La presente investigación aborda la novela de fin de siglo XX en Colombia entre 1990 y 2005 desde una orientación panorámica. El estudio se plantea desde el punto de vista de la escritura y se elabora a través del análisis de algunas novelas del periodo a partir de los conceptos mundo, autor, fragmento. Para ello se centra en las novelas Rosario Tijeras de Jorge Franco, Entre fantasmas de Fernando Vallejo, y Pavana del ángel de Roberto Burgos Cantor. Así las cosas el estudio presenta tres capítulos centrales. En la introducción se explica el propósito de la investigación. El primer capítulo trabaja el concepto de mundaneidad en la obra de Rosario Tijeras de Jorge Franco, dialogando con la novela Después de todo de Piedad Bonnett y El anarquista jubilado de Roberto Rubiano. El segundo capítulo intenta delimitar el concepto de autor y la forma como se configura en Entre fantasmas de Fernando Vallejo, para ello se pone en diálogo con Asuntos de un hidalgo disoluto de Héctor Abad Faciolince, Amirbar de Álvaro Mutis, Érase una vez el amor pero tuve que matarlo de Efraim Medina Reyes y Vida feliz de un joven llamado Esteban de Santiago Gamboa. El tercer capítulo analiza el modo como se presenta el fragmento en la novela Pavana del ángel de Roberto Burgos Cantor, novela que se inscribe en la tradición literaria de Colombia y, en particular, del Caribe colombiano. Dicha novela se pone en relación con la novela Opio en las nubes de Rafael Chaparro Madiedo y se relaciona también con la novela Los cuadernos de N. de Nicolás Suescún. Finalmente, en las conclusiones se busca fijar las líneas generales del camino que se ha seguido en esta investigación. / This research studies the romance on the end of the twentieth century in Colombia between 1990 and 2005 in a panoramic orientation. The analysis is approached from the point of view of writing and is made through the analysis of some novels of the period from the concepts of world, author and fragment. This research, also, is focused on the novels Rosario Tijeras by Jorge Franco, Entre fantamas by Fernando Vallejo and Pavana del angel by Roberto Burgos Cantor. On this way, the study presents three chapters; the introduction presents the purpose of the research and its explanation. The first chapter works with the concept of worldliness in the romance Rosario Tijeras by Jorge Franco, in a direct dialogue with the novel Después de todo by Piedad Bonnett and El anarquista jubilado by Roberto Rubiano. The second chapter attempts to define the concept of author and how it is configured in Entre fantasmas by Fernando Vallejo, for that purpose, it is brought into dialogue with Memorias de un hidalgo disoluto by Héctor Abad Faciolince, Amirbar by Alvaro Mutis, Érase una vez el amor pero tuve que matarlo by Efraim Medina Reyes and Vida feliz de un joven llamado Esteban by Santiago Gamboa. The third chapter discusses how the fragment is presented in Pavana del ángel by Roberto Burgos Cantor, a novel that is part of the literary tradition of Colombia and in particular, the Colombian Caribbean. This novel is set in relation to the novel Opio en las nubes by Rafael Chaparro Madiedo and also relates to the romance Los cuadernos de N., by Nicolás Suescún. The conclusion tries to define the way this research was developed.

This thesis explores two approaches to fragment-based drug discovery. First, protein target CK2 was chosen due to its importance in the cancer phenotype. A literature fragment, NMR154L, proved to be a promising compound for fragment development, due to its binding at the interface site of the protein rather than the highly conserved ATP pocket. Analogues were synthesised of this fragment leading to a candidate with a better IC50. Additionally, computer modelling of the interface site suggested that a series of spirocyclic compounds would inhibit this protein. These were synthesised and tested in vitro. Results from these tests were analysed and informed the synthesis of new inhibitors with the aid of crystal structures and computer modelling. Secondly, to address the lack of spirocyclic scaffolds in fragment screening libraries a number of diversity-orientated synthetic campaigns were undertaken. The first of these utilised glycine as starting material. Two terminal alkenes were installed. The alkenes were linked and the amino and acidic residues cyclised. This allowed for the formation of a diverse range of spirocyclic scaffolds from this one starting material. Having established chemistry for linking amino and acidic residues a campaign with dehydroalanine was under taken. This would allow for the installation of the second ring by pericyclic chemistry as well as using chemistry previously established. This pericyclic chemistry was also applied to synthesising spirocycles from rings with exocyclic double bonds. These being readily installed from Wittig chemistry, this allowed utilisation of starting materials which contained a cyclic ketone. Of these azetidinone was a good candidate due to the fact it was a commercially available building block and allowed access to spirocycles containing a 4-membered ring; an underrepresented ring size. Finally, computation analysis was carried out on the library to assess it diversity and any potential biological targets which these fragments may inhibit.

