Ubiquitin ligase RNF125 targets PD-L1 for ubiquitination and degradation

As a critical immune checkpoint molecule, PD-L1 is expressed at significantly higher levels in multiple neoplastic tissues compared to normal ones. PD-L1/PD-1 axis is a critical target for tumor immunotherapy, blocking the PD-L1/PD-1 axis is recognized and has achieved unprecedented success in clinical applications. However, the clinical efficacy of therapies targeting the PD-1/PD-L1 pathway remains limited, emphasizing the need for the mechanistic elucidation of PD-1/PD-L1 expression. In this study, we found that RNF125 interacted with PD-L1 and regulated PD-L1 protein expression. Mechanistically, RNF125 promoted K48-linked polyubiquitination of PD-L1 and mediated its degradation. Notably, MC-38 and H22 cell lines with RNF125 knockout, transplanted in C57BL/6 mice, exhibited a higher PD-L1 level and faster tumor growth than their parental cell lines. In contrast, overexpression of RNF125 in MC-38 and H22 cells had the opposite effect, resulting in lower PD-L1 levels and delayed tumor growth compared with parental cell lines. In addition, immunohistochemical analysis of MC-38 tumors with RNF125 overexpression showed significantly increased infiltration of CD4+, CD8+ T cells and macrophages. Consistent with these findings, analyses using The Cancer Genome Atlas (TCGA) public database revealed a positive correlation of RNF125 expression with CD4+, CD8+ T cell and macrophage tumor infiltration. Moreover, RNF125 expression was significantly downregulated in several human cancer tissues, and was negatively correlated with the clinical stage of these tumors, and patients with higher RNF125 expression had better clinical outcomes. Our findings identify a novel mechanism for regulating PD-L1 expression and may provide a new strategy to increase the efficacy of immunotherapy

Study on the Interaction between Soil and the Five-Claw Combination of a Mole Using the Discrete Element Method

A mole is a born digger spending its entire existence digging tunnels. The five claws of a mole’s hand are combinative to cut soil powerfully and efficiently. However, little was known in detail about the interaction between the soil and the five-claw combination. In this study, we simulated the soil cutting process of the five-claw combination using the discrete element method (DEM) as an attempt for the potential design of soil-engaging tools to reduce soil resistance. The five-claw combination moved horizontally in the soil bin. Soil forces (draught and vertical forces) and soil failure (soil rupture distance ratio) were measured at different rake angles and speeds. Results showed that the draught and vertical forces varied nonlinearly as the rake angle increased from 10 to 90°, and both changed linearly with the speed increasing from 1 to 5 m/s. The curve of the soil rupture distance ratio with rake angles could be better described using a quadric function, but the speed had little effect on the soil rupture distance ratio. Notably, the soil rupture distance ratio of the five-claw combination in simulation was on average 19.6% lower than the predicted ratio of simple blades at different rake angles indicating that the five-claw combination could make less soil failure and thereby produce lower soil resistance. Given the draught and vertical forces, the performance of the five-claw combination was optimized at the rake angle of 30°