecimento aos estudantes.

論文(哲學碩士)--香港中文大學硏究院歷史學部,1994. / 參考文獻: leaves 1-14 (last group) / [馬木池]. / 圖表索引 / 前言 / Chapter 第一章 --- 清前期潮州地區書院的發展 / Chapter (一） --- 書院的廢毀時期--順治元年至康熙二〇年 / Chapter (二) --- 書院的恢復期--康、雍時期 / Chapter (三） --- 書院發展的高峰期--乾隆時期 / Chapter (四) --- 書院發展的沉寂期--嘉、道、咸時期 / Chapter 第二章 --- 清前期潮州地方社會與書院發展的關係 / Chapter (一） --- 清前期潮州地方社會問題 / Chapter (二） --- 清前期地方官治潮政策分析 / Chapter 第三章 --- 清前期地方官與書院 / Chapter (一） --- 地方官與書院的興修 / Chapter (二） --- 地方官與書院經費 / Chapter (三） --- 地方官與書院的運作 / Chapter 第四章 --- 清前期地方士紳與書院 / Chapter (一） --- 清初潮州地區推廣「官話」政策的成敗--以潮籍為主的書院院長 / Chapter (二） --- 書院院長與地方社會 / 總結 / 參考書目

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2016-10-13T18:50:52Z No. of bitstreams: 1 2015 - Vitor Sueth Santiago.pdf: 10611307 bytes, checksum: 28bcb538332e756e608d3f04694b22b6 (MD5) / Made available in DSpace on 2016-10-13T18:50:52Z (GMT). No. of bitstreams: 1 2015 - Vitor Sueth Santiago.pdf: 10611307 bytes, checksum: 28bcb538332e756e608d3f04694b22b6 (MD5) Previous issue date: 2015-10-16 / CAPES / FAPERJ / CAPES-PROCAD / This work aimed to characterize the trypanocidal activity of curcumin, as well as synthesise a set of structurally-related compounds to investigate the relationships between chemical structure and biological activity (SAR). The isolation of natural curcumin was carried along with two other natural curcuminoides, which together with a third (cyclocurcumin) formed the very first set of derivatives subjected to a screening against epimastigotes forms of T. cruzi (Dm28c strain). This screening pointed out the 1,3-diketone moiety as well as the methoxyl- group in the position 3 of the aromatic ring as potencial pharmacophores. Then, a set of synthetic analogues were prepared based on rational changes on the three structural subunits present in curcumin. These synthetic derivatives were subjected to the same screening, and three of them showed superior trypanocidal activity compared to the natural product. Then, taking the informations obtained from this first screening, the synthesis of constrained analogues were performed which showed an interesting result based on the ring-size of the derivatives. In parallel, a series of 1,3-pyrimidine derivatives were prepared, based on potential bioisosteric relationships between the 1,3-diketone moiety and the 1,3-pyrimidine heterocycle. All the derivatives obtained were tested against T. cruzi, and those shown trypanocidal activity were submited to a cell viability assay, where three of the synthetic derivatives demonstrated selective toxicity against the parasite: (E) ? 2 - (4 ? hydroxy - 3-methoxybenzylidene) ? 6 - ((E) ? 3 - (4 ? hydroxy ? 3 - methoxyphenyl) acryloyl) cyclohexanone; (2E,6E) - 2,6 ? bis (4 ? hydroxy ? 3 -methoxybenzylidene) cyclohexanone and 4,4 '- ((1E,1'E) - (2 ? chloropyrimidine - 4,6 - diyl) bis (ethene - 2,1 - diyl)) bis (2 -methoxyphenol). These derivatives were tested in an assay of infected macrophages, and they prove to be toxic for both parasite forms (trypomastigote and amastigote). The investigation of the probable mechanism of action started with a scanning/transmission electronic microscopy of the curcumin-treated parasites in a sublethal dose. The analysis of ultraestructural changes in parasite treated cells suggested the enzyme CYP51 as well as tubulin as possible targets for curcumin. The HPLC analysis of the membrane lipids of treated parasites showed no difference when compared to non treated control. The flow cytometry analysis showed a characteristic profile similar to those compounds who binds to tubulin and disrupts microtubules. To improve this hypothesis, the T. cruzi tubulin was modelled by homology and the curcuminoids were docked at the literature known curcumin site. The results obtained showed a good correlation between the best-scored poses obtained from the docking study and the experimental IC50 values obtained from the assays of the natural derivatives against parasite cells. / Este trabalho teve como principal objetivo a caracteriza??o da atividade tripanocida da curcumina, bem como a s?ntese diversos derivados estruturalmente an?logos a fim de investigar rela??es entre a estrutura qu?mica e a atividade biol?gica. O isolamento da curcumina da matriz natural foi realizado juntamente com outros dois curcuminoides, que em conjunto com um terceiro (ciclocurcumina) formou o primeiro conjunto de compostos submetido a uma triagem biol?gica sobre formas epimastigotas de T. cruzi (cepa Dm28c). Nesta triagem foi detectado como farmac?foro a subunidade 1,3-dicetona e o grupamento metoxila na posi??o 3 do anel arom?tico. Em seguida, foi sintetizada uma cole??o de derivados com modifica??es em tr?s subunidades estruturais da curcumina, os quais foram submetidos a uma triagem frente ao parasito. Tr?s dos an?logos sint?ticos apresentaram atividade t?xica frente ao parasito de maneira superior ao produto natural. Em seguida, usando informa??es da primeira triagem, procedeu-se para a s?ntese de an?logos estruturalmente restritos, os quais apresentaram um importante resultado acerca dos aspectos conformacionais associados ao tamanho do anel utilizado para a restri??o. Em paralelo foi sintetizada uma s?rie de derivados estruturalmente originais explorando a potencial rela??o bioisost?rica entre a subunidade 1,3-dicetona e o anel pirimid?nico. Ap?s triagem de todos os derivados frente a formas epimastigotas de T. cruzi, foi realizado um ensaio de viabilidade celular onde tr?s derivados sint?ticos demonstraram toxicidade seletiva frente ao parasito nas concentra??es testadas: (E) -2- (4-hidr?xi-3-metoxibenzilideno) ? 6 - ((E) ? 3 - (4 - hidr?xi- 3- -metoxifenil) acriloil) cicloexanona, (2E,6E) -2,6-bis (4 ? hidr?xi ? 3 - metoxibenzilideno) cicloexanona e 2-cloro-4,4'- ((1E,1'E) ? pirimidina - 4,6 - diilbis (eteno - 2,1-diil)) bis (2-metoxifenol). Estes derivados foram utilizados em um modelo de macr?fagos infectados, onde provaram ser t?xicos tanto para formas tripomastigotas quanto para formas amastigotas do parasito. Na investiga??o do prov?vel mecanimo de a??o desta classe de compostos, os parasitos tratados com curcumina foram submetidos ? microscopia eletr?nica, onde foram observadas altera??es ultraestruturais no parasito que sugerem como alvos a CYP51 e a tubulina. O ensaio de quantifica??o dos lip?dios n?o-saponific?veis da membrana celular de T. cruzi sugere que n?o houve inibi??o de CYP51, ao passo que a citometria de fluxo das culturas tratadas mostrou um perfil caracter?stico de subst?ncias que atuam sobre os microt?bulos das c?lulas, se ligando ? tubulina. Foi ent?o constru?da por modelagem molecular um modelo de tubulina de T. cruzi onde os curcuminoides naturais ativos foram ancorados, e as pontua??es do ancoramento foram coerentes com os valores de CI50 encontrados.