Browsing by Author "Yang, Y."

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    An Enhancer-Driven Stem Cell–Like Program Mediated by SOX9 Blocks Intestinal Differentiation in Colorectal Cancer
    (W.B. Saunders, 2022) Liang, X.; Duronio, G.N.; Yang, Y.; Bala, P.; Hebbar, P.; Spisák, S.; Sahgal, P.; Singh, H.; Zhang, Y.; Xie, Y.; Cejas, P.; Long, H.W.; Bass, A.J.; Sethi, N.S.
    Background and Aims: Genomic alterations that encourage stem cell activity and hinder proper maturation are central to the development of colorectal cancer (CRC). Key molecular mediators that promote these malignant properties require further elucidation to galvanize translational advances. We therefore aimed to characterize a key factor that blocks intestinal differentiation, define its transcriptional and epigenetic program, and provide preclinical evidence for therapeutic targeting in CRC. Methods: Intestinal tissue from transgenic mice and patients were analyzed by means of histopathology and immunostaining. Human CRC cells and neoplastic murine organoids were genetically manipulated for functional studies. Gene expression profiling was obtained through RNA sequencing. Histone modifications and transcription factor binding were determined with the use of chromatin immunoprecipitation sequencing. Results: We demonstrate that SRY-box transcription factor 9 (SOX9) promotes CRC by activating a stem cell–like program that hinders intestinal differentiation. Intestinal adenomas and colorectal adenocarcinomas from mouse models and patients demonstrate ectopic and elevated expression of SOX9. Functional experiments indicate a requirement for SOX9 in human CRC cell lines and engineered neoplastic organoids. Disrupting SOX9 activity impairs primary CRC tumor growth by inducing intestinal differentiation. By binding to genome wide enhancers, SOX9 directly activates genes associated with Paneth and stem cell activity, including prominin 1 (PROM1). SOX9 up-regulates PROM1 via a Wnt-responsive intronic enhancer. A pentaspan transmembrane protein, PROM1 uses its first intracellular domain to support stem cell signaling, at least in part through SOX9, reinforcing a PROM1-SOX9 positive feedback loop. Conclusions: These studies establish SOX9 as a central regulator of an enhancer-driven stem cell–like program and carry important implications for developing therapeutics directed at overcoming differentiation defects in CRC. © 2022
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    Seven-level boosting active neutral point clamped inverter using cross-connected switched capacitor cells
    (Institution of Engineering and Technology jbristow@theiet.org, 2020) Jagabar Sathik, M.J.; Sandeep, N.; Almakhles, D.; Bhatnagar, K.; Yang, Y.; Blaabjerg, F.
    In this study, an active neutral point clamped-type boosting switched-capacitor multilevel inverter (SCMLI) with selfvoltage balancing capability is proposed. In the proposed topology, a novel switched capacitor cell is used, which has eightswitches and two diodes. The presented topology has reduced power component count with self-boosting and balancingabilities. The distinctive features of the proposed topology are highlighted and benchmarked against other recent 7L-SCMLItopologies. To validate the feasibility of the proposed topology, experimental tests are performed on a 1 kW prototype hardwaresetup. © 2020 The Institution of Engineering and Technology.