HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS–RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome–lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.
This paper presents a 5GS/s 8-bit 40-way timeinterleaved SAR ADC fabricated in 65nm CMOS. Two-level hierarchical interleaving is employed, resulting in 4 sub-ADCs each operating at 1.25GS/s at the topmost level with front-end track and hold samplers. The sub-ADCs use capacitive C-2C DACs to minimize the input capacitance and area. A novel background timing skew calibration method is used which requires no redundant signal paths. After calibration, the ADC achieves an SNDR of 33.3dB at Nyquist and consumes 138.6mW from a 1V supply with a 5GS/s sampling rate, yielding an FOM of 738fJ/conv-step. The individual sub-ADC achieves an SNDR of 37.9dB at Nyquist and consumes 34.2mW, yielding an FOM of 428fJ/conv-step.
Benign prostatic hyperplasia (BPH) is one of the most common conditions experienced by aging males and a frequent cause of bladder outlet obstruction and macroscopic haematuria. Giant prostatic hyperplasia (GPH) is an extremely rare form of prostatic hyperplasia. We present a case of a patient with GPH of 800 mL. To our knowledge, this is the fourth largest prostatic hyperplasia ever reported in the literature.
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