The role of the MLL/AF4 fusion oncogene in acute lymphoblastic leukaemia maintenance

PhD ThesisThe chromosomal rearrangement t(4;11)(q21;q23) marks an aggressive acute lymphoblastic leukaemia (ALL) subtype particularly prevalent in infants and associated with poor outcome. This cytogenetic abnormality encodes the fusion oncogene MLL/AF4, which plays a pivotal role in cell death resistance; however, the underlying molecular processes are not fully understood. Therefore, to gain further insight, RNAi-mediated ablation of MLL/AF4 in the t(4;11)-positive ALL cell line SEM was combined with global gene expression profiling and concomitant apoptosis inhibitor studies. Phenotypically, MLL/AF4 depletion impaired proliferation, cell cycle progression, clonogenicity and caused a strong apoptosis induction. Global transcriptome analysis found up-regulation of proapoptotic and anti-proliferative genes, while mitogenic signalling mediators and stemness-related markers were down-regulated. Supplementing MLL/AF4-depleted cells with the pan-caspase inhibitor zVAD suppressed apoptosis, but failed to abrogate cell death. Subsequent gene expression profiling showed induction of genes implicated in the necroptotic cell death pathway. Interestingly, addressing this using established necroptosis inhibitors did not rescue the phenotype. Finally, the cytokine ANGIOPOIETIN-1 (ANGPT1) was identified as a novel MLL/AF4-modulated gene; MLL/AF4 knock-down correlated with a substantial decrease of ANGPT1 levels. Concordantly, screening an B-precursor ALL patient cohort found ANGPT1 to be highly overexpressed in t(4;11)-positive ALL. Although no correlation with clinical prognostic factors could be established, ANGPT1 was found to contribute to the leukaemic phenotype, as RNAi-mediated ANGPT1 depletion impaired proliferation and viability in vitro and impinged on disease development in vivo. Concluding, it was found that t(4;11)-positive ALL cells display a high degree of oncogene addiction towards MLL/AF4, since depletion strongly perturbed the leukaemic phenotype, compromising survival and self-renewal. Furthermore, ANGPT1 was identified as a novel proleukaemic factor cooperating with MLL/AF4 in maintaining the disease

Elucidation of the molecular and bionergetic mechanisms underlying the resistance to oxidatives stress and the pro-recovery effect of H2O2- preconditioned adipose-derived stem cells

209 p.In the field of regenerative medicine, it has been pointed out the relevance of human adipose derived stem cells (hASCs) for cell therapy. They can be easily obtained, have low immunogenicity, and secrete soluble factors that could regulate neuroinflammation and oxidative stress. However, their transplantation at the site of injury results in a low percentage of survival and engraftment, mainly due to the harsh microenvironment they encounter. To address this issue, it is imperative to pre-adapt cells, so that they resist harmful environmental factors such as oxidative stress. In this study, we preconditioned hASCs (PC-hASCs) with low doses of H2O2 and evaluated their resistance to an oxidative stress insult. PC-hASCs displayed lower levels of ROS, apoptosis and cytotoxicity than hASCs, indicating their increased capacity to resist to oxidative stress. In addition, we analyzed the molecular and bioenergetic mechanisms underlying the survival and adaptation of PC-hASCs under oxidative stress. On these conditions, PC-hASCs i, reduce intracellular ROS levels by overexpressing the transcription factor NRF2 and their related antioxidant enzymes HO-1, SOD-1, GPx-1, and CAT; ii, reduce the secretion of pro-inflammatory molecules COX-2 and IL-1ß by attenuating the expression of NF-kB, and iii, increase the total ATP production rate by adapting their metabolism in order to meet the bioenergetic demand required to survive. Finally, we evaluated the therapeutic role of PC-hASCs to overcome the deleterious effect of oxidative stress in an oligodendroglial cell population, and proved that PC-hASCs restored cell viability and diminished the intracellular ROS levels of these damaged oligodendrocytes by promoting their antioxidant response.Altogether, these findings support that PC-hASCs, given their beneficial advantages, might be considered an important breakthrough in cell¿based therapies

