Source-specific probabilistic health risk assessment of heavy metals in surface water of the Yangtze River Basin.

The detrimental effects of heavy metal accumulation on both ecosystems and public health have raised widespread concern. Source-specific risk assessment is crucial for developing effective strategies to prevent and control heavy metal contamination in surface water. This study aims to investigate the contamination characteristics of heavy metals in the Yangtze River Basin, identifying the pollution sources, assessing the risk levels, and further evaluating the health risks to humans. The results indicated that the average concentrations of heavy metals were ranked as follows: zinc (Zn) > arsenic (As) > copper (Cu) > chromium (Cr) > cadmium (Cd) > nickel (Ni) > lead (Pb), with average concentrations of 38.02 µg/L, 4.34 µg/L, 2.53 µg/L, 2.10 µg/L, 1.17 µg/L, 0.84 µg/L, and 0.32 µg/L, respectively, all below the WHO 2017 standards for safe drinking water. The distribution trend indicates higher concentrations in the upper and lower reaches and lower concentrations in the mid-reaches of the river. By integrating the Absolute Principal Component Scores-Multiple Linear Regression (APCS-MLR) receptor model and Positive Matrix Factorization (PMF) model, the main sources of heavy metals were identified as industrial activities (APCS-MLR: 41.3 %; PMF: 42.1 %), agricultural activities (APCS-MLR: 30.1 %; PMF: 27.4 %), and unknown mix sources (APCS-MLR: 29.1 %; PMF: 30.4 %). The calculation of the hazard index (HI) for both children and adults was <1, indicating no non-carcinogenic or carcinogenic risks. Based on the source-specific risk assessment, agricultural activities contribute the most to non-carcinogenic risks, while industrial activities pose the greatest contribution to carcinogenic risks. This study offers a reference for monitoring heavy metals and controlling health risks to residents, and provides crucial evidence for the utilization and protection of surface water in the Yangtze River Basin.

Prognostic and clinicopathological significance of MMP12 in various cancers: a meta-analysis and bioinformatics analysis.

Background: Cancer is one of the top causes of mortality worldwide. The matrix metalloproteinase MMP12 is highly expressed in some cancers, but there is a lack of meta-analyses proving the correlation between MMP12 and cancer. Materials & methods: A literature search was performed using Web of Science, PubMed and other databases. Quantitative meta-analysis of the data was carried out. The Cancer Genome Atlas was further used to validate our results. Results: High MMP12 expression was associated with poorer overall survival and poorer 5-year overall survival. Elevated expression of MMP12 predicted shorter overall survival in six cancers and worse disease-free survival in four malignancies based on validation using the Gene Expression Profiling Interactive Analysis online analysis tool. Conclusion: Elevated MMP12 expression is likely a marker of poor prognosis in various cancers.

What is this summary about? This study looked at how a gene called MMP12 affects the survival time and health of cancer patients. The MMP12 gene makes a protein that helps cancer cells grow. We studied information from 38 research studies involving 9582 patients. We wanted to learn how the gene MMP12 is connected to the prognosis and survival of people who have cancer. What was the result? The study found that patients with less MMP12 tended to live longer. Based on this, we can say that having less of the protein MMP12 may be better for patients. By contrast, high levels of MMP12 were linked to more advanced cancer stages, so this protein may aid cancer growth. What do these results mean? These findings can help doctors diagnose cancer and predict what might happen to patients. If we can control this gene, we might find new treatments to stop cancer from growing and help people live longer. However, we need to do more research to be sure about these findings and to understand this gene better.

Prognostic and clinicopathological significance of TRIM21 in various cancers: A meta and bioinformatic analysis.

