Design and fabrication of an on-chip micro flow cytometer with integrated micro-lens

Microsystem Technologies - In this paper, the design and fabrication of an on-chip micro flow cytometer chip with integrated micro-lens with a size of...     

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.     

Bulging in incremental sheet forming of cold bonded multi-layered Cu clad sheet: Influence of forming conditions and bending

Bulge is a defect that causes geometrical inaccuracy and premature failure in the innovative incremental sheet forming (ISF) process. This study has two-fold objectives: (1) knowing the bulging behavior of a Cu clad tri-layered steel sheet as a function of forming conditions, and (2) analyzing the bending effect on bulging in an attempt to identify the associated mechanism. A series of ISF tests and bending analysis are performed to realize these objectives. From the cause-effect analysis, it is found that bulge formation in the layered sheet is sensitive to forming conditions in a way that bulging can be minimized utilizing annealed material and performing ISF with larger tool diameter and step size. The bending under tension analysis reveals that the formation of bulge is an outgrowth of bending moment that the forming tool applies on the sheet during ISF. Furthermore, the magnitude of bending moment depending upon the forming conditions varies from 0.046 to 10.24 N·m/m and causes a corresponding change in the mean bulge height from 0.07 to 0.91 mm. The bending moment governs bulging in layered sheet through a linear law. These findings lead to a conclusion that the bulge defect can be overcome by controlling the bending moment and the formula proposed can be helpful in this regards.