Epithelial–Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)—TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2—are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.
The equivalence of triangle-comparison-based pulse width modulation (TCPWM) and space vector based PWM (SVPWM) during linear modulation is well-known. This paper analyses triangle-comparison based PWM techniques (TCPWM) such as sine-triangle PWM (SPWM) and common-mode voltage injection PWM during overmodulation from a space vector point of view. The average voltage vector produced by TCPWM during overmodulation is studied in the stationary (a-b) reference frame. This is compared and contrasted with the average voltage vector corresponding to the well-known standard two-zone algorithm for space vector modulated inverters. It is shown that the two-zone overmodulation algorithm itself can be derived from the variation of average voltage vector with TCPWM. The average voltage vector is further studied in a synchronously revolving (d-q) reference frame. The RMS value of low-order voltage ripple can be estimated, and can be used to compare harmonic distortion due to different PWM methods during overmodulation. The measured values of the total harmonic distortion (THD) in the line currents are presented at various fundamental frequencies. The relative values of measured current THD pertaining to different PWM methods tally with those of analytically evaluated RMS voltage ripple.
Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs) - TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, FOXC2 - are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2, GRHL1/2). Here, using mechanism-based mathematical modeling, we show that the transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote phenotypic shift toward a more epithelial state, an observation suggested by negative correlation of KLF4 with EMT-TFs and with transcriptomic based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at an epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.
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