BACKGROUND: Tripartite motif-containing protein 21 (TRIM21), a member of the ubiquitin ligase family, makes a significant contribution to the ubiquitination of multiple tumor marker proteins associated with tumor cell proliferation, metastasis and selective apoptosis. As the research further develops, an increasing number of studies have manifested that the TRIM21 expression level can be considered an indicator of cancer prognosis. However, the interrelationship between TRIM21 and multiple forms of carcinogens has not been demonstrated in a meta-analysis. METHODS: We performed a systematic literature retrieval in various electronic databases including PubMed, Embase, Web of Science, Wanfang and China National Knowledge Infrastructure. Besides, the hazard ratio (HR) and the pooled relative risk (RR) were integrated in the assessment of cancer incidence and cancer mortality by Stata SE15.1. Additionally, we used an online database based on The Cancer Genome Atlas (TCGA) to further validate our results. RESULTS: A total of 17 studies were included, totaling 7239 participants. High expression of TRIM21 was significantly correlated with better OS (HR = 0.74; 95% CI: 0.57-0.91; P < .001) and progression-free survival (PFS) (HR = 0.66; 95% CI: 0.42-0.91; P < .001). We found that high TRIM21 expression predicted significant impact on clinical characteristics like decreased lymph node metastasis (RR = 1.12; 95% CI: 0.97-1.30; P < .001), tumor stage (RR = 1.06; 95% CI: 0.82-1.37; P < .001) and tumor grade (RR = 1.07; 95% CI: 0.56-2.05; P < .001). However, TRIM21 expression had no significant impact on other clinical characteristics such as age (RR = 1.06; 95% CI: 0.91-1.25; P = .068), sex (RR = 1.04; 95% CI: 0.95-1.12; P = .953), or tumor size (RR = 1.14; 95% CI: 0.97-1.33; P = .05). Based on the Gene Expression Profiling Interactive Analysis (GEPIA) online analysis tool, TRIM21 was significantly downregulated in 5 cancers while significantly upregulated in 2 cancers, and the descending expression of TRIM21 predicted shorter OS in 5 cancers, worse PFS in 2 malignancies, while the elevated expression of TRIM21 predicted shorter OS and worse PFS in 2 carcinomas. CONCLUSIONS: TRIM21 could serve as a new biomarker for patients with solid malignancies and could be a potential therapeutic target for patients.

A meta-analysis and bioinformatics analysis of P4HB expression levels in the prognosis of cancer patients.

BACKGROUND: P4HB (prolyl 4-hydroxylase, beta polypeptide) is a human chromosomal gene that encodes an endoplasmic reticulum (ER) molecular chaperone protein with oxidoreductase, chaperone and isomerase activities. Recent studies indicated that P4HB may have clinical significance, with elevated P4HB expression reported in cancer patients, but its impact on tumor prognosis is not yet clear. To our knowledge, this is the first meta-analysis to show an association between P4HB expression and the prognosis of various cancers. METHODS: We conducted a systematic literature search in the PubMed, PubMed Central, Web of Science, Embase, CNKI, Wanfang and Weipu databases, followed by a quantitative meta-analysis using Stata SE14.0 and R statistics software 4.2.1. The hazard ratio (HR) and relative risk (RR) were analyzed to evaluate the relationships of P4HB expression levels with overall survival (OS), disease-free survival (DFS), and clinicopathological parameters of cancer patients. Subsequently, P4HB expression in various cancer types was validated using the Gene Expression Profiling Interactive Analysis (GEPIA) online database. RESULTS: Ten articles containing the data of 4121 cancer patients were included in the analysis, and a significant correlation of high P4HB expression with apparently shorter OS was found (HR, 1.90; 95% CI, 1.50-2.40; P < 0.01), while there was no significant correlation with gender (RR, 1.06; 95% CI, 0.91-1.22; P = 0.084), or age. Additionally, GEPIA online analysis revealed significant upregulation of P4HB in 13 types of cancer. Among them, P4HB overexpression was associated with shorter OS in 9 and worse DFS in 11 cancer types. CONCLUSIONS: Upregulation of P4HB is correlated with worse prognosis in various cancers, which could provide new ideas for the development of P4HB-related diagnostic biomarkers and new therapeutic targets.

Anti-Na+/K+-ATPase DR antibody attenuates UUO-induced renal fibrosis through inhibition of Na+/K+-ATPase α1-dependent HMGB1 release.

Reduced Na+/K+-ATPase (NKA) activity and NKAα1 expression are engaged in the pathologies of renal diseases. NKA-mediated Src activation is not the only reason for NKA-related renal fibrosis. In this study, we found that genetic reduction of NKAα1 exhibited exacerbated tubulointerstitial lesions and fibrosis in the UUO mice model. Activation of NKAα1 with an antibody against the extracellular DR region of the NKAα1 subunit (DRm217) prevented UUO-induced tubulointerstitial lesions, preserved kidney function, and decrease renal fibrosis. Further studies revealed that NKAα1 deficiency mice exhibited high inflammation factors expression when they suffered UUO surgery, compared with NKAα1+/+ (WT) mice. DRm217 alleviated inflammatory cell infiltration, suppress NF-κB phosphorylation, and decreased inflammatory factors expression in the UUO mice model. Released HMGB1 can trigger the inflammatory response and contribute to renal fibrosis. Knockdown of NKA in renal tubular cells or in NKAα1+/- mice was associated with more susceptibility to HMGB1 release in the UUO mice model. DRm217 exerted its antifibrotic effect via inhibiting HMGB1 release. Furthermore, AMPK activation participates in the effect of DRm217 on inhibiting HMGB1 release. Our findings suggest that NKAα1 is a regulator of renal fibrosis and its DR-region is a novel target on it.

