The degradation of TGR5 mediated by Smurf1 contributes to diabetic nephropathy

Summary: The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy

Three-Dimensional Geological Modeling of the Shallow Subsurface and Its Application: A Case Study in Tongzhou District, Beijing, China

Three-dimensional (3D) geological models are currently needed and used independently for urban development. The main difficulty in constructing a 3D geological model of a shallow subsurface is to determine the stratigraphic distribution. Highly variable properties and geometries of geological units beneath lead to difficulty. It is key to find a practicable and efficient way to construct a model in practical work. This study takes Tongzhou District (Beijing) as a case; 476 boreholes (40 newly drilled and 436 existing engineering boreholes) were utilized combined with the cross-section method to construct an integrated 3D geological model. The framework and analyses contributed to the following applications: (1) High-quality information from new boreholes and existing engineering boreholes were used to define stratigraphy and build cross-sections. (2) The resulting geological model (up to 50 m beneath Tongzhou area) shows many details of the shallow subsurface. This includes 10 major layers which were grouped into three cyclothems representing cyclic sequences of clay, interbedded silt, sand, and gravel with variable quantities of lenses. (3) The new model was used as a tool to visualize the depth and geometry variations below ground and to characterize a large variety of properties (for example, the compression modulus analyzed in this paper) that each unit contains, and then to evaluate the underground geological conditions. (4) An analysis of a dynamic monitoring model based on the resulting 3D model indicated that the geological units (sand and silty clay) at depths between 30 m and 40 m, with an average vertical deformation of 0.97 mm, from July 2019 to September 2020, are suitable for underground construction, from the perspective of vertical stability in the study area. Monitoring models that take time into consideration based on a 3D framework will be further explored

Three-Dimensional Geological Modeling of the Shallow Subsurface and Its Application: A Case Study in Tongzhou District, Beijing, China

Three-dimensional (3D) geological models are currently needed and used independently for urban development. The main difficulty in constructing a 3D geological model of a shallow subsurface is to determine the stratigraphic distribution. Highly variable properties and geometries of geological units beneath lead to difficulty. It is key to find a practicable and efficient way to construct a model in practical work. This study takes Tongzhou District (Beijing) as a case; 476 boreholes (40 newly drilled and 436 existing engineering boreholes) were utilized combined with the cross-section method to construct an integrated 3D geological model. The framework and analyses contributed to the following applications: (1) High-quality information from new boreholes and existing engineering boreholes were used to define stratigraphy and build cross-sections. (2) The resulting geological model (up to 50 m beneath Tongzhou area) shows many details of the shallow subsurface. This includes 10 major layers which were grouped into three cyclothems representing cyclic sequences of clay, interbedded silt, sand, and gravel with variable quantities of lenses. (3) The new model was used as a tool to visualize the depth and geometry variations below ground and to characterize a large variety of properties (for example, the compression modulus analyzed in this paper) that each unit contains, and then to evaluate the underground geological conditions. (4) An analysis of a dynamic monitoring model based on the resulting 3D model indicated that the geological units (sand and silty clay) at depths between 30 m and 40 m, with an average vertical deformation of 0.97 mm, from July 2019 to September 2020, are suitable for underground construction, from the perspective of vertical stability in the study area. Monitoring models that take time into consideration based on a 3D framework will be further explored