The effects of BDNF rs6265 and FGF21 rs11665896 polymorphisms on alcohol use disorder-related impulsivity in Han Chinese adults.

Introduction: Patients with alcohol use disorder (AUD) often experience repeated withdrawal. Impulsivity is the most relevant factor influencing successful withdrawal. Brain-derived neurotrophic factor (BNDF) and fibroblast growth factor 21 (FGF21) are associated with impulsivity. Previous studies on the differential effects of BDNF or FGF21 on impulsivity have focused on single-gene effects and have inconsistent results. We aim to investigate the effects of BDNF rs6265 and FGF21 rs11665896, individually and together, on impulsivity during alcohol withdrawal in patients with AUD. Methods: We recruited 482 adult Han Chinese males with AUD and assessed their impulsivity using the Barratt Impulsivity Scale. Genomic DNA was extracted and genotyped from peripheral blood samples. Statistical analysis was conducted on the data. Results: The T-test and 2 × 2 analysis of variance were used to investigate the effects of the genes on impulsivity. There was a significant BDNF × FGF21 interaction on no-planning impulsiveness (F = 9.15, p = 0.003, η2p = 0.03). Simple main effects analyses and planned comparisons showed that BDNF rs6265 A allele × FGF21 rs11665896 T allele was associated with higher no-planning impulsiveness. Finally, hierarchical regression analyses revealed that only the interaction of BDNF and FGF21 accounted for a significant portion of the variance in no-planning impulsiveness. Conclusion and significance: The combination of BDNF rs6265 A allele and FGF21 rs11665896 T allele may increase impulsivity and discourage alcohol withdrawal. Our study provides a possible genetic explanation for the effects of associated impulsivity in patients with AUD from the perspective of gene-gene interactions.

Ferrostatin-1 specifically targets mitochondrial iron-sulfur clusters and aconitase to improve cardiac function in Sirtuin 3 cardiomyocyte knockout mice.

AIMS: Ferroptosis is a form of iron-regulated cell death implicated in ischemic heart disease. Our previous study revealed that Sirtuin 3 (SIRT3) is associated with ferroptosis and cardiac fibrosis. In this study, we tested whether the knockout of SIRT3 in cardiomyocytes (SIRT3cKO) promotes mitochondrial ferroptosis and whether the blockade of ferroptosis would ameliorate mitochondrial dysfunction. METHODS AND RESULTS: Mitochondrial and cytosolic fractions were isolated from the ventricles of mice. Cytosolic and mitochondrial ferroptosis were analyzed by comparison to SIRT3loxp mice. An echocardiography study showed that SIRT3cKO mice developed heart failure as evidenced by a reduction of EF% and FS% compared to SIRT3loxp mice. Comparison of mitochondrial and cytosolic fractions of SIRT3cKO and SIRT3loxp mice revealed that, upon loss of SIRT3, mitochondrial, but not cytosolic, total lysine acetylation was significantly increased. Similarly, acetylated p53 was significantly upregulated only in the mitochondria. These data demonstrate that SIRT3 is the primary mitochondrial deacetylase. Most importantly, loss of SIRT3 resulted in significant reductions of frataxin, aconitase, and glutathione peroxidase 4 (GPX4) in the mitochondria. This was accompanied by a significant increase in levels of mitochondrial 4-hydroxynonenal. Treatment of SIRT3cKO mice with the ferroptosis inhibitor ferrostatin-1 (Fer-1) for 14 days significantly improved preexisting heart failure. Mechanistically, Fer-1 treatment significantly increased GPX4 and aconitase expression/activity, increased mitochondrial iron­sulfur clusters, and improved mitochondrial membrane potential and Complex IV activity. CONCLUSIONS: Inhibition of ferroptosis ameliorated cardiac dysfunction by specifically targeting mitochondrial aconitase and iron­sulfur clusters. Blockade of mitochondrial ferroptosis may be a novel therapeutic target for mitochondrial cardiomyopathies.

Balanced Solution versus Normal Saline in Predicted Severe Acute Pancreatitis: A Stepped Wedge Cluster Randomized Trial.

