The topic of this work is the motif of nature in regionalists’ poetry of interwar period. The poems of Tadeusz Lopalewski, Witold Hulewicz, Wanda Niedzialkowska- Dobaczewska, and Eugenia Kobylinska are analyzed in this paper. All these poets called regionalists. The aim of this paper is not to analyze or evaluate all the poetry of the above mentioned authors but only those pieces of their creative work which deal with the motif of nature. So this master’s thesis analyses the motif of nature in the regionalists’ poetry of interwar period. The poems concerning nature are described in this work, stylistic and artistic devices of describing nature are discussed as well. The objects of this paper are: 1. To show the methods to describe the views of Vilnius. 2. To point out the most important motifs of the countryside in the poetry of Tadeusz Lopalewski, Witold Hulewicz, Wanda Niedzialkowska- Dobaczewska, and Eugenia Kobylinska. The landscapes of Vilnius are often related to people’s feature, their abilities to understand and feel. The regionalists idealize and glorify this nature. According to them the nature is exceptional and unusual. The poetry of regionalists reveals the features of romanticism and the “New Polish” styles in which the nature is personified and reflects the inner world of the lyrical object. The first part of the paper deals with the discussion of the nature of Vilnius in the poetry of the above mentioned authors. On the ground of the analysis of their... [to full text]

The development of new and effective drugs is strongly affected by the need to identify drug targets and to reduce side effects. Unfortunately, resolving these issues depends partially on a broad and thorough understanding of the biological function of many proteins, and the experimental determination of protein function is expensive and time consuming. In response to this problem, algorithms for computational function prediction have been designed to expand experimental impact by finding proteins with predictably similar function, mapping experimental knowledge onto very similar, unstudied proteins. This thesis seeks to develop one method that can identify useful geometric and chemical similarities between well studied and unstudied proteins. Our approach is to identify matches of geometric and chemical similarity between motifs , representing known functional sites, and substructures of functionally uncharacterized proteins ( targets ). It is commonly hypothesized that the existence of a match could imply that the target contains an active site similar to the motif. We have designed the MASH ( M atch A ugmentation with S tatistical H ypothesis Testing) pipeline, a software tool for computing matches. MASH is the first method to match point-based motifs, developed in earlier work, that represent functional sites as points in space with ranked priorities and alternative chemical labels. MASH is also first to match cavity-aware motifs, a novel contribution of this work, that extend point-based motifs with volumetric information describing active clefts critical to protein function. Controlled experiments demonstrate that matches for both types of motifs can identify cognate active sites. However, motifs can also identify matches to functionally unrelated proteins. For this reason, we developed M otif Profiling (MP), the first method for motif refinement that reduces geometric similarity to functionally unre lated proteins. MP is implemented in two forms: Geometric Sieving (GS) refines point-based motifs and Cavity Scaling (CS) refines cavity-aware motifs. Controlled experimentation demonstrates that GS and CS identify motif refinements that have more matches to functionally related proteins and less matches to functionally unrelated proteins. This thesis demonstrates the importance of computational tools for matching and refining motifs, emphasizing the applicability of large-scale geometric and statistical analysis for functional annotation. / National Science Foundation, National Library of Medicine, AMD, Cray

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

L'intérêt des composés organiques fluorés est de nos jours de plus en plus important en raison de leur large domaine d'application. Par exemple, dans le domaine de la chimie médicinale, la présence d'un atome de fluor altère sensiblement les propriétés physicochimiques des molécules et permet très souvent une amélioration de leur profil thérapeutique.Dans ce contexte, notre laboratoire s'intéresse au développement de nouveaux fluoropeptidomimétiques dans le but de pallier les différents problèmes associés aux peptides (pauvre biodisponibilité, flexibilité conformationnelle). Parmi les différents peptidomimétiques connus, le motif fluorooléfine (CF=CH) peut être considéré comme unisostère de la liaison peptidique du à ses similarités stériques et électroniques.Dans le but de proposer un mode d'accès général aux pseudopeptides fluorés comportant une fluorooléfine à la place du lien peptidique, nous avons développé une nouvelle stratégie basée sur une étape d'addition nucléophile de réactifs organométalliques sur des N-(tertbutanesulfinyl)-a-fluoroénimines chirales. Cette méthodologie nous permet de contrôler le centre asymétrique du côté N-terminal du peptide.Nous avons ensuite appliqué cette stratégie à la synthèse de composés biologiquement actifs tels que le 26RFa, un neuropeptide impliqué dans le contrôle et la régulation de la prise alimentaire. Dans ce contexte, plusieurs dipeptides fluorés ont été synthétisés puis incorporés au sein de l'heptapeptide qui ont donné lieu à des études de relations structureactivité.

