54 research outputs found

    Democratizing machine learning

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    Modelle des maschinellen Lernens sind zunehmend in der Gesellschaft verankert, oft in Form von automatisierten Entscheidungsprozessen. Ein wesentlicher Grund dafür ist die verbesserte Zugänglichkeit von Daten, aber auch von Toolkits für maschinelles Lernen, die den Zugang zu Methoden des maschinellen Lernens für Nicht-Experten ermöglichen. Diese Arbeit umfasst mehrere Beiträge zur Demokratisierung des Zugangs zum maschinellem Lernen, mit dem Ziel, einem breiterem Publikum Zugang zu diesen Technologien zu er- möglichen. Die Beiträge in diesem Manuskript stammen aus mehreren Bereichen innerhalb dieses weiten Gebiets. Ein großer Teil ist dem Bereich des automatisierten maschinellen Lernens (AutoML) und der Hyperparameter-Optimierung gewidmet, mit dem Ziel, die oft mühsame Aufgabe, ein optimales Vorhersagemodell für einen gegebenen Datensatz zu finden, zu vereinfachen. Dieser Prozess besteht meist darin ein für vom Benutzer vorgegebene Leistungsmetrik(en) optimales Modell zu finden. Oft kann dieser Prozess durch Lernen aus vorhergehenden Experimenten verbessert oder beschleunigt werden. In dieser Arbeit werden drei solcher Methoden vorgestellt, die entweder darauf abzielen, eine feste Menge möglicher Hyperparameterkonfigurationen zu erhalten, die wahrscheinlich gute Lösungen für jeden neuen Datensatz enthalten, oder Eigenschaften der Datensätze zu nutzen, um neue Konfigurationen vorzuschlagen. Darüber hinaus wird eine Sammlung solcher erforderlichen Metadaten zu den Experimenten vorgestellt, und es wird gezeigt, wie solche Metadaten für die Entwicklung und als Testumgebung für neue Hyperparameter- Optimierungsmethoden verwendet werden können. Die weite Verbreitung von ML-Modellen in vielen Bereichen der Gesellschaft erfordert gleichzeitig eine genauere Untersuchung der Art und Weise, wie aus Modellen abgeleitete automatisierte Entscheidungen die Gesellschaft formen, und ob sie möglicherweise Individuen oder einzelne Bevölkerungsgruppen benachteiligen. In dieser Arbeit wird daher ein AutoML-Tool vorgestellt, das es ermöglicht, solche Überlegungen in die Suche nach einem optimalen Modell miteinzubeziehen. Diese Forderung nach Fairness wirft gleichzeitig die Frage auf, ob die Fairness eines Modells zuverlässig geschätzt werden kann, was in einem weiteren Beitrag in dieser Arbeit untersucht wird. Da der Zugang zu Methoden des maschinellen Lernens auch stark vom Zugang zu Software und Toolboxen abhängt, sind mehrere Beiträge in Form von Software Teil dieser Arbeit. Das R-Paket mlr3pipelines ermöglicht die Einbettung von Modellen in sogenan- nte Machine Learning Pipelines, die Vor- und Nachverarbeitungsschritte enthalten, die im maschinellen Lernen und AutoML häufig benötigt werden. Das mlr3fairness R-Paket hingegen ermöglicht es dem Benutzer, Modelle auf potentielle Benachteiligung hin zu über- prüfen und diese durch verschiedene Techniken zu reduzieren. Eine dieser Techniken, multi-calibration wurde darüberhinaus als seperate Software veröffentlicht.Machine learning artifacts are increasingly embedded in society, often in the form of automated decision-making processes. One major reason for this, along with methodological improvements, is the increasing accessibility of data but also machine learning toolkits that enable access to machine learning methodology for non-experts. The core focus of this thesis is exactly this – democratizing access to machine learning in order to enable a wider audience to benefit from its potential. Contributions in this manuscript stem from several different areas within this broader area. A major section is dedicated to the field of automated machine learning (AutoML) with the goal to abstract away the tedious task of obtaining an optimal predictive model for a given dataset. This process mostly consists of finding said optimal model, often through hyperparameter optimization, while the user in turn only selects the appropriate performance metric(s) and validates the resulting models. This process can be improved or sped up by learning from previous experiments. Three such methods one with the goal to obtain a fixed set of possible hyperparameter configurations that likely contain good solutions for any new dataset and two using dataset characteristics to propose new configurations are presented in this thesis. It furthermore presents a collection of required experiment metadata and how such meta-data can be used for the development and as a test bed for new hyperparameter optimization methods. The pervasion of models derived from ML in many aspects of society simultaneously calls for increased scrutiny with respect to how such models shape society and the eventual biases they exhibit. Therefore, this thesis presents an AutoML tool that allows incorporating fairness considerations into the search for an optimal model. This requirement for fairness simultaneously poses the question of whether we can reliably estimate a model’s fairness, which is studied in a further contribution in this thesis. Since access to machine learning methods also heavily depends on access to software and toolboxes, several contributions in the form of software are part of this thesis. The mlr3pipelines R package allows for embedding models in so-called machine learning pipelines that include pre- and postprocessing steps often required in machine learning and AutoML. The mlr3fairness R package on the other hand enables users to audit models for potential biases as well as reduce those biases through different debiasing techniques. One such technique, multi-calibration is published as a separate software package, mcboost

