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Hyperhomocysteinemia (HHcy) is a risk factor for various cardiovascular diseases. However, the mechanism underlying HHcy-aggravated vascular injury remains unclear. Here we show that the aggravation of abdominal aortic aneurysm by HHcy is abolished in mice with genetic deletion of the angiotensin II type 1 (AT1) receptor and in mice treated with an AT1 blocker. We find that homocysteine directly activates AT1 receptor signalling. Homocysteine displaces angiotensin II and limits its binding to AT1 receptor. Bioluminescence resonance energy transfer analysis reveals distinct conformational changes of AT1 receptor upon binding to angiotensin II and homocysteine. Molecular dynamics and site-directed mutagenesis experiments suggest that homocysteine regulates the conformation of the AT1 receptor both orthosterically and allosterically by forming a salt bridge and a disulfide bond with its Arg 167 and Cys 289 residues, respectively. Together, these findings suggest that strategies aimed at blocking the AT1 receptor may mitigate HHcy-associated aneurysmal vascular injuries. High homocysteine plasma levels are associated with cardiovascular diseases. Here, Li and colleagues find that homocysteine aggravates vascular injury by direct binding to the angiotensin II type 1 receptor (AT1R), identifying AT1R inhibition as a potential strategy to counteract the deleterious vascular effects of hyperhomocysteinemia.

G protein-coupled receptors (GPCRs) represent promising therapeutic targets due to their involvement in numerous physiological processes mediated by downstream G protein- and β-arrestin-mediated signal transduction cascades. Although the precise control of GPCR signaling pathways is therapeutically valuable, the molecular details for governing biased GPCR signaling remain elusive. The Angiotensin II type 1 receptor (AT1R), a prototypical class A GPCR with profound implications for cardiovascular functions, has become a focal point for biased ligand-based clinical interventions. Herein, we used single-molecule live-cell imaging techniques to evaluate the changes in stoichiometry and dynamics of AT1R with distinct biased ligand stimulations in real time. It was revealed that AT1R existed predominantly in monomers and dimers and underwent oligomerization upon ligand stimulation. Notably, β-arrestin-biased ligands induced the formation of higher-order aggregates, resulting in a slower diffusion profile for AT1R compared to G protein-biased ligands. Furthermore, we demonstrated that the augmented aggregation of AT1R, triggered by activation from each biased ligand, was completely abrogated in β-arrestin knockout cells. These findings furnish novel insights into the intricate relationship between GPCR aggregation states and biased signaling, underscoring the pivotal role of molecular behaviors in guiding the development of selective therapeutic agents.

Water allocation can be evaluated from various economic, environmental, food security, and climate aspects. This paper was conducted to develop an optimal water allocation strategy with an economic framework. Game theory has been used to determine the planning structure. A co-operative technique based on the core solution, Shepley value, and nucleolus solution has been incorporated into the decision-making system and the results of the proposed model have been calculated based on the long-term information of the downstream cropping pattern in the Zhanghe irrigation network, Hubei Province, China. Five components of rice planting including growth period, yield production, water consumption, selling price, and cultivated area have been evaluated to find the optimal scenarios. Results showed that the application of co-operative game theory can improve the economic index and water-saving potential in agriculture. Furthermore, the proposed simulation confirmed that the economic effects were important for understanding and planning for irrigation efficiency and water-saving potential.

Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6 -mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy. CDK4/6 inhibition is a promising therapeutic approach to treat cancer, but it is challenged by resistance development. Here, the authors show that the RNA binding protein LRPPRC forms a positive feedback loop with CDK6 and inhibiting LRPPRC with the FDA-approved gossypol acetate overcomes CDK4/6 inhibition resistance.

The total concentrations of Cd in bulk sediments and those of the BCR sequential extraction fractions of sediments from inlets of the Four Rivers that feed Dongting Lake were determined using ICP-MS techniques. The results suggested that Cd was heterogeneously distributed in the inlet sediments of the rivers, with the highest degree of enrichment in sediments from the Xiangjiang River. The Cd anomaly was defined as Cd enrichment in sediments with an EF (enrichment factor) > 10.0, and it was identified in the inlet sediments of the Xiangjiang River. Cd in the sediments was dominated by acid-soluble Cd at a proportion of 23.9–69.8 (%) compared to its total concentrations in the sediments. The inlet sediments of the Four Rivers were contaminated with Cd, with the highest degree of contamination in the inlet sediments of the Xiangjiang River. The Cd contamination as well as the Cd anomaly in the sediments were closely related to the industrial activities (e.g. smelting and refining for ore minerals) in the areas, and Cd contamination at high levels may represent an ecological risk for the lake watershed. Cd contamination of the inlet sediments may also impact the lake basin sediments and is harmful to the lake ecological system, particularly for sediments of the Xiangjiang River. Therefore, it is essential to control and treat Cd contamination in the inlet sediments for ecological environmental protection of lake watersheds.

The shear strength and bearing characteristics of lunar soil have a strong connection with its compactness. The compactness varies significantly with depth and has an important effect on engineering activities on the lunar surface. In this study, lunar soil simulant samples of four compactness levels were prepared to explore the relationship between compactness and cone tip resistance in static cone penetration tests (CPTs). The compactness values at different depths were measured layer by layer, and CPTs were carried out. The results indicate that the cone tip resistance continuously increases with the increase in the penetration depth until it reaches a peak, and then remains constant for a certain depth. The cone tip resistance after the normalization of the overburden stress gradually increases and then decreases after reaching the peak. Models of the relationship between cone tip resistance before and after normalization and compactness were constructed using a regression algorithm. The variation in lunar soil compactness with depth can be determined by measuring cone tip resistance with this model. The research findings can provide a theoretical basis for in situ testing, site selection for lunar bases, and other related aspects on the lunar surface.

