A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice

The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist—an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo

Anisotropy in mechanical properties and fracture behavior of an oxide dispersion Fe20Cr5Al alloy

Anisotropy of fracture toughness and fracture behavior of Fe20Cr5Al oxide dispersion-strengthened alloy has been investigated by means of compression tests, hardness tests, and wedge splitting test. The results show a small effect of the compression direction on yield strength (YS) and strain hardening. The YS is minimum for longitudinal direction and maximum for the tangential direction. The transverse plastic strain ratio is similar for tangential and longitudinal directions but very different from that in normal direction. Hardness depends on the indentation plane; it is lower for any plane parallel to the L-T plane and of similar magnitude for the other orthogonal planes, i.e., the L-S and T-S planes. Macroscopically, two failure modes have been observed after wedge-splitting tests, those of LS and TS specimens in which fracture deviates along one or two branches normal to the notch plane, and those of LT, TL, SL, and ST specimens in which fracture propagates along the notch plane. Besides LT and TL specimens present delaminations parallel to L-T plane. Both, the fracture surface of branching cracks and that of the delaminations, show an intergranular brittle fracture appearance. It is proposed that the main cause of the delamination and crack branching is the alignment in the mesoscopic scale of the ultrafine grains structure which is enhanced by the 〈110〉- texture of the material and by the presence in the grain boundaries of both yttria dispersoids and impurity contaminations. An elastoplastic finite element analysis was performed to study what stress state is the cause of the branches and delaminations. It is concluded that the normal to the crack branches and/or the shear stress components could determine the crack bifurcation mechanism, whereas the delamination it seems that it is controlled by the magnitude of the stress component normal to the delamination plane. © The Minerals, Metals & Materials Society and ASM International 2014.Peer Reviewe

DsbL and DsbI form a specific dithiol oxidase system for periplasmic arylsulfate sulfotransferase in uropathogenic Escherichia coli

Disulfide bond formation in the Escherichia coli periplasm requires the transfer of electrons from substrate proteins to DsbA, which is recycled as an oxidant by the membrane protein DsbB. The highly virulent, uropathogenic E. coli strain CFT073 contains a second, homologous pair of proteins, DsbL and DsbI, which are encoded in a tri-cistronic operon together with a periplasmic, uropathogen-specific arylsulfate sulfotransferase (ASST). We show that DsbL and DsbI form a functional redox pair, and that ASST is a substrate of DsbL/DsbI in vivo. DsbL is the most reactive oxidizing thioredoxin-like protein known to date. In contrast to DsbA, however, DsbL oxidizes reduced RNaseA with a much lower rate and prevents unspecific aggregation of reduced insulin. The 1.55 A resolution crystal structure of reduced DsbL provides insight into the reduced state of thioredoxin-like dithiol oxidases at high resolution, and reveals an unusual cluster of basic residues stabilizing the thiolate anion of the nucleophilic active-site cysteine. We propose that the DsbL/DsbI pair of uropathogenic E. coli was acquired as an additional, specific redox couple that guarantees biological activity of ASST

Structural analysis of vascular endothelial growth factor receptor-2/ligand complexes by small-angle X-ray solution scattering

Receptor tyrosine kinases play essential roles in tissue development and homeostasis, and aberrant signaling by these molecules is the basis of many diseases. Understanding the activation mechanism of these receptors is thus of high clinical relevance. We investigated vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), which regulate blood and lymph vessel formation. We analyzed the structural changes in the extracellular receptor domain that were induced by ligand binding and that represent the initial step in transmembrane signaling, culminating in the activation of the intracellular receptor kinase domain. High-resolution structural information for the ligand binding domain became available recently, but the flexibility of the extracellular domain and inhomogeneous glycosylation of VEGFRs have prevented the production of highly diffracting crystals of the entire extracellular domain so far. Therefore, we chose to further investigate VEGFR structure by small-angle X-ray scattering in solution (SAXS). SAXS data were combined with independent distance restraint determination obtained by mass spectrometric analysis of chemically cross-linked ligand/receptor complexes. With these data, we constructed a structural model of the entire extracellular receptor domain in the unbound form and in complex with VEGF

Notch Impact Behavior of Oxide Dispersion Strengthened (ODS) Fe20Cr5Al alloy

In this paper tensile tests and LS and LT notched Charpy impact tests were performed at the temperature range between -196 and 200 °C on an oxide dispersion strengthened (ODS) Fe20Cr6Al0.5Y2O3 hot-rolled tube. The absorbed energy values in the range of high-temperatures of LS notched specimens is considerably higher than those of LT notched specimens; however such values tend to converge as temperature increases. Ductile fracture on the normal planes to RD with delaminations parallel to the tube surface were observed in the temperature range between RT and 200 °C. Delaminations of crack divider type were observed in LT specimens, whereas delaminations of crack arrester type were observed in LS specimens. The yttria particles in the grain boundaries and the transverse plastic anisotropy are the possible causes of that the delaminations were parallel to the tube surfacePM 2000 is a trademark of Plansee GmbH. The authors acknowledge the financial support of the Spanish Ministerio de Economia e Innovacio´ n (MINECO) in the form of a Coordinate Project in the Energy Area of Plan Nacional 2009 (ENE2009-13766-C04-01). G.P. acknowledges MINECO for financial support in the form of PhD Research Grant (FPI). This research was supported by ORNL’s Shared Research Equipment (SHaRE) User Facility, which is sponsored by the Office of Basic Energy Sciences, U.S. Department of EnergyPeer reviewe