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The Global ETD Search service is a free service for researchers
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Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
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MicroRNA Target Prediction via Duplex Formation Features and Direct Binding EvidenceLekprasert, Parawee January 2012 (has links)
<p>MicroRNAs (miRNAs) are small RNAs that have important roles in post-transcriptional gene regulation in a wide range of species. This regulation is controlled by having miRNAs directly bind to a target messenger RNA (mRNA), causing it to be destabilized and degraded, or translationally repressed. Identifying miRNA targets has been a large area of focus for study; however, a lack of generally high-throughput experiments to validate direct miRNA targeting has been a limiting factor. To overcome these limitations, computational methods have become crucial for understanding and predicting miRNA-gene target interactions.</p><p>While a variety of computational tools exist for predicting miRNA targets, many of them are focused on a similar feature set for their prediction. These commonly used features are complementarity to 5'seed of miRNAs and evolutionary conservation. Unfortunately, not all miRNA target sites are conserved or adhere to canonical seed complementarity. Seeking to address these limitations, several studies have included energy features of mRNA:miRNA duplex formation as alternative features. However, different independent evaluations reported conflicting results on the reliability of energy-based predictions. Here, we reassess the usefulness of energy features for mammalian target prediction, aiming to relax or eliminate the need for perfect seed matches and conservation requirement.</p><p>We detect significant differences of energy features at experimentally supported human miRNA target sites and at genome-wide interaction sites to Argonaute (AGO) protein family members, which are essential parts of the miRNA machinery complex. This trend is confirmed on data sets that assay the effect of miRNAs on mRNA and protein expression changes, where a statistically significant change in expression is noted when compared to the control. Furthermore, our method also allows for prediction of strictly imperfect sites, as well as non-conserved targets.</p><p>Recently, new methods for identifying direct miRNA binding have been developed, which provides us with additional sources of information for miRNA target prediction. While some computational target predictions tools have begun to incorporate this information, they still rely on the presence of a seed match in the AGO-bound windows without accounting for the possibility of variations. </p><p>We investigate the usefulness of the site level direct binding evidence in miRNA target identification and propose a model that incorporates multiple different features along with the AGO-interaction data. Our method outperforms both an ad hoc strategy of seed match searches as well as an existing target prediction tool, while still allowing for predictions of sites other than a long perfect seed match. Additionally, we show supporting evidence for a class of non-canonical sites as bound targets. Our model can be extended to predict additional types of imperfect sites, and can also be readily modified to include additional features that may produce additional improvements.</p> / Dissertation
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Micro RNA-Mediated regulation of the full-length and truncated isoforms of human neurotrophic tyrosine kinase receptor type 3 (NTRK 3)Guidi, Mònica 13 January 2009 (has links)
Neurotrophins and their receptors are key molecules in the development of thenervous system. Neurotrophin-3 binds preferentially to its high-affinity receptorNTRK3, which exists in two major isoforms in humans, the full-length kinaseactiveform (150 kDa) and a truncated non-catalytic form (50 kDa). The twovariants show different 3'UTR regions, indicating that they might be differentiallyregulated at the post-transcriptional level. In this work we explore howmicroRNAs take part in the regulation of full-length and truncated NTRK3,demonstrating that the two isoforms are targeted by different sets of microRNAs.We analyze the physiological consequences of the overexpression of some of theregulating microRNAs in human neuroblastoma cells. Finally, we providepreliminary evidence for a possible involvement of miR-124 - a microRNA with noputative target site in either NTRK3 isoform - in the control of the alternativespicing of NTRK3 through the downregulation of the splicing repressor PTBP1. / Las neurotrofinas y sus receptores constituyen una familia de factores crucialespara el desarrollo del sistema nervioso. La neurotrofina 3 ejerce su funciónprincipalmente a través de una unión de gran afinidad al receptor NTRK3, del cualse conocen dos isoformas principales, una larga de 150KDa con actividad de tipotirosina kinasa y una truncada de 50KDa sin dicha actividad. Estas dos isoformasno comparten la misma región 3'UTR, lo que sugiere la existencia de unaregulación postranscripcional diferente. En el presente trabajo se ha exploradocomo los microRNAs intervienen en la regulación de NTRK3, demostrando que lasdos isoformas son reguladas por diferentes miRNAs. Se han analizado lasconsecuencias fisiológicas de la sobrexpresión de dichos microRNAs utilizandocélulas de neuroblastoma. Finalmente, se ha estudiado la posible implicación delmicroRNA miR-124 en el control del splicing alternativo de NTRK3 a través de laregulación de represor de splicing PTBP1.
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