Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment.

The ankle-link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization and signaling role remain unclear. By establishing Adgrv1 Y6236fsX1 mutant mice as a model of the deafness-associated human Y6244fsX1 mutation, the authors show here that the Y6236fsX1 mutation disrupts the interaction between adhesion G protein-coupled receptor V subfamily member 1 (ADGRV1) and other ALC components, resulting in stereocilia disorganization and mechanoelectrical transduction (MET) deficits. Importantly, ADGRV1 inhibits WHRN phosphorylation through regional cAMP-PKA signaling, which in turn regulates the ubiquitination and stability of USH2A via local signaling compartmentalization, whereas ADGRV1 Y6236fsX1 does not. Yeast two-hybrid screening identified the E3 ligase WDSUB1 that binds to WHRN and regulates the ubiquitination of USH2A in a WHRN phosphorylation-dependent manner. Further FlAsH-BRET assay, NMR spectrometry, and mutagenesis analysis provided insights into the architectural organization of ALC and interaction motifs at single-residue resolution. In conclusion, the present data suggest that ALC organization and accompanying local signal transduction play important roles in regulating the stability of the ALC.

[Spatialization and Spatio-temporal Dynamics of Energy Consumption Carbon Emissions in China].

The adverse effects of global climate change on human production and life are becoming increasingly prominent. Responding to climate change has become a severe challenge faced by human society, and the reduction in greenhouse gas emissions has gradually become a common action by all countries. Therefore, analyzing carbon emissions through scientific methods has become an important foundation for responding to the national "dual carbon" strategy. This study used provincial-level carbon emission statistics, combined with nighttime light data and population data, and assigned carbon emissions to the grid scale. It also analyzed the temporal and spatial characteristics and evolution characteristics of carbon emissions in China in 2000, 2005, 2010, 2015, and 2018, as well as the correlation between carbon emissions and the economy. The results showed that:① from 2000 to 2018, the total CO2 emissions in China continued to grow, but the growth rate slowed over time. The average annual growth rate of carbon emissions dropped from 9.9% in 2000-2010 to 7.4% in 2010-2018. From the perspective of spatial distribution, carbon-free areas were mainly distributed in the northwest uninhabited area and northeast forest and mountainous areas, low-carbon emissions were mainly distributed in the vast small and medium-sized cities and towns, and high-carbon emissions were concentrated in northern, central, eastern coastal, and western provincial capitals and urban agglomerations. ② Carbon emissions had high-value or low-value agglomerations at prefecture-level cities; this agglomeration tended to stabilize as a whole and had strengthened after 2005. Low-low agglomeration areas were mainly distributed in the western contiguous areas and Hainan Island. With economic and social development, low-low agglomeration areas began to fragment and reduce in size; high-high agglomeration areas were mainly distributed in the Beijing-Tianjin-Hebei urban agglomeration, Taiyuan urban agglomeration, Yangtze River Delta urban agglomerations, and Pearl River Delta urban agglomerations, and the scale was gradually strengthened and consolidated; high-low and low-high agglomeration areas mainly appeared in neighboring cities with large differences in economic development levels. ③ Carbon emissions in most parts of China were relatively stable. The areas where carbon emissions had changed were mainly distributed in the peripheral areas of provincial capitals and key cities, and there was a circle structure with no changes in the central urban area and changes in carbon emissions in the peripheral areas. ④ The overall process of urban development in China from 2000 to 2018 followed a shift from "low emission-low income" to "high emission-low income" to "high emission-high income" and finally to "low emission-high income." The growth rate of carbon emissions in China is slowing down. Under the background of the "dual carbon" strategy, different regions face different carbon emission reduction tasks and pressures due to different carbon emission situations. Therefore, the differentiated carbon emissions policy should be implemented by regions and industries.

[Progresses of alpine treeline formation mechanism.] / é«˜å±±æž—çº¿å½¢æˆæœºç†ç ”ç©¶è¿›å±•.

Alpine treelines represent one of the most distinct vegetation boundaries between canopy closed montane forest and treeless alpine vegetation. This transitional ecotone is highly sensitive to global and regional climate change and is considered as an ideal indicator of such changes. Treeline studies have evolved from morphological description to various hypotheses of treeline formation. Although individual hypothesis may provide reasonable explanation locally, a generalized hypothesis that is applicable on the global scale is still lacking. Temperature is considered the limited factor controlling the distribution of alpine treeline as low temperature restricts biochemical processes of tree growth. However, which particular biochemical processes are affected by low temperature remains unknown. This paper summarized the mechanisms of treeline formation with a focus on how low temperature affects photosynthesis characteristics, nutrient characteristics, non-structural carbohydrate (NSC) and antioxidant system. We also reviewed the key issues and future perspectives in treeline research.

Constitutive Gαi coupling activity of very large G protein-coupled receptor 1 (VLGR1) and its regulation by PDZD7 protein.

The very large G protein-coupled receptor 1 (VLGR1) is a core component in inner ear hair cell development. Mutations in the vlgr1 gene cause Usher syndrome, the symptoms of which include congenital hearing loss and progressive retinitis pigmentosa. However, the mechanism of VLGR1-regulated intracellular signaling and its role in Usher syndrome remain elusive. Here, we show that VLGR1 is processed into two fragments after autocleavage at the G protein-coupled receptor proteolytic site. The cleaved VLGR1 ß-subunit constitutively inhibited adenylate cyclase (AC) activity through Gαi coupling. Co-expression of the Gαiq chimera with the VLGR1 ß-subunit changed its activity to the phospholipase C/nuclear factor of activated T cells signaling pathway, which demonstrates the Gαi protein coupling specificity of this subunit. An R6002A mutation in intracellular loop 2 of VLGR1 abolished Gαi coupling, but the pathogenic VLGR1 Y6236fsx1 mutant showed increased AC inhibition. Furthermore, overexpression of another Usher syndrome protein, PDZD7, decreased the AC inhibition of the VLGR1 ß-subunit but showed no effect on the VLGR1 Y6236fsx1 mutant. Taken together, we identified an independent Gαi signaling pathway of the VLGR1 ß-subunit and its regulatory mechanisms that may have a role in the development of Usher syndrome.

[The effect of human placenta-derived mesenchymal stem cells on cord blood CD8(+);T cells activation, cellcycle and secretion of IL-17].

AIM: To study the effect of human placenta-derived mesenchymal stem cells (hPMSCs) on cord blood CD8(+);T cell activation, cell cycle and secretion of IL-17, and to provide the theoretical basis for it application in the cell-based therapies. METHODS: hPMSCs were isolated from mature placenta by the method of digestion. Then hPMSCs were cultured, expanded in vitro, and were used in test after the third passage. CD8(+);T cells were sorted from cord blood with immunomagetic beads. FCM was used to analyze the expression of early activation phenotype, cell cycle of cord blood CD8(+);T cells and cytokine secretion. RESULTS: CD8(+);T cells stimulated by PHA in the presence of hPMSCs were arrested at G0/G1 phase. The expression of the early activation marker CD25 and CD69 of cord blood CD8(+);T cells was inhibited in the presence of hPMSCs. While, IL-17secretion of cord blood CD8(+);T cells stimulated by PMA was increased. CONCLUSION: hPMSCs can suppress the activation of cord blood CD8(+);T cells by altering T cell cycle; up-regulate the level of IL-17 secreted by cord blood CD8(+);T cells.