Hypoxia, a critical pathological driver in conditions ranging from inflammatory diseases to cancer, profoundly disrupts the homeostatic interplay between neutrophils and endothelial cells. This review synthesizes current knowledge on the multifaceted mechanisms through which hypoxia, largely via the hypoxia-inducible factor (HIF) signaling axis, reprograms both cell types to create a self-perpetuating cycle of inflammation and vascular injury. We delineate how hypoxia induces a hyperactivated state in neutrophils, characterized by metabolic shifts, enhanced adhesion, a heightened secretory profile, and the release of neutrophil extracellular traps (NETs). Concurrently, hypoxia compromises endothelial barrier integrity, increases permeability, and promotes a pro-adhesive phenotype through the upregulation of adhesion molecules like E-selectin, ICAM-1, and VCAM-1. The crosstalk between these activated cells is further mediated through emerging pathways including ferroptosis and extracellular vesicle signaling. This synergistic interaction culminates in microvascular dysfunction, characterized by leukocyte stasis, capillary occlusion, and impaired tissue perfusion. By examining specific disease models—including cerebral ischemia-reperfusion injury, acute lung injury, high-altitude pulmonary edema, venous thrombosis, and neurodegenerative diseases—we highlight the central role of this dysregulated axis in disease pathogenesis. Finally, we discuss the translational implications of these findings, proposing that targeting key nodes of this interaction, such as specific adhesion cascades, NETs formation, or novel cell death pathways, offers promising therapeutic strategies for a spectrum of hypoxia-related disorders.

BACKGROUND:Gut microbiota (GM) has been increasingly implicated in cancer development through immune modulation, metabolic regulation, and systemic inflammatory pathways. Although observational studies have suggested a potential link between GM dysbiosis and bladder cancer (BC), these findings remain susceptible to confounding and reverse causation. To our knowledge, few studies have applied a Mendelian randomisation (MR) framework to systematically evaluate the gut-bladder axis from a genetic perspective. METHODS:We performed a two-sample MR analysis to examine associations between genetically predicted GM composition and BC risk. Genetic instruments for 119 GM taxa were obtained from the MiBioGen consortium. Summary-level genetic association data for BC were derived from the UK Biobank. The inverse variance weighted (IVW) method was used as the primary analytical approach, complemented by Mendelian randomisation-Egger regression (MR-Egger) and weighted median methods. Sensitivity analyses were conducted to assess heterogeneity and horizontal pleiotropy. Instrumental variants were further mapped to host genes to perform exploratory functional annotation and pathway enrichment analyses. RESULTS:In the primary IVW analysis, five GM taxa demonstrated nominal associations with BC risk. Higher genetically predicted abundance of Oscillibacter (OR = 0.706, 95% CI: 0.564-0.883) and Oscillospira (OR = 0.668, 95% CI: 0.490-0.910) was associated with lower risk, whereas Lachnospiraceae (FCS020 group) was associated with increased risk (OR = 1.406, 95% CI: 1.070-1.847). However, none of the associations remained statistically significant after Bonferroni correction for multiple testing. Sensitivity analyses revealed no evidence of significant heterogeneity or directional pleiotropy, and estimates were broadly consistent across MR methods. CONCLUSIONS:In this MR study, we identified nominal associations between genetically predicted GM composition and BC risk. As none of the findings remained statistically significant after correction for multiple testing, these results should be interpreted with caution. Further replication in independent cohorts and mechanistic investigations into the role of candidate taxa are warranted to clarify the potential involvement of the gut-bladder axis in bladder carcinogenesis.

