Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are ...initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.
Fiber-optic Bragg grating strain sensors hold a great deal of potential for structural monitoring because of their exceptional stability and demonstrated potential for long-term monitoring. This ...sensing technology takes advantage of a spectrally encoded signal which provides inherent immunity from signal intensity fluctuations which plague many other fiber-optic and electronic sensing techniques. This results in measurement stability and lead/interconnect insensitivity which permit longterm and intermittent monitoring with high resolution and accuracy. Fiber-optic grating sensors are intrinsic to the optical fiber, thus capitalizing on its extremely small size and inherent strength and durability. Recent results are provided from a sensor array installed in a road bridge. The strain sensors are attached to both steel and carbon-fiber-reinforced plastic prestressing tendons, which are embedded in the precast girders of the bridge. Measurements of traffic loads and the relaxation behaviour of the tendons are presented. The potential of fiber grating technology is briefly discussed including its application in long-gage strain-sensing and strain-distribution measurements.
The effect of switching losses on the efficiency of a switch mode power converter and methods adopted for its improvement using an energy recovery lossless snubber has been presented. A comparative ...analysis of various types of soft switching techniques along with effects of dissipative and nondissipative snubbers on efficiency of the converter has been carried out before zeroing in on the selected scheme. The selected snubber serves the dual function of a turn-on and turn-off snubber and thereby reducing the switching losses both during turn-on and turn-off transients, resulting in improved efficiency of the converter. A detailed design procedure of the snubber for high-power applications taking into account various effects such as diode reverse recovery, diode voltage stress, and minimum and maximum duty cycle limits, has been presented in this paper. Importance of practical aspects in layout to minimize wiring inductance is also highlighted. A high-power prototype of buck converter has been developed to experimentally validate the theoretical design and analytical observations.
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