L'objectif de ce travail est la généralisation, dans le contexte des 1-motifs, des accouplements de hauteurs construits par B. Mazur et J. Tate sur les variétés abéliennes. Suite à leur approche, nous considérons de ρ-splittings de la biextension de Poincaré d’un 1-motif et nous demandons qu'ils soient compatibles avec la linéarisation canonique associée à la biextension. Nous établissons donc des résultats concernant l'existence de tels ρ-splittings. Quand ρ est non-ramifié, celle-ci est garanti si l'accouplement de monodromie du 1-motif pris en considération est non-dégénéré. Pour ρ ramifié, le ρ-splitting se construit à partir d'une paire de scindages des filtrations de Hodge des réalisations de de Rham du 1-motif et de son dual. Ceci généralise des résultats précédents de R. Coleman and Y. Zarhin pour les variétés abéliennes. Ces ρ-splittings sont ensuite utilisés pour définir un accouplement global entre les points rationnels d'un 1-motif et de son dual. Également, nous fournissons des accouplements locaux entre les zéro-cycles et les diviseurs sur une variété, qui est fait en appliquant les résultats précédents à ses 1-motifs de Picard et d’Albanese. / The purpose of this work is to generalize, in the context of 1-motives, the height pairings constructed by B. Mazur and J. Tate on abelian varieties. Following their approach, we consider ρ-splittings of the Poincaré biextension of a 1-motive and require that they be compatible with the canonical linearization associated to the biextension. We establish results concerning the existence of such ρ-splittings. When ρ is unramified this is guaranteed if the monodromy pairing of the 1-motive considered is non-degenerate. For ramified ρ, the ρ-splitting is constructed from a pair of splittings of the Hodge filtrations of the de Rham realizations of the 1-motive and its dual. This generalizes previous results by R. Coleman and Y. Zarhin for abelian varieties. These ρ-splittings are then used to define a global pairing between rational points of a 1-motive and its dual. We also provide local pairings between zero cycles and divisors on a variety, which is done by applying the previous results to its Picard and Albanese 1-motives.

Made available in DSpace on 2014-06-12T15:59:34Z (GMT). No. of bitstreams: 2 arquivo5182_1.pdf: 7099391 bytes, checksum: 9ae548e6659db775935f03eac2fa2f35 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2006 / Um dos principais objetivos da biologia molecular é descobrir o funcionamento de redes complexas de interação entre elementos celulares. Nas últimas décadas um grande volume de dados biológicos vem sendo produzido assim como modelos computacionais que fazem uso destes dados. Os métodos computacionais para Reconstrução de Redes de Genes apresentam-se como uma ferramenta importante para auxiliar no estudo e entendimento desta complexidade. Este trabalho apresenta uma proposta para Reconstrução de Redes de Genes que utiliza-se de diferentes fontes de dados e incorpora conhecimento biológico com o objetivo de melhorar a qualidade da inferência. Comparou-se a abordagem proposta com um trabalho anterior. Foram realizados experimentos com dados artificiais e dados reais de S. cerevisiae. O modelo proposto apresentou melhores resultados que o anterior em todos os critérios de avaliação para experimentos com dados artificiais. Na avaliação com dados reais a nova abordagem apresentou uma pequena melhora em apenas uma das configurações testadas

Human immunodeficiency virus type 1 (HIV-1) is a major public health concern because it cannot yet be prevented by vaccination. Mucosal surfaces are the primary sites for the HIV-1 transmission. Vaccine capable of protecting HIV-1 depends on the induction of long term mucosal immune responses. In the infected individuals, anti HIV-1 epitope can generate neutralizing antibodies and have protective effects. Vaccine which can induce local mucosal immunity may prevent HIV-1 replication within local tissues prior to systemic dissemination. The 2F5 human monoclonal antibody (MAb) has HIV-1 neutralizing activity. A conserved linear sequence ELDKWA which is present within the envelope glycoprotein of HIV virus is an epitope of 2F5 MAb. Expression of anti HIV-1 ELDKWA epitope on the cell surface of L. plantarum via anchor protein can be a strategy to develop HIV-1 vaccines. Lactobacillus plantarum are probiotics and have cell surface displaying ability. The aim of this study was to express anti HIV-1 2F5 epitope ELDKWA on the L. plantarum NC8 cell surface using muropeptidase (MurO) of L. plantarum CCUG 9289. The expression of recombinant protein MurO. 2F5 in L. plantarum NC8 was determined by Western blot following cloning techniques. BLASTP analysis showed that MurO has two putative lysine motif (LysM) domains that can bind to peptidoglycan. Our results suggest that MurO of L. plantarum can be used as an anchor protein for anti HIV-1 ELDKWA epitope expression in L. plantarum. This implies that using L. plantarum together with anchor protein MurO could effectively be used as a vaccine delivery system against HIV-1 infection.

Protein synthesis is frequently dysregulated in cancer cells; such conditions are known to favor aberrant cell growth and proliferation which lead to cancer. LARP1 is a novel target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a circuitry often hyperactivated in cancer which regulates cell growth and proliferation primarily through the regulation of protein synthesis. I aimed to determine if LARP1 plays a role in cancer progression by comparing its expression in normal versus cancer tissues. My results demonstrate that LARP1 expression is altered (lost or overexpressed) in various cancers and correlates with cancer patients survival. My systematic bioinformatics assessment, the results of my functional assays assessing the effect of LARP1 knockdown on cancer cells, together with my antibody validation do not only provide new insights for its role in cancer progression and mRNA translation, but also emphasizes the potential of LARP1 as a cancer therapeutic target.

