60 research outputs found

    Regenerative Approaches in Huntington’s Disease: From Mechanistic Insights to Therapeutic Protocols

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    Huntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the exon-1 of the IT15 gene encoding the protein Huntingtin. Expression of mutated Huntingtin in humans leads to dysfunction and ultimately degeneration of selected neuronal populations of the striatum and cerebral cortex. Current available HD therapy relies on drugs to treat chorea and control psychiatric symptoms, however, no therapy has been proven to slow down disease progression or prevent disease onset. Thus, although 24 years have passed since HD gene identification, HD remains a relentless progressive disease characterized by cognitive dysfunction and motor disability that leads to death of the majority of patients, on average 10–20 years after its onset. Up to now several molecular pathways have been implicated in the process of neurodegeneration involved in HD and have provided potential therapeutic targets. Based on these data, approaches currently under investigation for HD therapy aim on the one hand at getting insight into the mechanisms of disease progression in a human-based context and on the other hand at silencing mHTT expression by using antisense oligonucleotides. An innovative and still poorly investigated approach is to identify new factors that increase neurogenesis and/or induce reprogramming of endogenous neuroblasts and parenchymal astrocytes to generate new healthy neurons to replace lost ones and/or enforce neuroprotection of pre-existent striatal and cortical neurons. Here, we review studies that use human disease-in-a-dish models to recapitulate HD pathogenesis or are focused on promoting in vivo neurogenesis of endogenous striatal neuroblasts and direct neuronal reprogramming of parenchymal astrocytes, which combined with neuroprotective protocols bear the potential to re-establish brain homeostasis lost in HD

    Post-transcriptional mechanisms controlling neurogenesis and direct neuronal reprogramming

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    Neurogenesis is a tightly regulated process in time and space both in the developing embryo and in adult neurogenic niches. A drastic change in the transcriptome and proteome of radial glial cells or neural stem cells towards the neuronal state is achieved due to sophisticated mechanisms of epigenetic, transcriptional, and post-transcriptional regulation. Understanding these neurogenic mechanisms is of major importance, not only for shedding light on very complex and crucial developmental processes, but also for the identification of putative reprogramming factors, that harbor hierarchically central regulatory roles in the course of neurogenesis and bare thus the capacity to drive direct reprogramming towards the neuronal fate. The major transcriptional programs that orchestrate the neurogenic process have been the focus of research for many years and key neurogenic transcription factors, as well as repressor complexes, have been identified and employed in direct reprogramming protocols to convert non-neuronal cells, into functional neurons. The post-transcriptional regulation of gene expression during nervous system development has emerged as another important and intricate regulatory layer, strongly contributing to the complexity of the mechanisms controlling neurogenesis and neuronal function. In particular, recent advances are highlighting the importance of specific RNA binding proteins that control major steps of mRNA life cycle during neurogenesis, such as alternative splicing, polyadenylation, stability, and translation. Apart from the RNA binding proteins, microRNAs, a class of small non-coding RNAs that block the translation of their target mRNAs, have also been shown to play crucial roles in all the stages of the neurogenic process, from neural stem/progenitor cell proliferation, neuronal differentiation and migration, to functional maturation. Here, we provide an overview of the most prominent post-transcriptional mechanisms mediated by RNA binding proteins and microRNAs during the neurogenic process, giving particular emphasis on the interplay of specific RNA binding proteins with neurogenic microRNAs. Taking under consideration that the molecular mechanisms of neurogenesis exert high similarity to the ones driving direct neuronal reprogramming, we also discuss the current advances in in vitro and in vivo direct neuronal reprogramming approaches that have employed microRNAs or RNA binding proteins as reprogramming factors, highlighting the so far known mechanisms of their reprogramming action

    Study of non-genomic action of TGF-β and activin in cell responses that are mediated through Rho GTPases and actin cytoskeleton in cancer cells

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    The present study presents a novel mechanism which regulates the shortand long-term actin reorganization through Rho GTPase signaling and controls cellular responses such as cytoskeleton organization, EMT and invasiveness in normal and tumor cells.Στην παρούσα διατριβή παρουσιάζεται ένας νέος μηχανισμός που ρυθμίζει τη γρήγορη και παρατεταμένη αναδιοργάνωση της ακτίνης μέσω των Rho GTPασών και ελέγχει διάφορες κυτταρικές διεργασίες, όπως η οργάνωση του κυτταροσκελετού, η ΕΜΤ και η διεισδυτικότητα τόσο σε φυσιολογικά, όσο και σε καρκινικά κύτταρ

    Populating an Allergens Ontology Using Natural Language Processing and Machine Learning Techniques

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    Abstract. Ontologies are becoming increasingly important in the biomedical domain since they enable the re-use and sharing of knowl-edge in a formal, homogeneous and unambiguous way. In the rapidly growing field of biomedicine, knowledge is usually evolving and there-fore an ontology maintenance process is required to keep the ontological knowledge up-to-date. This paper presents our approach for populating a formally defined ontology for the allergen domain exploiting PubMed ab-stracts on allergens and using natural language processing and machine learning techniques. This approach is composed of two stages: locating initially instances of ontology concepts in the PubMed corpus, and find-ing at a 2nd stage instances ’ properties and relations between instances.

    Assessing the performance of the European Union in Central and Eastern Europe and in its neighbourhood

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    Introduction to: East European Politics Special Issue: Assessing the Performance of the European Union in Central and Eastern Europe and in its Neighbourhood. The goal of this Special Issue is to examine the performance of EU policies and processes as well as their impact in the ‘wider’ Eastern Europe. We make both a conceptual and an empirical contribution. Conceptually, we link the literature on EU policy and its impact in ‘wider’ Eastern Europe with the literature on performance and distinguish between processdriven and outcome-driven performance of the EU. Under process-driven performance we evaluate the nature of the capabilities and the mechanisms and procedures used by the European Union in order to pursue its stated objectives. Subsequently, under outcome-driven performance we examined whether or not EU goals or objectives have been achieved on the basis of the effects these have. Drawing on insights from enlargement, post-enlargement and ENP partner countries, the empirical contributions to this volume examine both the processdriven and outcome-driven performance of the EU through addressing two sets of questions: (1) what is the correlation between the EU's outcome-driven performance and its internal processes of preference formation (process-driven performance)?; and (2) what is the relationship between the EU’s outcome-driven performance and the context of rewards/threats through which the EU engages with its partners? This introductory article therefore unpacks the notion of performance, proposes three modes of operationalization of performance and provides insights from the contributions to this Special Issue

    De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

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    Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a novel syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome 2 . We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals. </p
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