Understanding rock behavior under cutting tools is critical for enhancing cutting processes and forecasting rock behavior in engineering contexts. This study examines the link between mechanical properties and indentation crater morphology of six rocks using a conical indenter until initial fracture. Through indentation testing, mechanical properties (indentation stiffness index k and hardness index HI) were assessed, and crater morphology was analyzed using a 3D laser profilometer. The rocks were categorized into three groups based on specific energy: Class I (slate, shale), Class II (sandstone, marble), and Class III (granite, gneiss). The morphological features of their indentation craters were analyzed both quantitatively and qualitatively. The linear model was used to establish the relationship between crater morphology indices and mechanical properties, with model parameters determined by linear regression. Key findings include: (1) Fracture depth, cross-sectional area, and contour roundness are independent morphological indicators, serving as characteristic parameters for crater morphology, with qualitative and quantitative analyses showing consistency; (2) Post-classification linear fitting revealed statistically significant morphological prediction models, though patterns varied across rock categories due to inherent properties like structure and grain homogeneity; (3) Classification by specific energy revealed distinct mechanical and morphological differences, with significant linear relationships established for all three indicators in Classes II and III, but only roundness showing significance in Class I (non-significant for cross-sectional area and depth). However, all significant models exhibited limited explanatory power (R2 = 0.220–0.635), likely due to constrained sample sizes. Future studies should expand sample sizes to refine these findings.

Metal matrix diamond composite samples were fabricated by selective laser melting (SLM) at different forming parameters to investigate the feasibility and new challenges when SLM is applied to diamond tools manufacturing. The surface topographies, Rockwell hardness, compactness, microstructure, and diamond thermal damage of the samples were investigated in this study. The fabricated samples had high porosity and relatively low Rockwell hardness and compactness, and some ridge-shaped bulges and textures were observed at the edges and surfaces. Microstructure analyses showed that diamond particles were homogeneously distributed and metallurgically bonded within the metal matrix. The thermal damage pits on the diamond crystals along the scanning direction were the dominant damage type for SLM, which was completely different from conventional vacuum brazing and hot-pressing sintering. Although some challenges need to be further studied, our results demonstrate that SLM has great potential to propel the development of metal matrix diamond tools.

Endocytosis is essential for the maintenance of protein and lipid compositions in the plasma membrane and for the acquisition of materials from the extracellular space. Clathrin-dependent and -independent endocytic processes are well established in yeast and animals; however, endocytic pathways involved in cargo internalization and intracellular trafficking remain to be fully elucidated for plants. Here, we used transgenic green fluorescent protein-flotillin1 (GFP-Flot1) Arabidopsis thaliana plants in combination with confocal microscopy analysis and transmission electron microscopy immunogold labeling to study the spatial and dynamic aspects of GFP-Flot1-positive vesicle formation. Vesicle size, as outlined by the gold particles, was ∼100 nm, which is larger than the 30-nm size of clathrin-coated vesicles. GFP-Flot1 also did not colocalize with clathrin light chain-mOrange. Variable-angle total internal reflection fluorescence microscopy also revealed that the dynamic behavior of GFP-Flot1-positive puncta was different from that of clathrin light chain-mOrange puncta. Furthermore, disruption of membrane microdomains caused a significant alteration in the dynamics of Flot1-positive puncta. Analysis of artificial microRNA Flot1 transgenic Arabidopsis lines established that a reduction in Flot1 transcript levels gave rise to a reduction in shoot and root meristem size plus retardation in seedling growth. Taken together, these findings support the hypothesis that, in plant cells, Flot1 is involved in a clathrin-independent endocytic pathway and functions in seedling development.

Terrestrial ecosystems in Hunan Province have undergone marked yet spatially heterogeneous vegetation changes under concurrent climate change and intensifying human activities. The aim of this study is to resolve how vegetation responses vary among land-use types by quantifying kernel Normalized Difference Vegetation Index (kNDVI) dynamics during 2000–2023 using precipitation, temperature, and solar radiation, coupled with trend analysis and a partial-derivative-based attribution. Mean kNDVI increased overall at 0.0016 yr−1; vegetation improved over 76.30% of the area, whereas 5.72% of the area experienced degradation. Built-up land exhibited the largest degraded fraction (35.04%). Human activities and temperature emerged as the dominant drivers of kNDVI change, contributing 62.25% and 27.92%, respectively, while precipitation (3.08%) and solar radiation (6.77%) played comparatively minor roles. Spatially, human activities primarily controlled vegetation dynamics in plains and urban clusters (~78% of the area), whereas temperature constrained vegetation in high-elevation mountain ranges. Analysis along the human footprint (HFP) gradient reveals that driver composition remains steady in resilient ecosystems (farmland and forest), despite increasing anthropogenic pressure, whereas fragile ecosystems (grassland and bareland) exhibited pronounced volatility and heightened sensitivity to environmental constraints. These findings provide a quantitative basis for developing sustainable ecological security strategies, incorporating region-specific measures such as adaptive afforestation, sustainable agricultural management, and strict ecological protection, to enhance ecosystem resilience by prioritizing the climate resilience of mountain forests and the stability of fragile grassland systems.