A thermal perspective of flash sintering: The effect of AC current ramp rate on microstructure evolution

In flash sintering experiments, the thermal history of the sample is key to understanding the mechanisms underlying densification rate and final properties. By combining robust temperature measurements with current-ramp-rate control, this study examined the effects of the thermal profile on the flash sintering of yttria-stabilized zirconia, with experiments ranging from a few seconds to several hours. The final density was maximized at slower heating rates, although processes slower than a certain threshold led to grain growth. The amount of grain growth observed was comparable to a similar conventional thermal process. The bulk electrical conductivity correlated with the maximum temperature and cooling rate. The only property that exhibited behavior that could not be attributed to solely the thermal profile was the grain boundary conductivity, which was consistently higher than conventional in flash sintered samples. These results suggest that, during flash sintering, athermal electric field effects are relegated to the grain boundary.     

Discovery of Affinity-Based Probes for Btk Occupancy Assays

Bruton's tyrosine kinase (Btk) is an attractive target for the treatment of a wide array of B-cell malignancies and autoimmune diseases. Small-molecule covalent irreversible Btk inhibitors targeting Cys481 have been developed for the treatment of such diseases. In clinical trials, probe molecules are required in occupancy studies to measure the level of engagement of the protein by these covalent irreversible inhibitors. The result of this pharmacodynamic (PD) activity provides guidance for appropriate dosage selection to optimize inhibition of the drug target and correlation of target inhibition with disease treatment efficacy. This information is crucial for successful evaluation of drug candidates in clinical trials. Based on the pyridine carboxamide scaffold of a novel solvent-accessible pocket (SAP) series of covalent irreversible Btk inhibitors, we successfully developed a potent and selective affinity-based biotinylated probe 12 (2-[(4-{4-[5-(1-{5-[(3aS,4S,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanamido}-3,6,9,12-tetraoxapentadecan-15-amido)pentanoyl]piperazine-1-carbonyl}phenyl)amino]-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide). Compound 12 has been used in Btk occupancy assays for preclinical studies to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon.