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Purpose: The integrator subunit (INTS) family, a group exclusive to metazoans, participates in various biologic processes. However, their roles in hepatocellular carcinoma (HCC) remain largely unexplored. Methods: Public databases were utilized to investigate the transcriptional and protein expression, and clinical relevance of the INTS family in HCC. Meanwhile, the effects of INTS13 knockdown and overexpression on cell proliferation and apoptosis were studied using HCC cell lines. Results: The mRNA expression of most INTSs were higher in tumor than normal tissues. Higher expression of INTS1/2/3/4/7/8/9/11/12/13 were correlated with poorer overall survival (OS) in Kaplan-Meier Survival Analysis. Multivariate analysis revealed higher level of INTS13 was an independent prognostic factor for shorter OS. Furthermore, genetic alteration of INTS3/6/7/8/9/10 were found in HCC patients and was associated with shorter disease-free survival and progression-free survival. INTS1/2/3/5/7/11/13/14 were associated with activation of tumor-induced immune response and immune infiltration in HCC. Knockdown of INTS13 inhibited cell proliferation and induced apoptosis in HCC cell lines, while overexpression of INTS13 had the opposite effect. Conclusion: Our results indicate that INTS13 is an independent prognostic biomarker in HCC. Furthermore, INTS13 enhances cell proliferation and decreases cell apoptosis in HCC cell lines leading to a poorer OS in HCC patients.

Background: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent liver disease worldwide and lack of research on the diagnostic utility of mitochondrial regulators in NAFLD. Mitochondrial dysfunction plays a pivotal role in the development and progression of NAFLD, especially oxidative stress and acidity β-oxidative overload. Thus, we aimed to identify and validate a panel of mitochondrial gene expression biomarkers for detection of NAFLD. Methods: We selected the GSE89632 dataset and identified key mitochondrial regulators by intersecting DEGs, WGCNA modules, and MRGs. Classification of NAFLD subtypes based on these key mitochondrial regulatory factors was performed, and the pattern of immune system infiltration in different NAFLD subtypes were also investigated. RF, LASSO, and SVM-RFE were employed to identify possible diagnostic biomarkers from key mitochondrial regulatory factors and the predictive power was demonstrated through ROC curves. Finally, we validated these potential diagnostic biomarkers in human peripheral blood samples and a high-fat diet-induced NAFLD mouse model. Results: We identified 25 key regulators of mitochondria and two NAFLD subtypes with different immune infiltration patterns. Four potential diagnostic biomarkers (BCL2L11, NAGS, HDHD3, and RMND1) were screened by three machine learning methods thereby establishing the diagnostic model, which showed favorable predictive power and achieved significant clinical benefit at certain threshold probabilities. Then, through internal and external validation, we identified and confirmed that BCL2L11 was significantly downregulated in NAFLD, while the other three were significantly upregulated. Conclusion: The four MRGs, namely BCL2L11, NAGS, HDHD3, and RMND1, are novel potential biomarkers for diagnosing NAFLD. A diagnostic model constructed using the four MRGs may aid early diagnosis of NAFLD in clinics.

Globally, natural landscapes and their recreational ecosystem services (RES) are both under threat from anthropogenic activities and environmental changes. But the demand for RES increases with the development of human living standards. Therefore, mapping and assessing the supply–demand relationships of RES is crucial for landscape planning, management, and human well-being. This study aimed to study the relationships between supply and demand of RES in Shandong province, China, quantify the supply, demand, and supporting capacity of RES, analyze the degree of matching and coupling between the supply and demand of RES, and explore the effect of terrain gradient to RES. The results indicated that the average value of coupling coordination (CCD) between supply–demand of RES in Shandong province was 0.45, which is a mild balance. According to the supply–demand matching types, areas with low supply-high demand accounted for 6.62%, indicating a serious shortage matching of supply and demand. Using hotel quantity and roads as indicators of the supporting capacity of RES, the overall coordination between landscape aesthetic quality (LAQ) and regional hotel quantity shows a mild imbalance (0.38), while that with the regional road density shows a good balance (0.60). Furthermore, the scenery spots density, RES supply, RES supply–demand CCD and support capacity CCD shows an upward trend with the increase of elevation and slope, an “increased-decreased-increased” trend with the increase of terrain niche index. This study provides spatial matching of RES supply and demand in Shandong province. Optimizing land-use structures and improving natural resource allocation were proposed to boost coordination of RES supply and demand.

Gastric cancer (GC) is difficult to characterize due to its heterogeneity, and the complicated heterogeneity leads to the difficulty of precisely targeted therapy. The spatially heterogeneous composition plays a crucial role in GC onset, progression, treatment efficacy, and drug resistance. In recent years, the technological advancements in spatial omics has shifted our understanding of the tumor microenvironment (TME) from cancer-centered model to a dynamic and variant whole. In this review, we concentrated on the spatial heterogeneity within the primary lesions and between the primary and metastatic lesions of GC through the TME heterogeneity including the tertiary lymphoid structures (TLSs), the uniquely spatial organization. Meanwhile, the immune phenotype based on spatial distribution was also outlined. Furthermore, we recapitulated the clinical treatment in mediating spatial heterogeneity in GC, hoping to provide a systematic view of how spatial information could be integrated into anti-cancer immunity.

Microplastics (MPs) were considered as emerging pollutants in soil. Cadmium (Cd) is the typical heavy metal contaminant in paddy soil in China. It was not unraveled that the effects of the existence of MPs on soil properties and Cd adsorption after rice growth in paddy soil, one of the most important soil types in China. In this study, several typical MPs in dosage of 0.5% (w/w) with different particle sizes, including polyethylene (PE, 200μm), polyacrylonitrile (PAN, 200μm), and polyethylene terephthalate (PET, 200 and 10μm), were selected and aged for a rice season (∼6 months) in paddy soil by column experiments. Some essential physicochemical properties of paddy soil collected from different treatments and the adsorption performance of typical metal contaminants (cadmium, Cd) in paddy soil with MPs coexisting were compared. The results indicated that the 6-month existence of 200μmMPs increased water content (15.94% to 26.08-30.30%), pH value (7.05 to 7.16–7.33), organic matter (OM) content (15.1 gkg −1 to 18.2–22.9 gkg −1), the percentage of soil sand and Cd adsorption capacity of paddy soil, whereas decreased soil cation exchange capacity (CEC), the percentage of soil clay and silt. The adsorption experiments of Cd in soil showed that the adsorption behavior was consistent with the pseudo-second order and Langmuir isotherm model, and the addition of MPs would increase the adsorption capacity of Cd in soil. Besides, the particle size of MPs was found to be one of the dominant factors, in which MPs with smaller particle size (10μm) favored the increase of water content, pH, OM content, CEC, and adsorption performance with Cd. The results of this study could provide a supplemental understanding of the effect of MPs input on the paddy soil ecosystem, including the soil properties and the bioavailability and transport of metal in paddy soil.

Gastric cancer (GC) remains one of the most common malignancies worldwide. Despite immune-checkpoint inhibitors (ICIs) has revolutionized cancer treatment and obtained durable clinical responses, only a fraction of GC patients benefit from it. As an important component of T cells, regulatory T cells (Tregs) play a vital role in the pathogenesis of GC, keep a core balance between immune suppression and autoimmunity, and function as predictive biomarkers for prognosis of GC patients. In this review, we discuss the role of Tregs in the pathogenesis of GC, and targeting Tregs via influencing their transcription factor, migration, co-stimulatory receptors, immune checkpoints, and cytokines. We also focus on the currently important findings of Tregs metabolism including amino acid, fatty acid, and lactic acid metabolism of GC. The emerging role of microbiome and clinical combined therapy in modulating Tregs in GC treatment is also summarized. Meanwhile, this review recapitulates a novel regulator, magnesium, is involved in mediating Tregs in GC. These research advances on Treg-related strategies provide new insights and challenges for GC progression, treatment, and prognosis. And we hope our review can stimulate further discovery and implication of mediators and pathways targeting Tregs.

