Made available in DSpace on 2014-12-17T15:12:16Z (GMT). No. of bitstreams: 1 LauroECO_DISSERT.pdf: 1085358 bytes, checksum: dabb613523ffd286861b94e7cca78e0f (MD5) Previous issue date: 2012-03-30 / The present work focuses in the question of being-wit-others (Mitsein) on Martin Heidegger s philosophy. To do so, it takes base on his pivotal scripts, such as Being and Time and Na Introduction to Philosophy, in which this theme is scrutinized. The development line adopted in this work consists in advancing the existential connection between the being-with-others question attained to Dasein s ontological relation in its terms of authenticity and inauthenticity. So on, it is necessary to comment ? others philosophical elements that surround this alterity relationship, analyzing phenomenologically how being-in-the-world inflicts the Dasein in its deepest and more important choice aspects, which can direct Dasein to its authenticity or inauthenticity. Facing this decisory context, also shall be observed the way Dasein finds to share the truth in accordance with its interaction with others, and how this mode of being summarizes all ontological structure of man s comprehension. The truth works as an integrative element from which the Dasein cannot escape, being-with-others is an existential situation that Dasein is not able to stop itself from living (its life-in-progress). This work also contemplates the apparent contradiction of Dasein s been always unfolded in The They mode of being, in its everydayness and being like that interacting with others. As along as this question is developed, the work explains how it is possible to be authentic and resolute (as much as inauthentic) as the Dasein interscts with others, even though, there is no pre-defined rule for these ways of relationship between the Dasein and the others / O presente trabalho centra esfor?os na quest?o do ser-com os outros debatido na filosofia de Martin Heidegger. Para tanto, toma como base os seus escritos mais exponenciais, principalmente os seus excertos das obras Ser e Tempo e Introdu??o ? Filosofia, nos quais o tema ? pormenorizado. A linha de desenvolvimento no estudo feito consiste em perscrutar a liga??o existente entre a quest?o do Dasein para com os outros e como essa rela??o pode ser tomada em seus aspectos de autenticidade e inautenticidade. Para tanto, ? necess?rio tangenciar outros elementos filos?ficos atinentes a essa rela??o de alteridade, analisando fenomenologicamente como o modo de ser-no-mundo do Dasein o influencia em seus termos decis?rios mais profundos, os quais o direcionam para a autenticidade ou para a inautenticidade. Diante desse contexto decis?rio do Dasein, observa-se tamb?m a forma de compartilhar a verdade de acordo com a intera??o com os outros, e como esse modo de ser singulariza toda a estrutura ontol?gica de compreens?o do homem segundo esse elemento integrativo do qual ele n?o pode escapar, ser-com os outros ? uma situa??o existencial da qual o Dasein n?o se pode furtar a viv?-la. O trabalho tamb?m contempla a aparente contradi??o do Dasein estar sempre lan?ado no modo de ser impessoal na lida com os outros, explicando como ? poss?vel haver autenticidade (bem como tamb?m inautenticidade) nas intera??es com os outros, sem que haja uma regra definida previamente para tais formas de se relacionar com eles

This article seeks to highlight two dimensions of ethics. Understood as aconcept that refers, initially, to a mode of being, and also alludes to an “ought to be”. Starting from this, the aim is to establish some basis to discuss the problems deriving from this double dimension of ethics, stemming from certain ancient Greek philosoph- ical ideas, in particular from Aristotle’s ethics and certain statements from modern philosophy, emphasizing some relevant concepts of Kant’s moral theory. Using said arguments, the final purpose is to call attention to the dilemma in ethics. / Este artículo busca destacar dos dimensiones de la ética, concebida como un concepto que alude, inicialmente, a un modo de ser y que también refiere a un deber ser. A partir de esto se apunta a establecer algunas bases para la problematización y discusión sobre esta doble dimensión de la ética, atendiendo a algunos postulados de la filosofía antigua griega, en particular, de la ética aristotélica, y a determinadas afirmaciones de la filosofía moderna, enfatizando conceptos importantes de la moral kantiana. Con dichas herramientas, finalmente, se busca llamar la atención sobre el carácter dilemático de la ética.

