Covalent Allosteric Inhibitors of Akt Generated Using a Click Fragment Approach

Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties.     

Geometrically non‐linear damage interface based on regularized strong discontinuity

The contribution of this paper concerns the fracture modelling of an interface with a fixed internal material surface in the context of geometrically non‐linear kinematics. Typical applications are composite laminates and adhesive/frictional joints in general. In the model development, a key feature is the concept of regularized strong discontinuity, which provides a regular deformation gradient within the interface. The deformation gradient within the interface is formulated in a multiplicative structure with a continuous part and a discontinuous part, whereby the interface deformation is interpreted as a transformation between the material damaged configuration and the actual spatial configuration. In analogy with the continuum formulation of hyper‐inelasticity, a constitutive framework is defined for the relation between the induced material traction and the displacement jump vector, which are defined on the material damaged interface configuration. Within this framework, a simple, but yet still representative, model for the delamination problem is proposed on the basis of a damage–plasticity coupling for the interface. The model is calibrated analytically in the large deformation context with respect to energy dissipation in mode I so that a predefined amount of fracture energy is dissipated. The paper is concluded with a couple of numerical examples that display the properties of the interface. Copyright © 2002 John Wiley & Sons, Ltd.     

Crystallization kinetics of V2AlC

X-ray amorphous V₂AlC and hexagonal (V,Al)₂C_x thin films were synthesized by magnetron sputtering from a compound target with the composition of V₂AlC. The crystallization kinetics was investigated by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). During continuous heating up to 1200 °C, one exothermal peak is observed between 565 and 675 °C. XRD data suggest that the DSC peak is associated with the formation of V₂AlC. The activation energy of crystallization of V₂AlC is ~ 308 kJ/mol based on the Kissinger approach. This value is close to the 287 kJ/mol activation energy obtained here for the transformation of magnetron sputtered (V,Al)₂C_x thin films to V₂AlC. The here reported phase formation temperature of V₂AlC is about 800 °C lower than during hot pressing of elemental powders.     

Some Aspects of the Melting and Dephosphorization Mechanism of Hydrogen-DRI

To meet the future environmental challenges, hydrogen direct reduced iron (H-DRI) is expected to constitute the principal material for virgin steel production. For an efficient value chain, knowledge of the melting mechanism and dephosphorization mechanism of H-DRI is needed. The in situ melting behavior, the melting mechanism, and the dephosphorization mechanism during heating of H-DRI are investigated experimentally at 1773 and 1873 K. It is found that the melting rate of H-DRI varies with the reduction degree (91–99.5%), increasing with decreasing reduction degree. An autogenous slag forms during heating and flows through the pores of the H-DRI, thus increasing its effective thermal conductivity. The fraction of filled pores varies with reduction degree explaining the difference in melting rate. At this stage, the dissolution of apatite is initiated and completed upon melting of the metal phase. A gradual reversion of phosphorus from the autogenous slag to the liquid metal is observed after complete melting. The rate of reversion is discussed based on the properties of the H-DRI, for example, reduction degree and carbon addition.     

On the applicability of word sense discrimination on 201 years of modern english

As language evolves over time, documents stored in long- term archives become inaccessible to users. Automatically, detecting and handling language evolution will become a necessity to meet user’s information needs. In this paper, we investigate the performance of modern tools and algorithms applied on modern English to find word senses that will later serve as a basis for finding evolution. We apply the curvature clustering algorithm on all nouns and noun phrases extracted from The Times Archive (1785–1985). We use natural language processors for part-of-speech tagging and lemmatization and report on the performance of these processors over the entire period. We evaluate our clusters using WordNet to verify whether they correspond to valid word senses. Because The Times Archive contains OCR errors, we investigate the effects of such errors on word sense discrimination results. Finally, we present a novel approach to correct OCR errors present in the archive and show that the coverage of the curvature clustering algorithm improves. We increase the number of clusters by 24 %. To verify our results, we use the New York Times corpus (1987–2007), a recent collection that is considered error free, as a ground truth for our experiments. We find that after correcting OCR errors in The Times Archive, the performance of word sense discrimination applied on The Times Archive is comparable to the ground truth.     