Este trabalho trata de atentar o Olhar para a cidade, especificamente em áreas de grande movimentação de transeuntes em São Paulo. E perceber a Cor como participante dos muitos elementos que compõem a cidade e a caracterizam -- como identidade de um lugar e como parte da memória das pessoas que a vivenciam. Pelo registro de percursos através de ensaio fotográfico, e pelo registro de fragmentos através de recurso pictórico, verifica-se a expressividade da Cor. / This study deals with an attempt to look at the city, specifically São Paulo, and perceive color as a participant of the many elements that constitute and characterize it -- as the identity of a place and part of the memory of those who experience the city. This has been done in high-traffic areas of passersby, where the city is even more fragmented and receives the most experienced interference in their daily life, by proposing two ways to capture and record the color: by the route, recorded in a photo essay, and by the fragments, recorded in a pictorial way -- linking people\'s memory to the colors of the places. In both cases, it appears that color expressiveness always depends on its functions and context; it is a matter of relationship between colors.

La glycoprotéine VI (GP VI) des plaquettes sanguines humaines est le récepteur principal du collagène, composé le plus thrombogénique d'une paroi vasculaire lésée. Ainsi, GPVI est souvent considérée comme une cible de premier plan pour développer des tests diagnostiques ou des stratégies thérapeutiques innovantes, efficaces et sûres afin d'améliorer encore la prise en charge des accidents ischémiques. Les anticorps monoclonaux et leurs fragments actifs produits par ingénierie moléculaire constituent aujourd'hui une nouvelle classe de biomolécules en plein essor avec des propriétés bien adaptées à des applications thérapeutiques et diagnostiques. Notre groupe a produit plusieurs anticorps monoclonaux anti-GPVI par immunisation génique de souris. Ces anticorps ont une affinité élevé pour leur cible. Ils de distinguent les uns des autres par leur spécificité épitopique ainsi que par les effets engendrés par leur liaison à GPVI. Parmi ces anticorps, l'un présente un fort potentiel diagnostique parce qu'il reconnait les formes mono- et dimériques de GPVI, mais sa liaison aux plaquettes peut induire une activation ou la perte de GPVI. Un autre anticorps présente un fort potentiel thérapeutique parce que ses fragments actifs monovalents obtenus par papaïnolyse neutralisent l'interaction entre les plaquettes et le collagène, sans activer les plaquette. Cependant, l'origine xénogénique de cet anticorps est responsable d'une forte immunogénicité qui en interdit des applications en médecine humaine. Dans cette étude, nous avons conçus un fragments variable d'anticorps simple chaine (scFv) utile pour quantifier l'expression de la GPVI à la surface des plaquettes sanguines. Ce scFv a été reformaté de façon à lui insérer un motif de reconnaissance de la Protéine L (PpL) qui facilite sa détection et sa purification sans avoir recours à un peptide "drapeau". Nous avons également humanisé et créé plusieurs fragments d'anticorps recombinants monovalents inhibiteurs de l'interaction GPVI / collagène. Ces fragments d'anticorps présentent un potentiel thérapeutique élevé. / Human platelets glycoprotein VI (GPVI) is evidenced to be a platelet receptor of major importance in the occurrence of arterial thrombosis. Thus, it can be considered to be of great interest in diagnosis and therapeutic of atheriosclerotic diseases. Antibodies are powerful molecules which can be used in both diagnostic as well as for therapeutic purposes due to their unique characteristics. Monoclonal and recombinant antibodies have antigen restricted specificity, high affinity and can be used in various assays. Moreover, the good knowledge of their structure and molecular engineering facilities now allows the antibody modulation according to desired properties.Our group has already produced several monoclonal antibodies to human GPVI by gene gun immunization against the immunoadhesin hGPVI-Fc, which differ in fine epitopespecificity, affinity and other functional properties (Lecut et al. 2003). One, 3J24, with diagnostic potential while the other, 9O12, has a therapeutic potential because it blocks the binding of GPVI to collagen. Its Fab fragment has been extensively characterized in vitro,ex vivo and in vivo for its antithrombotic properties.Here, we designed and reshaped a single-chain antibody fragment (scFv) based on 3J24variable domains for the quantification of GPVI with diagnostic potential. We were also involved in the design, production and functional evaluation of humanized anti-GPVI recombinant antibody fragments (scFvs and Fabs) with therapeutic properties.

