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Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6-activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum-associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined with anti-T cell immunoglobulin mucin-3 (anti-Tim-3) therapy in animal models. A positive correlation between IL-6 and PD-L1 expression was also observed in hepatocellular carcinoma patient tumor tissues. These results identify a mechanism regulating PD-L1 glycosylation initiation and suggest the combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy.

Hypertension is a leading global health threat and a major cardiovascular disease. Since clinical interventions are effective in delaying the disease progression from prehypertension to hypertension, diagnostic prediction models to identify patient populations at high risk for hypertension are imperative. Both PubMed and Embase databases were searched for eligible reports of either prediction models or risk scores of hypertension. The study data were collected, including risk factors, statistic methods, characteristics of study design and participants, performance measurement, etc. From the searched literature, 26 studies reporting 48 prediction models were selected. Among them, 20 reports studied the established models using traditional risk factors, such as body mass index (BMI), age, smoking, blood pressure (BP) level, parental history of hypertension, and biochemical factors, whereas 6 reports used genetic risk score (GRS) as the prediction factor. AUC ranged from 0.64 to 0.97, and C-statistic ranged from 60% to 90%. The traditional models are still the predominant risk prediction models for hypertension, but recently, more models have begun to incorporate genetic factors as part of their model predictors. However, these genetic predictors need to be well selected. The current reported models have acceptable to good discrimination and calibration ability, but whether the models can be applied in clinical practice still needs more validation and adjustment.

GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specific Gata4 heterozygote embryos recapitulated the AVSDs observed in germline Gata4 heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs. Gata4 mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream of Hh components: Gata4 activated a cis-regulatory element at Gli1 in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged in Smoothened mutants, and Hh pathway genes were unchanged in Pten mutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominant Gata4 mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.

The use of satellite imagery for surface deformation monitoring has been steadily increasing. However, the study of extracting deformation slopes from deformation data requires further advancement. This limitation not only poses challenges for subsequent studies but also restricts the potential for deeper exploration and utilization of deformation data. The LT-1 satellite, China’s largest L-band synthetic aperture radar satellite, offers a new perspective for monitoring. In this study, we extracted deformation slopes in Chongqing and its surrounding areas of China based on deformation data generated by LT-1. Twelve factors were selected to analyze their influence on slope deformation, including elevation, topographic position, slope, landcover, soil, lithology, relief, average rainfall intensity, and distances to rivers, roads, railways, and active faults. A total of 5863 deformation slopes were identified, covering an area of 140 km2, mainly concentrated in the central part of the study area, with the highest area density reaching 0.22%. Among these factors, average rainfall intensity was found to have the greatest impact on deformation slope. These findings provide valuable information for geological disaster early warning and management in Chongqing and surrounding areas, while also demonstrating the practical value of the LT-1 satellite in deformation monitoring.

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1 , Mafb , and Mrc1 , along with TSG-6 ligand Cd44 , predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. TSG-6 inhibition in combination with ICT improves therapy response and survival in pancreatic tumor-bearing mice by reducing macrophages expressing immunosuppressive phenotypes and increasing CD8 T cells. Overall, our findings propose TSG-6 as a therapeutic target to enhance ICT response in non-responsive tumors. Pancreatic ductal carcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) enriched in stromal cells. Here the authors show that TSG-6-positive cancer associated fibroblasts modulate myeloid cell responses and that TSG-6 targeting improves response to immune checkpoint inhibitors in preclinical PDAC models.

Alfalfa ( ) is the most important perennial forage crop cultivated globally. However, extreme environmental conditions, such as freezing stress, can significantly impact alfalfa's growth and development. The potential mechanisms through which alfalfa responds to freezing stress remain largely unexplored. In this study, we analyzed the physiological indices, transcriptomes and proteomes of the cold-tolerant alfalfa cultivar \"Dongnong NO.1\" and the cold-sensitive cultivar \"Bara 218TR\" at -5°C. The results indicated that the levels of antioxidant enzyme and osmoregulatory substances in \"Dongnong NO.1\" were significantly higher than in \"Bara 218TR\". Additionally, the levels of malondialdehyde (MDA) and relative electrolyte leakage (REL) were found be lower in \"Dongnong NO.1\" than in \"Bara 218TR\". Further transcriptomic analysis revealed that the differentially expressed genes (DEGs) found in both alfalfa cultivars were predominantly enriched in the AP2/ERF-ERF transcription factor family and in multiple signaling pathways. Weighted gene co-expression network analysis (WGCNA) revealed that the physiological processes associated with freezing stress tolerance in the two alfalfa cultivars are closely linked to DEGs that regulate protein synthesis, calcium signaling, the inhibition of iron toxicity, and the reduction of cell wall stiffness. Proteomics analysis indicates that differentially abundant proteins (DAPs) respond to frost damage by maintaining protein stability, antioxidant defense, and metabolic regulation. Integrated transcriptomic and proteomic analyses indicate that pathways related to carbohydrate metabolism, biotic stress defense, cell wall modification, and phenylpropanoid biosynthesis are key to alfalfa's response to frost damage. This study improves our understanding of the molecular mechanisms underlying alfalfa's freezing resistance and provides insights for the further screening and in-depth investigation of candidate genes with potential functions against freezing stress.