    Advances in the Treatment of Renal Cell Carcinoma

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    This Special Issue of Cancers focuses on new advances in the treatment of renal cell carcinoma, both surgical and pharmacological (and combinations of these), and novel approaches to tackle treatment resistance and improve our understanding of this phenomenon

    Structure-Preserving Model Reduction of Physical Network Systems

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    This paper considers physical network systems where the energy storage is naturally associated to the nodes of the graph, while the edges of the graph correspond to static couplings. The first sections deal with the linear case, covering examples such as mass-damper and hydraulic systems, which have a structure that is similar to symmetric consensus dynamics. The last section is concerned with a specific class of nonlinear physical network systems; namely detailed-balanced chemical reaction networks governed by mass action kinetics. In both cases, linear and nonlinear, the structure of the dynamics is similar, and is based on a weighted Laplacian matrix, together with an energy function capturing the energy storage at the nodes. We discuss two methods for structure-preserving model reduction. The first one is clustering; aggregating the nodes of the underlying graph to obtain a reduced graph. The second approach is based on neglecting the energy storage at some of the nodes, and subsequently eliminating those nodes (called Kron reduction).</p

    Advanced Bariatric and Metabolic Surgery

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    Bariatric surgery has gained importance in the last 20 years because of the high prevalence of global obesity, and the vast understating of the physiological and pathological aspects of obesity and associated metabolic syndromes. This book has been written by a number of highly outstanding authors and pioneering bariatric surgeons from all over the world. The intended audience for this book includes all medical professionals involved in caring for bariatric patients. The chapters cover the choice of operation, preoperative preparation including psychological aspect, postoperative care and management of complication. It also extends to concept and result of metabolic surgery and scarless bariatric surgery

    FAIR and bias-free network modules for mechanism-based disease redefinitions

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    Even though chronic diseases are the cause of 60% of all deaths around the world, the underlying causes for most of them are not fully understood. Hence, diseases are defined based on organs and symptoms, and therapies largely focus on mitigating symptoms rather than cure. This is also reflected in the most commonly used disease classifications. The complex nature of diseases, however, can be better defined in terms of networks of molecular interactions. This research applies the approaches of network medicine – a field that uses network science for identifying and treating diseases – to multiple diseases with highly unmet medical need such as stroke and hypertension. The results show the success of this approach to analyse complex disease networks and predict drug targets for different conditions, which are validated through preclinical experiments and are currently in human clinical trials

