Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1. We further show that methylation enhances the chromatin sequestration of cGAS in a UHRF1-dependent manner. Blocking cGAS methylation enhances cGAS-mediated antitumor immunity and suppresses colorectal tumorigenesis. Clinically, cGAS methylation in human cancers correlates with poor prognosis. Thus, our results indicate that nutrient stress promotes cGAS activation via reversible methylation, and suggest a potential therapeutic strategy for targeting cGAS methylation in cancer treatment.

The characterization of tumor microenvironment infiltration and the construction of predictive index based on cuproptosis-related gene in primary lung adenocarcinoma.

Objective: We aimed to use the cancer genome atlas and gene expression omnibus databases to explore the characterization of tumor microenvironment (TME) infiltration and construct a predictive index of prognosis and treatment effect based on cuproptosis-related genes (CRGs) in primary lung adenocarcinoma (LUAD). Methods: We described the alterations of CRGs in 954 LUAD samples from genetic and transcriptional fields and evaluated their expression patterns from three independent datasets. We identified two distinct molecular subtypes and found that multi-layer CRG alterations were correlated with patient clinicopathological features, prognosis, and TME cell infiltrating characteristics. Then, a cuproptosis scoring system (CSS) for predicting the prognosis was constructed, and its predictive capability in LUAD patients was validated. Results: Two molecular subtypes of cuproptosis (Copper Genes cluster A and cluster B) in LUAD were identified. Copper Genes cluster B had better survival than those with Copper Genes cluster A (p <0.01). Besides, we found that the infiltration of activated CD4+ T cells, natural killer T cells, and neutrophils was stronger in cluster A than in cluster B. Then, we constructed a highly accurate CSS to predict the prognosis, targeted therapy effect, and immune response. Compared with the low-CSS subgroup, the mutations of the TP53, MUC16, and TTN genes were more common in the high-CSS subgroup, while the mutation of TP53, TTN, and CSMD3 genes were more common in the low-CSS subgroup than in high-CSS subgroup. The low-score CSS group had an inferior survival than high-score CSS group (p <0.01). In addition, CSS presented good ability to predict the immune response (area under curve [AUC], 0.726). Moreover, AZD5363 and AZD8186 were the inhibitors of AKT and PI3K, respectively, and had lower IC50 and AUC in the low-score CSS group than it in the high-score CSS group. Conclusions: CRGs are associated with the development, TME, and prognosis of LUAD. Besides, a scoring system based on CRGs can predict the efficacy of targeted drugs and immune response. These findings may improve our understanding of CRGs in LUAD and pave a new path for the assessment of prognosis and the development of more effective targeted therapy and immunotherapy strategies.

Air pollution characteristics, health risks, and source analysis in Shanxi Province, China.

China is confronting an unprecedented air pollution problem. This study discussed the characteristics of air pollution and its risks on human health and conducted source analysis combined with local development in Shanxi Province in 2016 and 2017. Results demonstrated that the air pollution situation in Shanxi was deteriorating, with Taiyuan, Yangquan, Changzhi, Jincheng, Jinzhong, and Linfen being heavily polluted districts. Particulate matter (PM) was considered the major pollutant, but nitrogen dioxide and ozone showed a dominant trend recently. Furthermore, the health risks evaluated on the basis of a comprehensive air quality index (AAQI) and an aggregated risk index revealed a relatively high-risk level in Shanxi. Among the pollutants, the largest contributor was PM, followed by sulfur dioxide and ozone. Southern Shanxi had the largest pollution level and health risks, whereas Datong was the least polluted region. Source analysis suggested that the main driving forces of air pollution, besides natural factors, were urbanization, population size, civil vehicles, coal-based heavy industries, and high-energy consumption. Therefore, strengthening urban greening, vigorously adjusting and optimizing the industrial structure, and formulating a multi-domain cooperative control regime on air pollution, especially PM and ozone, should be promoted.

Examination of a coupling coordination relationship between urbanization and the eco-environment: a case study in Qingdao, China.

A better understanding of the relationship between urbanization and the eco-environment is necessary to guide sustainable urban development and formulate environmental policies. In this study, the city of Qingdao was taken as an example. We evaluated the quantitative evolution of the relationship between urbanization and the eco-environment development from 2000 to 2018 by establishing the comprehensive index system and applying it to the coupling coordination model. Results showed the following: (1) The economic urbanization and eco-environment states offer the greatest contribution to the urbanization and eco-environment systems, respectively. (2) The coupling coordination relationship between urbanization and eco-environment conforms to an S-shaped curve, and the two systems have gradually moved from a "seriously uncoordinated and urbanization lag" stage at the beginning into a "good coordination and eco-environment lag" stage by the end of the research period. (3) Finally, the economic urbanization and response subsystems are essential determinants in the coupling relationship between urbanization and eco-environment. The research results can help the government better understand the complex coupling relationship and then formulate sustainable urbanization development strategies to better balance urbanization and eco-environmental protection.

Source analysis and risk assessment of heavy metals in development zones: a case study in Rizhao, China.

The effects of heavy metal pollution in parks have caused widespread concern. This study investigated the concentrations and sources of eight heavy metals in the economic and technological development zone in Rizhao City. Geo-accumulation index ([Formula: see text]) and potential ecological risk index (PERI) were used to assess the pollution level of the development zone. Sources of heavy metals were analyzed through correlation analysis (CA) and principal component analysis (PCA). Descriptive statistics showed that many types of heavy metals accumulated in the development zone. The average concentrations of Pb, Cd, Hg, Ni, and Zn in the soil exceeded the background values of soil environment in Shandong Province. [Formula: see text] showed that only Hg in the soil was at the non-pollution to moderate pollution level. Meanwhile, sediments were polluted by Hg, Cd, and Zn, with their pollution level being higher than that of the soil. PERI showed that the soil presented moderate risk level and that the river sediment showed severe risk level. Hg and Cd exhibited the highest potential ecological risk. The results of the CA and PCA showed that the main sources of heavy metal pollution in the development zone are industrial activities, followed by atmospheric factors. Focus should thus be directed toward heavy metal pollution in development zones to protect human health and the soil environment.

Soil heavy metal contamination and health risk assessment associated with development zones in Shandong, China.

Heavy metal pollution in soils of development zones has attracted wide attention. In this study, soil heavy metal pollution levels and health risks in 15 selected development zones in Shandong Province were investigated for the first time. Geo-accumulation and potential ecological risk indexes were used to assess pollution levels, and health risk was assessed using the US Environmental Protection Agency model. The soil was contaminated by various heavy metals, among which Hg was dominant. A total of 19% of the monitoring sites showed moderate ecological risk level, and low risk level was observed in general. Pollution control of Hg and Cd in each development zone must be strengthened. Health risk analysis showed that noncarcinogenic and carcinogenic risk levels for adults and children were acceptable or nearly acceptable. Positive matrix factorization model was used to identify three possible sources of heavy metal pollution, namely, industrial sources, atmospheric deposition, and transportation. Some specific measures should be taken to prioritize the control of Hg, As, and Cr for protecting the soil environment and human health, especially vulnerable groups, such as children.