Afin de déjouer les défenses immunitaires de l’hôte et créer les niches nécessaires à leur survie, les bactéries pathogènes mettent on œuvre de nombreux mécanismes ciblant les voies de signalisation de la cellule hôte. L’un de ces mécanismes repose sur la sécrétion de protéines bactériennes dans les cellules cibles afin de moduler directement leurs réseaux de signalisation. Cependant, les signaux, les senseurs et les effecteurs impliqués dans ces régulations sont encore peu ou mal connus. La détection de l’environnement dans la cellule hôte lors de l'infection est l’élément clé d’une réponse adaptée, et les systèmes de signalisation basés sur les mécanismes de phosphorylation sont indispensables à l'adaptation hôte-pathogène. L’aspect innovant de ce projet repose sur l’étude du rôle des Ser/Thr kinases et phosphatases sécrétées lors des interactions hôte-pathogène, modifiant ainsi la réponse globale de l’hôte durant l’infection. Pendant ma thèse, j’ai tout d’abord étudié le rôle d’une nouvelle protéine kinase bactérienne identifiée chez Coxiella burnetii, nommée CstK (Coxiella serine threonine Kinase). C. burnetii, l’agent étiologique de la zoonose appelée fièvre Q, modifie les défenses de la cellule hôte, permettant sa réplication dans des vacuoles spécifiques à l’intérieur de la cellule hôte. Par ailleurs, la sécrétion d’un grand nombre d’effecteurs bactériens est indispensable au détournement du phagosome par Coxiella. Nous ainsi avons démontré que cette potentielle protéine kinase, identifiée in silico dans le génome de C. burnetii, est capable de s’autophosphoryler et par conséquent possède une activité kinase. De plus, nous avons identifié différentes protéines spécifiques de la cellule hôte interagissant avec CstK à l'aide du modèle amibe Dictyostelium discoideum, un phagocyte professionnel eucaryote, permettant des études génétiques et biochimiques. Dans la deuxième partie de mon projet, je me suis intéressée au rôle d’une probable protéine sécrétée, la tyrosine phosphatase PtpA, durant l’infection par Staphylococcus aureus. Bien connue dans les hôpitaux, où elle est responsable de nombreuses maladies nosocomiales, cette bactérie possède un grand nombre de facteurs de virulence, responsables d’infections variées, et l’apparition exponentielle de souches multi-résistantes en font un problème majeur. Ce pathogène est capable d’envahir et de persister dans un grand nombre de types cellulaires différents chez l’Homme, en sécrétant des protéines effectrices qui vont moduler les réponses cellulaires. Nous avons démontré que PtpA était sécrétée durant la phase de croissance bactérienne, et pu déterminer que PtpA possédait une activité tyrosine phosphatase, régulée par la tyrosine kinase CapA1B2 de S. aureus. Enfin, en utilisant le modèle D. discoideum, nous avons pu identifier des protéines de l’hôte qui interagissent avec PtpA, mais leur rôle dans l’infection n’est pas encore connu. / Bacterial pathogens have developed diverse strategies towards host signalling pathways, in order to subvert the immune response and/or create permissive niches for their survival. One such strategy is based on the secretion of bacterial signalling proteins into the target host cells, thereby directly modulating the status of host signalling networks. Because the mechanisms involved are largely intractable to most in vivo analyses, very little is known about the signals, sensors, and effectors mediating these adaptations. Sensing the host environment is a key component to execute appropriate developmental programs, and the eukaryotic-like phosphosignaling systems in prokaryotes are emerging as equally important regulatory systems as the well-known eukaryotic systems, but the study of their functions is still in its infancy. The innovative aspect of this project resides in the study of the emerging role of secreted Ser/Thr kinases and phosphatases in the control of host-pathogen interactions thus modifying the global host response during infection. During my thesis, I first investigated the role of a novel bacterial protein kinase identified in Coxiella burnetii that we named CstK (Coxiella serine threonine Kinase). C. burnetii, the etiological agent of the emerging zoonosis Q fever, subverts host cell defenses, permitting its intracellular replication in specialized vacuoles within host cells. Secretion of a large number of bacterial effectors into host cell is absolutely required for rerouting the Coxiella phagosome. We demonstrated that this putative protein kinase identified by in silico analysis of the C. burnetii genome is able to autophosphorylate and undergoes in vitro phosphorylation. Moreover, we identified specific host cell proteins interacting with CstK, by the use of the model amoeba Dictyostelium discoideum, an eukaryotic professional phagocyte amenable to genetic and biochemical studies. In the second part of my project, I was interested in the role of a putative secreted protein tyrosine phosphatase (PtpA) during Staphylococcus aureus infection. Well-known in hospital-acquired diseases, this bacteria produces multiple virulence factors that lead to various severe diseases, and the increase of multi-resistant strains is a major concern. This pathogen has the ability to invade and persist in a number of different human host cell types, secreting effector proteins to modulate cellular responses. Here we demonstrated that PtpA is secreted during the bacterial growth. We also determined that PtpA presents a tyrosine phosphatase activity that is regulated by the tyrosine protein kinase CapA1B2 of S. aureus. At last, using the D. discoideum model, we identified some host proteins that interact with PtpA, but their link with infection still remain to be studied.