To assess the therapeutic relevance of BRIP1 in gastric cancer (GC), we examine its functional role in conferring resistance to anoikis within GC cells and elucidate the oncogenic signaling pathways modulated by BRIP1. By integrating the Cancer Genome Atlas (TCGA) and Gene Set Enrichment Analysis (GSEA) databases with Least Absolute Shrinkage and Selection Operator (LASSO) regression, a novel risk score to stratify GC patients based on prognosis was generated, and a significantly differentially expressed gene, BRIP1, was validated through reverse transcription quantitative polymerase chain reaction (RT-qPCR). Protein expression associated with apoptosis, cell cycle, and epithelial-mesenchymal transformation (EMT) was quantified via RT-qPCR and Western blot (WB). 5-Ethynyl-2 '-deoxyuridine (EdU) and cell counting kit-8 (CCK-8) assays were conducted to quantify proliferative activity. The protein level in axillary tumor tissues of nude mice was detected by immunohistochemistry (IHC). We established an eight-gene anoikis-related prognostic risk assessment model (DUSP1, VCAN, P3H2, TXNIP, BRIP1, FGD6, GPX3, and RLN2) for GC. Multivariate Cox regression confirmed the risk score as an independent prognostic factor. Among these genes, BRIP1 showed significant differential expression between tumor and normal tissues, as well as normal gastric mucosal epithelial cells and GC cells. Mechanistically, BRIP1 conferred anoikis resistance to GC cells by suppressing the generation of reactive oxygen species (ROS). We found that the PI3K inhibitor LY294002 counteracted BRIP1-driven oncogenic effects, which was evidenced by restored expression of key regulators governing apoptosis, cell cycle progression, and EMT, in addition to suppressed proliferation in GC cells. BRIP1 is postulated to function upstream of the PI3K/Akt signaling cascade. This study establishes a risk scoring model and identifies BRIP1 as a potential prognostic marker for GC.

High-altitude pulmonary edema (HAPE) is a severe condition associated with high-altitude environments, and its molecular mechanism has not been fully elucidated. This study systematically analyzed the DNA methylation status of HAPE patients and healthy controls using reduced-representation bisulfite sequencing (RRBS) and 850K DNA methylation chips, identifying key differentially methylated regions (DMRs). Targeted bisulfite sequencing (TBS) revealed significant abnormalities in DMRs of five genes, azurocidin 1 (AZU1), growth factor receptor bound protein 7 (GRB7), mannose receptor C-type 2 (MRC2), RUNX family transcription factor 3 (RUNX3), and septin 9 (SEPT9). The abnormal expression of AZU1 was validated using peripheral blood leukocytes from HAPE patients and normal controls, as well as rat lung tissue, indicating its potential importance in the pathogenesis of HAPE. To further validate the function of AZU1, we conducted experimental studies using a hypobaric hypoxia injury model in Human Umbilical Vein Endothelial Cells (HUVEC). The results showed that AZU1 was significantly upregulated under hypobaric hypoxia. Knocking down AZU1 mitigates the reduction in HUVEC proliferation, angiogenesis, and oxidative stress damage induced by acute hypobaric hypoxia. AZU1 induces cellular oxidative stress via the p38/mitogen-activated protein kinase (p38/MAPK) signaling pathway. This study is the first to elucidate the mechanism of AZU1 in HAPE via the p38/MAPK pathway, offering novel insights into the molecular pathology of HAPE and laying a foundation for future diagnostic and therapeutic strategies.

Widespread environmental contamination with benzyl butyl phthalate (BBP) has raised concerns due to its high potential for bioaccumulation and male reproductive toxicity. However, the mechanisms underlying BBP-induced male reproductive damage remain unclear. As the adjacent Sertoli cell-formed blood-testis barrier (BTB) creates a privileged niche for spermatogenesis and may serve as the first target of reproductive toxicants, we mainly focused on the detrimental effect of BBP on Sertoli cells and the BTB in this study. C57BL/6 mice were administered BBP via oral gavage at doses ranging from 0 to 400 mg/kg/day for 60 consecutive days. A comprehensive investigation was performed to estimate testicular BBP levels, sperm parameters, histological alterations, functional permeability of the Sertoli cell-based BTB, and ferroptosis in mice. Isolated Sertoli cells were further used to explore and validate the role of ferroptosis in BBP-induced BTB disruption. The results showed that permeation of BBP into the testis induced reduction in sperm quantity and quality, accompanied by fractured BTB ultrastructure, compromised permeable 'fence' functions of BTB, decreased expressions of tight junction proteins (TJP1 and OCLN) and paracellular transepithelial electrical resistance (TER) of Sertoli cells. Moreover, BBP exposure significantly increased intracellular iron content, promoted lipid peroxidation, and activated ferroptosis in the testis of mice and primary Sertoli cells, which was involved in BBP-induced disruption of BTB integrity and function as confirmed by the ferroptosis inhibitors. In mechanism, BBP specifically downregulated the intracellular iron exporter ceruloplasmin (CP) level to inhibit Fe2+ export and the oxidization of Fe2+ into less toxic Fe3+, thus exacerbating ferroptosis in Sertoli cells. Overexpression of CP significantly suppressed ferroptosis and alleviated BBP-induced BTB disruption. These findings reveal the role of CP-mediated iron homeostasis in regulating Sertoli cell ferroptosis and BTB function, providing new insights into the mechanisms of BBP-related reproductive toxicity.