A partir da leitura do livro Mínimos, Múltiplos e Comuns de João Gilberto Noll, este trabalho busca empreender um estudo sobre as relações entre a escrita do artista e tempo na figura dos instantes ficcionais, observando a questão do microrrelato e da exigência fragmentária (cf.P. Lacoue-Labarthe e Jean-Luc Nancy), na perspectiva do inacabado/unidade, o que projeta uma hipótese de conjunto constelar para a escrita de João Gilberto Noll. Inicialmente realiza-se uma reflexão de alguns temas importantes na fortuna crítica sobre o escritor, com a intenção de saber como estes reverberam na sua escrita para, em seguida, tratar do fragmento e suas perspectivas estéticas de inacabamento e de totalidade, com relação ao tempo e como dessas questões surge a metáfora crítica do instante ficcional. As leituras críticas usadas como operadores nortearam-se a partir das noções de fragmento (romântico), e de Acontecimento, relacionadas ao par conceitual Cronos/Aiôn deleuziano / Based on the reading of Mínimos, múltiplos e comuns, by João Gilberto Noll, this work seeks to undertake a study on the relationship between the artist writing and the time in the figure of "fictional instants, noting the issue of the micro-relate and the fragmentary requirement (cf.P. Lacoue-Labarthe and Jean-Luc Nancy), in the view of the unfinished / unit, which casts a whole constellate hypothesis on the writing of João Gilberto Noll. Initially, a reflection on some important topics that are recurrent in the critical fortune of the writer is carried out with the intention of finding out how they reverberate in his writings; then, the fragment and its aesthetics perspectives of incompleteness and wholeness are treated with respect to time; finally, it is observed how, from these issues, the critical metaphor of the fictional instant takes place. The critical readings used as operators have been guided by the notions of the fragment (romantic), and Event which is related to the conceptual pair Cronos / Aeon Deleuzian

Submitted by Natália Fernanda da Silva Trigo null (ntrigo@ymail.com) on 2017-03-12T22:09:09Z No. of bitstreams: 1 DISSERTACAO.pdf: 2622143 bytes, checksum: 4ae65c0ffcd4ae74cfdf9533a570c462 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-17T14:32:13Z (GMT) No. of bitstreams: 1 trigo_nfs_me_sjrp.pdf: 2622143 bytes, checksum: 4ae65c0ffcd4ae74cfdf9533a570c462 (MD5) / Made available in DSpace on 2017-03-17T14:32:13Z (GMT). No. of bitstreams: 1 trigo_nfs_me_sjrp.pdf: 2622143 bytes, checksum: 4ae65c0ffcd4ae74cfdf9533a570c462 (MD5) Previous issue date: 2017-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O presente trabalho analisa de que maneira as reflexões teórica sobre a criação poética de Novalis, que se materializam nos fragmentos de Pólen, relacionam-se com os poemas que compõem os Hinos à Noite. Procuramos analisar a relação dialética que as duas obras estabelecem que consiste no fato dos fragmentos possuírem características da poesia e de suas ideias estarem presente nos poemas. Analisamos os fragmentos que refletem sobre as teorias românticas acerca da poesia e do poético, compreendendo como se constitui nessa obra o pensamento crítico de Novalis sobre poesia e linguagem, estabelecendo, depois, ligações com os poemas, associando a reflexão crítica presente em Pólen com alguns elementos poéticos marcantes nos Hinos como o misticismo, a ideia de conhecimento, o símbolo, a valorização da Noite, da Morte e do Amor. Compreendemos que as duas obras estabelecem uma conexão de ideias, pois, entendemos os Hinos como uma poesia transcendental, sobre a qual Novalis teorizou em seus fragmentos, além disso, analisamos que os símbolos do Amor e da Morte estão presentes em ambas as obras e são construídos a partir de características em comum. Refletimos ainda que as duas obras se aproximam também no aspecto formal, uma vez que em ambas Novalis faz experimentações formais: em Pólen temos o desenvolvimento do fragmento como gênero, enquanto nos Hinos temos o poema em prosa e em verso. Verificamos, então, que Novalis dissolve as fronteiras entre poesia, teoria e crítica, tanto em relação as reflexões propostas e a linguagem utilizada quanto a composição formal, criando, com isso, uma maneira original de se pensar e se