1,721,851 research outputs found
Notch signalling in development and disease: Maml1 and Jagged1 not always on the shadow of Notch
Full text linkThe Notch signalling is an evolutionary conserved pathway from flies to vertebrates, that regulates a large spectrum of cellular processes, such as proliferation, differentiation and cell death. The intracellular domain of Notch receptors controls the transcription of the target genes through the presence of different factors such as ligands and transcriptional co-activators, whose presence permits the activation of the pathway. Moreover, different studies have highlighted the importance of Notch pathway components, that play a fundamental role in development and the onset of several diseases, often with Notch-independent mechanisms.
In this thesis, I report novel observations about Maml1 and Jagged1 proteins directly involved in development/differentiation processes and neoplastic transformation in a Notch-independent manner.
In mammals, Maml1 belongs to a family of proteins, also including Maml2 and Maml3, which act as transcriptional coactivators for Notch signalling. Maml1 has been recently shown to act as a coactivator in other cell signalling pathways. Of note, we have demonstrated that Maml1 empowers Sonic Hedgehog signalling pathway, regulating the transcriptional activity of Gli proteins, via a novel Notch-independent mechanism. So far, scientific research on Maml1 has been generally focused on its activity as a transcriptional coactivator, while overlooking its role in the post-transcriptional regulation. Interestingly, our preliminary data suggest a novel role for Maml1 in the post- translational regulation of Gli1, being able to prevent its degradation mediated by Itch, an E3 ubiquitin-protein ligase. Therefore, we propose a dual role for Maml1, both as transcriptional co-activator of important transcriptional factors and post-translational regulator of target proteins, regulating Itch activity directly. This study tries to shed light on the molecular mechanism that regulates the stability and activity of Gli1 mediated by Maml1 and seeks to provide a new integrated level of regulation in Shh/Gli pathway, that might lead to future therapeutic approaches directed against Shh-driven tumours.
Moreover, several evidences reported that, similarly to Notch receptors, the DSL ligands undergo the same proteolytic cleavages that result in the release of an intracellular fragment. Jagged1 is a substrate for catalytic activity of the Metalloprotease ADAM17 (A Disintegrin and Metalloproteinase) and presenilin/γ-secretase complex activity that releases a soluble intracellular fragment (Jag1-ICD), which translocates into the nucleus. Recently, several studies linked the expression levels of Jagged1 with the development and/or progression of solid tumours. Jagged1 role in Colorectal Cancer (CRC) is linked to the development and progression of the tumour. CRC is characterized by well-known genetic defects and about 50% of the cases harbour oncogenic RAS mutations. Herein, we demonstrate that Jagged1 is constitutively processed in CRC tumours with mutant Kras, ultimately triggering an intrinsic reverse signalling via its nuclear-targeted intracellular domain (Jag1-ICD). We provide evidence that the processing occurs when a Kras/Erk/ADAM17 signalling axis is switched on, demonstrating that Jagged1 is a novel target of Kras signalling pathway. Notably, we show that Jag1-ICD promotes tumour growth and epithelial-mesenchymal transition, enhancing CRC progression and chemoresistance both in vitro and in vivo. Our data pinpoint a novel role for Jagged1 in CRC tumour biology that may go beyond its effect on canonical Notch activation and suggest that Jag1-ICD may behave as a novel oncogenic driver, able to sustain tumour pathogenesis and to confer chemoresistance, through a non-canonical mechanism. By unveiling the Kras/Erk/ADAM17/Jagged1 signalling axis, we provide new mechanistic insights on CRC tumour biology and highlight a novel attractive target for CRC therapy
Des mots et des femmes. Rencontres linguistiques
No full textPer delineare la storia della “parola” presa o data alle donne, nonché la loro presenza e la loro influenza nelle diverse epoche nel discorso letterario e giornalistico francofono, in opere di riferimento come i dizionari e le enciclopedie, abbiamo raccolto i punti di vista di specialisti di vari ambiti scientifici provenienti da diversi paesi. In che modo è integrata la donna nella definizione di una norma linguistica o nella creazione neologica? Quali sono le parole che la descrivono o che le sono rivolte? Quali figure femminili emergono dalle diverse opere analizzate, veri e propri vettori delle nostre culture e società ? Dall’amante alla straniera, dall’intellettuale alla meretrice, dall’operaia alla donna di potere, le differenti sfaccettature della donna, messa a nudo o screditata, restituiscono una visione dinamica della condizione femminile
Geometry of quasiminimal phase transitions
No full textWe consider the quasiminima of the energy functional ∫ Ω A(x, ∇ u) + F(x, u) dx, where A(x, ∇ u) ∼ |∇ u|p and F is a double-well potential. We show that the Lipschitz quasiminima, which satisfy an equipartition of energy condition, possess density estimates of Caffarelli-Cordoba-type, that is, roughly speaking, the complement of their interfaces occupies a positive density portion of balls of large radii. From this, it follows that the level sets of the rescaled quasiminima approach locally uniformly hypersurfaces of quasiminimal perimeter. If the quasiminimum is also a solution of the associated PDE, the limit hypersurface is shown to have zero mean curvature and a quantitative viscosity bound on the mean curvature of the level sets is given. In such a case, some Harnack-type inequalities for level sets are obtained and then, if the limit surface if flat, so are the level sets of the solution
Flattening results for elliptic PDEs in unbounded domains with applications to overdetermined problems
No full textSemilinear elliptic PDEs are dealt with, either in the half-space or in overdetermined settings. We obtain several new results and also give new proofs of celebrated theorems by exploiting some geometric analysis of level sets, a geometric inequality and a pointwise gradient estimate
Space-time-frequency processing of synthetic aperture radar signals
No full textThe subject of this work is the detection and high resolution microwave imaging of objects moving on the ground and observed by an airborne radar. The proposed approach is based on a combined space-time and time-frequency processing. The space-time processing makes use of a linear array antenna and exploits the radar motion for filtering the received echoes in order to improve as much as possible the signal-to-disturbance ratio. The signal is then mapped onto the time-frequency domain, by computing its Wigner-Ville distribution, for a further filtering and for estimating its instantaneous frequency, necessary for the formation of a high resolution image of the moving objec
Rigidity results for elliptic PDEs with uniform limits: an abstract framework with applications
Full text linkWe provide an abstract framework for a symmetry result arising in a conjecture of G.W. Gibbons and we apply it to the fractional Laplace operator, to the elliptic operators with constant coefficients, to the quasilinear operators, and to elliptic fully nonlinear operators with possible gradient dependence
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