Abstract The Z-disk is a sophisticated structure that connects adjacent sarcomeres in striated muscle myofibrils. α-Actinin provides strength to the Z-disks by crosslinking the actin filaments of adjacent sarcomeres. α-Actinin is an antiparallel homodimer, composed of an N-terminal actin binding domain (ABD), the central rod domain, and two pairs of C-terminal EF-hands. The PDZ-LIM domain proteins interact with α-actinin at the Z-disk. Of these proteins, only the actinin-associated LIM protein (ALP), Z-band alternatively spliced PDZ-containing protein (ZASP/Cypher) and C-terminal LIM protein (CLP36) have a ZASP/Cypher-like (ZM) motif consisting of 26-27 conserved residues in the internal region between the PDZ and LIM domains. The aim of this work was to understand the molecular interplay between the ZM-motif containing members of the PDZ-LIM proteins and α-actinin. To unveil the biological relevance of the interaction between the PDZ-LIM proteins and α-actinin, naturally occurring human ZASP/Cypher mutations were analyzed. Two interaction sites were found between ALP, CLP36 and α-actinin using recombinant purified proteins in surface plasmon resonance (SPR) analysis. The PDZ domain of ALP and CLP36 recognized the C-terminus of α-actinin, whereas the internal regions bound to the rod domain. Further characterization showed that the ALP internal region adopts and extended conformation when interacting with α-actinin and that the ZM-motif partly mediated the interaction, but did not define the entire interaction area. ZASP/Cypher also interacted and competed with ALP in binding to the rod domain. The internal fragments containing the ZM-motif were important for co-localization of ALP and ZASP/Cypher with α-actinin at the Z-disks and on stress fibers. The absence of ALP and ZASP/Cypher in focal contacts indicates that other interacting molecules, for instance vinculin and integrin, may compete in binding to the rod in these areas or additional proteins are required in targeting to these locations. The co-localization of the ZASP/Cypher with α-actinin could be released by disrupting the stress fibers leading to an accumulation of α-actinin in the cell periphery, whereas ZASP/Cypher was not in these areas. This suggests that an intact cytoskeleton is important for ZASP/Cypher interaction with α-actinin. Earlier studies have shown that mutations in the ZASP/Cypher internal region are associated with muscular diseases. These mutations, however, did not affect ZASP/Cypher co-localization with α-actinin or the stability of ZASP/Cypher proteins. The Z-disk possesses a stretch sensor, which is involved in triggering hypertrophic growth as a compensatory mechanism to increased workloads. α-Actinin is a docking site of molecules that are involved in hypertrophic signaling cascades mediated by calsarcin-calcineurin and protein kinase C (PKC) isoforms. The internal interaction site may be involved in targeting PKCs, which bind to the LIM domains of ZASP/Cypher, to the Z-disks. The similar location of the internal interaction site with calsarcin on the rod suggests that ZASP/Cypher, ALP and CLP36 may regulate calsarcin-mediated hypertrophic signaling.

Regulation and function of protein-coding genes are increasingly well-understood, but no comparable evidence exists for non-coding RNA (ncRNA) genes, which appear to be more numerous than protein-coding genes. We developed a novel machine-learning model to distinguish promoters of long ncRNA (lncRNA) genes from those of protein-coding genes. This represents the first attempt to make this distinction based on properties of the associated gene promoters. From our analyses, several transcription factors (TFs), which are known to be regulated by lncRNAs, also emerged as potential global regulators of lncRNAs, suggesting that lncRNAs and TFs may participate in bidirectional feedback regulatory network. Our results also raise the possibility that, due to the historical dependence on protein-coding gene in defining the chromatin states of active promoters, an adjustment of these chromatin signature profiles to incorporate lncRNAs is warranted in the future. Secondly, we developed a novel method to infer functions for lncRNA and microRNA (miRNA) transcripts based on their transcriptional regulatory networks in 119 tissues and 177 primary cells of human. This method for the first time combines information of cell/tissueVspecific expression of a transcript and the TFs and transcription coVfactors (TcoFs) that control activation of that transcript. Transcripts were annotated using statistically enriched GO terms, pathways and diseases across cells/tissues and associated knowledgebase (FARNA) is developed. FARNA, having the most comprehensive function annotation of considered ncRNAs across the widest spectrum of cells/tissues, has a potential to contribute to our understanding of ncRNA roles and their regulatory mechanisms in human. Thirdly, we developed a novel machine-learning model to identify LD motif (a protein interaction motif) of paxillin, a ncRNA target that is involved in cell motility and cancer metastasis. Our recognition model identified new proteins not previously known to harbor LD motifs and we experimentally confirmed some of our predicted motifs. This novel discovery will expand our knowledge of cancer metastasis and will facilitate therapeutic targeting linking specific ncRNAs via paxillin proteins to diseases. Finally, through bioinformatics approaches, we identified lncRNAs as markers that distinguish classical from alternative activation of macrophage. This result may have good use in the diagnosis of infectious diseases.