    Understanding the disease and supporting clinical decisions

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    Barrett’s esophagus (BE) is a recognized premalignant condition of the distal esophagus that constitutes the major risk factor for the development of esophageal adenocarcinoma (EA). Despite the known low rates of BE progression to EA, the incidence of both has increased profoundly over the last decades and esophageal malignancy remains to be a deadly cancer with high morbidity and mortality unless diagnosed at early stages. Current BE clinical management has revealed unsuccessful in reverting this worrisome epidemiological picture and a major hurdle has been the incapacity to discriminate among BE patients those who have a higher risk of malignant progression. In fact, to this date, besides dysplasia none of the existing clinical and histologic criteria could anticipate malignant progression. It is therefore imperative to find reliable molecular biomarkers to guide medical practice and improve the standard of care for BE patients. The global aim of this thesis was to better understand the pathways underlying BE malignant progression and thereby identify reliable biomarkers relevant for the diagnosis, prognosis and management of BE patients thus contributing to an improved understanding of BE biology and an optimized support for clinical decisions. To accomplish these challenging goals an unbiased and a hypothesis-driven strategies were followed. Through the unbiased approach, a meta-analysis of transcriptome datasets and subsequent experimental validation in a cohort BE patients in follow-up was used to define a gene set associated with BE cancer development and, therefore, identify early biomarkers predictive of BE malignant progression. In silico analysis singled out two genes, CYR61 and TAZ as candidate predictive markers for BE malignant progression and experimental validation using quantitative PCR and immunohistochemistry revealed that both genes are upregulated and overexpressed in non-dysplastic BE index biopsies from progressors years before cancer development when compared with index biopsies from BE patients that did not progressed. We also found that EMT and stemness-related genes were also significantly over represented in BE associated with progression. Together, these results support that CYR61 and TAZ are promising early biomarkers to stratify BE patients according to their cancer risk and suggest a novel mechanist route for BE neoplastic progression. Using an hypothesis-driven approach, we explored when and how centrosome abnormalities arise along BE malignant pathway, from the early premalignant condition stage to metastatic disease, by establishing an accurate method to identify and score centrosomes, at the single-cell level, in patient samples and cell lines. We found that centrosome amplification arises as early as the premalignant condition of patients that progress to malignancy and significantly expands at dysplasia stage, which is dependent of p53 loss of function, being then present along cancer progression, namely in EA and metastasis. So, these finding suggest that centrosome amplification could contribute to BE initiation and malignant progression. Considering that centrosome amplification is specific of patients that progress to cancer, this could be further explored to be translated into useful tools to be used in the clinical setting and potentially improve its diagnosis, prognosis and treatment. Moreover, given widespread occurrence of both p53 mutations and centrosome abnormalities in human tumors, our findings are likely to be extended to other cancers. Collectively, both research avenues suggest the existence of different cellular and molecular abnormalities dictating different pathological propensity for malignant progression in BE, right from the beginning, and this could be further explored to trace a cancer risk profile for every patient and guide medical decisions and improve patient care.O esófago de Barrett (EB) é uma reconhecida condição pré-maligna que surge no esófago distal associada ao refluxo gastroesofágico crónico e constitui o maior factor de risco para o desenvolvimento do adenocarcinoma esofágico (AE). Apesar da taxa de progressão maligna do EB ser baixa, a incidência de ambos tem aumentado drasticamente nas últimas décadas. Como agravante, esta neoplasia em estadios avançados está associada a taxas elevadas de morbilidade e mortalidade a menos que diagnosticada e tratada em estadios iniciais, pelo que todos os doentes com EB são integrados em programas de vigilância com vista à detecção precoce de progressão neoplásica. Contudo, esta prática clínica tem-se mostrado ineficaz para reverter este cenário epidemiológico e um dos factores limitantes relaciona-se com o facto da displasia continuar a ser o único marcador de risco de progressão maligna e não haver marcadores moleculares e clínicos que possam predizer e estratificar o potencial maligno do EB. É assim urgente encontrar biomarcadores sensíveis e específicos capazes de guiar a prática médica, melhorar a relação custo-benefício dos programas de vigilância, mas principalmente a qualidade de vida dos doentes com EB. O objectivo principal desta tese foi descobrir novas vias moleculares subjacentes à progressão maligna do EB de forma a identificar biomarcadores fidedignos passíveis de serem aplicados à clínica apoiando o diagnóstico, prognóstico e manejo destes doentes, e assim contribuir para aprofundar o conhecimento relativo ao processo de cancerigénese desta doença e potencialmente melhorar a abordagem clínica aos doentes com EB. Para tal foram seguidas duas linhas de investigação diferentes. De modo a encontrar biomarcadores com potencial preditivo para progressão maligna em doentes com EB foi realizada uma meta-análise de dados de transcriptomas previamente publicados, seguida de uma validação experimental utilizando amostras de EB de doentes acompanhados no programa de vigilância do Instituto Português de Oncologia Francisco Gentil. Esta estratégia permitiu identificar dois promissores biomarcadores, o CYR61 e o TAZ, capazes de estratificar o risco de progressão maligna do EB, não só pela sua expressão diferencial ser a mais significativa na análise bioinformática mas porque a validação experimental revelou que estes dois genes se encontravam sobreexpressos logo na primeira biopsia (vários anos antes do desenvolvimento de cancro) onde foi feito o diagnóstico de EB dos doentes que progrediram comparativamente com a expressão detetada no EB dos não progressores. Adicionalmente, foram ainda identificados outros genes diferencialmente expressos em EB associados a progressão maligna, cujas funções estão associadas a fenótipos de células estaminais e fenómenos de transição epitélio-mesenquimal (TEM) em cancro. Assim, foi também descoberto um potencial novo processo molecular associado ao desenvolvimento de cancro em EB. Paralelamente, e considerando que alterações numéricas dos centrossomas podem estar presentes ao longo da progressão maligna em EB e assim contribuir para o seu processo de cancerigénese, decidimos explorar quando e como surgem as alterações numéricas dos centrossomas ao longo da progressão do EB, desde a condição prémaligna até às metástases ganglionares, tanto em amostras de doentes como em linhas celulares, usando um método de dupla marcação por imunofluorescência para identificar e quantificar fidedignamente o número de centrossomas por célula. Esta análise revelou a existência de células com centrossomas supranumerários logo na fase de metaplasia dos doentes que progrediram para cancro, e que a sua incidência aumenta significativamente na fase de displasia, a qual é dependente da perda de função do gene supressor tumoral p53, estando também depois presentes ao longo das restantes fases de progressão. Estes resultados sugerem assim que a desregulação dos centrossomas pode contribuir para a iniciação e progressão neoplásica do EB. No futuro será importante aprofundar o contributo dos centrossomas na cancerigénese do EB e tentar perceber qual o seu impacto no diagnóstico, prognóstico e tratamento destes doentes. Uma vez que tanto as alterações numéricas dos centrossomas como a perda de função do p53 são achados prevalentes em cancro, os resultados deste estudo poderão ser relevantes para outros modelos tumorais. Em conjunto, os resultados obtidos sugerem que a propensão maligna não é igual em todos os EB. Logo muito cedo no processo, aqueles cujo risco de virem a desenvolver cancro é maior sofrem alterações moleculares e celulares passíveis de serem detetadas e utilizadas como biomarcadores preditivos estratificando o risco de progressão maligna, e desta forma orientar as decisões clínicas, adequar tempos de vigilância e melhorar a abordagem terapêutica

