Diabetes Mellitus is a group of diseases, prevalence and incidence of which is on the rise not only in the Czech Republic, but also worldwide. This diploma work aims to analyze market situation and opportunities for modern oral anti-diabetic drugs. This work also designs suitable positioning for new OADs of Novartis -- Galvus and Eucreas.

No description available.

Inwardly rectifying potassium (IRK/Kir) channels regulate intracellular K+ concentrations and membrane potential. Disruption of Kir2.1 causes dominantly inherited Andersen Tawil Syndrome (ATS). ATS patients suffer from cardiac arrhythmias, periodic paralysis, and cognitive impairment. These symptoms are consistent with current understanding of the role of ion channels in muscle cells and neurons. However, ATS symptoms also include craniofacial and digital deformities such as cleft palate, dental defects, wide set eyes, low set ears, and crooked or fused digits. These developmental defects were not consistent with current understanding of developmental signaling or previously described roles for ion channels. We found that phenotypes exhibited by the Kir2.1 knockout mouse recapitulate ATS symptoms. The Kir2.1 knockout mouse phenotypes are strikingly similar to those that occur when Transforming Growth Factor β/Bone Morphogenetic Protein (TGFβ/BMP) signaling is disrupted. Based on this observation, we hypothesized that Kir2.1 may play a role in TGFβ/BMP signaling. We tested this hypothesis using Drosophila melanogaster. We reduced a Kir2.1 homologue Irk2 by siRNA, eliminated the Irk2 channel with a deficiency, and abolished heteromeric Irk channel function with a dominant negative Irk2. Reduction of Irk2 function caused wing patterning defects and size reduction that are similar to BMP/Decapentaplegic (DPP) mutant phenotypes. Ubiquitous expression of Irk2DN is lethal. Wing specific Irk2DN expression caused severe defects compared to irk2Df demonstrating that Irk channels are heteromeric. We found that two downstream targets of Dpp were reduced in irk2Df and siRNA expressing wing discs showing that Dpp requires Irk2 activity. We found that wing specific expression of Irk2DN completely prevents Mad phosphorylation and induces apoptosis. Suppression of apoptosis does not rescue MAD phosphorylation showing that apoptosis is caused by lack of an external signal. We systemically tested the components of the Dpp signaling cascade to find at what point in Dpp signaling Irk2 is required. We found that Irk2 is not directly required for the intracellular propagation of the Dpp signal. Irk2DN could not eliminate the phosphorylation of Mad by a constitutively activated Tkv. We showed that Irk2 affects Dpp spread across the disc. We speculate that Irk2 affects the endocytic pathway that transports Dpp from medial cells to lateral cells. We tested the impact of irk2DN on the development of the Drosophila eye where Irk2 is expressed and Dpp is required for normal patterning. We found that abolition of Irk channels causes eye defects that are similar to those that occur with the loss of Dpp signaling. Trachea development also depends on Dpp. Blocking Irk2 in the developing trachea results in severe defects. We conclude that Irk2 plays a global role in Dpp signaling. Kir/Irk channels could be therapeutic targets to treat diseases that are impacted by TGFβ/BMP signaling, such as cancer. Furthermore, the demonstration that Irk2 is a node for BMP-like signaling could be used to control cell fate decisions for regenerative medicine or stem cell therapeutics.

No description available.

