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...     

High performance laser with nanopatterned active layer by selective area epitaxy

Lasers containing a nanopatterned active layer demonstrating excellent threshold characteristics are presented. The nanopatterned active layer is fabricated using high-resolution electron beam lithography and selective-area metal organic chemical vapour deposition crystal growth. Results demonstrating an order of magnitude improvement over previous results are reported.     

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.     

A Novel Ordered Nanopore Array Diode Laser

In this work, we have created a new type of structure, the nanopore active layer, for achieving quantization of carrier states in a semiconductor. The nanopore structure consists of a periodic two-dimensional array of localized energy barriers perturbing an otherwise conventional quantum well. This perturbation leads to the formation of intraband forbidden energy gaps which are observed experimentally.     

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.     

Organization of the visual reticular thalamic nucleus of the rat

The visual sector of the reticular thalamic nucleus has come under some intense scrutiny over recent years, principally because of the key role that the nucleus plays in the processing of visual information. Despite this scrutiny, we know very little of how the connections between the reticular nucleus and the different areas of visual cortex and the different visual dorsal thalamic nuclei are organized. This study examines the patterns of reticular connections with the visual cortex and the dorsal thalamus in the rat, a species where the visual pathways have been well documented. Biotinylated dextran, an anterograde and retrograde tracer, was injected into different visual cortical areas [17; rostral 18a: presumed area AL: (anterolateral); caudal 18a: presumed area LM (lateromedial); rostral 18b: presumed area AM (anteromedial); caudal 18b: presumed area PM (posteromedial)] and into different visual dorsal thalamic nuclei (posterior thalamic, lateral geniculate nuclei), and the patterns of anterograde and retrograde labelling in the reticular nucleus were examined. From the cortical injections, we find that the visual sector of the reticular nucleus is divided into subsectors that each receive an input from a distinct visual cortical area, with little or no overlap. Further, the resulting pattern of cortical terminations in the reticular nucleus reflects largely the patterns of termination in the dorsal thalamus. That is, each cortical area projects to a largely distinct subsector of the reticular nucleus, as it does to a largely distinct dorsal thalamic nucleus. As with each of the visual cortical areas, each of the visual dorsal thalamic (lateral geniculate, lateral posterior, posterior thalamic) nuclei relate to a separate territory of the reticular nucleus, with little or no overlap. Each of these dorsal thalamic territories within the reticular nucleus receives inputs from one or more of the visual cortical areas. For instance, the region to the reticular nucleus that is labelled after an injection into the lateral geniculate nucleus encompasses the reticular regions which receive afferents from cortical areas 17, rostral 18b and caudal 18b. These results suggest that individual cortical areas may influence the activity of different dorsal thalamic nuclei through their reticular connections.