The gut microbiota has been implicated in the development of rheumatoid arthritis (RA), but whether these associations reflect causal relationships remains unclear. We conducted a two-sample Mendelian randomization analysis to investigate the potential causal effects of gut microbial taxa on RA risk. Summary-level data from the MiBioGen consortium (n = 13,266) and a large RA genome-wide association study (n = 97,173) were used. Multiple Mendelian randomization methods and sensitivity analyses were applied to ensure robustness. Four microbial taxa showed nominal associations with RA. Increased abundance of Catenibacterium, Desulfovibrio, and Ruminiclostridium 6 was associated with a higher risk of RA, while Lachnospiraceae (UCG008) appeared to have a protective effect. Although these associations did not meet Bonferroni-corrected significance, results were consistent across analytical methods with no evidence of pleiotropy or heterogeneity. This study provides genetic evidence supporting a potential causal link between specific gut microbes and RA risk. The findings highlight host immune modulation as a possible pathway connecting the gut microbiome to RA and identify candidate taxa for future mechanistic and therapeutic research.

Background: Human exposure to heavy metals occurs through multiple pathways in daily life. However, the effects of mixed heavy metal exposure on accelerated aging in the elderly U.S. population remains unclear. This study aims to investigate the association between heavy metal concentrations in blood and urine and the onset of accelerated aging. Methods; A total of 2530 individuals were included in the blood metals analysis and 716 individuals in the urine metals analysis in this study. GrimAge acceleration (AgeAccelGrim) was calculated as the residuals from regressing DNA methylation GrimAge on chronological age. Weighted multivariable logistic regression models were applied to analyze the relationship between metal exposure with AgeAccelGrim. Bayesian kernel machine regression (BKMR) was performed to estimate the effects of individual metals or metals mixtures and AgeAccelGrim. Results: We found that blood cadmium (Cd) concentration was positively associated with an increased risk of AgeAccelGrim in both females and males, with odds ratios (OR) of 5.73 (95 % confidence interval (95 % CI): 1.88-17.41, P trend = 0.008) and 14.25 (95 % CI: 4.88-41.62, P trend < 0.001), respectively. Moreover, these associations were more pronounced for urinary Cd compared to blood Cd. Blood lead (Pb) was also associated with a 3.52-fold (95 % CI: 1.21-10.24, P trend = 0.007) increase in AgeAccelGrim risk among males. BKMR confirmed the aforementioned findings, identifying Cd as the most significant contributor to accelerated aging. Conclusions: Exposure to heavy metals, either individually or in mixture, was positively associated with accelerated biological aging. These associations were more pronounced in males.

>Acute mountain sickness（AMS） is an illness caused by hypoxia due to rapid ascent to altitudes above 2,500 m. Symptoms include headache,nausea, vomiting, and loss of appetite, all of which usually improve within 1 to 2 days. However,untreated AMS can progress to life-threatening conditions such as high-altitude cerebral and pulmonary edema（HACE and HAPE, respectively） [1] .

Objectives:This study investigated association between long-term PM2.5 exposure and lung cancer incidence, focusing on Jiangsu Province, China. We aimed to explore the effects of historical PM2.5 with time lags and build a prediction model using machine learning methods. Study design:An ecological epidemiology study. Methods:Lung cancer incidence data from Jiangsu Province (2014-2018) were combined with annual PM2.5 concentration data from satellite sources for the previous 10 years (lag 0 to lag 9). Correlation and grey correlation analyses were performed to evaluate the lagged relationship between PM2.5 exposure and lung cancer incidence. To address the multicollinearity problem in the data, ridge regression, support vector regression, and back propagation artificial neural network were employed. The combined prediction model was constructed using the optimal weighting method. Results:The incidence of lung cancer was significantly correlated with PM2.5 concentration at different historical time points, with the strongest correlation at lag 9. The combined prediction model that integrates multiple prediction methods showed higher accuracy and reliability in predicting lung cancer incidence than a single model. Conclusion:Long-term exposure to PM2.5, especially exposure with a long lag time, is closely related to lung cancer incidence. The integrated machine learning prediction model can be used as a reliable tool to assess the health risks of air pollution.