Drought stress severely impacts plant productivity, particularly in non-cultivated species such as .L. However, the role of rhizosphere and endophytic bacterial communities in enhancing drought tolerance remains underexplored. We used 16S rRNA amplicon sequencing to investigate microbial communities in the rhizosphere, roots, bulbs, and leaves of under simulated drought conditions using PEG-6000 (CK, 5%, 15%, 25%) and post-rehydration recovery. Alpha and beta diversity, phylogenetic relationships, and functional predictions were analyzed. Drought stress reduced rhizosphere bacterial diversity by 42% but increased leaf diversity by 52%. The 15% PEG treatment marked a key threshold for community shifts. and were significantly enriched under drought, and functional predictions indicated their involvement in osmotic regulation and phytohormone synthesis. Post-rehydration partially restored microbial composition in aerial tissues but not in the rhizosphere. These findings suggest that drought induces niche-specific microbial adaptations and that bacterial community structure plays a critical role in drought resilience. This study provides insights into plant-microbe interactions and offers a basis for developing microbial strategies to improve drought tolerance in species.

Dominant mutations of Gata4, an essential cardiogenic transcription factor (TF), were known to cause outflow tract (OFT) defects in both human and mouse, but the underlying molecular mechanism was not clear. In this study, Gata4 haploinsufficiency in mice was found to result in OFT defects including double outlet right ventricle (DORV) and ventricular septum defects (VSDs). Gata4 was shown to be required for Hedgehog (Hh)-receiving progenitors within the second heart field (SHF) for normal OFT alignment. Restored cell proliferation in the SHF by knocking-down Pten failed to rescue OFT defects, suggesting that additional cell events under Gata4 regulation is important. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion, which is associated with abnormal EMT and cell proliferation in Gata4 haploinsufficiency. The genetic interaction of Hh signaling and Gata4 is further demonstrated to be important for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA). Restoration of Hedgehog signaling renormalized SHF cell proliferation and migration, and rescued OFT defects in Gata4 haploinsufficiency. In addition, there was enhanced Gata6 expression in the SHF of the Gata4 heterozygotes. The Gata4-responsive repressive sites were identified within 1kbp upstream of the transcription start site of Gata6 by both ChIP-qPCR and luciferase reporter assay. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development.

Background MYB transcription factors play a crucial regulatory role in plant growth and stress response. The gene EpMYB , obtained from Endocarpon pusillum , a dominant lichen in the Tengger Desert, was transferred to creeping bentgrass to explore its effects on plant growth and response to abiotic stress. Results Compared to wild-type (WT), transgenic (TG) plants exhibited a faster growth rate, a significantly higher number of leaves per tiller, increased internode length, and longer maximum leaf length. However, some of the leaves were severely twisted. Additionally, the antioxidant enzyme content, lignin content and drought tolerance of the TG plants was significantly enhanced. RNA-seq analysis revealed that differentially expressed genes (DEGs) in the TG-vs-WT were primarily associated with pathways such as photosynthesis, wax biosynthesis, lipid metabolism, and flavonoid biosynthesis. By comparing the TG (Drought treatment)-vs-TG and WT (Drought treatment)-vs-WT groups, numerous DEGs related to growth, development, and stress tolerance were identified, including aldehyde decarbonylase gene( CER1 ), lignin synthesis gene ( HCT ), adenylate dimethylallyltransferase gene ( IPT ), peroxin-10 gene ( PEX10 ), among others. These results suggest that the EpMYB gene enhances the drought tolerance of transgenic creeping bentgrass by regulating photosynthesis, antioxidant enzyme activity, lignin synthesis, wax synthesis, and lipid metabolism. Conclusion These findings suggest that the EpMYB gene functions as a positive regulator of plant growth and development, while also playing a crucial role in the plant’s response to drought stress. Furthermore, this study demonstrates the feasibility of selecting specific functional genes from stress-tolerant microorganisms and applying them to plants to enhance stress resistance.

ABSTRACT Photodynamic therapy (PDT) represents a promising noninvasive modality for the selective targeting of tumors. However, its clinical utility is often constrained by the aggregation-induced quenching of photosensitizers and suboptimal reactive oxygen species (ROS) generation. In contrast, gene therapy has exhibited potent antitumor efficacy through the specific silencing of oncogenic targets. In this study, we developed a cationic photosensitizer-based nanocarrier, PEI-PEG-PpIX, designed to deliver the shRNA-BLM plasmid (p-shBLM). The PEI-PEG-PpIX/p-shBLM complex demonstrated a threefold increase in ROS production compared to free PpIX, along with a 57.5% enhancement in transfection efficiency. When this method was combined with photodynamic therapy for the treatment of neuroblastoma, the system significantly suppressed tumor cell proliferation, resulting in an 83.67% tumor growth inhibition rate in murine models. This outcome effectively demonstrates the synergistic integration of gene therapy and photodynamic therapy. Furthermore, the multifunctional nature of this platform enables real-time tumor imaging, thereby facilitating image-guided diagnosis and therapeutic monitoring. Overall, this strategy presents a noninvasive, efficient, and targeted approach to cancer treatment, offering valuable insights for future translational applications.