OBJECTIVE: To compare the effect of balanced multielectrolyte solutions(BMES) versus normal saline(NS) for intravenous fluid on chloride levels and clinical outcomes.in patients with predicted severe acute pancreatitis (pSAP). SUMMARY BACKGROUND DATA: Isotonic crystalloids are recommended for initial fluid therapy in acute pancreatitis, but whether the use of BMES in preference to NS confers clinical benefits is unknown. METHODS: In this multicenter, stepped-wedge, cluster-randomized trial, we enrolled patients with pSAP (APACHE II score ≥8 and C-reactive protein >150 mg/L) admitted within 72 hours of the advent of symptoms. The study sites were randomly assigned to staggered start dates for one-way crossover from the NS phase (NS for intravenous fluid) to the BMES phase(Sterofudin for intravenous fluid). The primary endpoint was the serum chloride concentration on trial day3. Secondary endpoints included a composite of clinical and laboratory measures. RESULTS: Overall, 259 patients were enrolled from eleven sites to receive NS(n=147) or BMES(n=112). On trial day3, the mean chloride level was significantly lower in patients who received BMES(101.8 mmol/L(SD4.8) versus 105.8 mmol/L(SD5.9), difference -4.3 mmol/L [95%CI -5.6 to -3.0 mmol/L];P<0.001). For secondary endpoints, patients who received BMES had less systemic inflammatory response syndrome(19/112,17.0% versus 43/147,29.3%, P=0.024) and increased organ failure-free days (3.9 d(SD2.7) versus 3.5days(SD2.7), P<0.001) by trial day7. They also spent more time alive and out of ICU(26.4 d(SD5.2) versus 25.0days(SD6.4), P=0.009) and hospital(19.8 d(SD6.1) versus16.3days(SD7.2), P<0.001) by trial day30. CONCLUSIONS: Among patients with pSAP, using BMES in preference to NS resulted in a significantly more physiological serum chloride level, which was associated with multiple clinical benefits(Trial registration number: ChiCTR2100044432).

Superconductivity in Ca-intercalated bilayer graphene: C2CaC2.

The deposition and intercalation of metal atoms can induce superconductivity in monolayer and bilayer graphenes. For example, it has been experimentally proved that Li-deposited graphene is a superconductor with critical temperature Tc of 5.9 K, Ca-intercalated bilayer graphene C6CaC6 and K-intercalated epitaxial bilayer graphene C8KC8 are superconductors with Tc of 2-4 K and 3.6 K, respectively. However, the Tc of them are relatively low. To obtain higher Tc in graphene-based superconductors, here we predict a new Ca-intercalated bilayer graphene C2CaC2, which shows higher Ca concentration than the C6CaC6. It is proved to be thermodynamically and dynamically stable. The electronic structure, electron-phonon coupling (EPC) and superconductivity of C2CaC2 are investigated based on first-principles calculations. The EPC of C2CaC2 mainly comes from the coupling between the electrons of C-pz orbital and the high- and low-frequency vibration modes of C atoms. The calculated EPC constant λ of C2CaC2 is 0.75, and the superconducting Tc is 18.9 K, which is much higher than other metal-intercalated bilayer graphenes. By further applying -4% biaxial compressive strain to C2CaC2, the Tc can be boosted to 26.6 K. Thus, the predicted C2CaC2 provides a new platform for realizing superconductivity with the highest Tc in bilayer graphenes.

TrialView: An AI-powered Visual Analytics System for Temporal Event Data in Clinical Trials.

Randomized controlled trials (RCT) are the gold standards for evaluating the efficacy and safety of therapeutic interventions in human subjects. In addition to the pre-specified endpoints, trial participants' experience reveals the time course of the intervention. Few analytical tools exist to summarize and visualize the individual experience of trial participants. Visual analytics allows integrative examination of temporal event patterns of patient experience, thus generating insights for better care decisions. Towards this end, we introduce TrialView, an information system that combines graph artificial intelligence (AI) and visual analytics to enhance the dissemination of trial data. TrialView offers four distinct yet interconnected views: Individual, Cohort, Progression, and Statistics, enabling an interactive exploration of individual and group-level data. The TrialView system is a general-purpose analytical tool for a broad class of clinical trials. The system is powered by graph AI, knowledge-guided clustering, explanatory modeling, and graph-based agglomeration algorithms. We demonstrate the system's effectiveness in analyzing temporal event data through a case study.

Screening performance of COPD-PS scale, COPD-SQ scale, peak expiratory flow, and their combinations for chronic obstructive pulmonary disease in the primary healthcare in Haicang District, Xiamen City.

