Computational design of BclxL inhibitors that target transmembrane domain interactions.

Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains (TMDs) have not been examined thoroughly despite their importance. Here, we developed a computational approach to design sequences that specifically modulate protein-protein interactions in the membrane. To illustrate this method, we demonstrated that BclxL can interact with other members of the B cell lymphoma 2 (Bcl2) family through the TMD and that these interactions are required for BclxL control of cell death. Next, we designed sequences that specifically recognize and sequester the TMD of BclxL. Hence, we were able to prevent BclxL intramembrane interactions and cancel its antiapoptotic effect. These results advance our understanding of protein-protein interactions in membranes and provide a means to modulate them. Moreover, the success of our approach may trigger the development of a generation of inhibitors targeting interactions between TMDs.

Intra-Helical Salt Bridge Contribution to Membrane Protein Insertion.

Salt bridges between negatively (D, E) and positively charged (K, R, H) amino acids play an important role in protein stabilization. This has a more prevalent effect in membrane proteins where polar amino acids are exposed to a hydrophobic environment. In transmembrane (TM) helices the presence of charged residues can hinder the insertion of the helices into the membrane. It is possible that the formation of salt bridges could decrease the cost of membrane integration. However, the presence of intra-helical salt bridges in TM domains and their effect on insertion has not been properly studied yet. In this work, we show that potentially salt-bridge forming pairs are statistically over-represented in TM-helices. We then selected some candidates to experimentally determine the contribution of these electrostatic interactions to the translocon-assisted membrane insertion process. Using both in vitro and whole cell systems, we confirm the presence of intra-helical salt bridges in TM segments during biogenesis and determined that they contribute ∼0.5 kcal/mol to the apparent free energy of membrane insertion (ΔGapp). Our observations suggest that salt bridge interactions can be stabilized during translocon-mediated insertion and thus could be relevant to consider for the future development of membrane protein prediction software.

Integrating Virtual Worlds with Tangible User Interfaces for Teaching Mathematics: A Pilot Study.

This article presents a pilot study of the use of two new tangible interfaces and virtual worlds for teaching geometry in a secondary school. The first tangible device allows the user to control a virtual object in six degrees of freedom. The second tangible device is used to modify virtual objects, changing attributes such as position, size, rotation and color. A pilot study on using these devices was carried out at the "Florida Secundaria" high school. A virtual world was built where students used the tangible interfaces to manipulate geometrical figures in order to learn different geometrical concepts. The pilot experiment results suggest that the use of tangible interfaces and virtual worlds allowed a more meaningful learning (concepts learnt were more durable).

A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib.

BACKGROUND & AIMS: Sorafenib (SOR) is the standard of care for patients with hepatocellular carcinoma (HCC) and portal vein invasion (PVI), based on the results of phase 3 trials. However, radioembolization (RE) using yttrium-90 microspheres has been shown to achieve higher response rates and better survival in large cohorts and phase 2 trials. This study aimed to compare survival of HCC patients with PVI treated by RE or SOR. METHODS: Survival among patients with HCC and PVI treated with RE or SOR in four Spanish hospitals between 2005 and 2013 was analysed retrospectively. Kaplan-Meier survival curves were plotted and baseline variables tested for prognostic value using the log-rank test. A multivariate prognostic model including variables identified in the univariate analysis and adjusted by a propensity score based on factors that may determine the probability of exposure to RE was generated using Cox regression analyses. RESULTS: After a median follow-up of 6 months, 60 deaths had occurred: 38 and 22 in SOR and RE groups respectively. Median survival was 6.7 months (95%CI 5.2-8.1 months) for the entire cohort, and 8.8 months (95%CI 1.8-15.8) in the RE group and 5.4 months (95%CI 2.7-8.1) in the SOR group (P = 0.047). The difference in survival was still statistically significant when 13 patients in the RE group who started SOR after a median time of 8 months were censored from the analysis. CONCLUSIONS: In a cohort of patients with HCC and PVI treatment with RE was associated with a more prolonged survival compared with SOR.

Developing Mixed Reality Educational Applications: The Virtual Touch Toolkit.

In this paper, we present Virtual Touch, a toolkit that allows the development of educational activities through a mixed reality environment such that, using various tangible elements, the interconnection of a virtual world with the real world is enabled. The main goal of Virtual Touch is to facilitate the installation, configuration and programming of different types of technologies, abstracting the creator of educational applications from the technical details involving the use of tangible interfaces and virtual worlds. Therefore, it is specially designed to enable teachers to themselves create educational activities for their students in a simple way, taking into account that teachers generally lack advanced knowledge in computer programming and electronics. The toolkit has been used to develop various educational applications that have been tested in two secondary education high schools in Spain.