Iodine Atoms: A New Molecular Feature for the Design of Potent Transthyretin Fibrillogenesis Inhibitors

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant. Up to now, TTR aggregation inhibitors have been designed looking at various structural features of this binding channel others than its ability to host iodine atoms. In the present work, greatly improved inhibitors have been designed and tested by taking into account that thyroid hormones are unique in human biochemistry owing to the presence of multiple iodine atoms in their molecules which are probed to interact with specific halogen binding domains sitting at the TTR binding channel. The new TTR fibrillogenesis inhibitors are based on the diflunisal core structure because diflunisal is a registered salicylate drug with NSAID activity now undergoing clinical trials for TTR amyloid diseases. Biochemical and biophysical evidence confirms that iodine atoms can be an important design feature in the search for candidate drugs for TTR related amyloidosis

Accurate and Efficient Algorithm for Computing Structure Functions from the Spatial Distribution of Thermal Properties in Electronic Devices

An accurate and efficient algorithm is presented, which allows deriving the structure function of a discretized 3-D heat conduction problem. In this approach, the partial thermal conductances and capacitances in the structure function are computed in terms of weighted spatial averages of thermal resistivity and volumetric heat capacity. As a result, the exact influence of all materials and geometric details on each part of the structure function is determined. The approach is validated on a state-of-the-art SiGe heterojunction bipolar transistor (HBT) for high-frequency applications

Dependency on the TYK2/STAT1/MCL1 axis in anaplastic large cell lymphoma

10.1038/s41375-018-0239-1Leukemia333696-70