Objectives: This study aimed to evaluate the screening performance of COPD-PS questionnaire, COPD-SQ questionnaire, peak expiratory flow (PEF), COPD-PS questionnaire combined with PEF, and COPD-SQ questionnaire combined with PEF for chronic obstructive pulmonary disease (COPD). Methods: This was a cross-sectional study. We distributed self-designed surveys and COPD screening scales (COPD-PS questionnaire and COPD-SQ questionnaire) to residents who underwent physical examination in five community health centers in Haicang District, Xiamen City, from February 2023 to May 2023, and measured their lung function and PEF with a portable device. We used logistic regression to obtain the coefficients of COPD-PS questionnaire, COPD-SQ questionnaire, and PEF, and plotted the receiver operating characteristic curves of each tool for diagnosing COPD and moderate-to-severe COPD. We evaluated and compared the optimal cut-off points and scores of sensitivity, specificity, Youden index, and area under the curve (AUC) values, and assessed the screening efficiency of different methods. Results: Of the 3,537 residents who completed the COPD-SQ questionnaire, COPD-PS questionnaire, and spirometry, 840 were diagnosed with COPD. We obtained the coefficients of COPD-PS questionnaire combined with peak expiratory flow (PEF), and COPD-SQ questionnaire combined with PEF, by logistic regression as -0.479-0.358 × PEF +0.321 × COPD-PS score and - 1.286-0.315 × PEF +0.125 × COPD-SQ score, respectively. The sensitivity of diagnosing COPD by COPD-SQ questionnaire, COPD-PS questionnaire, PEF, COPD-PS questionnaire combined with PEF, and COPD-SQ questionnaire combined with PEF were 0.439, 0.586, 0.519, 0.586, 0.612 respectively, and the specificity were 0.725, 0.621, 0.688, 0.689, 0.663 respectively, with ROC values of 0.606 (95%CI: 0.586-0.626), 0.640 (0.619-0.661), 0.641 (0.619-0.663), 0.678 (0.657-0.699), 0.685 (0.664-0.706) respectively. The sensitivity of diagnosing GOLD II and above by COPD-SQ questionnaire, COPD-PS questionnaire, PEF, COPD-PS questionnaire combined with PEF, and COPD-SQ questionnaire combined with PEF were 0.489, 0.620, 0.665, 0.630, 0.781 respectively, and the specificity were 0.714, 0.603, 0.700, 0.811, 0.629 respectively, with ROC values of 0.631 (95%CI: 0.606-0.655), 0.653 (0.626-0.679), 0.753 (0.730-0.777), 0.784 (0.762-0.806), 0.766 (0.744-0.789) respectively. Conclusion: Our study found that the accuracy of COPD screening by COPD-SQ questionnaire and COPD-PS questionnaire can be improved by combining the results of PEF. The screening performance of COPD-SQ questionnaire combined with PEF is relatively better. In future research, further studies are needed to optimize the performance of screening tools and understand whether their use will affect clinical outcomes.

Endothelial specific prolyl hydroxylase domain-containing protein 2 deficiency attenuates aging-related obesity and exercise intolerance.

Obesity and exercise intolerance greatly reduce the life quality of older people. Prolyl hydroxylase domain-containing protein 2 (PHD2) is an important enzyme in modulating hypoxia-inducible factor-alpha (HIF) protein. Using vascular endothelial cell-specific PHD2 gene knockout (PHD2 ECKO) mice, we investigated the role of endothelial PHD2 in aging-related obesity and exercise capacity. Briefly, PHD2 ECKO mice were obtained by crossing PHD2-floxed mice with VE-Cadherin (Cdh5)-Cre transgenic mice. The effect of PHD2 ECKO on obesity and exercise capacity in PHD2 ECKO mice and control PHD2f/f mice were determined in young mice (6 to 7 months) and aged mice (16-18 months). We found that aged PHD2 ECKO mice, but not young mice, exhibited a lean phenotype, characterized by lower fat mass, and its ratio to lean weight, body weight, or tibial length, while their food uptake was not reduced compared with controls. Moreover, as compared with aged control mice, aged PHD2 ECKO mice exhibited increased oxygen consumption at rest and during exercise, and the maximum rate of oxygen consumption (VO2 max) during exercise. Furthermore, as compared with corresponding control mice, both young and aged PHD2 ECKO mice demonstrated improved glucose tolerance and lower insulin resistance. Together, these data demonstrate that inhibition of vascular endothelial PHD2 signaling significantly attenuates aging-related obesity, exercise intolerance, and glucose intolerance.

