Thesis (M.A.)--Trinity Evangelical Divinity School, 1993. / Abstract. Includes bibliographical references (leaves 102-104).

Submitted by Estagiário SPT BMHS (spt@fgv.br) on 2012-01-12T12:51:41Z No. of bitstreams: 1 000060899.pdf: 3522230 bytes, checksum: 43c61e609f9a21d24827be738fda325c (MD5) / Made available in DSpace on 2012-01-12T12:52:05Z (GMT). No. of bitstreams: 1 000060899.pdf: 3522230 bytes, checksum: 43c61e609f9a21d24827be738fda325c (MD5) Previous issue date: 1993 / A partir d'une perspective spécifique, cette dissertação traite une problématique qui se constitue comme une des principales provocations qui se présentent à la reflexion contemporaine. 11 s'agit de ce qu'il convient d'appeler 'crise de la civilisation'; selon la perspective qui nous avons adoptée dans ce travail, cette crise est intimement liée à l'hégémonie dont une conception unilatéral de la raison a pris possession. Nous discutons ce theme en suivant la pensée de Carl Gustav JUNG -ce penseur qui doit être considéré un precurseur par rapport à l'approche de cette question et de ses conséquences pour l'humanité. Etant donné que la pensée de JUNG n'est pas amplement connue en dehors du domaine de la psychologie analytique, nous avons senti la nécessité de procéder à la pré sentation de quelques concepts fondamentaux forgés par lui, avant de discuter notre thématique spécifique. Dans un second moment, nous n?us occupons de la discussion du proces par lequel le rationalisme parvient à l'hégémonie qu'on lui concéde aujourd'hui, en analysant, ensuite, la réflexion que JUNG a développé en vue de surmonter le caractere unilatéral de la raison. Dans ce contexte, sa théorie de la synchronicité est spécialement soulignée par nous. / Esta dissertação aborda, desde uma perspectiva específica, uma problemática que se constitui em um dos maiores desafios que se apresentam para a reflexão contemporânea. Trata-se do que convém denominar de crise de civilização, estreitamente vinculada -para a perspectiva adotada nestas linhas- à hegemonia detentada por uma compreensão unilateral da razão. O tema é discutido seguindo o pensamento de um pensador -Carl Gustav JUNG- que deve ser considerado um precursor na abordagem desta questão e de suas consequências para o destino da humanidade. Não sendo o pensamento de JUNG amplamente conhecido fora da área de influência da psicologia analítica, pareceu necessário, antes de discutir a temática específica que constitui o objetivo desta dissertação, proceder à apresentação de alguns dos conceitos fundamentais por ele elaborados. Em um segundo momento é discutido o processo no qual o racionalismo atinge a hegemonia que hoje detenta, para analisar depois a reflexão desenvolvida por Jung na procura de superar a unilateralidade da razão, outorgando particular destaque à sua teoria da sincronicidade.

Postnatal depression is detrimental to maternal health and wellbeing, associated with poor developmental outcomes in children, and has prevalence estimates ranging from 13-60%; as such it is of significant public health concern and its origins are of interest from an evolutionary perspective. A growing movement within evolutionary research highlights the utility of evolutionary theory to elucidate the origins of health issues and indicate both novel approaches to treatment and prevention. A relatively longstanding, yet largely untested, existing evolutionary approach to postnatal depression proposes that it is a mechanism facilitating maternal investment decisions. More recently it has also been framed, somewhat complementarily, as the result of an evolutionary mismatch. Using the responses to a retrospective survey study which collected the complete reproductive histories of women and was uniquely designed to capture their experiences of postnatal depression, the first data chapter of this thesis explores whether there is support for adaptationist hypotheses that postnatal depression exhibits good design as a mechanism guiding maternal reproductive trade-offs. The results, combined with critiques put forward here and by other authors, suggest an alternative approach to postnatal depression is warranted. A limitation of both evolutionary and more traditional approaches to postnatal depression is that the commonly recognised risk factors for the condition fail to capture all the women who develop the condition. Recent developments in research into general depression, as opposed to postnatal depression, have highlighted the role of the immune system in symptom aetiology. This has led to a number of evolutionary researchers proposing that depression reflects an evolved inflammatory response to biological and social threat, with perceived social threat acting as an indicator of the likelihood of imminent biological threat. Inflammation then acts as the ultimate risk factor in the causal pathway to depression, and by extension postnatal depression, and suggests more attention needs to be paid to the social perceptions of women during pregnancy and early motherhood. Data chapters 3-6 explore the social pressures surrounding women about motherhood, the role such pressures play in generating feelings of shame (an emotional marker of social threat causally linked to general depression development), and the ability of shame to predict postnatal depression. Particular attention is paid to pressures surrounding socially approved levels of maternal investment, namely in the form of bonding. Bonding is of interest due to the documented association between postnatal depression and poor bonding as well as the pressures placed on women in contemporary, developed populations, highlighted by sociologists and feminist scholars, as a result of the emphasis on the importance bonding for child development. The role of social isolation, another form of social threat linked to general depression, in postnatal depression risk is also assessed. In so doing, a new model for maternal emotional investments is developed based on embodied capital theory and the results of two further data sets are presented - the first is a longitudinal survey study tracking women across the perinatal period assessing their experience of social pressure, shame, and postnatal depression, and the second an experimental priming study designed to assess if social threat can be primed using popular and social media relating to mothering. Results derived from these studies are supportive of the perception of social threat being a largely unrecognised risk factor in postnatal depression and the thesis concludes with a discussion of the public health implications which stem from this novel insight.

Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-04-25T19:04:21Z No. of bitstreams: 1 DissER.pdf: 752664 bytes, checksum: 521aece49e66912a8051885516ab0cd7 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-02T12:46:36Z (GMT) No. of bitstreams: 1 DissER.pdf: 752664 bytes, checksum: 521aece49e66912a8051885516ab0cd7 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-02T12:46:43Z (GMT) No. of bitstreams: 1 DissER.pdf: 752664 bytes, checksum: 521aece49e66912a8051885516ab0cd7 (MD5) / Made available in DSpace on 2017-05-02T12:50:18Z (GMT). No. of bitstreams: 1 DissER.pdf: 752664 bytes, checksum: 521aece49e66912a8051885516ab0cd7 (MD5) Previous issue date: 2016-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / In this works we will study G-graded algebras and G-graded polynomial identities, where G is an additive group. For main result we will describe a finite basis for Zn-graded polynomial identities of the matrix algebra of order n x n, with entries in a field F, This study will be divided into two stages: when the field F has characteristic zero and when the field F is infinite. These results were described by Vasilovsky [18] in 1999 and Azevedo [2] in 2006. / Nesta dissertação estudaremos álgebras G-graduadas e identidades polinomiais G-graduadas, onde G é um grupo aditivo. Como resultado principal descreveremos uma base finita para as identidades polinomiais Zn-graduadas da álgebra das matrizes n x n, com entradas em um corpo F, Este estudo será subdividido em duas etapas: quando o corpo F for de característica zero e quando o corpo F for infinito. Estes resultados foram descritos por Vasilovsky [18] em 1999 e por Azevedo [2] em 2006

L'objectif principal de ma thèse était de développer de nouvelles technologies et des outils pour l’étude de l’activation des récepteurs couplés aux protéines G (GPCR).À la surface de la cellule se trouve une multitude de récepteurs qui jouent un rôle critique dans la communication cellule-cellule, dont les GPCR, une famille de récepteur utilisant les protéines G intracellulaires pour transmettre leurs signaux. Le ciblage de ces récepteurs à des fins thérapeutique est innovant et très prometteur. Mais à ce jour seuls quelques médicaments ciblant les GPCR ont été mis sur le marché, en partie en raison d'un manque d'outils permettant le suivi de leur action sur les cellules natives.L’objectif de cette thèse est donc de développer des tests simples pour suivre l’activation de n’importe quel GPCR. Pour développer ce type de test, nous avons décidé d'utiliser des fragments d'anticorps appelés nanobodies. Les anticorps sont des protéines du sang produites en réponse à un antigène spécifique qui sont capable de le neutraliser. Les nanobodies correspondent au domaine variable de certains anticorps de camélidés. En raison de leur faible taille (13 kDa) et de leur site de liaison à l'antigène réduit, les nanobodies se lient souvent à des cavités et présentent une grande sensibilité aux changements de conformation de l'antigène. / The main objective of my thesis was to develop technologies and tools to study activation of G protein-coupled receptors (GPCRs).The cell surface is displaying a multitude of receptors, who play critical roles in cell-cell communication. Among them, GPCRs represent a large family relying on the use of intracellular G proteins for their signaling. Targeting these receptors for therapies is very promising and innovative. So far, only few new drugs have been put on the market, partly due to a lack of tools enabling the follow-up of their action on native cells.The aim of this thesis is thus to develop simple assays to study activation of any GPCRs. To develop this kind of test, we used antibody fragments called nanobodies. Antibodies are blood protein produced in response to and counteracting a specific antigen. Nanobodies correspond to antibody fragments derived from the variable domain of a special class of camelid antibodies. Because of their small size (13 kDa) and reduced antigen binding site, nanobodies often bind cavities and show a high sensitivity to antigen conformational changes.

