1,721,003 research outputs found
MSEL-1L: L'OROLOGIO MOLECOLARE DEL DIFFERENZIAMENTO NEURALE
Full text linkThe gene SEL-1L codifies for a protein involved in the retrotranslocation of misfolded peptides from the lumen on the endoplasmic reticulum to the cytoplasm, where they are degraded by the ubiquitin-proteasome mechanism in the ERAD (Endoplasmic Reticulum Associated Degradation) pathway.
Recently, it was found that the murine protein mSEL-1L (murine SEL-1L) plays an essential role during embryonic development, since its homozygous deletion is lethal during mid-gestation, altering the correct organogenesis. This transgenic model allowed us to investigate mSEL-1L contribution in differentiation and brain development in vivo and to study its role in neural stem cell (NSC) biology in vitro, focusing on its relationship with Notch signaling.
We have shown that during embryogenesis, mSEL-1L expression is ubiquitous in the developing brain with high levels detected in the ventricular regions, densely populated by neural progenitors. As development proceeds, mSEL-1L protein levels significantly decrease, allowing the detection of rare cells still expressing the protein only in the ventricular zones and in the dentate gyrus, the only adult neurogenic ¡§niches¡ ̈ in which a population of undifferentiated and quiescent NSCs is retained. It has been subsequently proved that mSEL-1L expression plays as essential role in directing and ensuring a harmonious NSC differentiation, as the protein deletion is associated with an early cellular differentiation that determines the progenitor pull depletion, both in vivo and in vitro. In particular, mSEL-1L absence in vivo compromises the corticogenesis, because it affects the correct sequence of neurogenic and astrogliogenic phases, altering both the residual stem cell population and its differentiated progeny. The similarity of this transgenic model with Notch mutants led us to investigate the possible involvement of mSEL-1L with this pathway. Co-immunoprecipitation analysis has revealed an interaction between these two proteins, while expression studies have shown a specific inhibition of Notch-1 signaling associated to mSEL-1L down-regulation. The expression of the nuclear activated form of the receptor, as well as that of its main effectors HES-1 and HES-5, are significantly inhibited when mSEL-1L is totally or partially depleted, promoting an erroneous up-regulation of the transcriptional factor Neurogenin-2 (NGN-2) and the following increase of the neuronal marker ƒÒIII¡VTubulin expression.
The main NSC properties primarily governed by Notch pathway, such as self-renewal, differentiation, proliferation and cell survival, are drastically affected by mSEL-1L misregulation. Moreover, mSEL-1L deficient mouse models show significant vasculogenic and angiogenic defects during embryonic development, probably due to an alteration of Notch signaling.
The proper control of mSEL-1L expression is therefore of paramount importance to enable the correct embryonic development, as well as its regulation during differentiation by specific and sophisticated mechanisms. In fact, it has emerged that mSEL-1L is abundantly expressed in mouse embryonic stem cells (ESCs) and is maintained stable through their in vitro differentiation into neural progenitors (NEPs) first, and then into radial glia-like NSCs, while its expression is inhibited during their final maturation into neurons, astrocytes and oligodendrocytes. So, the protein is not affected by passing from a state of pluripotency (ESCs), to multipotency (NEPs), up to tripotency (NSCs), but it must be silenced to ensure
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NSC terminal differentiation. In fact, it has been demonstrated that mSEL-1L expression is regulated in a post-transcriptional way by mmu-miR-183. This microRNA, whose expression is induced during differentiation both in vitro and in vivo, is able to negatively regulate mSEL-1L, as well as other proteins with an important function in stemness, such as ƒÒ-Integrin and Bmi-1. Differently, mmu-miR-183 down-modulation can promote an increase in the protein levels in NSCs derived from the telencephalic cortex of embryos with only one mSEL-1L functional allele (mSEL-1L HET), ensuring a high protein expression, although in presence of a reduced quantity of its messenger.
In conclusion, this research has highlighted an ERAD-independent role of mSEL-1L concerning NSC biology, a role that is essential to guarantee the proper embryonic development and the homeostasis of the whole organism. Therefore, the protein appears as a sort of ¡§molecular clock¡ ̈ that can drive the transition from a stemness state to a differentiate one, only when it is appropriate. The data here presented may provide a good starting point for the development of specific therapeutic strategies for degenerative pathologies and for regenerative medicine applications
Is stem cell chromosomal stability affected by cryopreservation conditions?
No full textThe use of in vitro cultured stem cells in cell therapy, must meet at least two requirements: the preservation of a normal genetic karyotype and maintenance of integrity during long term-culturing and storage in liquid nitrogen tanks. Here we report on the karyological characterization of neural stem cells derived from adult (ANS) subentricular zone (SVZ), mouse fetal cotex cells, mESCs cells NS46 (LC-1) and related engineered clones as well as Neurospheres from the mouse striatum Li-4. The results show a series of chromosomal aberrations present in these cells in agreement with previous reports. On the other hand, karyotyping of the human neural stem cell lines derived from hESCs (H9-hNCPC) and fetal cerebellum (CB541) showed a stable genomic asset with few chromosomal aberration. These results underscore the importance of performing routine cytogenetic analysis before using the cells to produce chimeric mice or in studies of lineage specific differentiation. We are also evaluating the use of Cell microarray for high-throughput screening of stem cell differentiation by immunocytochemical analysis. With this technique we were able to follow the expression of neural differentiation markers and the involvement of SEL1L gene in stem cell self-renewal
Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery
No full textIntroduction: Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells.Areas covered: In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field.Expert opinion: The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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