N-nitrosamines in electroplating and printing/dyeing industrial wastewater treatment plants: Removal efficiency, environmental emission, and the influence on drinking water.

The discharge of industrial wastewater containing high concentrations of N-nitrosamines to the aquatic environment can impair downstream source waters and pose potential risks to human health. However, the transport and fate of N-nitrosamines in typical industrial wastewater treatment plants (IWWTPs) and the influence of these effluents on source water and drinking water are still unclear. This study investigated nine N-nitrosamines in four full-scale electroplating (E-) and printing/dyeing (PD-) IWWTPs, two drinking water treatment plants (DWTPs) in the lower reaches of these IWWTPs, and the corresponding tap water in South China. The total concentrations of N-nitrosamines (∑NAs) were 382-10,600, 480-1920, 494-789, and 27.9-427 ng/L in influents, effluents, source water, and tap water, respectively. The compositions of N-nitrosamine species in different influents varied a lot, while N-nitrosodi-n-butylamine (NDBA) and N-nitrosodimethylamine (NDMA) dominated in most of the effluents, source water, and tap water. More than 70 % N-nitrosamines were removed by wastewater treatment processes used in E-IWWTPs such as ferric-carbon micro-electrolysis (Fe/C-ME), while only about 50 % of N-nitrosamines were removed in PD-IWWTPs due to the use of chlorine reagent or other inefficient conventional processes such as flocculation by cationic amine-based polymers or bio-contact oxidation. Therefore, the mass fluxes of N-nitrosamines discharged from these industrial wastewaters to the environment in the selected two industrial towns were up to 14,700 mg/day. The results based on correlation and principal component analysis significantly demonstrated correlations between E-and PD-effluents and source water and tap water, suggesting that these effluents can serve as sources of N-nitrosamines to local drinking water systems. This study suggests that N-nitrosamines are prevalent in typical IWWTPs, which may infect drinking water systems. The findings of this study provide a basis data for the scientific evaluation of environmental processes of N-nitrosamines.

Analysing N-nitrosamine occurrence and sources in karst reservoirs, Southwest China.

N-nitrosamines in reservoir water have drawn significant attention because of their carcinogenic properties. Karst reservoirs containing dissolved organic matter (DOM) are important drinking water sources and are susceptible to contamination because of the fast flow of various contaminants. However, it remains unclear whether N-nitrosamines and their precursor, DOM, spread in karst reservoirs. Therefore, this study quantitatively investigated the occurrence and sources of N-nitrosamines based on DOM properties in three typical karst reservoirs and their corresponding tap water. The results showed that N-nitrosamines were widely spread, with detection frequencies > 85%. Similar dominant compounds, including N-nitrosodimethylamine, N-nitrosomethylethylamine, N-nitrosopyrrolidine, and N-nitrosodibutylamine, were observed in reservoirs and tap water, with average concentrations of 4.7-8.9 and 2.8-6.7 ng/L, respectively. The average carcinogenic risks caused by these N-nitrosamines were higher than the risk level of 10-6. Three-dimensional fluorescence excitation-emission matrix modeling revealed that DOM was composed of humus-like component 1 (C1) and protein-like component 2 (C2). Fluorescence indicators showed that DOM in reservoir water was mainly affected by exogenous pollution and algal growth, whereas in tap water, DOM was mainly affected by microbial growth with strong autopoietic properties. In the reservoir water, N-nitrosodiethylamine and N-nitrosopiperidine were significantly correlated with C2 and biological indicators, indicating their endogenously generated sources. Based on the principal component analysis and multiple linear regression methods, five sources of N-nitrosamines were identified: agricultural pollution, microbial sources, humus sources, degradation processes, and other factors, accounting for 46.8%, 36.1%, 7.82%, 8.26%, and 0.96%, respectively. For tap water, two sources, biological reaction processes, and water distribution systems, were identified, accounting for 75.7% and 24.3%, respectively. Overall, this study presents quantitative information on N-nitrosamines' sources based on DOM properties in typical karst reservoirs and tap water, providing a basis for the safety of drinking water for consumers.

Risk factors of post-operative diarrhoea in patients with pancreatic cancer after neoadjuvant chemotherapy: A retrospective cohort study.