produzir as obras literárias, suas teorias e suas críticas. / The present work studies the way the theoretical reflection about the poetic creation of Novalis, that are present in the fragments of Pollen, have a relation with the poems of the Hymns to the Night. We analyze the dialectics relation that the two works have, which is the fragment having characteristics of poetry and the ideas of the fragments being present in the poems. We analyze the fragments that reflect the romantic theories about poetry and poetic, understanding how the critical thoughts by Novalis about poetry and language are made, establishing, after that, connections with the poems, and linking the critical reflection that’s in Pollen with some important poetic elements of the Hymns, as the mysticism, the idea of knowledge, the symbol, the valorization of Night, Death and Love. We recognize that the two works have a connection of ideas, because we understand the Hymns as the transcendental poetry, that Novalis theorized in his fragments. Furthermore, we analyze that the symbols of Love and Death are in both works and made with sharing characteristics. We also reflect that both works have similarities in the formal aspect, once that in both Novalis make formal experimentations: in Pollen we have the development of the fragment as a genre, and in the Hymns the poem in prose and verse. We also verified that Novalis dissolves the frontiers among poetry, theory and criticism, in relation to the proposed reflections and the language used as well as the formal composition, creating, with this, a new way of thinking and producing the literary compositions, their theory and their criticism.

Submitted by Cássia Santos (cassia.bcufg@gmail.com) on 2015-02-27T12:50:00Z No. of bitstreams: 2 Dissertação - Greice Japolla - 2014.pdf: 735093 bytes, checksum: 4795f79b674744556e9029a8e9b99c2f (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2015-03-04T11:45:39Z (GMT) No. of bitstreams: 2 Dissertação - Greice Japolla - 2014.pdf: 735093 bytes, checksum: 4795f79b674744556e9029a8e9b99c2f (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-03-04T11:45:39Z (GMT). No. of bitstreams: 2 Dissertação - Greice Japolla - 2014.pdf: 735093 bytes, checksum: 4795f79b674744556e9029a8e9b99c2f (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014-02-11 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Bovine herpesvirus type 1 ( BHV - 1 ) is recognized as an important pathogen of economic losses in cattle , these animals causing diseases known as infectious bovine rhinotracheitis ( IBR ) , infectious pustular vulvovaginitis , infectious balanoposthitis and neurological disorders . For effective control of these diseases, the correct diagnosis is necessary, but none of the available tests enables a quick result made the field. Considering this, the aim of this study was to construct a combinatorial antibody library, for it to be used in the future development of new diagnostic approaches . Two breed White Leghorn chickens were immunized with 105.5 TCID50/ml of BoHV - 1, birds were necropsied , their spleens removed for total RNA extraction , cDNA synthesis , amplification of gene fragments encoding the light chain ( VL ) and heavy ( VH ) and production of scFv ( v) fragments. These fragments were cloned into vectors fagomidiais expressed as fusion proteins on filamentous phage and amplified by infection of E. coli. Selection of viral particles ( fused scFv) binding to the BHV -1 ( biopanning ) by six cycles were performed. The affinity of the scFv antibody library BHV -1 observed in ELISA shows that the produced fragments are reactive to HIV, the use of such antibodies in the development of new diagnostic platforms is possible . The sequencing results showed a reduction of variability in comparison to the dot blot previously performed, and a desirable feature of this process , however, it was possible to sequence the clones efficiently, it has been found , therefore, a need to further analyze the shape of results / O herpesvírus bovino tipo 1 (BoHV-1) é reconhecido como um importante patógeno de perdas econômicas em bovinos, causando nestes animais enfermidades conhecidas como Rinotraqueite Infecciosa Bovina (IBR), vulvovaginite pustular