Made available in DSpace on 2016-03-15T19:40:38Z (GMT). No. of bitstreams: 1 Marcos Malta Campos.pdf: 466983 bytes, checksum: e34e360a58b6aa4ed21bde8fb800caac (MD5) Previous issue date: 2009-02-19 / Fundo Mackenzie de Pesquisa / This research aimed a daseinsanalytical understanding of the teenager Christopher s being-in-the-world (protagonist of the novel The Curious Incident of the Dog in the Night-Time), explaining the relationships of the character with others who are presented in his world. Christopher s manifestations can also be diagnosed as Asperger s Syndrome, according to DSM-IV-TR. The phenomenological method described by Giorgi was used to emerge the Christopher s being-with others phenomena, following a daseinsanalytical understanding based on the contributions of Martin Heidegger in his Zollikon Seminars. These seminars exposed Daseinsanalysis as an instrument able to understand healthy and sick existence, from appropriated concepts to human being. The research found out that Christopher get on with others predominantly in strangeness, seeing people many times as potently nocuous and seeking lonesomeness. The phenomena being-with others was demonstrated in Christopher s life, which suggests that this study confirms some of Heidegger s postulations. / Esta pesquisa teve por objetivo realizar uma compreensão daseinsanalítica do ser-no-mundo do adolescente Christopher, protagonista do romance O Estranho Caso do Cachorro Morto, explicitando as relações do personagem com as pessoas de seu mundo. O adolescente descrito no livro pode ser diagnosticado com Transtorno de Asperger, de acordo com critérios do DSM-IV-TR. Utilizou-se do método fenomenológico, conforme descrito por Giorgi, para realizar a emersão do fenômeno ser-com os outros do referido personagem, seguindo-se compreensão daseinsanalítica embasada nas contribuições do filósofo Martin Heidegger nos Seminários de Zollikon. Estes seminários visaram expor a Daseinsanalyse como instrumento capaz de compreender o existir sadio e o existir doente em geral a partir de concepções próprias à existência humana. Os principais resultados da análise apontam que Christopher relaciona-se com os outros predominantemente no modo da estranheza, enxergando as pessoas muitas vezes como potencialmente nocivas e buscando o isolamento. O fenômeno existencial ser-com foi concretamente demonstrado na vida do personagem, o que leva a pensar que em alguns momentos da análise o estudo ganhou um certo caráter de confirmação de postulações heideggerianas.

