Kirsten rat sarcoma viral oncogene homolog(KRAS)mutation is associated with the poor prognosis of colorectal cancer(CRC)patients,but the therapeutic strategies targeting KRAS are limited,and novel intervention strateg...Kirsten rat sarcoma viral oncogene homolog(KRAS)mutation is associated with the poor prognosis of colorectal cancer(CRC)patients,but the therapeutic strategies targeting KRAS are limited,and novel intervention strategies are urgently needed.The dysfunction of deubiquitinases(DUBs)is widely involved in the progression of malignancy,and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites.In our study,through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry(LC–MS/MS)analysis,we identified that ubiquitin-specific protease 10(USP10)functions as a potent DUB regulating KRAS mutants'activity.Mechanistically,USP10 directly binds to and promotes KRAS variants'activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6,K11,K27 and K29-linkage;while the activated KRAS mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337,therefore forming a positive feedback circuit and synergistically promoting KRAS-mutant CRC growth.Moreover,we found that USP10 is elevated in KRAS-mutant CRC tissues and depletion of USP10 preferentially impeded KRAS-mutant CRC growth in vitro/in vivo.Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting KRAS-mutant CRC growth,but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.展开更多
This work presents modelling aspects of automatic gain control （AGC） loops based on linear-in-dB variable gain amplifiers （VGAs）. In these loops, the VGA control voltage is also an excellent received signal streng...This work presents modelling aspects of automatic gain control （AGC） loops based on linear-in-dB variable gain amplifiers （VGAs）. In these loops, the VGA control voltage is also an excellent received signal strength indicator （RSSI）. The VGA gain is however nonlinearly related to the control voltage. Moreover, VGAs and detectors undergo nonlinear compression under high input amplitudes during settling transients. The main contribution in this work is a proposed nonlinear model based on simple and readily available components from the ＂analogLib＂ and ＂functional＂ libraries in CADENCE design environment -making it very easy and fast to build and simulate-that captures the nonlinear effects of AGC loops. The model is capable of verifying the AGC loop stability and capturing the loop dynamics with high accuracy compared to time consuming circuit level simulations. This provides insights into system level parameters such as AGC loop bandwidth, phase margin, settling time as well as estimating the AGC range and RSSI voltage vs. input power. Measurement results from a fabricated AGC prototype are in good agreement with simulation and modelling results thus validating the proposed modelling approach.展开更多
基金supported by the Natural Science Foundation of China(U21A20420,82173836,82304517)Zhejiang Provincial Natural Science Foundation(LQ23H310009,China).
文摘Kirsten rat sarcoma viral oncogene homolog(KRAS)mutation is associated with the poor prognosis of colorectal cancer(CRC)patients,but the therapeutic strategies targeting KRAS are limited,and novel intervention strategies are urgently needed.The dysfunction of deubiquitinases(DUBs)is widely involved in the progression of malignancy,and DUBs are considered ideal anti-tumor targets due to their well-defined structures and catalytic sites.In our study,through DUB inhibitors screening and liquid chromatography-tandem mass spectrometry(LC–MS/MS)analysis,we identified that ubiquitin-specific protease 10(USP10)functions as a potent DUB regulating KRAS mutants'activity.Mechanistically,USP10 directly binds to and promotes KRAS variants'activity across different mutants by removing the latter’s non-proteolytic ubiquitination chains mainly containing K6,K11,K27 and K29-linkage;while the activated KRAS mutants reciprocally upregulate USP10 levels by phosphorylating the latter at Thr42/Ser337,therefore forming a positive feedback circuit and synergistically promoting KRAS-mutant CRC growth.Moreover,we found that USP10 is elevated in KRAS-mutant CRC tissues and depletion of USP10 preferentially impeded KRAS-mutant CRC growth in vitro/in vivo.Our findings not only uncover the critical roles of the USP10/KRAS positive feedback circuit in promoting KRAS-mutant CRC growth,but also offer novel therapeutic strategies for CRC patients harboring KRAS variants across different mutants by targeting USP10.
文摘This work presents modelling aspects of automatic gain control （AGC） loops based on linear-in-dB variable gain amplifiers （VGAs）. In these loops, the VGA control voltage is also an excellent received signal strength indicator （RSSI）. The VGA gain is however nonlinearly related to the control voltage. Moreover, VGAs and detectors undergo nonlinear compression under high input amplitudes during settling transients. The main contribution in this work is a proposed nonlinear model based on simple and readily available components from the ＂analogLib＂ and ＂functional＂ libraries in CADENCE design environment -making it very easy and fast to build and simulate-that captures the nonlinear effects of AGC loops. The model is capable of verifying the AGC loop stability and capturing the loop dynamics with high accuracy compared to time consuming circuit level simulations. This provides insights into system level parameters such as AGC loop bandwidth, phase margin, settling time as well as estimating the AGC range and RSSI voltage vs. input power. Measurement results from a fabricated AGC prototype are in good agreement with simulation and modelling results thus validating the proposed modelling approach.