Dynamic Facial Expressions Prime the Processing of Emotional Prosody

Evidence suggests that emotion is represented supramodally in the human brain. Emotional facial expressions, which often precede vocally expressed emotion in real life, can modulate event-related potentials (N100 and P200) during emotional prosody processing. To investigate these cross-modal emotional interactions, two lines of research have been put forward: cross-modal integration and cross-modal priming. In cross-modal integration studies, visual and auditory channels are temporally aligned, while in priming studies they are presented consecutively. Here we used cross-modal emotional priming to study the interaction of dynamic visual and auditory emotional information. Specifically, we presented dynamic facial expressions (angry, happy, neutral) as primes and emotionally-intoned pseudo-speech sentences (angry, happy) as targets. We were interested in how prime-target congruency would affect early auditory event-related potentials, i.e., N100 and P200, in order to shed more light on how dynamic facial information is used in cross-modal emotional prediction. Results showed enhanced N100 amplitudes for incongruently primed compared to congruently and neutrally primed emotional prosody, while the latter two conditions did not significantly differ. However, N100 peak latency was significantly delayed in the neutral condition compared to the other two conditions. Source reconstruction revealed that the right parahippocampal gyrus was activated in incongruent compared to congruent trials in the N100 time window. No significant ERP effects were observed in the P200 range. Our results indicate that dynamic facial expressions influence vocal emotion processing at an early point in time, and that an emotional mismatch between a facial expression and its ensuing vocal emotional signal induces additional processing costs in the brain, potentially because the cross-modal emotional prediction mechanism is violated in case of emotional prime-target incongruency

Physicochemical and sensory characteristics of pan bread samples available in the brazilian market

Pan bread samples available in the Brazilian market were evaluated for their physicochemical and sensory characteristics. Twelve pan breads, seven white and five whole grain breads, were evaluated. Moisture, water activity (Aw), firmness, and color (L*, a*, b*) of the crumb were evaluated on the first, fourth, seventh, and tenth days after purchasing the breads. Specific volume was evaluated on the first day of analysis with averages of 4.72 and 4.70 mL/g for the white and whole grain breads, respectively. The average results on the first day of analysis were: 37.03% and 41.23% moisture, 0.954 and 0.966 Aw, 276.27 and 267.83 gf firmness, 74.73 and 64.45 L* values, 0.37 and 3.85 a* values, and 15.51 and 18.98 b* values for the white and whole grain breads, respectively. The samples showed an increase in firmness, reduction in moisture and Aw, and no color changes over time. A survey conducted prior to the acceptance test showed that the three most important factors influencing purchase were taste (19.6%), tenderness (16.8%), and expiration date of the product (14.3%). The results showed that 37.2% of the panelists preferred white bread, 62.8% preferred bread with fibers, and 82.6% would probably or definitely buy white bread with fibers344746754CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQSem informaçã

La representación femenina y el discurso orientalista en Los nombres del aire de Alberto Ruy-Sánchez

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.[À l'origine dans / Was originally part of : Thèses et mémoires - FAS - Département de littératures et de langues modernes

Blockade of the Interaction of Calcineurin with FOXO in Astrocytes Protects Against Amyloid-βInduced Neuronal Death