Objective To construct a prognostic risk scoring model for gastric cancer(GC)anoikis-related genes(ARGs)based on least absolute shrinkage and selection operator(LASSO)regression,and analyze the relationship between anoikis and prognosis of gastric cancer as well as the significance of the model in immunotherapy and chemotherapy of gastric cancer patients.Methods Differentially expressed prognostic anoikis-related genes(ARGs)in gastric cancer and adjacent tissues were screened through The Cancer Genome Atlas(TCGA)database and the Molecular Signatures Database(MSigDB);key anoikis genes were selected based on LASSO regression analysis to construct a prognostic risk scoring model,and patients were divided into high-risk and low-risk groups with the median risk score as the cutoff point.Gene expression levels in gastric cancer clinical samples and cells were detected by real-time quantitative PCR(RT-qPCR);Kaplan-Meier(KM)survival curves,univariate and multivariate Cox regression analyses were used to verify the predictive efficiency of the prognostic risk scoring model for the prognosis of gastric cancer patients;CIBERSORT and ESTIMATE algorithms were used to analyze the immune cell infiltration levels in patients with different risk groups;the correlation between risk scores and immune checkpoint expression levels in gastric cancer patients was analyzed using the R package"ggplot2"and"ggExtra",and the correlation between tumor mutation burden(TMB)and risk scores was assessed;chemotherapy drug sensitivity analysis was used to evaluate the value of the constructed prognostic risk scoring model in gastric cancer chemotherapy.Results Six key ARGs(VCAN,FEN1,BRIP1,CNTN1,P3H2,DUSP1)were screened out based on LASSO regression analysis,and a prognostic risk scoring model was constructed.RT-qPCR detection showed that VCAN,FEN1,and BRIP1 genes were highly expressed in gastric cancer tissues and cells(P＜0.05),while CNTN1,P3H2,and DUSP1 genes were lowly expressed(P＜0.05);Kaplan-Meier survival curve analysis found that the survival rate of patients in the high-risk group was significantly lower than that in the low-risk group(P＜0.001),and there were statistically significant differences in survival rate and TMB levels between high-and low-risk group patients(P＜0.05);univariate and multivariate analyses showed that tumor stage,age,and risk score were significantly associated with survival in gastric cancer patients(P＜0.05);immune cell infiltration analysis showed that the tumor immune matrix score was significantly higher in the high-risk group than in the low-risk group(P＜0.05),and the constructed prognostic risk scoring model can be used as an indicator of the tumor immune microenvironment(TIME)status;analysis using the R package"ggplot2"and"ggExtra"showed that the risk score of the constructed model was positively correlated with the upregulated expression of immune checkpoints TIM3,VISTA,TIGIT,BTLA,and B7-H3(r=0.26,0.40,0.16,0.26,0.21,P＜0.05),and TMB level was negatively correlated with risk score(R=-0.4,P＜0.05);the constructed prognostic risk scoring model can be used to guide chemotherapy for gastric cancer patients.Conclusion The prognostic risk scoring model constructed based on anoikis-related genes can be used to predict the prognosis of gastric cancer patients;the risk genes in the model can serve as potential targets for gastric cancer treatment,providing a reference for individualized treatment of gastric cancer.

Objective To compare the impact of two pesticide dose forms on Blattella germanica (B. germanica)resistance enzymes.The micro-drop technique was utilized on subcultured B. germanica, and the metabolic enzyme activity was assessed.Using spectrophotometry, the relative enzyme activities of B.germanica were determined.Profile analysis was used to compare the enzyme activities of beta-cypermethrin in both nanoemulsion and traditional emulsion forms.Findings: The suppression percentages of the acetylcholinesterase enzyme (AchE), GST, and P450-O demethylases across different pesticide formulations were analyzed using regression equations, yielding F=31.18, P<0.001; F=9.18, P<0.001; and F=4.58, P<0.02.Conclusion: The suppression of AchE, GST, and P450-O demethylase by beta-cypermethrin nanoemulsion was more significant compared to the beta-cypermethrin emulsifiable concentrate.The study concluded that beta-cypermethrin nanoemulsion had a significant impact on insect detoxifying enzymes compared to beta-cypermethrin emulsifiable concentrate due to their numerous advantages.