    In situ and in vitro models to investigate the role of oestrogen and oestrogen metabolism in pulmonary vascular disease

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    Pulmonary arterial hypertension is an incurable vasculopathy, which affects significantly more women than men. Hence, female sex hormones may be intimately involved in the initiation and progression of disease pathogenesis. Indeed, current evidence suggests dysregulated oestrogen biosynthesis and metabolism, result in microenvironment favouring excessive proliferation of pulmonary artery smooth muscle cells, leading to significant vascular remodelling. Impairment of signalling via the bone morphogenetic protein receptor II (BMPRII) signalling pathway might also be partially accountable for increased cellular proliferation, and the sex dimorphism associated with the disease. Much of the currently available evidence regarding the pathophysiological mechanism of this vasculopathy was gained using experimental animal models of pulmonary hypertension, we aimed to develop and employ in situ and in vitro models to investigate the role of oestrogen and its metabolism in pulmonary arterial hypertension. Signalling through aryl hydrocarbon receptor results in altered expression of Phase I and II metabolising enzymes, including oestrogen metabolising enzymes. Using an in-silico approach, we demonstrated that the importance of aryl hydrocarbon receptor in experimental animal model of pulmonary hypertension induced by exposure to Sugen 5416 and chronic hypoxia. Initial quantitative real-time polymerase chain reaction analysis revealed that expression of CYP1A1 gene might be decreased in cultured pulmonary arterial smooth muscle cells from female patients, rats exposed to chronic hypoxia and Smad1 heterozygous mice. CYP1A1 gene expression was, however, greatly increased in the Sugen 5416/hypoxic experimental animal model. We further demonstrated that in this specific model several genes under the transcriptional activation of the aryl hydrocarbon receptor, such as NAD(P)H quinone dehydrogenase 1 and aryl hydrocarbon receptor repressor, are increased. In vitro stimulation of human pulmonary arterial smooth muscle cells with Sugen 5416, which is a potent agonist of the aryl hydrocarbon receptor, resulted in increased expression of CYP1A1 and 1B1. We further demonstrated by employing R.E.A.P. fractionation protocol, that stimulation of smooth muscle cells with Sugen 5416 resulted in the translocation of the aryl hydrocarbon receptor from the cytoplasm to the nucleus, where it was able to exert its transcriptional activity. The blockade of the aryl hydrocarbon receptor pathway by CH223191, resulted in attenuated expression of these oestrogen metabolising enzymes only in smooth muscle cells derived from pulmonary arteries of control subjects. In human pulmonary microvascular endothelial cells, simulation with Sugen 5416 and aryl hydrocarbon receptor inhibitor, FICZ, increased apoptosis of these cells as assessed via reduced cell number and increased cleavage of Caspase 3. Hence, Sugen 5416 may induce vascular injury, leading to initiation of pathophysiological mechanisms of experimental PH. Even though the aryl hydrocarbon receptor pathway interacts with hypoxia-inducible factor signalling, we showed that stimulation of pulmonary artery smooth muscle cells does not alter mediators involved in the latter pathway. Furthermore, we showed that sex dimorphism might exist in the basal expression of mediators involved in the hypoxia-inducible factors signalling pathway (HIFs). In smooth muscle cells derived from pulmonary arteries of female PAH patients, the expression of HIF1α was significantly increased, while the regulators of HIF1α proteasomal degradation were significantly decreased. Equally, in smooth muscle cells derived from pulmonary arteries of male PAH patients, protein expression regulators of HIF1α proteasomal degradation were significantly decreased. In vitro, we demonstrated that there a possible synergy exists between the aryl hydrocarbon receptor and hypoxia-inducible factor signalling pathways, where co-stimulation with Sugen 5416 and hypoxia resulted in increased proliferation of smooth muscle cells derived from pulmonary arteries of female PAH. We also aimed to develop and employ an in vitro model to investigate the role of oestrogen and its metabolism in the pathophysiological mechanism of pulmonary arterial hypertension, and to quantitatively assess