infecciosa, balanopostite infecciosa e desordens neurológicas. Para um efetivo controle destas enfermidades, o diagnóstico correto se faz necessário, porém nenhuma dos testes disponíveis possibilita um resultado rápido feito a campo. Considerando isto, o objetivo deste estudo foi construir uma biblioteca combinatorial de anticorpos, para que esta seja futuramente utilizada no desenvolvimento de novas abordagens diagnósticas. Duas galinhas da raça White Leghorn foram imunizadas com 105,5 DICC50/mL de BoHV-1, as aves foram necropsiadas, seus baços retirados para extração de RNA total, síntese de cDNA, amplificação dos fragmentos gênicos codificantes das cadeias leve (VL) e pesada (VH) e produção de fragmentos scF(v). Estes fragmentos foram clonados em vetores fagomidiais, expressos como proteínas de fusão em bacteriófagos filamentosos e amplificados pela infecção de bactérias E.coli. Foi realizada a seleção de partículas virais (scFv fusionados) ligantes ao BoHV-1 (biopanning) através de seis ciclos. A afinidade da biblioteca de anticorpos scFv ao BoHV-1 observada no teste de ELISA mostra que os fragmentos produzidos são reativos ao vírus, sendo possível a utilização destes anticorpos no desenvolvimento de novas plataformas de diagnóstico. Os resultados de sequenciamento mostraram uma diminuição da variabilidade em comparação ao dot blot realizado anteriormente, sendo uma característica desejável neste processo, porém não foi possível sequenciar os clones de modo eficiente, verificando-se, portanto, a necessidade de analisar de forma mais aprofundada os resultados obtidos .

Esta dissertação propõe uma leitura de Lecciones para una liebre muerta (2005a) e El gran vidrio (2007) do escritor Mario Bellatin. Analisamos tais obras no que diz respeito à reelaboração estética que elas promovem de duas formas narrativas, o romance e a autobiografia. Neste sentido, as noções teóricas do pós-estruturalismo francês, desenvolvidas pelos chamados filósofos da linguagem (Barthes, Blanchot, Derrida e Foucault), como a escritura, o fragmento, o gênero enquanto horizonte de criação artística (não como norma) e a transgressão foram fundamentais para abordar as novas propostas que as referidas obras de Bellatin comportam. O romance e a autobografia propuseram-se, historicamente, a traçar a vida. Aquele ao ambicionar uma forma totalizante que reconstituiria o sentido perdido na existência empírica e esta ao visar ao entendimento de si. Assim, perscrutamos o lugar que o mundo bellatiniano confere ao vivido ao trabalhá-lo nesses gêneros. Nossa hipótese é a de que, ao apostar na exacerbação de alguns recursos formais, tais como: a figuração de si, a abertura a outras linguagens artísticas, a fragmentação do relato e a retomada da própria obra, a literatura bellatiniana desvela um universo singular que tensiona os ideais da modernidade literária, sem romper, em definitivo, com eles. Lecciones para una liebre muerta permitiu-nos colocar a pergunta acerca da existência de uma nova configuração do romance no contexto da contemporaneidade ou da explicitação de sua ineficácia simbólica no presente. Por outra parte, El gran vidrio possibilitou-nos indagar acerca do estatuto do discurso de si num cenário cultural que reconfigurou a noção do sujeito / This dissertation proposes a reading of Lecciones para una liebre muerta (2005a) and El gran vidrio (2007) written by Mario Bellatin. These works were analyzed concerning the aesthetic reworking they put forward of two narrative features: the novel and the autobiography. In this sense, the theoretical notions of the French post-structuralism, developed by the so called philosophers of language (Barthes, Blanchot, Derrida e Foucault), such as the writing, the fragment, the genre appearing as a guidance for the artistic creation instead of a norm and the transgression were central to approach the new proposals embraced by the aforementioned works of Bellatin. Both the novel and the autobiography have had the purpose, historically, to trace life. The former by ambitioning a totalizing form that would recompose the meaning lost in the empirical existence, and the latter by aiming the understanding of the self. Therefore, it has been explored this place which the bellatinian world has granted