Les cellules solaires organiques sont une technologie très prometteuse grâce à leur faible-coût de fabrication, leur flexibilité et leur légèreté. Actuellement, elles ne sont qu’au stade du prototype à cause de leurs faibles rendements et leur courte durée de vie. L’une des voies les plus étudiées pour améliorer le rendement est la conception de nouveaux matériaux photo-actifs. Lors de cette thèse, deux séries de semi-conducteurs donneurs d’électrons. La première série comprend trois oligomères, chacun composé de trois unités de diketopyrrolopyrrole (DPP) qui est un chromophore très étudié dans la littérature. Ces oligomères ont la particularité d’absorber dans le proche infra-rouge. En intercalant différents groupements donneurs d’électrons entre les DPPs, différentes torsions sont obtenues le long de leur squelette. Ceci a permis d’établir qu’un oligomère plan a une plus grande cristallinité et par conséquent transporte mieux les charges, atteignant une mobilité de trou de 10-3 cm². V-1.s-1. Cependant, cette forte cristallinité entraîne une hétérojonction volumique défavorable et un faible rendement photovoltaïque (<1%). La deuxième série est composée de quatre petites molécules combinant une unité 3,3’-(ethane-1,2-diylidene)bis(indolin-2-one) (EBI) avec différents groupements donneurs d’électrons: thiophène (EBI-T), benzofurane (EBI-BF) and bithiophène (EBI-2T)). Les dérivés EBI ont été testés dans les transistors à effet de champ et dans les cellules solaires en tant que semi-conducteurs donneurs. La meilleure mobilité de trou de 0,021 cm².V-1.s-1 a été mesurée avec EBI-BF grâce à sa conformation plane alors que le PCE maximal de 1.92% est obtenu avec EBI-2T grâce à son large spectre d’absorption et une morphologie adéquate. / Organic solar cells appear as a promising technology within photovoltaic field owing to their low-cost fabrication and their great flexibility enabling a widespread distribution. For now, they are still at the prototype stage due to their limited efficiency and lifetimes. Many efforts were realized in designing new materials as they are involved in every steps of the photovoltaic process and thus they dictate the cell efficiency. Along this thesis, two series of electron-donating semi-conductors were designed and synthesized. The first series consist in three oligomers containing three diketopyrrolopyrrole units, a well-studied chromophore. Those oligomers absorb up to the near infra-red region, a very interesting feature for light harvesting. Through the engineering of electron-rich spacers, various twists were generated in the oligomers backbone. The oligomer showing a coplanar conformation appears to be the most crystalline and thus exhibits the best charge transport properties with a hole mobility of 10-3 cm².V-1.s-1.iiiHowever, bulk heterojunction organic solar cells, this high crystallinity results in an unfavorable morphology and a PCE inferior to 1%. As for the second series, the four small molecules combined 3,3’-(ethane-1,2-diylidene)bis(indolin-2-one) (EBI), an electron deficient unit, and various electron-rich units such as thiophene (EBI-T), benzofuran (EBI-BF) and bithiophene (EBI-2T). Among EBI derivatives, EBI-BF demonstrated the highest hole mobility of 0.021 cm².V-1.s-1 in field effect transistors due to its coplanar conformation. Meanwhile, in bulk heterojunction solar cells, the highest PCE of 1.92% was obtained with EBI-2T:PC61BM blend owing to a more appropriate morphology and the broadest absorption spectrum of EBI-2T.

Ever since the formation of the Democratic Progressive Party in 1986, the party campaigned on Taiwanese nationalism and de jure independence. It was the party in Taiwan known for its unwavering stance in the “One China Policy”: it recognizes itself as the sole legitimate China. In light of the 2016 presidential elections, the DPP lead by Tsai Ing-Wen changed their usual secessionist rhetoric towards China to one that is much more moderate in stance. Tsai Ing-Wen has pledged to “maintain the cross-strait status quo”, a sharp contrast in opinion for the party. How can this change be explained? Is the Democratic Progressive Party of Taiwan self-regulating its language? What is the DPP self-regulating in response to? This study will look at whether the pressure is coming internally from the constituency or externally from China's military and economic pressure.

No description available.

