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YAP/TAZ in the regulation of epidermal stem cell fate and glioblastoma cell behavior
No full textCells within a tissue respond to mechanical forces and changes in the physical properties of the external microenvironment; the two transcriptional regulators YAP and TAZ transduce these physical inputs into biological responses. In this scenario the epidermis is a point in case as it represents a real mechanosensitive tissue for its structure and functions. In the first part of this thesis, we showed that YAP/TAZ regulation by cell shape and rigidity of the extracellular matrix (ECM) controls the balance between proliferation and differentiation in epidermal SCs. Furthermore, we established a new functional link between YAP and Notch both in vitro and in vivo. Indeed, YAP/TAZ are active in a high tension microenvironment where they promote epidermal stemness through the inhibition of Notch signaling, a key factor for epidermal differentiation. On contrary, YAP/TAZ inhibition by low mechanical forces induces Notch signaling activation, loss of SC traits and differentiation. Molecularly, we found that YAP/TAZ, by regulating the expression of Notch Delta-like ligands through distant enhancers, sustain Notch ‘cis-inhibition’ and preserve stemness of epidermal progenitor cells. Moreover, YAP/TAZ positively regulate the expression of the ubiquitinligase NEDD4L that fosters Notch receptor degradation and inhibits ligand-independent activation of the signaling. Thus YAP/TAZ integrates mechanical inputs with cell–cell communication signals to regulate epidermal SC fate.
In the second part, we described the role of YAP and TAZ in cancer, in particular by investigating their function in Glioblastoma Multiforme (GBM), the most frequent brain malignancy and the one with the poorest prognosis. The preliminary results shown here, demonstrated that YAP/TAZ are necessary to promote mouse astrocyte de-differentiation and gliomaspheres formation. Moreover, YAP/TAZ are required to sustain glioma sphere selfrenewal and stability. The highly malignant properties of GBM likely rely on their intrinsic plasticity, the ability to revert spontaneously to a cancer stem cell state after differentiation.
YAP/TAZ play a fundamental role also in this aspect of GBM biology, as we found that GBM cell de-differentiation is impaired in the absence of these two transcriptional coactivators.Le cellule all'interno di un tessuto rispondono alle forze meccaniche e alle variazioni delle proprietà fisiche dell'ambiente extracellulare; i due regolatori trascrizionali YAP e TAZ traducono questi input fisici in risposte biologiche. In questo contesto, la pelle rappresenta un caso esemplare di tessuto che per la sua struttura e le sue funzioni viene definito come meccano-responsivo. Nella prima parte di questa tesi mostriamo che la regolazione di YAP e TAZ mediata dalla forma della cellula e dalla rigidità della matrice extracellulare (ECM) controlla l'equilibrio tra proliferazione e differenziamento nelle cellule staminali dell’epidermide. Con questo lavoro abbiamo dunque stabilito un nuovo collegamento funzionale tra YAP e Notch sia in vitro che in vivo. YAP e TAZ sono trascrizionalmente attivi quando le cellule sono sottoposte ad alta tensione meccanica e, attraverso l'inibizione della via di segnale Notch, mantengono le caratteristiche staminali di queste cellule. Al contrario, l'inibizione di YAP e TAZ condizionata da forze che inducono bassa tensione meccanica nelle cellule, induce l'attivazione del segnale di Notch, fattore chiave per il differenziamento dell’epidermide, la perdita di proprietà staminali e il differenziamento. Abbiamo infatti scoperto che YAP e TAZ si legano a enhancers che attivano l'espressione dei ligandi di Notch i quali vanno ad agire come inibitori "in cis" e quindi preservano le caratteristiche staminali delle cellule progenitrici. Inoltre, YAP e TAZ regolano positivamente l'espressione della ubiquitina-ligasi NEDD4L, la quale promuove la degradazione del recettore Notch e inibisce l'attivazione del segnale. Così YAP e TAZ integrano gli inputs meccanici con le vie di comunicazione delle cellule per regolare il comportamento delle cellule staminali dell’epidermide.
Nella seconda parte di questo lavoro, abbiamo descritto il ruolo di YAP e TAZ nel cancro, in particolare studiando la loro funzione nel Glioblastoma Multiforme (GBM), uno dei più frequenti tumori cerebrali e con la prognosi più infausta. I risultati preliminari mostrati qui dimostrarono che YAP e TAZ sono necessari per promuovere la conversione degli astrociti in cellule con comportamento staminale e la formazione di glioma sfere. Inoltre, YAP e TAZ sono necessari per sostenere l’auto rinnovamento e la stabilità di queste sfere. Le proprietà altamente maligne del glioblastoma sono probabilmente causate dalla sua intrinseca plasticità, la capacità di ritornare spontaneamente a uno stato di cellule staminali del cancro dopo il differenziamento. YAP e TAZ svolgono un ruolo fondamentale in quest’aspetto della biologia del tumore, in quanto il de-differenziamento delle cellule di glioblastoma è severamente compromesso in assenza di questi due co-attivatori trascrizionali
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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