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Neural precursor cell expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, is commonly upregulated in human hepatocellular carcinoma (HCC) and functions as an oncogenic factor in the progression of HCC, but the molecular mechanism needs be further explored. In this study, we found that NEDD4 could facilitate the proliferation of HCC cells, which was associated with regulating the ERK signaling. Further investigation showed that protocadherin 17 (PCDH17) was a potential substrate of NEDD4, and restoration of PCDH17 could block the facilitation of ERK signaling and HCC cells proliferation induced by NEDD4 overexpression. Whereafter, we confirmed that NEDD4 interacted with PCDH17 and promoted the Lys33-linked polyubiquitination and degradation of it via the proteasome pathway. Finally, NEDD4 protein level was found to be inversely correlated with that of PCDH17 in human HCC tissues. In conclusion, these results suggest that NEDD4 acts as an E3 ubiquitin ligase for PCDH17 ubiquitination and degradation thereby promoting the proliferation of HCC cells through regulating the ERK signaling, which may provide novel evidence for NEDD4 to be a promising therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

To explore the deformation behavior and failure strength of sulfate saline silty clay at a temperature of -10℃ and confining pressures of 6~10 MPa, we have performed low-temperature triaxial shear tests on sulfate saline silty clay in Hexi region of Gansu province, China. The variation trend of deviatoric stress, volumetric strain and initial deformation modulus with confining pressure were analyzed. The results demonstrated that the stress-strain curve of frozen sulfate saline silty clay was hyperbolic and the deviatoric stress increased as the axial strain increased and was eventually constant. Owing to particle breakage and melting of ice, when the confining pressure, σ3>6 the strength decreased as the confining pressure increased and the sample exhibited volumetric shrinkage throughout the entire confining-pressure range. A constitutive model of frozen sulfate saline silty clay under high confining pressure has been proposed in combination with the Duncan Chang model and the validity of the model has been confirmed by comparison with test data. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury-mediated (IRI-mediated) primary graft dysfunction (PGD) adversely affects both short- and long-term outcomes after lung transplantation, a procedure that remains the only treatment option for patients suffering from end-stage respiratory failure. While B cells are known to regulate adaptive immune responses, their role in lung IRI is not well understood. Here, we demonstrated by intravital imaging that B cells are rapidly recruited to injured lungs, where they extravasate into the parenchyma. Using hilar clamping and transplant models, we observed that lung-infiltrating B cells produce the monocyte chemokine CCL7 in a TLR4-TRIF-dependent fashion, a critical step contributing to classical monocyte (CM) recruitment and subsequent neutrophil extravasation, resulting in worse lung function. We found that synergistic BCR-TLR4 activation on B cells is required for the recruitment of CMs to the injured lung. Finally, we corroborated our findings in reperfused human lungs, in which we observed a correlation between B cell infiltration and CM recruitment after transplantation. This study describes a role for B cells as critical orchestrators of lung IRI. As B cells can be depleted with currently available agents, our study provides a rationale for clinical trials investigating B cell-targeting therapies. [ABSTRACT FROM AUTHOR]