Gastrointestinal (GI) cancers, one of the most lethal cancers nowadays, have caused millions of deaths. The tumor microenvironment (TME) is a complex ecosystem containing multiple cells, such as immune cells, cancer cells, and endothelial cells. Tumor-associated macrophages (TAMs), the predominant cells infiltrating the TME, have been verified to play a crucial role in regulating tumor progression. Noncoding RNAs (ncRNAs) are involved in mediating tumor-infiltrating immune cells, including TAMs. GI cancer cells produce various ncRNAs to modulate TAM infiltration and polarization. Meanwhile, ncRNAs play a pivotal role in macrophage and cancer cell metabolic reprogramming. Furthermore, macrophages mediate the impact of ncRNAs on chemoresistance, metastasis, and progression of GI cancer. In this review, we summarize recent research advances in the crosstalk between macrophages and GI cancer regulated by ncRNAs. Moreover, we propose the promising role of ncRNAs as potential targets and prognostic biomarkers in cancer treatment, hoping to facilitate the identification of new targets for immunotherapy.

Background: Our understanding of the impact of long-term exposures to PM2.5 constituents and sources on mortality is limited. Objectives: To examine associations between long-term exposures to PM2.5 constituents and sources and cause-specific mortality in US older adults. Methods: We obtained demographic and mortality data for 15.4 million Medicare beneficiaries living within the conterminous United States (US) between 2000 and 2008. We assessed PM2.5 constituents exposures for each beneficiary and used factor analysis and residual-based methods to characterize PM2.5 sources and mixtures, respectively. In age-, sex-, race- and site- stratified Cox proportional hazard models adjusted for neighborhood socio-economic status (SES), we assessed associations of individual PM2.5 constituents, sources, and mixtures and cause-specific mortality and examined modification of these associations by participant demographics and location of residence. We assessed the robustness of our findings to additional adjustment for behavioral risk factors and to alternate exposure definitions and exposure windows. Results: Hazard ratios (HR) were highest for all causes of death, except COPD, for PM2.5 constituents and the coal combustion-related PM2.5 components, with no evidence of confounding by behavioral covariates. We further found Pb and metal-related PM2.5 components to be significantly associated with increased HR of all causes of death, except COPD and lung cancer mortality, and nitrate (NO3–) and silicon (Si) and associated source-related PM2.5 components (traffic and soil, respectively) to be significantly associated with increased all-cause, CVD, respiratory and all cancer-related mortality HR. Associations for other examined constituents and mortality were inconsistent or largely null. Our analyses of mixtures were generally consistent with these findings. Mortality HRs were greatest for minority, especially Black, low-income urban, younger, and male beneficiaries. Discussion: PM2.5 components related to coal combustion, traffic, and to a lesser extent, soil were strongly associated with mortality from CVD, respiratory disease, and cancer.

Background: The impact of long-term exposure to nitrogen dioxide (NO2) on cause-specific mortality is poorly understood. Objective: To assess mortality risks associated with long-term NO2 exposure and evaluate confounding of this association. Methods: We examined the association between 12-month moving average NO2 exposure and cause-specific mortality in 14.1 million US Medicare beneficiaries between 2000 and 2008. Associations were examined using age, gender, and race-stratified and state-adjusted Poisson regression models. We assessed the potential for confounding by PM2.5 and behavioral covariates and unmeasured confounding by decomposing NO2 into its spatial and spatio-temporal components. Results: We found significant associations between 12-month NO2 exposure and increased mortality from all-causes [risk ratio (RR): 1.052; 95% CI: 1.051, 1.054; per 10 ppb], cardiovascular (CVD) (1.133; 95% CI: 1.130, 1.137) and respiratory disease (1.050; 95% CI: 1.044, 1.056), all cancers (1.021; 95% CI: 1.017, 1.025), ischemic heart disease (IHD) (1.221; 95% CI: 1.217, 1.226), cerebrovascular (CBV) disease (1.092; 95% CI: 1.085, 1.100), and for the first time pneumonia (1.275; 95% CI: 1.263, 1.287). Associations generally remained positive and statistically significant after adjustment for PM2.5 and behavioral factors. Conclusions: Our findings provide additional evidence of the increased risk posed by long-term NO2 exposures on increased mortality from all-causes, CVD, respiratory disease, IHD, CBV, and cancer and provide new evidence of their impact on mortality from pneumonia. Unmeasured confounding of these associations was present, however, demonstrating the need to understand sources of this confounding.