Search

The IBTK gene encodes the IBtkα protein that is a substrate receptor of E3 ubiquitin ligase, Cullin 3. We have previously reported the pro-tumorigenic activity of Ibtk in MYC-dependent B-lymphomagenesis observed in Eμ-myc transgenic mice. Here, we provide mechanistic evidence of the functional interplay between IBtkα and MYC. We show that IBtkα, albeit indirectly, activates the β-catenin-dependent transcription of the MYC gene. Of course, IBtkα associates with GSK3β and promotes its ubiquitylation, which is associated with proteasomal degradation. This event increases the protein level of β-catenin, a substrate of GSK3β, and results in the transcriptional activation of the MYC and CCND1 target genes of β-catenin, which are involved in the control of cell division and apoptosis. In particular, we found that in Burkitt’s lymphoma cells, IBtkα silencing triggered the downregulation of both MYC mRNA and protein expression, as well as a strong decrease of cell survival, mainly through the induction of apoptotic events, as assessed by using flow cytometry-based cell cycle and apoptosis analysis. Collectively, our results shed further light on the complex puzzle of IBtkα interactome and highlight IBtkα as a potential novel therapeutic target to be employed in the strategy for personalized therapy of B cell lymphoma.

The upgrading of bridges located in seismic areas and built according to obsolete codes is becoming a priority task for highway administrations. Among the possible upgrading strategies, the use of fiber-reinforced plastic (FRP) jackets is gaining widespread acceptance. In this paper, a design equation is proposed to determine the optimal thickness of FRP jackets, to enhance the ductility of existing reinforced-concrete (RC) bridge piers with circular cross sections. The design procedure stems from the definition of an upgrading index, given as the ratio of the target to available ductility at the pier base section, to be attained through FRP jacketing. The available ductility is that identified through the usual assessment procedures on the RC member set for upgrade, whereas the target ductility is evaluated based on the expected actions on the bridge. The upgrading index is initially defined in general terms and is subsequently extended to the case of piers built in seismic regions. It results in a simple expression in terms of easily computable quantities, such as the ultimate strain and the peak strength of concrete, before and after upgrading. A parametric study on old-code-designed bridge pier sections, upgraded with either glass or carbon fiber jackets, is performed based on a fiber-section model equipped with a newly developed FRP-confined concrete model. This study shows that the index, despite its simplicity, yields excellent predictions of the ductility increase obtained through FRP wrapping, and it is therefore used to develop a design equation. The equation allows the design of the optimal thickness of FRP jackets in terms of the desired upgrading index, mechanical characteristics of the selected composite material, and quantities defining the initial state of the pier section. The design procedure has been applied to available experimental tests of a scaled bridge pier wrapped with FRP and tested to failure, and it has been demonstrated to be very effective.

Worldwide research has now reached a level of integration where an effort towards the harmonization of procedures is absolutely needed. Such harmonization may regard, for example, the various steps that lead to the definition of capacity models to be included in design codes, specifically: definition of the test setup, quantities to be measured, identification of the basic variables influencing the phenomenon, distinction between average values and other fractiles, disaggregation of the model in different parts accounting for me-chanics, fine-tuning and randomnesses, and, finally, assessment of the model against the experimental results. Test results and ensuing model developed according to this procedure would naturally lend themselves to be easily shared among the scientific community and would facilitate the task of calibrating the partial coeffi-cients, with the ambitious aim of attaining a uniform reliability level among all capacity equations. This paper, based on previous author works, proposes the application of a procedure for the development of capacity design equations to the capacity model of concrete confined with FRP. The procedure has been applied, with some improving, to a new capacity model proposal and to the one included in the Italian Instructions CNR DT 200–2004. The comparison has the aim of evaluating the uncertainties of the assumed model (both of the me-chanical model and of the basic variables) to obtain a constant level of structural reliability and to outline the implication that a not very well calibrated equation could have in the definition of the characteristic value.