oestrogen metabolism in this model. We showed that stimulation with 2-methoxyoestrogens increased expression of prostacyclin synthase in pulmonary microvascular endothelial cells from female control subject. Using immunoblotting technique, we further demonstrated that in smooth muscle cells derived from pulmonary arteries of male control subjects 2-methoxyoestradiol increased protein expression of Id3 and had no significant effect in smooth muscle cells derived from pulmonary arteries of female control subjects. It appears that in female pulmonary artery smooth muscle cells 2-methoxyoestradiol increased the expression of p27/Kip1 in a concentration-dependent manner. In fact, in vitro stimulation with 2-methoxyoestradiol attenuated serum-induced proliferation in smooth muscle cells derived from pulmonary arteries of control subjects of both sexes. In smooth muscle cells derived from pulmonary arteries of PAH patients, 2-methoxyoestradiol only reduced cellular proliferation in female cells, while having no effect in male cells. We have also examined the effects of 2- and 4-hydroxyoestradiol on serum-induced proliferation in pulmonary artery smooth muscle cells from male control subjects. Here we found both metabolites mediated attenuation of cellular proliferation, with 2-hydroxyoestradiol mediating its effects through its biotransformation into 2-methoxyoestradiol, as catechol-O-methyl transferase inhibition restored cellular proliferation. Inhibition of catechol-O-methyl transferase did not have an effect on 4-hydroxyoestradiol-mediated reduction of serum-induced proliferation. Using the in vitro model of pulmonary arterial hypertension employing pulmonary artery smooth muscle cells, we have assessed the effects of treprostinil on oestrogen metabolism in these cells using high performance liquid chromatography/flux analysis. We demonstrated that pulmonary artery smooth muscle cells derived from female and male PAH patients might metabolise 17β-oestradiol differently than those derived from control subjects. Moreover, treprostinil might affect the metabolism of 17β-oestradiol to oestrone, probably by affecting the activity of 17β-hydroxysteroid dehydrogenase type 2. Basal protein expression level as assessed by immunoblotting technique indicated that the latter enzyme might be increased in pulmonary artery smooth muscle cells derived from male PAH patients. To overcome certain shortcomings of high performance liquid chromatography/flux analysis for investigation of oestrogen metabolism, we aimed to develop and optimise a liquid chromatography tandem mass spectrometry approach. We have established the technique, and optimised separation of methoxyoestrogens and wash steps. The novel approach was used to assess oestrogen metabolism in in vitro model of pulmonary arterial hypertension, showing that smooth muscle cells derived from female PAH patients produce significantly more oestrone and 17α-isomer of oestradiol. Moreover, smooth muscle cells derived from male PAH patients metabolised the least 17β-oestradiol in comparison with female patient cells. Although the technique is now established, further optimisation is required to achieve reliable quantification of oestrogen metabolites in reasonable concentration ranges, as currently the method appears unreliable at concentration ranges for some oestrogen metabolites. Using a hypothesis-free metabolomic screen we also demonstrated that certain metabolic pathways associated with energy reactive oxygen species and L-tryptophan metabolism might be affected in pulmonary artery smooth muscle cells. Using in situ model we showed that induction of the aryl hydrocarbon receptor by Sugen 5416 leads to alterations in the expression of oestrogen metabolising enzymes, such as CYP1B1 and CYP1A1. Thereby possibly affecting the pathogenic mechanisms by introducing an imbalance of oestrogen metabolism. By using in vitro model of pulmonary arterial hypertension, we also showed methoxyoestrogen the role of methoxyoestrogens, 2-and 4-hydroxyoestrogens in the attenuation of cellular proliferation in pulmonary artery smooth muscle cells. Furthermore, we established oestrogen metabolic profile in pulmonary artery smooth muscle cells derived from controls and patients of both sexes and quantified these metabolites. We have therefore successfully applied in situ and in vitro approaches to investigate the role of oestrogen and oestrogen metabolism in the pathogenesis of pulmonary arterial hypertension