to the living by working it within these genres. Our hypothesis is that by waging on the exacerbation of some formal features, such as: the self-figuration, the opening to other artistic languages, the narrative fragmented and the resumption of the work itself, the bellatinian literature uncover an unique universe that tensions the ideals of the literary modernity, without rupturing ultimately with them. Lecciones para una liebre muerta has enabled us to position a question about the existence of a new configuration of the novel inside the context of the contemporaneity or about the explicitation of its symbolic ineffectiveness on the present. On the other hand, El gran vidrio allowed us to enquire the discourse status of the self in a cultural scenery that has reconfigured the notion of the subject

Previous studies suggest a degree of homology between eukaryotic replication, transcription and translation proteins and archaeal ones. Hence, Archaea are considered a simplified model for understanding the complex molecular machinery involved in eukaryotic DNA metabolism. DNA replication in eukaryotic cells is widely studied. In recent years, DNA replication studies expanded on the archaeal DNA replication machinery. P. abyssi was the first archaeon whose genome was fully sequenced. Genome sequencing and comparative genomics have highlighted an MCM-like protein in P. abyssi. In this study, I report the biochemical and structural characterisation of PabMCM. PabMCM is explored as model for understanding more complex eukaryotic MCM proteins and unravelling the biochemical mechanism by which MCM proteins release their helicase activity. The crenarchaeon Sulfolobus solfataricus possesses a simplified toolset for DNA replication compared to Eukaryotes. In particular, S. solfataricus has a subset of the eukaryotic Okazaki fragment maturation factors, among which there are a heterotrimeric DNA sliding clamp, (the proliferating cell nuclear antigen, PCNA), the DNA polymerase B1 (PolB1), the flap endonuclease (Fen1) and the ATP-dependent DNA ligase I (LigI). PCNA functions as a scaffold with each subunit having a specific binding affinity for each of the factors involved in Okazaki fragment maturation. Here, the 3D reconstruction of PCNA in complex with the Okazaki fragment maturation proteins PolB1, LigI and Fen1 is reported.

abstract: Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) are the leading causes of early onset dementia. There are currently no ways to slow down progression, to prevent or cure AD and FTD. Both AD and FTD share a lot of the symptoms and pathology. Initial symptoms such as confusion, memory loss, mood swings and behavioral changes are common in both these dementia subtypes. Neurofibrillary tau tangles and intraneuronal aggregates of TAR DNA Binding Protein 43 (TDP-43) are also observed in both AD and FTD. Hence, FTD cases are often misdiagnosed as AD due to a lack of accurate diagnostics. Prior to the formation of tau tangles and TDP-43 aggregates, tau and TDP-43 exist as intermediate protein variants which correlate with cognitive decline and progression of these neurodegenerative diseases. Effective diagnostic and therapeutic agents would selectively recognize these toxic, disease-specific variants. Antibodies or antibody fragments such as single chain antibody variable domain fragments (scFvs), with their diverse binding capabilities, can aid in developing reagents that can selectively bind these protein variants. A combination of phage display library and Atomic Force Microscopy (AFM)-based panning was employed to identify antibody fragments against immunoprecipitated tau and immunoprecipitated TDP-43 from human postmortem AD and FTD brain tissue respectively. Five anti-TDP scFvs and five anti-tau scFvs were selected for characterization by Enzyme Linked Immunosorbent Assays (ELISAs) and Immunohistochemistry (IHC). The panel of scFvs, together, were able to identify distinct protein variants present in AD but not in FTD, and vice versa. Generating protein variant profiles for individuals, using the panel of scFvs, aids in developing targeted diagnostic and therapeutic plans, gearing towards personalized medicine. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2018