Integration of Bulk RNA Sequencing and Single-Cell RNA Sequencing to Reveal Uveal Melanoma Tumor Heterogeneity and Cells Related to Survival.

Molecular classification based on transcriptional characteristics is often used to study tumor heterogeneity. Human cancer has different cell populations with distinct transcription in tumors, and their heterogeneity is the focus of tumor therapy. Our purpose was to explore the tumor heterogeneity of uveal melanoma (UM) through RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq). Based on the consensus clustering assays of the prognosis-related immune gene set, the immune subtype (IS) of UM and its corresponding immune characteristics were comprehensively analyzed. The heterogeneous cell groups and corresponding marker genes of UM were identified from GSE138433 using scRNA-seq analysis. Pseudotime trajectory analysis and SCENIC analysis were conducted to explore the trajectory of cell differentiation and the regulatory network of single-cell transcription factors (TFs). Based on 37 immune gene sets, UM was divided into two different immune subtypes (IS1 and IS2). The two kinds of ISs have different characteristics in prognosis, immune-related molecules, immune score, and immune cell infiltration. According to 11,988 cells of scRNA-seq data from six UM samples, 11 cell clusters and 10 cell types were identified. The subsets of C1, C4, C5, C8, and C9 were related to the prognosis of UM, and different TF-target gene regulatory networks were involved. These five cell subsets differentiated into 3 different states. Our results provided valuable information about the heterogeneity of UM tumors and the expression patterns of TFs in different cell types.

Immune classification and identification of prognostic genes for uveal melanoma based on six immune cell signatures.

Cutaneous melanoma could be treated by immunotherapy, which only has limited efficacy on uveal melanoma (UM). UM immunotyping for predicting immunotherapeutic responses and guiding immunotherapy should be better understood. This study identified molecular subtypes and key genetic markers associated with immunotherapy through immunosignature analysis. We screened a 6-immune cell signature simultaneously correlated with UM prognosis. Three immune subtypes (IS) were determined based on the 6-immune cell signature. Overall survival (OS) of IS3 was the longest. Significant differences of linear discriminant analysis (LDA) score were detected among the three IS types. IS3 with the highest LDA score showed a low immunosuppression. IS1 with the lowest LDA score was more immunosuppressive. LDA score was significantly negatively correlated with most immune checkpoint-related genes, and could reflect UM patients' response to anti-PD1 immunotherapy. Weighted correlation network analysis (WGCNA) identified that salmon, purple, yellow modules were related to IS and screened 6 prognostic genes. Patients with high-expressed NME1 and TMEM255A developed poor prognosis, while those with high-expressed BEX5 and ROPN1 had better prognosis. There was no notable difference in OS between patients with high-expressed LRRN1 and ST13 and those with low-expressed LRRN1 and ST13. NME1, TMEM255A, Bex5 and ROPN1 showed potential prognostic significance in UM.

Ubiquitin-dependent switch during assembly of the proteasomal ATPases mediated by Not4 ubiquitin ligase.

In the proteasome holoenzyme, the hexameric ATPases (Rpt1-Rpt6) enable degradation of ubiquitinated proteins by unfolding and translocating them into the proteolytic core particle. During early-stage proteasome assembly, individual Rpt proteins assemble into the hexameric "Rpt ring" through binding to their cognate chaperones: Nas2, Hsm3, Nas6, and Rpn14. Here, we show that Rpt ring assembly employs a specific ubiquitination-mediated control. An E3 ligase, Not4, selectively ubiquitinates Rpt5 during Rpt ring assembly. To access Rpt5, Not4 competes with Nas2 until the penultimate step and then with Hsm3 at the final step of Rpt ring completion. Using the known Rpt-chaperone cocrystal structures, we show that Not4-mediated ubiquitination sites in Rpt5 are obstructed by Nas2 and Hsm3. Thus, Not4 can distinguish a Rpt ring that matures without these chaperones, based on its accessibility to Rpt5. Rpt5 ubiquitination does not destabilize the ring but hinders incorporation of incoming subunits-Rpn1 ubiquitin receptor and Ubp6 deubiquitinase-thereby blocking progression of proteasome assembly and ubiquitin regeneration from proteasome substrates. Our findings reveal an assembly checkpoint where Not4 monitors chaperone actions during hexameric ATPase ring assembly, thereby ensuring the accuracy of proteasome holoenzyme maturation.