BackgroundAprepitant, fosaprepitant, and netupitant are three common neurokinin-1 receptor antagonists (NK-1RAs) used to prevent chemotherapy-induced nausea and vomiting, following highly or moderately emetogenic chemotherapy. Understanding their different adverse event (AE) profiles may help clinicians make appropriate treatment decisions.MethodsAll data collected from the FDA Adverse Event Reporting System (FAERS) database from the first quarter of 2004 to the fourth quarter of 2023 underwent disproportionality analysis to detect, evaluate, and compare AE signals of the three NK-1RAs.ResultsA total of 3,904, 1,123, and 243 AE reports related to aprepitant, fosaprepitant, and netupitant, respectively, were extracted from the FAERS database. Of these, more than 50% of respondents were female, and most of them were aged 45–65 years. General disorders and administration-site conditions, and gastrointestinal disorders were the most frequent signals in the system organ class of the three NK-1RA drugs. In addition, aprepitant was strongly associated with joint deposit (ROR = 26.27) and fosaprepitant was closely related to seizure-like phenomena (ROR = 26.90); two preferred terms (PTs) were not mentioned in the manual. Statistically, netupitant was likely to induce death (N = 63, ROR = 8.78, 95% CI: 6.75–11.42). Additionally, neutropenic colitis, colitis, and stomatitis were unique to netupitant. Furthermore, the AE profiles of the three NK-1RA drugs were different by gender.ConclusionThe AE profiles for aprepitant, fosaprepitant, and netupitant were different. In addition to paying attention to common AEs, clinicians need to pay attention to new emerging AEs, such as joint deposit, seizure-like phenomena, neutropenic colitis, colitis, and stomatitis, regarding the three NK-1RA drugs. Furthermore, the AE compositions of the three NK-1RA drugs were different in different genders, and clinicians should take these factors into account when selecting NK-1RAs for CINV treatment.

Globally, gastric cancer (GC) remains a major cause of death. Our prior study found lumican to be an important independent predictor of GCs poor overall survival and bioinformatics analysis suggested the MAPK pathway as a signaling cascade linked to lumican function. In our study, we observed that lumican exhibited a significant elevation in GC tissues and cells, hastening tumor proliferation in vivo in comparison to control groups. We also observed that knockdown of lumican effectively inhibited the proliferation, migration and invasion of AGS cells. On the contrary, overexpression of lumican promoted the proliferation, migration and invasion of AGS cells. We clarified that lumican was upstream of ERK in the MAPK pathway. In rescue assays, TBHQ further enhanced the promoting effect of lumican overexpression on cell migration and invasion and the increased expression of ERK 1/2 or p-ERK 1/2 levels. However, the increased expression of ERK 1/2 or p-ERK 1/2, migration and invasion were completely blocked by GDC-0994 in lumicanoverexpressing AGS cells with TBHQ treated. Molecular docking prediction revealed that the amino acid sequence of lumican binding to ERK1/2 may also regulate the ERK pathway. In conclusions, lumican is highly expressed in GC and promotes the proliferation, migration and invasion of GC cells by regulating ERK pathway. Consequently, lumican emerges as pivotal indicators for both diagnosis and treatment in GC cases.

Background: Over 5% of the world's population suffers from depression, and women are nearly twice as likely to experience it as men. However, the relationship between depressed symptoms and age at first birth (AFB) in women hasn't been thoroughly investigated. This study aimed to evaluate the relationship between AFB and depression in US women. Methods: We used data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES). A total of 9,515 women aged ≥ 20 who have completed Patient Health Questionnaire-9 (PHQ-9) and Reproductive Questionnaire data were selected for the study. PHQ-9 was used to assess depressive symptoms, and total scores ≥ 10 were identified as having depression. Multivariate regression models were performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), controlling for reproductive factors and other covariates, to analyze the association between age at first birth and the risk of depression in women. Results:In the weighted sample, the prevalence of depressive symptoms was 11.5% among women. Compared to participants with AFB of 27-29 years old (reference group), fully adjusted models showed that the ORs and 95% CI for women with AFB < 18, 18-21, and 21-23 years old were 4.55 (95% CI 1.99, 10.41), 2.10 (95% CI 1.12, 3.96), and 2.53 (95% CI 1.22, 5.23). Yet there was no significant difference between AFB of 24–26, or > 29 years compared to the reference group. Conclusion:Women with younger AFB are at higher risk for depression. Further research is needed to determine causal relationships and mechanisms between AFB and increased risk of depression.