Traditionally, in Speech Emotion Recognition, models require a large number of manually engineered features and intermediate representations such as spectrograms for training. However, to hand-engineer such features often requires both expert domain knowledge and resources. Recently, with the emerging paradigm of deep-learning, end-to-end models that extract features themselves and learn from the raw speech signal directly have been explored. A previous approach has been to combine multiple parallel CNNs with different filter lengths to extract multiple temporal features from the audio signal, and then feed the resulting sequence to a recurrent block. Also, other recent work present high accuracies when utilizing local feature learning blocks (LFLBs) for reducing the dimensionality of a raw audio signal, extracting the most important information. Thus, this study will combine the idea of LFLBs for feature extraction with a block of parallel CNNs with different filter lengths for capturing multitemporal features; this will finally be fed into an LSTM layer for global contextual feature learning. To the best of our knowledge, such a combined architecture has yet not been properly investigated. Further, this study will investigate different configurations of such an architecture. The proposed model is then trained and evaluated on the well-known speech databases EmoDB and RAVDESS, both in a speaker-dependent and speaker-independent manner. The results indicate that the proposed architecture can produce comparable results with state-of-the-art; despite excluding data augmentation and advanced pre-processing. It was reported 3 parallel CNN pipes yielded the highest accuracy, together with a series of modified LFLBs that utilize averagepooling and ReLU activation. This shows the power of leaving the feature learning up to the network and opens up for interesting future research on time-complexity and trade-off between introducing complexity in pre-processing or in the model architecture itself. / Traditionellt sätt, vid talbaserad känsloigenkänning, kräver modeller ett stort antal manuellt konstruerade attribut och mellanliggande representationer, såsom spektrogram, för träning. Men att konstruera sådana attribut för hand kräver ofta både domänspecifika expertkunskaper och resurser. Nyligen har djupinlärningens framväxande end-to-end modeller, som utvinner attribut och lär sig direkt från den råa ljudsignalen, undersökts. Ett tidigare tillvägagångssätt har varit att kombinera parallella CNN:er med olika filterlängder för att extrahera flera temporala attribut från ljudsignalen och sedan låta den resulterande sekvensen passera vidare in i ett så kallat Recurrent Neural Network. Andra tidigare studier har också nått en hög noggrannhet när man använder lokala inlärningsblock (LFLB) för att reducera dimensionaliteten hos den råa ljudsignalen, och på så sätt extraheras den viktigaste informationen från ljudet. Således kombinerar denna studie idén om att nyttja LFLB:er för extraktion av attribut, tillsammans med ett block av parallella CNN:er som har olika filterlängder för att fånga multitemporala attribut; detta kommer slutligen att matas in i ett LSTM-lager för global inlärning av kontextuell information. Så vitt vi vet har en sådan kombinerad arkitektur ännu inte undersökts. Vidare kommer denna studie att undersöka olika konfigurationer av en sådan arkitektur. Den föreslagna modellen tränas och utvärderas sedan på de välkända taldatabaserna EmoDB och RAVDESS, både via ett talarberoende och talaroberoende tillvägagångssätt. Resultaten indikerar att den föreslagna arkitekturen kan ge jämförbara resultat med state-of-the-art, trots att ingen ökning av data eller avancerad förbehandling har inkluderats. Det rapporteras att 3 parallella CNN-lager gav högsta noggrannhet, tillsammans med en serie av modifierade LFLB:er som nyttjar average-pooling och ReLU som aktiveringsfunktion. Detta visar fördelarna med att lämna inlärningen av attribut till nätverket och öppnar upp för intressant framtida forskning kring tidskomplexitet och avvägning mellan introduktion av komplexitet i förbehandlingen eller i själva modellarkitekturen.

