The nature of defocus fringes in scanning-transmission electron microscope images

Experimental observations have been made of the fringe contrast which appears at the terminating edges of thin objects in defocused, scanning-transmission electron micrographs. In general only a single bright fringe is present and the displacement and width of this fringe was found to vary linearly with defocus, indicating the contrast does not result from simple-Fresnel diffraction. A model for this contrast, based on the refraction of incident electrons by the object edge, is shown to explain the observed results.     

Binding Networks Identify Targetable Protein Pockets for Mechanism-Based Drug Design

The human genome codes only a few thousand druggable proteins, mainly receptors and enzymes. While this pool of available drug targets is limited, there is an untapped potential for discovering new drug-binding mechanisms and modes. For example, enzymes with long binding cavities offer numerous prerequisite binding sites that may be visited by an inhibitor during migration from a bulk solution to the destination site. Drug design can use these prerequisite sites as new structural targets. However, identifying these ephemeral sites is challenging. Here, we introduce a new method called NetBinder for the systematic identification and classification of prerequisite binding sites at atomic resolution. NetBinder is based on atomistic simulations of the full inhibitor binding process and provides a networking framework on which to select the most important binding modes and uncover the entire binding mechanism, including previously undiscovered events. NetBinder was validated by a study of the binding mechanism of blebbistatin (a potent inhibitor) to myosin 2 (a promising target for cancer chemotherapy). Myosin 2 is a good test enzyme because, like other potential targets, it has a long internal binding cavity that provides blebbistatin with numerous potential prerequisite binding sites. The mechanism proposed by NetBinder of myosin 2 structural changes during blebbistatin binding shows excellent agreement with experimentally determined binding sites and structural changes. While NetBinder was tested on myosin 2, it may easily be adopted to other proteins with long internal cavities, such as G-protein-coupled receptors or ion channels, the most popular current drug targets. NetBinder provides a new paradigm for drug design by a network-based elucidation of binding mechanisms at an atomic resolution.     

Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib,Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation

Telomere shortening is the main molecular mechanism of aging, but not the only one. The adaptive immune system also ages, and older organisms tend to develop a chronic pro-inflammatory status with low-grade inflammation characterized by chronic activation of the innate immune system, called inflammaging. One of the main stimuli that fuels inflammaging is a high nutrient intake, triggering a metabolic inflammation process called metainflammation. In this study, we report the anti-inflammatory activity of several senolytic drugs in the context of chronic inflammation, by using two different zebrafish models: (i) a chronic skin inflammation model with a hypomorphic mutation in spint1a, the gene encoding the serine protease inhibitor, kunitz-type, 1a (also known as hai1a) and (ii) a non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) model with inflammation induced by a high-fat diet. Our results show that, although these models do not manifest premature aging, the senolytic drugs dasatinib, navitoclax, and venetoclax have an anti-inflammatory effect that results in the amelioration of chronic inflammation.     

Solvent-free oxidation of benzyl alcohol using titania-supported gold–palladium catalysts: Effect of Au–Pd ratio on catalytic performance

The oxidation of benzyl alcohol with molecular oxygen under solvent-free conditions has been investigated using a range of titania-supported Au–Pd alloy catalysts to examine the effect of the Au–Pd ratio on the conversion and selectivity. The catalysts have been compared at high reaction temperature (160 °C) as well as at 100 °C, to determine the effect on selectivity since at lower reaction temperature the range of by-products that are formed are limited. Under these conditions the 2.5 wt.% Au–2.5 wt.% Pd/TiO₂ was found to be the most active catalyst, whereas the Au/TiO₂ catalyst demonstrated the highest selectivity to benzaldehyde. Toluene, formed via either a hydrogen transfer process or an oxygen transfer process, was observed as a major by-product under these forcing conditions.     

Processing of Particle-Stabilized Wet Foams Into Porous Ceramics

Direct foaming of colloidal suspensions is a simple and versatile approach for the fabrication of macroporous ceramic materials. Wet foams produced by this method can be stabilized by long-chain surfactants or by colloidal particles. In this work, we investigate the processing of particle-stabilized wet foams into crack-free macroporous ceramics. The processing steps are discussed with particular emphasis on the consolidation and drying process of wet foams. Macroporous alumina ceramics prepared using different consolidation and drying methods are compared in terms of their final microstructure, porosity, and compressive strength. Consolidation of the wet foam by particle coagulation before drying resulted in porous alumina with a closed-cell structure, a porosity of 86.5%, an average cell size of 35 μm, and a remarkable compressive strength of 16.3 MPa. On the other hand, wet foams consolidated via gelation of the liquid within the foam lamella led to porous structures with interconnected cells in the size range from 100 to 150 μm. The tailored microstructure and high mechanical strength of the macroporous ceramics can be of interest for the manufacture of bio-scaffolds, thermal insulators, impact absorbers, separation membranes, and light weight ceramics.     