High-altitude diseases, including acute mountain sickness (AMS), high-altitude cerebral edema (HACE), and high-altitude pulmonary edema (HAPE), are closely related to an individual’s ability to adapt to hypoxic environments. However, specific research in this field is relatively limited, and further biomarker research and clinical trials are needed to clarify the exact role and potential therapeutic applications of key genes in high-altitude diseases. This study focuses on the role of the STC1 gene in high-altitude diseases and explores its expression patterns in different types of cancer. By using gene expression data analysis and functional experiments, we identified STC1 as a key gene affecting the development of altitude sickness. In addition, we also conducted expression and mutation analysis on STC1 in various cancer samples and found significant differences in the expression of this gene in 13 types of malignant tumors, which is associated with the hypoxic state in the tumor microenvironment. In addition, STC1 is significantly associated with patient prognosis and influences tumor immunity by mediating six types of immune cells (CD8+T cells, CD4+T cells, neutrophils, macrophages, monocytes, and B cells) in the tumor microenvironment. The expression and diagnostic value of STC1 were confirmed through GEO datasets and qPCR testing, indicating consistency with the results of bioinformatics analysis. These results indicate that STC1 is not only an important factor in the adaptive response to high-altitude diseases but may also play a role in the adaptation of cancer to low-oxygen environments. Our research provides a new perspective and potential targets for the discovery of biomarkers for high-altitude diseases and cancer treatment.

Background:The fatal risk of high-altitude pulmonary edema (HAPE) is attributed to the inaccurate diagnosis and delayed treatment. This study aimed to identify the clinical characteristics and to establish an effective diagnostic nomogram for HAPE in habitual low altitude dwellers. Methods:A total of 1,255 individuals of Han Chinese were included in the study on the Qinghai-Tibet Plateau at altitudes exceeding 3,000 m. LASSO algorithms were utilized to identify significant predictors based on Akaike's information criterion (AIC), and a diagnostic nomogram was developed through multivariable logistic regression analysis. Internal validation was conducted through bootstrap resampling. Model performance was evaluated using ROC curves and the Hosmer-Lemeshow test. Results:The nomogram included eleven predictive factors and demonstrated high discrimination with an AUC of 0.787 (95% CI [0.757-0.817]) and 0.833 (95% CI [0.793-0.874]) in the training and validation cohorts, respectively. Calibration curves were assessed in both the training (P = 0.793) and validation datasets (P = 0.629). Confusion matrices revealed accuracies of 70.95% and 74.17% for the training and validation groups. Furthermore, decision curve analysis supported the use of the nomogram for patients with HAPE. Conclusion:We propose clinical features and column charts based on hematological parameters and demographic variables, which can be conveniently used for the diagnosis of HAPE. In high-altitude areas with limited emergency environments, a diagnostic model can provide fast and reliable diagnostic support for medical staff, helping them make better treatment decisions.

Background: Glyphosate is the most commonly used herbicide with potential neurotoxicity. However, limited epidemical evidence is found in the relationship between glyphosate and cognitive impairment, especially in the cognitive-disrupting sensitive elderly populations. Objective: This study aimed to examine the association of urinary glyphosate exposure with cognitive impairment in the United State (US) older adults. Methods: Cognitive impairment was determined by the following four tests: the Consortium to Establish a Registry for Alzheimer’s disease (CERAD) Immediate Recall test (IR), the CERAD Delayed Recall tests (DR), the Animal Fluency (AF) test and the Digit Substitution test (DSST). Survey weighted logistic regression and restricted cubic splines were applied to evaluate and visualize the association between glyphosate and cognitive impairment. Results: A total of 465 elderly adults were identified in the National Health and Nutrition Examination Survey (NHANES) 2013-2014 cycle, and among them, 83.87% individuals had detectable urinary levels of glyphosate (0.628 ng/mL in average). After adjusting for the potential covariates, glyphosate was significantly linked to increased DR and AF impairment, and the corresponding ORs were 1.52 (1.01 to 2.30, p = 0.049) and 1.69 (1.11 to 2.59, p = 0.019), respectively. No significant association was identified between glyphosate and IR or DSST impairment. The RCS plot further confirmed the linear and positive relationships between glyphosate and DR and AF impairment. Conclusions: These findings suggested that exposure to glyphosate might be associated with declined cognitive function in the elderly, and it might be prudent to evaluate cognitive outcomes for aged individuals with glyphosate exposures.

