Der Rest : (Gedicht)

Theodor Zlocisti

TRANSCRIPTIONAL AND POST-TRANSLATIONAL MECHANISMS CONTRIBUTE TO MAINTENANCE OF REST IN NEURAL TUMORS

The RE-1 silencing transcription factor (REST) is an important regulator of normal nervous system development. It negatively regulates neuronal lineage specification in neural progenitors by binding to its consensus RE-1 element(s) located in the regulatory region of its target neuronal differentiation genes. The developmentally coordinated down-regulation of REST mRNA and protein in neural progenitors triggers terminal neurogenesis. REST is overexpressed in pediatric neural tumors such as medulloblastoma and neuroblastoma and is associated with poor neuronal differentiation. High REST protein correlate with poor prognosis for patients with medulloblastoma, however similar studies have not been done with neuroblastoma patients. Mechanism(s) underlying elevated REST levels medulloblastoma and neuroblastoma are unclear, and is the focus of this thesis project. We discovered that transcriptional and post-translational mechanisms govern REST mis-regulation in medulloblastoma and neuroblastoma. In medulloblastoma, REST transcript is aberrantly elevated in a subset of patient samples. Using loss of function and gain of function experiments, we provide evidence that the Hairy Enhancer of Split (HES1) protein represses REST transcription in medulloblastoma cell lines, modulates the expression of neuronal differentiation genes, and alters the survival potential of these cells in vitro. We also show that REST directly represses its own expression in an auto-regulatory feedback loop. Interestingly, our studies identified a novel interaction between REST and HES1. We also observed their co-occupancy at the RE-1 sites, thereby suggesting potential for co-regulation of REST expression. Our pharmacological studies in neuroblastoma using retinoic acid revealed that REST levels are controlled by transcriptional and post-transcriptional mechanisms. Post-transcriptional mechanisms are mediated by modulation of E3 ligase or REST, SCFβ-TRCP, and contribute to resistance of some cells to retinoic acid treatment.

Potential REST Targets in Neural Stem Cells and Glioblastoma-Derived Stem Cells

Glioblastoma multiforme (GBM) tumors are the most common malignant primary brain tumors in adults. The current theory is that these tumors are caused by self-renewing glioblastoma-derived stem cells (GSCs). At the current time, the mechanisms that regulate self-renewal and other oncogenic properties of GSCs remain unknown. Recently, we found transcriptional repressor REST maintains self-renewal in neural stem cells (NSCs) and in GSCs. REST also regulates other oncogenic properties, such as apoptosis, invasion and proliferation. However, the mechanisms by which REST regulates these oncogenic properties are unknown. In an attempt to determine these mechanisms, we performed loss and gain-of-function experiments and genome-wide mRNA expression analysis in GSCs, and we were able to identify REST-regulated genes in GSCs. This was accomplished, after screening concordantly regulated genes in NSCs and GSCs, utilizing two RE1 databases, and setting two-fold expression as filters on the resulting genes. These results received further validation by qRT-PCR. Ingenuity Pathway Analysis (IPA) analysis further revealed the top REST target genes in GSCs were downstream targets of REST and/or involved in other cancers in other cell lines. IPA also revealed that many of the differentially-regulated genes identified in this study are involved in oncogenic properties seen in GBM, and which we believe are related to REST expression.

Los laberintos de la crítica : Rest lector de Borges

En el presente trabajo se examina el trabajo desarrollado por Jaime Rest en El laberinto del universo. Borges y el pensamiento nominalista en relación a la construcción de un objeto de lectura cuyo valor político se vuelve significativo a partir de la confrontación con un orden de verdad. En este sentido, se evalúa la disposición ética del dispositivo crítico, examinando los procesos de elección del corpus, las modalidades de enfoque y construcción del objeto de lectura y los modos de enunciación de la palabra crítica

Las funcionalidades Web 2.0 en la interface de usuario de los OPACs Web de Latinoamérica

Se presenta el proyecto de investigación aprobado y subsidiado en el marco de la Programación Científica UBACYT 2011-2014 sobre la problemática de las interfaces de usuario de los catálogos en línea de acceso público (OPACs) en entorno web de las bibliotecas nacionales, universitarias, especializadas y públicas de Latinoamérica, a fin de examinar las funcionalidades propias de las áreas de control de operaciones, formulación de la búsqueda y puntos de acceso, control de salida y asistencia al usuario, así como también las funcionalidades Web 2.0. Se adopta una metodología cuantitativa. Se plantea aplicar a una muestra representada por 102 unidades, extraída por muestreo aleatorio simple (de una población compuesta por 846 casos), la lista de funcionalidades que proporciona Hildreth (1982) actualizada; comparar, mediante un diseño experimental de muestras relacionadas, las variaciones producidas en cuanto a presencia/ausencia de funcionalidades y tipo de software adoptado en relación con la situación existente ya verificada en investigaciones previas; identificar, a partir de la observación de las interfaces de los OPACs que constituyen la muestra, la presencia/ausencia de funcionalidades Web 2.0; utilizar para ello como instrumento de recolección la lista de funcionalidades deseables en los OPACs 2.0 confeccionada por Margaix-Arnal (2007); aplicar diferentes pruebas estadísticas para describir las características de la interface de usuario de los OPACs Web de la región a partir del supuesto de que ha aumentado el uso de Sistemas Integrados de Gestión Bibliotecaria y la presencia de funcionalidades en aquellas unidades que han adoptado estos sistemas, aunque carecen aún de funcionalidades 2.0.