The phosphorylation-dependent PPIase (peptidyl prolyl isomerase), Pin1 (Protein interacting with NIMA#1), has been found to regulate cell cycle through a simple conformational change, the cis-trans isomerization of phospho-Ser/Thr-Pro amide bonds. A variety of key cell cycle regulatory phosphoproteins, including Cdc25 phosphatase,Cdc27, p53 oncogene, c-Myc oncogene, Wee1 kinase, Myt1 kinase, and NIMA kinas, have been confirmed as substrates of Pin1. Pin1 was also observed to be overexpressed in a variety of cancer cell lines, and the inhibitors of Pin1 showed antiproliferative activities towards these cancer cells. These results implied that Pin1 might serve as a potential anti-cancer drug target. Besides, Pin1 has an important neuroprotective function and represents a potential new therapeutic agent for Alzheimer's disease. In order to understand the interaction between Pin1 and Cdc25c and the role of Pin1 in the mechanism for the regulation of mitosis, two amide isosteres, Ser-Ψ[(Z)CH=C]-Pro-OH and Ser-Ψ[(E)CH=C]-Pro-OH were incorporated into two peptidomimetics derived from human Cdc25c. Phosphorylation of these two peptidomimetics by the incubation with Cdc2 was studied using LC-MS/MS technique. It was found that Cdc2 kinase was conformationally specific to its Cdc25c substrate. Only the trans conformer of Cdc25c at its Ser168-Pro position can be recognized and phosphorylated by Cdc2 kinase, thereby creating the binding site for Pin1. In an effort to improve the cell permeability of the charged inhibitors of Pin1, bisPOM (pivaloyloxymethyl) prodrug moiety was introduced to mask the phosphate group of Fmoc-pSer-Ψ[(Z)CH=C]-Pro-(2)-N-(3)-ethylaminoindole, which is one inhibitor of Pin1. Fmoc-pSer-Ψ[(Z)CH=C]-Pro-(2)-N-(3)-ethylaminoindole and its bisPOM prodrug were synthesized efficiently starting with Boc-Ser-Ψ[(Z)CH=C]-Pro-OH in 24% and 12% yields respectively. The charged inhibitor showed a moderate inhibition towards Pin1 (IC50 = 28.3 μM). Its antiproliferative activity towards A2780 ovarian cancer cells (IC50 = 46.2 μM) was significantly improved by its bisPOM prodrug (IC50 = 26.9 μM), which is comparable to the IC50 of the charged inhibitor towards Pin1 enzymatic activity. These results not only established the bisPOM strategy as an efficient prodrug choice for Pin1 inhibitors, but also added additional evidence for Pin1 as a potential anticancer drug target. / Ph. D.

Reversible protein phosphorylation is considered the universal language for intracellular communication in all living organisms. This process, catalysed by protein kinases and phosphatases, enables the translation of extracellular signals into cellular responses and also allows for adaptation to a constantly changing environment. In recent years, a number of bacterial eukaryotic-type Ser/Thr protein kinases and phosphatases have been identified. However, their precise functions and substrates are not yet well defined. The genome of opportunistic human pathogen Pseudomonas aeruginosa contains at least five genes encoding putative eukaryotic-type Ser/Thr protein kinases and phosphatases. In the first part of this study, we have attempted to establish the role of Ser/Thr protein kinase PpkA and phosphatase PppA, which belong to type VI secretion system H1-T6SS. Double mutant strain ∆pppA-ppkA was prepared in P. aeruginosa PAO1 background. Phenotypic studies revealed that the mutant grew slower than the wild-type strain in minimal media and exhibited reduced secretion of pigment pyocyanin. In addition, the mutant had altered sensitivity to oxidative and hyperosmotic stress conditions. Consequently, mutant cells had an impaired ability to survive in murine macrophages and an attenuated virulence in the...

Agostinho confere relevância especial às coisas simples. Na infância, cuja estatura é signo da humildade própria das coisas ínfimas, deleita-se com a verdade nos seus pequenos pensamentos sobre pequenas coisas. Este deleite, na alma da criança com mínimo de ser, remete à verdade de Deus, com máximo de ser. Com máximo de ser, Deus se humilha ao ponto de assumir a condição humana, nascer como criança e com humildade contrária à soberba anular o efeito da queda causada pela soberba. Fundamento da humildade que é, poderia ser pensado menor que o homem, pois sendo Deus se fez homem. Se assim fosse, o ser com máximo de ser seria, paradoxalmente, o ser com mínimo de ser. Mas não é, pois quando Deus desce à condição inferior é para elevar o homem à condição superior. Esta é a análise a que se propõe este trabalho. / Augustine confers special relevance to simple things. In infancy, whose stature is a sign of the humility characteristic of the lowest things, he delights in the truth in their small thoughts about small things. This delight, within the child with the least of being, remits to the truth of God, with the highest of being. Yet with highest of being, God humbles himself to the point of assuming the human condition, being born as a child and, with humility contrary to pride, nullifies the effect of the fall caused by pride. The foundation of humility that he is, he could be considered less than man, because being God he became man. If it were thus, the being with highest of being would, paradoxically, be the being with the least of being. But it is not like that, because when God descends to the inferior condition, hit is to elevate man to the superior condition. This is the analysis that this work proposes.

