Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

Shape Factor Effect on Inclusion Sedimentation in Aluminum Melts

Metallurgical and Materials Transactions B - The quality requirements of aluminum products are steadily increasing, and the presence of non-metallic inclusions have a large impact on the quality of...     

Super-Resolution Reconstruction of Images Based on Microarray Camera

In the field of images and imaging, super-resolution (SR) reconstruction of images is a technique that converts one or more low-resolution (LR) images into a highresolution (HR) image. The classical two types of SR methods are mainly based on applying a single image or multiple images captured by a single camera. Microarray camera has the characteristics of small size, multi views, and the possibility of applying to portable devices. It has become a research hotspot in image processing. In this paper, we propose a SR reconstruction of images based on a microarray camera for sharpening and registration processing of array images. The array images are interpolated to obtain a HR image initially followed by a convolution neural network (CNN) procedure for enhancement. The convolution layers of our convolution neural network are 3×3 or 1×1 layers, of which the 1×1 layers are used to improve the network performance particularly. A bottleneck structure is applied to reduce the parameter numbers of the nonlinear mapping and to improve the nonlinear capability of the whole network. Finally, we use a 3×3 deconvolution layer to significantly reduce the number of parameters compared to the deconvolution layer of FSRCNN-s. The experiments show that the proposed method can not only ameliorate effectively the texture quality of the target image based on the array images information, but also further enhance the quality of the initial high resolution image by the improved CNN.     

Supramolecular Assembly of Aminoethylene‐Lipopeptide PMO Conjugates into RNA Splice‐Switching Nanomicelles

Phosphorodiamidate morpholino oligomers (PMOs) are oligonucleotide analogs that can be used for therapeutic modulation of pre‐mRNA splicing. Similar to other classes of nucleic acid‐based therapeutics, PMOs require delivery systems for efficient transport to the intracellular target sites. Here, artificial peptides based on the oligo(ethylenamino) acid succinyl‐tetraethylenpentamine (Stp), hydrophobic modifications, and an azide group are presented, which are used for strain‐promoted azide‐alkyne cycloaddition conjugation with splice‐switching PMOs. By systematically varying the lead structure and formulation, it is determined that the type of contained fatty acid and supramolecular assembly have a critical impact on the delivery efficacy. A compound containing linolenic acid with three cis double bonds exhibits the highest splice‐switching activity and significantly increases functional protein expression in pLuc/705 reporter cells in vitro and after local administration in vivo. Structural and mechanistic studies reveal that the lipopeptide PMO conjugates form nanoparticles, which accelerate cellular uptake and that the content of unsaturated fatty acids enhances endosomal escape. In an in vitro Duchenne muscular dystrophy exon skipping model using H2K‐mdx52 dystrophic skeletal myotubes, the highly potent PMO conjugates mediate significant splice‐switching at very low nanomolar concentrations. The presented aminoethylene‐lipopeptides are thus a promising platform for the generation of PMO‐therapeutics with a favorable activity/toxicity profile.     

Evaluating the transfer of technology between application domains: a critical evaluation of the human component in the system

Technology can take many forms from the development of sophisticated electronics to the application of basic procedural principles. Technology transfer can also take several forms, however, in this case, it is the transfer of technological principles between application domains that is of primary interest. This paper presents a framework (the Five ‘M’s framework) that can be used to consider the likely success of technology transfer. The framework is based upon a sociotechnical system approach. The framework is illustrated with an evaluation of the introduction of intelligent cruise control into motor vehicles. It is argued that this is a technological concept first developed as an aerospace application in the form of the autopilot. In this case, it is argued that the transfer of this technology in its current form may potentially compromise safety.     

Doped silicon and NIS junctions for bolometer applications

We discuss the performance, of a normal metal hot electron bolometer (NHEB) that we have measured at 0.3 K. We found that the noise equivalent power was limited by the amplifier noise. To improve the NHEB power response and to make it more robust and reliable we propose to substitute the normal metal with heavily doped silicon. The heavily doped silicon behaves like a metal with lower carrier concentration and has a smaller electron–phonon thermal coupling. We have fabricated superconductor-doped silicon-superconductor contacts (S-Sm-S) and we have used them as thermometers and coolers.     

Implicit–Explicit Schemes for BGK Kinetic Equations

In this work a new class of numerical methods for the BGK model of kinetic equations is presented. In principle, schemes of any order of accuracy in both space and time can be constructed with this technique. The methods proposed are based on an explicit–implicit time discretization. In particular the convective terms are treated explicitly, while the source terms are implicit. In this fashion even problems with infinite stiffness can be integrated with relatively large time steps. The conservation properties of the schemes are investigated. Numerical results are shown for schemes of order 1, 2 and 5 in space, and up to third-order accurate in time.     

The ability of the Millon Clinical Multiaxial Inventory--Third Edition to detect malingering.

This study investigated the ability of the Millon Clinical Multiaxial Inventory--Third Edition (MCMI-III) to discriminate students malingering psychopathology (n=106) from bona fide psychiatric inpatients (n=202). Students were randomly assigned to a fake-bad or an honest-responding condition. Analyses investigated the ability of the modifier indices to discriminate fake-bad group participants from the psychiatric inpatients. Scale X raw cutoff score >178 yielded a positive predictive power (PPP) of 0.0, a negative predictive power (NPP) of 63.1, and a hit rate of 63.1%. Optimal cutoff scores were developed. Scale X Base Rate (BR) >84 provided a PPP of 55.6, an NPP of 72.1, and a hit rate of 65.2%. Scale Y BR