Abstract The genomic organization and mRNA expression of the human GNAL gene on chromosome 18p11.2, a region that has been associated with bipolar disorder and schizophrenia, was determined. The GNAL gene was shown to span over 80 kb and consist of twelve exons, and its structure was very similar to adenyl cyclase stimulating G protein GSα. The start site of transcription was revealed by 5'-RACE. Two polyadenylation signals were found, and 3'-RACE assay was used to verify the functional site. The GNAL gene was expressed as approximately 6 kb transcripts in various regions of the human brain, and no alternative splicing was detected. One informative CA-dinucleotide repeat of 11 alleles and 74% heterozygosity was found in intron 5, and two single nucleotide polymorphisms in introns 3 and 10 were detected by SSCP. During characterization of the GNAL gene, two previously unknown genes were found. A novel intronless gene C18orf2 coding for a functionally unknown protein was localized to intron 5 of the GNAL gene. By semiquatitative RT-PCR, C18orf2 mRNA was found to be moderately expressed in all tissues studied here. Another novel gene, metallophosphoesterase MPPE1, was found to reside adjacent to the 3'-end of the GNAL gene in a tail-to-tail orientation. The deduced amino acid sequence revealed a highly conserved metallophosphoesterase motif gDxH..(16-60)..GDxxdr..(13-34)..GNH[DE], which is typical for various phosphate hydrolyzing enzymes, especially serine/threonine protein phosphatases. The MPPE1 gene contained fourteen exons and spanned about 27 kb. MPPE1 was expressed as a single mRNA of 2.2 kb in various regions of the human brain but not in any other tissues. Four different alternatively spliced forms of MPPE1 were detected by RT-PCR, and each transcript was shown to partially overlap with the 3'-untranslated region of the GNAL gene.