A Tese Confissões | Não | Declaradas apresenta um conjunto de experimentos poéticos realizados entre 2011 e 2015, cujo foco toma o corpo - para além do masculino e feminino - como subjetividade encarnada. Neles estão incorporadas tanto as investigações no campo das práticas artísticas quanto as reflexões no plano conceitual. A criação de campos sensórios em desenhos, esculturas, fotografias, gravuras e videoperformances refere-se às práticas artísticas. Já o desenvolvimento ensaístico do texto sobre as noções de corpo e sua conversão em imagem - de subjetividade como objeto de encarnação e de corpo fluido em estado artístico - remete ao plano conceitual em que os resultados dos experimentos poéticos se rebatem e se multiplicam. Como desdobramento disso, ainda são desencadeadas ideias sobre questões de gênero na interação erótica e, numa outra perspectiva, são desenvolvidas reflexões sobre o sujeito múltiplo metaestável como resultante de um processo de individuação contínuo. A metodologia que está na base dos experimentos poéticos é a pesquisa da sensação, porém empreendida com o objetivo de criar zonas estéticas capazes de dissolver formas corporais culturalmente crista / This thesis, entitled Confessions | Not | Declared, presents a series of artistic experiments conducted between 2011 and 2015, focusing on the human body beyond the categories of male and female, taken as embodied subjectivity. These experiments embody both artistic practice-based research and theoretical considerations. Artistic practice refers to the creation of sensory fields in drawings, sculptures, photographs, prints and video performances. The theoretical analysis examined some notions of the human body converted into image: the notion of incarnated subjectivity and the notion of a flowing body in artistic state, and how these concepts related to the artistic experimentation. Furthermore, both ideas on gender issues in erotic interaction and, from a different perspective, reflections on a metastable, multiple subject resulting from a continuous process of individuation, were considered. Sensation research was the methodology underpinning the artistic experiments. With this approach, aesthetic zones were created that dissolved culturally constructed notions of human body forms, and the images produced, rather than mere images, were infused with story-telling power.

O presente trabalho é um estudo da noção de não ser em Parmênides. Este estudo se propõe a preencher uma falta que, ao longo do século XX e agora no XXI, foi se tornando cada vez maior, na medida em que crescia o interesse por essa noção extraordinária, que pertence ao universo da lógica e da ontologia antigas e da nossa atualidade. Para evidenciar essa noção o trabalho deixou de lado os demais aspectos do poema, principalmente o estatuto do ser, e se restringiu à análise da noção de não ser. Para tanto, foi desenvolvida uma metodologia que pudesse tornar claros tanto o problema inicial parmenidiano quanto a solução que ele propõe. Descobriu-se, então, uma habilidade específica de Parmênides em observar o comportamento da mente humana; com isto, o estudo esclareceu o papel do método de Parmênides para compensar a amechanie (falta de recursos) do homem comum na compreensão do mundo. Ele identifica o não ser como objeto virtual que enganosamente confunde aquele que se põe no caminho da pesquisa, pois, para Parmênides, o não ser é impossível. Com a noção desta impossibilidade ele determina, discute e aplica o método que garante a persuasão verdadeira, um autêntico princípio de não-contradição, mas diferente daquele de Aristóteles. A este princípio enunciado pela thea, para distingui-lo daquele do Estagirita, o autor dá o nome de Preceito da Deusa. / The present work is an inquiry into the notion of non-being in Parmenides. The study has the purpose of filling a lack that increased, along the XX century and now in the XXI, according to the growth of concern about this extraordinary notion, which belongs to the universe of ancient and modern logic and ontology. With the aim of making this notion evident, the work put aside the other aspects of the poem, mainly the statute of being, and was restricted to the analysis of the notion of non-being. For this reason, a methodology was developed that could make clear both the initial parmenidian problem and the solution that he offers. A specific ability was discovered, that of Parmenides as observer of the human mind; with this, the study made clear the role of Parmenides method to compensate the amechanie (lack of resource) of the common man in understanding the world. He identifies the non-being as a virtual object that deceptively confounds that who takes the way of inquiry, because, to Parmenides, non-being is impossible. With the notion of this impossibility, he determines, discusses and applies the method that certifies the true persuasion, an authentic principle of non-contradiction, albeit different of that of Aristotle. To this principle enunciated by the thea, to distinguish it from that of Stagirite, the author gives the name of Precept of the Goddess.