Intrinsic Structural Disorder Confers Cellular Viability on Oncogenic Fusion Proteins

Chromosomal translocations, which often generate chimeric proteins by fusing segments of two distinct genes, represent the single major genetic aberration leading to cancer. We suggest that the unifying theme of these events is a high level of intrinsic structural disorder, enabling fusion proteins to evade cellular surveillance mechanisms that eliminate misfolded proteins. Predictions in 406 translocation-related human proteins show that they are significantly enriched in disorder (43.3% vs. 20.7% in all human proteins), they have fewer Pfam domains, and their translocation breakpoints tend to avoid domain splitting. The vicinity of the breakpoint is significantly more disordered than the rest of these already highly disordered fusion proteins. In the unlikely event of domain splitting in fusion it usually spares much of the domain or splits at locations where the newly exposed hydrophobic surface area approximates that of an intact domain. The mechanisms of action of fusion proteins suggest that in most cases their structural disorder is also essential to the acquired oncogenic function, enabling the long-range structural communication of remote binding and/or catalytic elements. In this respect, there are three major mechanisms that contribute to generating an oncogenic signal: (i) a phosphorylation site and a tyrosine-kinase domain are fused, and structural disorder of the intervening region enables intramolecular phosphorylation (e.g., BCR-ABL); (ii) a dimerisation domain fuses with a tyrosine kinase domain and disorder enables the two subunits within the homodimer to engage in permanent intermolecular phosphorylations (e.g., TFG-ALK); (iii) the fusion of a DNA-binding element to a transactivator domain results in an aberrant transcription factor that causes severe misregulation of transcription (e.g. EWS-ATF). Our findings also suggest novel strategies of intervention against the ensuing neoplastic transformations

Quality control by Infrared Thermography of the infusion manufacturing process of composite automotive specimens

Abstract (Arial, 9pt, bold) In this study the main defects appearing in composite manufacturing by infusion process are investigated to develop specific quality control routines. The technology employed to analyze this process and carry out quality controls is infrared thermography which, due to the special configuration of infusion manufacturing, allows an on-line monitoring of the whole process. This study was conducted at laboratory level with different composite materials, determining the thermal behaviour of the zones undergoing anomalies. This way a complete procedure for anticipating defect initialization and stopping the manufacturing process in early stages was defined, enabling repair actions and saving time and costs

Effect of superelastic shape memory alloy wires on the impact behaviour of carbon fiber reinforced in situ polymerized poly(butylene terephthalate) composites

Low-velocity impact properties of shape memory alloy (SMA) wires and carbon fi ber reinforced poly (butylene terephthalate) obtained by resin transfer molding were characterized. At the subcritical regime the dissipated energy is not affected by the presence of the wires. However SMA has a positive effect on the maximum absorbed energy, since the maximum allowable load is higher. The contribution of the SMA wires to the higher impact performance of the hybrid composite is suggested to be due to their energy absorbing capability, and also to the high reversible force that acts as a healing force.Peer ReviewedPostprint (published version

Effect of superelastic shape memory alloy wires on the impact behaviour of carbon fiber reinforced in situ polymerized poly(butylene terephthalate) composites

Low-velocity impact properties of shape memory alloy (SMA) wires and carbon fi ber reinforced poly (butylene terephthalate) obtained by resin transfer molding were characterized. At the subcritical regime the dissipated energy is not affected by the presence of the wires. However SMA has a positive effect on the maximum absorbed energy, since the maximum allowable load is higher. The contribution of the SMA wires to the higher impact performance of the hybrid composite is suggested to be due to their energy absorbing capability, and also to the high reversible force that acts as a healing force.Peer Reviewe