X‐ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome

CLK2 inhibition has been proposed as a potential mechanism to improve autism and neuronal functions in Phelan–McDermid syndrome (PMDS). Herein, the discovery of a very potent indazole CLK inhibitor series and the CLK2 X‐ray structure of the most potent analogue are reported. This new indazole series was identified through a biochemical CLK2 Caliper assay screen with 30k compounds selected by an in silico approach. Novel high‐resolution X‐ray structures of all CLKs, including the first CLK4 X‐ray structure, bound to known CLK2 inhibitor tool compounds (e.g., TG003, CX‐4945), are also shown and yield insight into inhibitor selectivity in the CLK family. The efficacy of the new CLK2 inhibitors from the indazole series was demonstrated in the mouse brain slice assay, and potential safety concerns were investigated. Genotoxicity findings in the human lymphocyte micronucleus test (MNT) assay are shown by using two structurally different CLK inhibitors to reveal a major concern for pan‐CLK inhibition in PMDS.     

Global sensitivity analysis for calculating the contribution of genetic parameters to the variance of crop model prediction

Dynamic models are often used to predict the effects of farmers’ practices on crop yield, crop quality, and environment. These models usually include many parameters that must be estimated from experimental data before practical use. Parameter estimation is a difficult problem especially when some of the parameters vary across genotypes. These genetic parameters may be estimated from plant breeding experiments but this is very costly and requires a lot of experimental work. Moreover, some of the genetic parameters may account for only a very small part of the output variance and, so, do not deserve an accurate determination. This paper shows how methods of global sensitivity analysis can be used to evaluate the contributions of the genetic parameters to the variance of model prediction. Two methods are applied to a complex crop model for estimating the sensitivity indices associated to 13 genetic parameters. The results show that only five genetic parameters have a significant effect on crop yield and grain quality.     

Pre-clinical studies to validate the MITCH PCR™ Cup: a flexible and anatomically shaped acetabular component with novel bearing characteristics

A previous clinical study was undertaken to evaluate the safety and efficacy of an anatomically shaped, flexible acetabular cup. Clinical results achieved were satisfactory, although some deficiencies in the model were identified. Design changes to the original model have been implemented to improve both initial stability and long term biological fixation. This was achieved through modifications made to both the anchoring mechanism and by the application of an appropriate backing surface layer promoting bone on-growth. In addition, changes to the articulation couple have also been introduced to improve implant durability and bearing performance, utilising a carbon fibre reinforced polyetheretherketone—alumina couple. Simulated loading, in both models, was performed using Finite Element Analysis. Mechanical and tribological tests were also performed to ensure the robustness of the new optimised design. Bio-compatibility of the articulation couple was demonstrated using an animal model. Implantation of the device has been extensively tested and re-validated in vitro to achieve a favourable polar contact between cup and femoral head and establish a reproducible operative technique. This preliminary work is undertaken prior to commencing a post market surveillance study of the CE marked implant.     

Fracture of high volume fraction ceramic particle reinforced aluminium under multiaxial stress

Circumferentially notched cylindrical bars of high volume fraction Al₂O₃ particle reinforced aluminium are tested in tension to probe the role of tensile stress triaxiality on damage and failure of such materials. The transverse strain is monitored with a specially designed video extensometer. A significant dependence of the peak average stress and failure strain on notch radius is observed. Finite-element simulations of the tests are conducted on the basis of a micromechanical model derived from earlier studies of damage and failure of these composites under uniaxial tensile deformation (Journal of the Mechanics and Physics of Solids 2009;57:1781). The simulations show that stress and strain distributions within the notched composite samples deviate significantly from predictions of Bridgman’s simplified analysis. Comparison with data shows that, whereas calculations capture satisfactorily the evolution of the average composite flow stress as a function of notch radius at small strains, the notched samples damage faster and fail at strains lower than predicted. Two phenomena may explain the discrepancy, namely (i) damage coalescence beyond a threshold level, and (ii) the incapacity of the matrix to sustain large hydrostatic stresses, which results from the presence of internal surfaces (cracked particles and possibly matrix voiding).     

Experimental methods in chemical engineering: Transmission electron microscopy—TEM

Thanks to an accelerating voltage in the range of 30 to 300 kV, an electron beam can pass through a thin specimen and form an image with sub-Ångström spatial resolution. When impinging on a thin crystalline specimen, the fast electrons scatter and diffract. The transmitted electron pattern depends on the local thickness, density, crystal structure, and chemical nature of the sample. The transmission electron microscope (TEM) shapes the incoming electron beam using magnetic lenses onto the specimen and, using a different set of magnetic lenses, focuses the projected electron pattern to a camera. The final image magnification and contrast are controlled using the parameters from the electron gun, apertures positioned along the optical path, and magnetic lenses. With this combination of lens and aperture, TEM offers two possible modes of operation: (a) imaging, including high-resolution electron microscopy to reveal the size, shape, crystallinity, and morphology of materials; and (b) diffraction, to determine the crystalline nature of a region of interest of a thin film, particle, or collection of particles. Chemical engineers have taken advantage of both of these modes to analyze their samples and inform their research. A bibliometric study conducted using the WoS database places TEM as one of the preferred microscopy tools to study advanced materials such as thin films, nanomaterials, and composites used in particular for the development of applications related to energy storage and conversion (catalysis, photocatalysis, electrochemistry, and batteries) and environment (adsorption, waste-water treatment, and filtration).     

Fog computing: from architecture to edge computing and big data processing

The Journal of Supercomputing - Cloud computing plays a vital role in processing a large amount of data. However, with the arrival of the Internet of Things, huge data are generated from these...     

Polymer Films Composed of Surface‐Bound Nanofilaments with a High Aspect Ratio,Molecularly Imprinted with Small Molecules and Proteins

Hierarchically nanostructured materials that combine two or more levels of structuring and that exhibit a combination of useful features have gained considerable interest over recent years. Here, the generation of surface‐bound nanofilaments with a high aspect ratio by nanomolding on a nanoporous template surface is described. The filaments, at the same time, carry molecularly imprinted binding sites. The dye fluorescein and the protein myoglobin are used as model templates for imprinting. The surfaces exhibit specific binding as revealed by fluorescence microscopy. The wetting properties of the surfaces depend on the dimensions of the nanofilaments and on the nature of the polymer. It is believed that these materials can potentially be useful for applications in biosensors and biochips.     

Canonical visual size for real-world objects.

Real-world objects can be viewed at a range of distances and thus can be experienced at a range of visual angles within the visual field. Given the large amount of visual size variation possible when observing objects, we examined how internal object representations represent visual size information. In a series of experiments which required observers to access existing object knowledge, we observed that real-world objects have a consistent visual size at which they are drawn, imagined, and preferentially viewed. Importantly, this visual size is proportional to the logarithm of the assumed size of the object in the world, and is best characterized not as a fixed visual angle, but by the ratio of the object and the frame of space around it. Akin to the previous literature on canonical perspective, we term this consistent visual size information the canonical visual size. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Diffusional kurtosis imaging (DKI) incorporation into an intravoxel incoherent motion (IVIM) MR model to measure cerebral hypoperfusion induced by hyperventilation challenge in healthy subjects

Magnetic Resonance Materials in Physics, Biology and Medicine - The objectives were to investigate the diffusional kurtosis imaging (DKI) incorporation into the intravoxel incoherent motion (IVIM)...