BackgroundHigh altitude pulmonary edema (HAPE) is an idiopathic, noncardiogenic form of pulmonary edema that occurs at high altitudes. It is characterized by a severe clinical course and carries a significant mortality risk. Despite its clinical relevance, the molecular mechanisms underlying HAPE are not well understood.MethodsWe conducted whole-transcriptome RNA sequencing on blood samples from 6 pairs of HAPE patients and healthy controls to identify differentially expressed (DE) mRNAs, miRNAs, circRNAs, lncRNAs, along with alternative splicing (AS) events, gene fusions, and novel transcripts. To explore the regulatory dynamics, we constructed ceRNA networks and analyzed immune cell infiltration patterns, further annotating the biological functions of these transcripts. For empirical validation, we selected five circRNAs from the ceRNA network and conducted RT-qPCR on 50 paired samples. Additionally, we assessed the correlations between circRNA expression levels and clinical data to evaluate their diagnostic potential.ResultsWe observed 2,023 differentially expressed mRNAs (DEmRNAs), 84 DEmiRNAs, 200 DEcircRNAs, and 3,573 DElncRNAs. A total of 139 ‘A3SS’ events, 103 ‘A5SS’ events, 545 ‘MXE’ events, 14 ‘RI’ events, and 1,482 ‘SE’ events were identified in the AS events analysis between the two groups. Two ceRNA networks were constructed. T cells, follicular helper, and Macrophages M1 cells exhibited the strongest positive correlation (R=0.82), while naive B cells and memory B cells demonstrated the strongest negative correlation (R=-0.62). In total, the expression of three circRNAs was significantly different in a larger cohort. Hsa_circ_0058497, hsa_circ_0081006, and hsa_circ_0083220 demonstrated consistent with the RNA sequencing results. These three circRNAs strongly correlate with clinical indicators and exhibit potential as diagnostic biomarkers. Finally, we verified five genes (CXCR4, HSD17B2, ANGPTL4, TIMP3, N4BP3) that were differentially expressed in endothelial cells under normoxia and hypoxia through bioinformatics and RT-qPCR analyses.ConclusionThis study elucidates the differential expression of coding and non-coding RNAs (ncRNAs) in HAPE, identifies new transcripts and genes, and enhances our understanding of the transcriptional characteristics of HAPE. Moreover, it highlights the potential role of circRNAs in advancing the diagnosis and treatment of HAPE.

Background The enhancer of rudimentary homolog (ERH) has been shown to play significant roles in tumorigenesis and progression. However, few systematic pan-cancer analyses about ERH have been described.Methods From the tumor immune estimation resource web server2.0 (TIMER2.0), the Genotype-Tissue Expression database (GTEx) and the Gene Expression Profile Interactive Analysis version 2 (GEPIA2) databases, we explored the expression profiles and prognostic significance of ERH in 33 cancers. The Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA) databases were further used to examine the differential expression of ERH at the protein level. The genetic alteration profile was obtained from the cBioPortal. The correlation between ERH expression and the quantities of immune infiltrating cells was examined by the TIMER tool. Spearman's correlation test was conducted to analyze the association between ERH expression status and a number of prognostic indicators, including immune checkpoints, TMB, MSI, immune neoantigen, MMR genes, and DNA methyltransferases. Protein-Protein Interaction analyses were performed in the String and GeneMANIA databases, and enrichment analysis and predicted signaling pathways were identified through GO and KEGG. To make our results convincing, we validated them in six datasets in the Gene Expression Omnibus (GEO) database. In addition, we verified the expression of ERH between gastric cancer tissues and adjacent normal tissues by RT-qPCR.Results ERH expression was elevated in numerous tumors, and it was associated with the patient's prognosis. Furthermore, the quantities of immune infiltrating cells and immune checkpoint genes were remarkably associated with ERH. TMB and MSI were related to ERH expression in 14 and 15 cancer types, respectively. Moreover, the expression of ERH was strongly associated with MMR defects in multiple cancer types, and almost all tumors showed co-expression of ERH and four DNA methyltransferases. The results of GO and KEGG analysis confirmed that ERH potentially impacts several important signaling pathways. Both the GEO datasets and the RT-qPCR experiment validated our previous analysis.Conclusion Our pan-cancer analysis demonstrated the characterization of ERH in multiple tumors. ERH may be a valuable novel biological indicator for assessing immunotherapy efficacy and prognosis in various malignancies.