An XPS study of the oxidation of pyrite and pyrites in coal

X-ray Photoelectron Spectroscopy (XPS) was used to study mineral, synthetic and coal-associated pyrites, oxidized for various time intervals at low temperatures with humid air or oxygen. This was done to find out if XPS could detect, monitor and clarify pyrite surface-oxidative changes that influence surface-dependent coal-cleaning methods such as froth flotation, and could provide a means of directly analysing coal sulphur, by determining if oxidizing conditions existed which would effectively eliminate the surface pyrite whose XPS peak may occur at the same energy as the organic sulphur peak of coal. The conditions of study were as follows: a mineral and two coals containing pyrite were exposed to air at 24 ± 3 ° C and 33 ± 8% relative humidity up to 600 h; two mineral pyrites were exposed to oxygen at 100% relative humidity and 35 ° C for up to 200 h; and the two mineral and a synthetic pyrite were exposed to oxygen at 100% relative humidity and 55 ° C for up to 300 h and at 72°C for 25 h. The results indicated that the XPS S2p pyrite peak at ≈169 eV and the surface-oxidation-product(s) peak(s) at ≈163 eV could be detected and followed with XPS, although no conclusions could be made about the oxidation mechanism. The pyrite XPS peak became small compared to that of its oxidation products when the synthetic and mineral pyrites were exposed to 55 ° C oxygen at 100% relative humidity for 300 h. These conditions may prove useful in trying to determine directly the organic sulphur in coal.     

Thermodynamic interpretation of solute–polymer interactions at infinite dilution

Heats of solution at infinite dilution of solutes in poly(ethyl methacrylate) were estimated using gas–liquid chromatography over a temperature range of 417.74 K–427.55 K. The heat of solution is related to solute polarizability and dipole moment. Contributions of specific interactions such as hydrogen bonding and charge-transfer complexing to the enthalpy of solution were also determined.     

Microelectronic package characterisation using scanning acoustic microscopy

In a highly competitive market, reliable techniques for manufacturing quality control of electronic devices are demanded. Characterisation of modern microelectronic package integrity becomes more difficult due to the continued miniaturisation of electronic device and the complexity of advanced micro-assembling technologies such as chip-scale packages and 3D IC stacks. In this paper, sparse representations of acoustic signals are sought to improve the scanning acoustic microscopy (SAM), a common non-destructive tool for failure analysis of microelectronic packages. Sparse representation of an ultrasonic signal is obtained by decomposing it in an overcomplete dictionary. Detection and location of ultrasonic echoes are then performed on the basis of the resulting redundant representation. The method offers a solution to the deconvolution problem for restoration of the ultrasonic reflectivity function. It can restore closely space overlapping echoes beyond the resolution of the conventional SAM system. It also produces high resolution and accurate estimates for ultrasonic echo parameters, i.e., time-of-flight, amplitude, centre frequency, and bandwidth. These merits of the proposed method are explored in various potential applications for microelectronic package characterisation.     

Exploring the impact of formulation and temperature shock on metered dose inhaler priming

The interplay between canister, valve design, formulation, and environmental temperature is crucial to dose retention in metered dose inhalers (MDIs). Previous studies that have utilized MDIs with polymeric capillary retention valves, have shown that exposure to environmental changes can create a temporary temperature gradient between the formulation retained in the metering chamber and the formulation reservoir in the metal canister, which can cause inconsistencies in the dose delivered to the patient. The purpose of this study was to more fully quantify these effects. This was achieved by deliberately varying the temperature difference between inhalers and environment within ranges representative of routine usage, and assessing the resulting loss of prime effect via shot weight and delivered dose testing.

The shot weights delivered by three fixed-dose commercial MDIs—Foster®, flutiform® and Seretide®, were investigated under different experimental conditions. Exposure to temperature changes of up to 15°C did not appear to affect unprimed shot weights (USW) or subsequent doses from the Foster product. In contrast, flutiform maintained prime at a temperature differential of 8.6°C, but delivered a low USW following exposure to a ΔT of 15°C under both realistic and controlled conditions. Seretide exhibited loss of prime at lower temperature differentials (ΔT 8.6°C) and a reduction in USW. The results suggest that the inclusion of ethanol in a solution-based formulation may inhibit loss of prime, leading to more robust performance in the face of temperature variations.

Delivered dose testing was carried out to assess the effect of loss of prime on the device ability to deliver a dose to within 80–120% of the label claim. The results suggest that the drainage of propellant from the metering chamber of suspension MDIs leaves active pharmaceutical ingredient (API) residue, causing an increase in subsequent doses once the prime has been restored. Taken together, the results provide valuable insight into the likely performance of MDIs subjected to routine daily use, highlighting design and formulation strategies that could be applied to make performance more robust.