    Orchestration of the neural stem cell fate by NRF2 and TAZ

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    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de lectura: 11-10-2019Neurogenesis is a multiple step process that must be tightly regulated or otherwise results in pathological events. Therefore, a deep characterization of the molecular mechanisms that control the biology of neural stem/progenitor cells (NSPCs) will provide a better understanding of the role of neurogenic niches and new therapeutic strategies for neurodegenerative diseases and brain tumours. In this thesis we have analyzed the regulation of NSCs fate by the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (NRF2), which is considered a master regulator of cellular homeostasis, and the Transcriptional co-activator with PDZ-binding motif (TAZ), a major effector of the Hippo pathway. NRF2 controls the expression of a wide battery of cytoprotective genes that have a tremendous impact on physiological responses such as inflammation, senescence or metabolism. However, its relevance in neurogenesis is just starting to be unveiled. On the other hand, TAZ is a major effector of the Hippo pathway, which plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. However, the implication of TAZ in neurogenesis has not been analyzed. In this study, we have identified NRF2 as a regulator of hippocampal NSCs self-renewal and differentiation. We show that genetic manipulation of NRF2 results in the modulation of NSPCs differentiation and proliferation capacity. To assess the functional relevance of NRF2 in neurogenesis under pathological conditions, we analyzed the impact of NRF2 deficiency in neurogenesis of the subgranular zone (SGZ) of the hippocampus in a mouse model of Alzheimer´s Disease (AD). We found that NRF2 deficiency results in an accelerated loss of NSCs, loss of synaptic plasticity measured as long term potentiation (LTP) and impaired the execution of cognitive tasks. At the molecular level, we have identified NRF2 enhancer sequences, termed Antioxidant Response Elements (AREs), in the promoter region of the TAZ coding gene. Consequently, we show that genetic and pharmacological manipulation of NRF2 results in the modulation of TAZ gene expression in NSPCs. These findings open a new window to understand the molecular mechanisms underlying NRF2 function in stemness. We have also established a novel role of TAZ as repressor of neuronal differentiation, based on the transcriptional repression of SOX2 and the basic helix-loop-helix (bHLH) factors ASCL1, NEUROG2 and NEUROD1. Data mining of The Cancer Genome Atlas showed a negative correlation between TAZ and the expression of these proneurogenic factors in lower grade gliomas and glioblastomas. We found that TAZ favours glioblastoma CSCs tumorigenic capacity and that genetic modulation of TAZ in these cells inversely correlated with proneurogenic genes expression. Due to the relevance of these proneurogenic factors in the ablation of glioblastoma cancer stem cells (CSCs), this novel TAZ/proneurogenic factors axis may have important implications in the development of this type of brain tumours. The characterization of molecular mechanism governing NSPCs fate provides new insights to harness these cells for brain repair. Overall, this thesis describes a novel role of NRF2 and TAZ in the control of neural stem cell fate, suggesting a new strategy to combat brain pathology
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