Lysosome-Targeting Bacterial Outer Membrane Vesicles for Tumor Specific Degradation of PD-L1.

Increased expression of immune check point genes, such as PD-L1, is one of the main reasons for immunosuppression, especially for colon cancer. Development of novel therapeutic strategies is of great importance to improve the prognosis. In this study, outer membrane vesicles (OMV) derived from Gram-negative bacteria are engineered to immune checkpoint blockade nanosystem for efficient elicitation of anti-tumor immunity. Briefly, the OMVs are engineered with Lyp1-Traptavidin (S52G, R53D mutant of streptavidin) fusion protein displayed on the surface. The Lyp-1 endows the OMV with the capacity to target tumor tissues, while the Traptavidin ensures easy decoration of biotinylated anti-PD-L1 and biotinylated M6P (mannose 6-phosphate). The simultaneously anchored anti-PD-L1 and M6P (ligand for cation-independent mannose 6-phosphate receptor) on the engineered OMVs coordinately direct the membrane PD-L1 to lysosome for degradation, and thus unleash the anti-tumor immunity. With syngeneic tumor model, the engineered OMVs are confirmed to boost immunity, inhibit cancer growth, and thus prolong survival. Together, A proposed OMV-based modular nanosystem that enables assembly of biotinylated anti-PD-L1 and M6P on the surface for tumor-targeted immune checkpoint blockade.

Enhanced deep potential model for fast and accurate molecular dynamics: application to the hydrated electron.

In molecular simulations, neural network force fields aim at achieving ab initio accuracy with reduced computational cost. This work introduces enhancements to the Deep Potential network architecture, integrating a message-passing framework and a new lightweight implementation with various improvements. Our model achieves accuracy on par with leading machine learning force fields and offers significant speed advantages, making it well-suited for large-scale, accuracy-sensitive systems. We also introduce a new iterative model for Wannier center prediction, allowing us to keep track of electron positions in simulations of general insulating systems. We apply our model to study the solvated electron in bulk water, an ostensibly simple system that is actually quite challenging to represent with neural networks. Our trained model is not only accurate, but can also transfer to larger systems. Our simulation confirms the cavity model, where the electron's localized state is observed to be stable. Through an extensive run, we accurately determine various structural and dynamical properties of the solvated electron.

Metabolome and Transcriptome Analysis Revealed the Pivotal Role of Exogenous Melatonin in Enhancing Salt Tolerance in Vitis vinifera L.

Vitis vinifera L. possesses high economic value, but its growth and yield are seriously affected by salt stress. Though melatonin (MT) has been widely reported to enhance tolerance towards abiotic stresses in plants, the regulatory role melatonin plays in resisting salt tolerance in grapevines has scarcely been studied. Here, we observed the phenotypes under the treatment of different melatonin concentrations, and then transcriptome and metabolome analyses were performed. A total of 457 metabolites were detected in CK- and MT-treated cell cultures at 1 WAT (week after treatment) and 4 WATs. Exogenous melatonin treatment significantly increased the endogenous melatonin content while down-regulating the flavonoid content. To be specific, the melatonin content was obviously up-regulated, while the contents of more than a dozen flavonoids were down-regulated. Auxin response genes and melatonin synthesis-related genes were regulated by the exogenous melatonin treatment. WGCNA (weighted gene coexpression network analysis) identified key salt-responsive genes; they were directly or indirectly involved in melatonin synthesis and auxin response. The synergistic effect of salt and melatonin treatment was investigated by transcriptome analysis, providing additional evidence for the stress-alleviating properties of melatonin through auxin-related pathways. The present study explored the impact of exogenous melatonin on grapevines' ability to adapt to salt stress and provided novel insights into enhancing their tolerance to salt stress.

Integrated Metabolomics and Transcriptomics Reveal the Key Role of Flavonoids in the Cold Tolerance of Chrysanthemum.

Chrysanthemum (Chrysanthemum morifolium, ground-cover Chrysanthemums), one of the important garden flowers, has a high ornamental and economic value. However, its ornamental value is significantly diminished by the low temperature experienced in northeastern China. Here, metabolomics and transcriptomics were performed on three Chrysanthemum cultivars before and after a low temperature to investigate the dynamic metabolite changes and the molecular regulatory mechanisms. The results showed that 1324 annotated metabolites were detected, among which 327 were identified as flavonoids derived from Chrysanthemum. The accumulation of metabolites and gene expression related to the flavonoid biosynthesis pathway significantly increased in the three cultivars under the low temperature, indicating flavonoid metabolism actively participates in the Chrysanthemum cold response. Specifically, the content of cyanidin and pelargonidin derivatives and the expression of anthocyanin biosynthesis genes significantly increases in XHBF, providing a reasonable explanation for the change in petal color from white to purple under the low temperature. Six candidate UDP-glycosyltransferase genes involved in the glycosylation of flavonoids were identified through correlation networks and phylogenetic analysis. CmNAC1, CmbZIP3, and other transcription factors potentially regulating flavonoid metabolism and responding to low temperatures were discovered by correlation analysis and weighted gene co-expression network analysis (WGCNA). In conclusion, this study elucidated the specific response of flavonoids to low temperatures in Chrysanthemums, providing valuable insights and metabolic data for investigating cold tolerance.

Identifying habitat modification by Chinese pangolin in subtropical forests of southern China.

The excavation of Chinese pangolin (Manis pentadactyla) is expected to alter habitat heterogeneity and thus affect the functioning and structure of forest ecosystems. In this study, the bioturbation of Chinese pangolin on forest soils in three regions (Heping, Tianjingshan, and Wuqinzhang) across Guangdong province was quantified. Overall, a mean of 2.66 m3·ha-1 and 83.1 m2·ha-1 of burrows and bare mounds, respectively, was excavated by Chinese pangolin; the disturbed soils had significantly lower water content and P, C, available N concentrations, but higher bulk density, pH, and microbial abundance than those undisturbed soils. The unevenness of habitat heterogeneity improvement was mainly ascribed to the stronger soil disturbance caused in resting burrows by pangolins. Patterns of altering habitat heterogeneity were site-specific, with high-intensity soil disturbance occurring most in shrubs, meadows, steep habitats at high elevations, and mountain tops in Heping, while in broad-leaved, coniferous and mixed coniferous and broad-leaved forests away from human settlements in Tianjingshan and upper mountains at high elevations far away from roads and human settlements in Wuqinzhang. Road networks are the main interference for the burrow distribution in Heping and Wuqinzhang and should be programmed.