BACKGROUND: Post-operative diarrhoea is a common adverse event after pancreatic surgery. While the risk factors for this condition have been identified, the increasing trend of administering chemotherapy before surgery might change these factors. This study aimed to identify the risk factors of post-operative diarrhoea in patients with pancreatic ductal adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. DESIGN: A retrospective cohort study. METHODS: Patients who underwent neoadjuvant chemotherapy and pancreatectomy because of PDAC between 2021 and 2023 were included. The preoperative characteristics of, operative details of and post-operative outcomes in patients with and without post-operative diarrhoea were collected and compared. The independent risk factors of post-operative diarrhoea were identified using logistic regression analysis. STROBE checklist was used. RESULTS: Post-operative diarrhoea occurred in 65 out of 145 (44.8%) patients during hospitalization. Elevated white blood cell count, advanced tumour stage, and late abdominal drain removal were independent risk factors for post-operative diarrhoea (p < .001, p = .006 and p = .009, respectively). CONCLUSIONS: Some perioperative factors influence post-operative diarrhoea in patients who undergo neoadjuvant chemotherapy. More attention should be paid to patients at a higher risk of post-operative diarrhoea, with an emphasis on high-quality management for these patients.

Occurrence and fate of N-nitrosamines in full-scale domestic wastewater treatment plants and their impact on receiving waters along the Lijiang River, China.

Domestic wastewaters contaminated with N-nitrosamines pose a significant threat to river ecosystems worldwide, particularly in urban areas with riparian cities. Despite widespread concern, the precise impact of these contaminants on receiving river waters remains uncertain. This study investigated eight N-nitrosamines in wastewater treatment plants (WWTPs) and their adjacent receiving river, the Lijiang River in Guilin City, Southwest China. By analyzing thirty wastewater samples from five full-scale WWTPs and twenty-three river water samples from Guilin, we quantified the mass loads of N-nitrosamines discharged into the surrounding watershed via domestic effluents. The results revealed that N-nitrosodimethylamine (10-60 ng/L), N-nitrosodiethylamine (3.4-22 ng/L), and N-nitrosopyrrolidine (not detected-4.5 ng/g) were predominant in influents, effluents, and sludge, respectively, with the overall removal efficiencies ranging from 17.7 to 65.6% during wastewater treatment. Cyclic activated sludge system and ultraviolet disinfection were effective in removing N-nitrosamines (rates of 59.6% and 24.3%), while chlorine dioxide disinfection promoted their formation. A total of 30.4 g/day of N-nitrosamine mass loads were observed in the Lijiang River water, with domestic effluents contributing about 31.3% (19.4 g/day), followed by livestock breeding wastewater (34.5%, 12.0 g/day), and unknown sources (24.7%, 7.5 g/day). These findings highlight the critical role of WWTPs in transporting N-nitrosamines to watersheds and emphasize the urgent need for further investigation into other potential sources of N-nitrosamine pollution within watersheds.

Identification of sedative-hypnotic compounds shared by five medicinal Polyporales mushrooms using UPLC-Q-TOF-MS/MS-based untargeted metabolomics.

BACKGROUND: Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active components for this application are not fully understood, restricting their universal recognition. PURPOSE: In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms. STUDY DESIGN AND METHODS: A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds. RESULTS: Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes [four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D)] were found to be the main sedative-hypnotic compounds shared by the five mushrooms. CONCLUSION: We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia.

p53 Acetylation Exerts Critical Roles in Pressure Overload-Induced Coronary Microvascular Dysfunction and Heart Failure in Mice.

BACKGROUND: Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure (HF) with preserved ejection fraction. At this point, there are no proven treatments for CMD. METHODS: We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98, K117, K161, and K162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KR could improve CMD and prevent the progression of hypertensive cardiac hypertrophy and HF. Wild-type and p534KR mice were subjected to pressure overload by transverse aortic constriction to induce cardiac hypertrophy and HF. RESULTS: Echocardiography measurements revealed improved cardiac function together with a reduction of apoptosis and fibrosis in p534KR mice. Importantly, myocardial capillary density and coronary flow reserve were significantly improved in p534KR mice. Moreover, p534KR upregulated the expression of cardiac glycolytic enzymes and Gluts (glucose transporters), as well as the level of fructose-2,6-biphosphate; increased PFK-1 (phosphofructokinase 1) activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α (hypoxia-inducible factor-1α) and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KR mice, as well as in p534KR mice after transverse aortic constriction. In vitro, p534KR significantly improved endothelial cell glycolytic function and mitochondrial respiration and enhanced endothelial cell proliferation and angiogenesis. Similarly, acetylation-deficient p534KR significantly improved coronary flow reserve and rescued cardiac dysfunction in SIRT3 (sirtuin 3) knockout mice. CONCLUSIONS: Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling and may provide a promising approach to improve hypertension-induced CMD and to prevent the transition of cardiac hypertrophy to HF.

