Sox2 has a critical role in embryonic stem (ES) cell maintenance and differentiation. Interestingly, its activity is highly dosagedependent. Although transcriptional regulation of Sox2 has been extensively studied, the mechanisms orchestrating its degradation remain unclear. In this study, we identified ubiquitin-conjugating enzyme E2S (Ube2s) as a novel effector for Sox2 protein degradation. Ube2s mediates K11-linked polyubiquitin chain formation at the Sox2-K123 residue, thus marking it for proteasome-mediated degradation. Besides its role in fine-tuning the precise level of Sox2, Ube2s reinforces the self-renewing and pluripotent state of ES cells. Importantly, it also represses Sox2-mediated ES cell differentiation toward the neural ectodermal lineage.

Uranium (U) is a well-known nephrotoxicant which forms precipitates in the lysosomes of renal proximal tubular epithelial cells (PTECs) after U-exposure at a cytotoxic dose. However, the roles of lysosomes in U decorporation and detoxification remain to be elucidated. Mucolipin transient receptor potential channel 1 (TRPML1) is a major lysosomal Ca2+ channel regulating lysosomal exocytosis. We herein demonstrate that the delayed administration of the specific TRPML1 agonist ML-SA1 significantly decreases U accumulation in the kidney, mitigates renal proximal tubular injury, increases apical exocytosis of lysosomes and reduces lysosomal membrane permeabilization (LMP) in renal PTECs of male mice with single-dose U poisoning or multiple-dose U exposure. Mechanistic studies reveal that ML-SA1 stimulates intracellular U removal and reduces U-induced LMP and cell death through activating the positive TRPML1-TFEB feedback loop and consequent lysosomal exocytosis and biogenesis in U-loaded PTECs in vitro. Together, our studies demonstrate that TRPML1 activation is an attractive therapeutic strategy for the treatment of U-induced nephrotoxicity.

In order to understand the seismic damage assessment of reinforced concrete column members, the coupling relationship between the capacity degradation and the accumulated hysteretic energy and the displacement history was considered. The energy-based damage index under the random variable amplitude loading history was proposed. On the basis of preliminary research, the corresponding relationship between the damage index and the construction member parameters and seismic parameters was established, the damage mechanism was analyzed according to the damage index, and then the performance-based design process was proposed. It was found that increase in the stirrup ratio can slow down the damage, and the slowing effect was initially fast and then slows. When the reinforcement ratio is doubled, the damage index decreased by 0.063. The longer the earthquake duration was, the more serious the damage was, and this phenomenon was more obvious when the ductility coefficient was larger. With the increase in the ductility coefficient, the damage continuously increased. Therefore, it is an effective way to decrease the damage by controlling the ductility coefficient. Among all the influencing factors, the fundamental period and seismic intensity contributed more significantly to the damage indicators. When the damage index (performance objective) was determined, the target stirrup ratio can be obtained according to the proposed performance design process, that is, this design process can be used in the performance-based design. The design method based on damage index can make up for the deficiency that the design method based on the ductility coefficient does not consider the earthquake duration.