Astrocytes actively participate in neuro-inflammatory processes associated to Alzheimer’s disease (AD), and other brain pathologies. We recently showed that an astrocyte-specific intracellular signaling pathway involving an interaction of the phosphatase calcineurin with the transcription factor FOXO3 is a major driver in AD associated pathological inflammation, suggesting a potential new druggable target for this devastating disease. We have now developed decoy molecules to interfere with calcineurin/FOXO3 interactions, and tested them in astrocytes and neuronal co-cultures exposed to amyloid-β (Aβ) toxicity. We observed that interference of calcineurin/FOXO3 interactions exerts a protective action against A-induced neuronal death and favors the production of a set of growth factors that we hypothesize form part of a cytoprotective pathway to resolve inflammation. Furthermore, interference of the A-induced interaction of calcineurin with FOXO3 by decoy compounds significantly decreased amyloid-β protein precursor (AβPP) synthesis, reduced the AβPP amyloidogenic pathway, resulting in lower Alevels, and blocked the expression of pro-inflammatory cytokines TNFα and IL-6 in astrocytes. Collectively, these data indicate that interrupting pro-inflammatory calcineurin/FOXO3 interactions in astrocytes triggered by Aβ accumulation in brain may constitute an effective new therapeutic approach in AD. Future studies with intranasal delivery, or brain barrier permeable decoy compounds, are warranted

Lenguajes de programación y relatos digitales. Propuesta de intervención: "InsecTIC’s"

La escuela tiene que evolucionar y adaptarse al ritmo que lo hace la sociedad, por ello es necesario renovar e introducir aprendizajes que preparen al alumnado para su futuro. Este trabajo presenta la investigación llevada a cabo sobre la utilidad de las TICs y los lenguajes de programación en el entorno educativo. Además, incluye una Propuesta Didáctica en la que se plantea el digital storytelling como un recurso idóneo para impulsar el pensamiento computacional y la expresión audiovisual.The school has to evolve and adapt to the same rhythm that society does, so it is necessary to renew and introduce learning that prepares students for their future. This document presents the research carried out on the usefulness of ICTs and programming languages in the educational environment. In addition, it includes a Didactic Proposal in which digital storytelling is proposed as an ideal resource to promote computational thinking and audiovisual expression.Grado en Educación Infanti

Regional welfare disparities : a leisure view analysis

El ocio, claro indicador del grado de desarrollo de las economías y exponente del bienestar de sus ciudadanos, se manifiesta en dos ámbitos fundamentales: el temporal y el monetario. Así, las actividades de ocio conllevan para el demandante una utilización intensiva de tiempo y, a menudo, también un gasto monetario. Lo anterior no significa, sin embargo, que tiempo y dinero empleado en ocio discurran siempre en paralelo, pues muchas de estas actividades consumen tiempo pero apenas generan un gasto monetario.\ud El objetivo de la presente comunicación es analizar las pautas que muestran los individuos de las distintas regiones españolas en sus decisiones de ocio, así como explicar los posibles motivos que las justifican. Uno de los factores explicativos más importantes será la existencia de diferencias de renta, pero con toda probabilidad, no el único.\ud Adicionalmente se trata de comprobar si las regiones más ricas son también las que disfrutan de más ocio, tanto en términos de gasto como de tiempo. Puesto que el nivel de bienestar alcanzado a través del ocio puede depender tanto del gasto realizado como del tiempo que se le dedique, el objetivo anterior se aborda considerando ambos puntos de vista.\ud Para ello se explota la información que ofrecen dos encuestas del INE: la Encuesta de Presupuestos Familiares y la Encuesta de Usos de Tiempo.Leisure, a clear economic development indicator and people wellbeing sign, has two main expressions: the temporal one and the monetary one. In fact, leisure includes very high time consumer activities and, frequently, high money consumer activities as well. However, it doesn¿t mean necessarily a correlation of these two variables, because there are a lot of leisure activities that imply time consumption but do not imply monetary spending.\ud The basic aim of this paper is to analyze the different leisure decision patterns across Spanish regions, and try to find possible explanatory factors. Income differences could be one of the most important factors but, very probably, not the unique one.\ud This paper also tries to prove if the richer regions are the ones which have more leisure, both in spending and time terms. Because welfare level could be related both to leisure money spending and leisure time use, this study considers these two points of view.\ud Data comes from two official statistics, both of them made by INE: Consumer Expenditure Survey and Time Use Survey