Les acides nucléiques riches en guanines ou en cytosines peuvent se replier sur eux-mêmes et former des systèmes tétramériques tels que les G-quadruplexes (G4) ou les i-motifs. Ces motifs, abondamment représentés dans certaines régions du génome humain semblent contribuer à la régulation cellulaire et suscitent depuis plusieurs années un intérêt grandissant. Ils sont notamment présents dans la région télomérique, mais aussi dans les promoteurs d’oncogènes ou au sein des génomes viraux et sont impliqués dans certaines pathologies humaines. Ils représentent ainsi des cibles thérapeutiques et diagnostiques potentielles. Cependant, les G4 adoptent in-vitro des topologies variées qui compliquent le développement de ligands spécifiques et affins. Dans ce contexte, le laboratoire a développé le concept du TASQ pour ‘‘Template Assembled Synthetic G-Quadruplex’’ dans le but d'accéder à des G4 se structurant en une topologie définie.Le premier chapitre décrit l’assemblage de mimes de motifs G4 contraints en une topologie unique. En utilisant un gabarit cyclodécapeptide rigide et différentes méthodes de conjugaison, nous avons assemblé des motifs G4 ARN parallèle et hybride ADN/ARN dérivant de la séquence télomérique ainsi qu’un motif G4 d’ADN présent dans la séquence promotrice du VIH-1. L’utilisation du concept TASQ nous a également permis de préparer un motif G-triplexe (G3), intermédiaire à la formation des motifs G4. Nous avons montré une forte stabilisation de tous les édifices G4 contraints ainsi préparés.Le second chapitre concerne les études de caractérisation et de sélection de ligands vis-à-vis des motifs G4 et G3 contraints. La caractérisation repose sur l’évaluation de l’affinité et de la sélectivité de différentes familles de ligands pour ces édifices, par résonance plasmonique de surface ou par interférométrie bio-couche. La sélection de ligands a été réalisée par la méthode SELEX dans le but d’obtenir des aptamères affins et spécifiques d’un motif G4 contraint. / Guanines or cytosines rich nucleic acids can fold into tetrameric G-quadruplexes (G4) or i-motifs structures. G4 motifs are found within the human genome and should contribute to cellular regulation. In particular G4 are found at telomeric region and also in promoters of oncogenes or within viral genomes. They are suspected of participating in the regulation of human pathologies and have therefore been envisioned as potential therapeutic and diagnostic targets. However, the intrinsic conformational polymorphism of G4 motifs complicates the development of specific and affine ligands. In this context, the laboratory has developed the TASQ concept for "Template Assembled Synthetic G-Quadruplex" with the aim to obtain a defined G4 topology.The first chapter reports on the assembly on the peptide template of RNA and DNA:RNA hybrid G4 structures that derive from the human telomeric sequence as well as of DNA G4 structure found within the HIV virus promoter. G-triplex (G3) motif which is supposed to be an intermediate during the formation of the G4 motifs has also been prepared. By using appropriate ligations of the oligonucleotide strands on the peptide template we were able to control the folding of G-quadruplex motifs and stabilize them.The second chapter reports the studies for the characterization and the selection of ligands against G4 and G3 motifs. The evaluation of the affinity and selectivity of different families of ligands for these constrain motifs was performed by using surface plasmon resonance or by bio-layer interferometry. The selection of ligands was carried out by the SELEX method in order to obtain affine and specific aptamers of a constrained G4 motif.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / The G-quadruplexes (G4s) are guanine-rich four-stranded DNA/RNA structures, which have been found throughout the human genome. G4s have been reported to affect chromatin structure and are involved in important biological processes at transcriptional and epigenetic levels. However, the underlying molecular mechanisms and locating of G4 still remain elusive due to the complexity of G4s. Taking advantage of the development of high-throughput sequencing technologies and machine learning approaches, we constructed this comprehensive investigation on G4 structures, including discovery of a novel marker for functional human hematopoietic stem cells and gained interest in G4 structure, exploring association between G4 and genomic factors by incorporating multi-omics data, and development of a deep-learningbased G4 prediction tool with G4 motif. First, we discovered ADGRG1 as a novel marker for functional human hematopoietic stem cells and its regulation through transcription activities. Our interest in G4s was stimulated while the transcription-related investigations. Next, we analyzed the genome-wide distribution properties of G4s and uncovered the associations of G4 with other epigenetic and transcriptional mechanisms to coordinate gene transcription. We explored that different-confidence G4 groups correlated differently with epigenetic regulatory elements and revealed that G4 structures could correlate with gene expression in two opposite ways depending on their locations and forming strands. Some transcription factors were identified to be over-represented with G4 emergence. We found distinct consensus sequences enriched in the G4 feet, with a high GC content in the feet of high-confidence G4s and a high TA content in solely predicted G4 feet. As for the last part, we developed a novel deep-learning-based prediction tool for DNA G4s with G4 motifs. Considering the classical G4 motif, we applied bi-directional LSTM model with attention method, which captures sequential information, and showed good performance in whole-genome level prediction of DNA G4s with the certified G4 pattern. Our comprehensive work investigated G4 with its functions and predictions and provided a better understanding of G4s on multi-omics level and computational information capture riding the wave of deep learning. / 2023-04-03

Interactions between DNA and ligands are important in the rational design of drugs and in research into DNA function. In particular, the interaction of DMZ with DNA structures named “G-quadruplexes” was considered. G-quadruplexes are structures present in telomeres and several oncogenes. The main purpose of this project was to provide a computational tool to study DNA ligand interactions using a variety of molecular modeling techniques that include molecular docking, molecular dynamics simulations (MD) and MM/PBSA (Molecular Mechanics/Poisson Boltzmann Surface Area). We investigated the binding modes and binding affinities of DMZ with c-MYC G-quadruplexes (G4s). We found that the conformation and structural design of the quadruplex can dramatically influence the binding profiles of the ligand. The binding free energies for each site were estimated by the MM/PBSA method. The binding of small molecules to DNA can result in the disruption of oncogene transcription, making it an effective anticancer strategy.