GaAs/AlGaAs nanowire heterostructures studied by scanning tunneling microscopy

We directly image the interior of GaAs/AlGaAs axial and radial nanowire heterostructures with atomic-scale resolution using scanning tunneling microscopy. We show that formation of monolayer sharp and smooth axial interfaces are possible even by vapor-phase epitaxy. However, we also find that instability of the ternary alloys formed in the Au seed fundamentally limits axial heterostructure control, inducing large segment asymmetries. We study radial core-shell nanowires, imaging even ultrathin submonolayer shells. We demonstrate how large twinning-induced morphological defects at the wire surfaces can be removed, ensuring the formation of wires with atomically flat sides.     

Surface charge sensitivity of silicon nanowires: size dependence

Silicon nanowires of different widths were fabricated in silicon on insulator (SOI) material using conventional process technology combined with electron-beam lithography. The aim was to analyze the size dependence of the sensitivity of such nanowires for biomolecule detection and for other sensor applications. Results from electrical characterization of the nanowires show a threshold voltage increasing with decreasing width. When immersed in an acidic buffer solution, smaller nanowires exhibit large conductance changes while larger wires remain unaffected. This behavior is also reflected in detected threshold shifts between buffer solutions of different pH, and we find that nanowires of width >150 nm are virtually insensitive to the buffer pH. The increased sensitivity for smaller sizes is ascribed to the larger surface/volume ratio for smaller wires exposing the channel to a more effective control by the local environment, similar to a surrounded gate transistor structure. Computer simulations confirm this behavior and show that sensing can be extended even down to the single charge level.     

Influence of Heat Treatment Parameters on the Carbide Morphology of PM High-Speed Steel HS 6-5-3-8

The influence of heat treatment parameters on the carbide morphology of the powder metallurgic high-speed steel HS 6-5-3-8 is examined. To that end, diverse heat treatment parameters are selected and applied by quenching dilatometry. In particular, different austenitizing temperatures, as well as an isothermal holding stage during quenching in the temperature regime of the transformation gap at temperatures between 450 and 600 °C, are produced. Extensive computer-aided image analysis is performed to investigate the carbide morphology. It is found that the circularity of the tungsten-rich M₆C carbides increases significantly after short holding times at a temperature of 550 °C due to the carbide precipitation from metastable and supersaturated austenite onto pre-existing carbides. Longer holding times lead to further growth of the carbides, while the circularity of the carbides does not change. It is further shown that the hardness of the isothermally treated material is increased, all other parameters being equal. Increased carbide circularity might be helpful for increasing the toughness while reaching the same hardness and wear resistance as the conventional heat-treated material. Moreover, it might be possible to enhance the austenitizing temperature with regain of positive carbide morphology properties during the isothermal holding stage. Thus, improved material properties could be achieved.     

High-Temperature Phase Equilibria of Duplex Stainless Steels Assessed with a Novel <Emphasis Type="Italic">In-Situ</Emphasis> Neutron Scattering Approach

Duplex stainless steels are designed to solidify with ferrite as the parent phase, with subsequent austenite formation occurring in the solid state, implying that, thermodynamically, a fully ferritic range should exist at high temperatures. However, computational thermodynamic tools appear currently to overestimate the austenite stability of these systems, and contradictory data exist in the literature. In the present work, the high-temperature phase equilibria of four commercial duplex stainless steel grades, denoted 2304, 2101, 2507, and 3207, with varying alloying levels were assessed by measurements of the austenite-to-ferrite transformation at temperatures approaching 1673 K (1400 °C) using a novel in-situ neutron scattering approach. All grades became fully ferritic at some point during progressive heating. Higher austenite dissolution temperatures were measured for the higher alloyed grades, and for 3207, the temperature range for a single-phase ferritic structure approached zero. The influence of temperatures in the region of austenite dissolution was further evaluated by microstructural characterization using electron backscattered diffraction of isothermally heat-treated and quenched samples. The new experimental data are compared to thermodynamic calculations, and the precision of databases is discussed.