abstract: Proper cell growth and differentiation requires the integration of multiple signaling pathways that are maintained by various post-translational modifications. Many proteins in signal transduction pathways are conserved between humans and model organisms. My dissertation characterizes four previously unknown manners of regulation in the Drosophila Decapentaplegic (Dpp) pathway, a pathway within TGF-beta family. First, I present data that the Dpp signal transducer, Mothers Against Dpp (Mad), is phosphorylated by Zeste-white 3 (Zw3), a kinase involved in the Wingless pathway. This phosphorylation event occurs independently of canonical phosphorylation of Mad by the Dpp receptor. Using ectopic expression of different alleles of Mad, I show that Zw3 phosphorylation of Mad occurs during the cell cycle in pro-neuronal cells and the loss of phosphorylation of Mad by Zw3 results in ectopic neuronal cells. Thus, Mad phosphorylation by Zw3 is necessary for cell cycle control in pro-neuronal cells. Second, I have shown that the regulator dSno, which has previously been shown to be a TGF-beta antagonist and agonist, is also a Wingless pathway antagonist. Loss of function flip-out clones and ectopic expression of dSno both resulted in changes of Wingless signaling. Further analysis revealed that dSno acts at or below the level of Armadillo (Arm) to inhibit target gene expression. Third, I have demonstrated that the protein Bonus, which is known to be involved in chromatin modification, is required in dorsal-ventral patterning. Further experiments discovered that the chromatin modifier is not only a necessary Dpp agonist, but it is also necessary for nuclear localization of Dorsal during Toll signaling. Last, I showed that longitudinal lacking-like (lola-like) is also required in dorsal-ventral patterning. The loss of maternally expressed lola-like prevents dpp transcription. This shows that lola-like is integral in the Dpp pathway. The study of these four proteins integrates different signaling pathways, demonstrating that the process of development is a web of connections rather than a linear pathway. / Dissertation/Thesis / Doctoral Dissertation Molecular and Cellular Biology 2014

Submitted by Gustavo Adolfo Martins Jotta Soares (profgustavoadolfo@gmail.com) on 2018-08-20T20:28:43Z No. of bitstreams: 1 fgv_dissertacao_gustavo_VF.pdf: 1174369 bytes, checksum: 13484b7307de172258d40696645c0b75 (MD5) / Approved for entry into archive by Janete de Oliveira Feitosa (janete.feitosa@fgv.br) on 2018-09-24T19:13:21Z (GMT) No. of bitstreams: 1 fgv_dissertacao_gustavo_VF.pdf: 1174369 bytes, checksum: 13484b7307de172258d40696645c0b75 (MD5) / Made available in DSpace on 2018-09-27T14:22:41Z (GMT). No. of bitstreams: 1 fgv_dissertacao_gustavo_VF.pdf: 1174369 bytes, checksum: 13484b7307de172258d40696645c0b75 (MD5) Previous issue date: 2018-06-25 / Merton’s portfolio optimization problem is the choice an investor must make of how much of its wealth it should consume and how much it should allocate between stocks and a risk-free asset in order to maximize the expected utility. The focus of this work was to solve two of the cases of the Merton problem. For this, we studied some fundamental themes, such as: Dynamic Principle Programming (DPP) and the Hamilton-Jacobi-Bellmann Equation (HJB Equation). In addition, we review some concepts of Stochastic Processes and some important results of Itô Calculus. Merton’s portfolio optimization problem is well known in finance and the central ideas for solving it are adaptable to solving other finance problems.

Made available in DSpace on 2014-06-12T22:59:59Z (GMT). No. of bitstreams: 2 arquivo4320_1.pdf: 763645 bytes, checksum: 4975bda035f0e72bf0e6bbbda5cc358d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2008 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / As propriedades fotofísicas dos íons lantanídeos têm motivado a busca por novos ligantes que possuam uma maior eficácia no processo de transferência de energia, contribuindo, portanto, para elevados rendimentos quânticos de emissão. A excitação direta dos íons é dificultada por causa da sua baixa absortividade molar, decorrente da natureza proibida das transições 4f-4f. A escolha de um ligante apropriado é muito importante para os processos luminescentes. Neste trabalho, os ligantes macrocíclicos (oligoéteres) chamados éteres coroa, especificamente, o 18-coroa-6, foi usado na síntese de compostos de coordenação precursores com Eu (III), Tb (III) e Gd (III). Com o interesse em remover moléculas de água, na primeira esfera de coordenação, utilizou-se o 2,3-bis(2-piridil)pirazina (2,3-dpp). Todos os complexos foram caracterizados por análise elementar e por métodos espectroscópicos (ultravioleta e infravermelho). O espectro de emissão de [Eu(18C6)(2,3-dpp)]Cl3 apresentou anormalidade da transição 5D0&#8594;7F4, indicando que o mesmo apresenta um ambiente de mais alta simetria em torno do íon Ln3+. Com a substituição das moléculas de água, houve um aumento na intensidade de luminescência, ficando evidenciado através dos cálculos das taxas radiativas