DNA Methylation and Chromatin Accessibility Impact Subgenome Expression Dominance in the Common Carp (Cyprinus carpio).

DNA methylation and chromatin accessibility play important roles in gene expression, but their function in subgenome expression dominance remains largely unknown. We conducted comprehensive analyses of the transcriptome, DNA methylation, and chromatin accessibility in liver and muscle tissues of allotetraploid common carp, aiming to reveal the function of epigenetic modifications in subgenome expression dominance. A noteworthy overlap in differential expressed genes (DEGs) as well as their functions was observed across the two subgenomes. In the promoter and gene body, the DNA methylation level of the B subgenome was significantly different than that of the A subgenome. Nevertheless, differences in DNA methylation did not align with changes in homoeologous biased expression across liver and muscle tissues. Moreover, the B subgenome exhibited a higher prevalence of open chromatin regions and greater chromatin accessibility, in comparison to the A subgenome. The expression levels of genes located proximally to open chromatin regions were significantly higher than others. Genes with higher chromatin accessibility in the B subgenome exhibited significantly elevated expression levels compared to the A subgenome. Contrastingly, genes without accessibility exhibited similar expression levels in both subgenomes. This study contributes to understanding the regulation of subgenome expression dominance in allotetraploid common carp.

DDAH1 recruits peroxiredoxin 1 and sulfiredoxin 1 to preserve its activity and regulate intracellular redox homeostasis.

Growing evidence suggests that dimethylarginine dimethylaminohydrolase 1 (DDAH1), a crucial enzyme for the degradation of asymmetric dimethylarginine (ADMA), is closely related to oxidative stress during the development of multiple diseases. However, the underlying mechanism by which DDAH1 regulates the intracellular redox state remains unclear. In the present study, DDAH1 was shown to interact with peroxiredoxin 1 (PRDX1) and sulfiredoxin 1 (SRXN1), and these interactions could be enhanced by oxidative stress. In HepG2 cells, H2O2-induced downregulation of DDAH1 and accumulation of ADMA were attenuated by overexpression of PRDX1 or SRXN1 but exacerbated by knockdown of PRDX1 or SRXN1. On the other hand, DDAH1 also maintained the expression of PRDX1 and SRXN1 in H2O2-treated cells. Furthermore, global knockout of Ddah1 (Ddah1-/-) or liver-specific knockout of Ddah1 (Ddah1HKO) exacerbated, while overexpression of DDAH1 alleviated liver dysfunction, hepatic oxidative stress and downregulation of PRDX1 and SRXN1 in CCl4-treated mice. Overexpression of liver PRDX1 improved liver function, attenuated hepatic oxidative stress and DDAH1 downregulation, and diminished the differences between wild type and Ddah1-/- mice after CCl4 treatment. Collectively, our results suggest that the regulatory effect of DDAH1 on cellular redox homeostasis under stress conditions is due, at least in part, to the interaction with PRDX1 and SRXN1.

Evaluation of the psychometrics of the Social Impact Scale and its association with depression among asymptomatic COVID-19 carriers.

BACKGROUND: COVID-19 carriers experience psychological stresses and mental health issues such as varying degrees of stigma. The Social Impact Scale (SIS) can be used to measure the stigmatisation of COVID-19 carriers who experience such problems. AIMS: To evaluate the reliability and validity of the Chinese version of the SIS, and the association between stigma and depression among asymptomatic COVID-19 carriers in Shanghai, China. METHOD: A total of 1283 asymptomatic COVID-19 carriers from Shanghai Ruijin Jiahe Fangcang Shelter Hospital were recruited, with a mean age of 39.64 ± 11.14 years (59.6% male). Participants completed questionnaires, including baseline information and psychological measurements, the SIS and Self-Rating Depression Scale. The psychometrics of the SIS and its association with depression were examined through exploratory factor analysis, confirmatory factor analysis and receiver operating characteristic analysis. RESULTS: The average participant SIS score was 42.66 ± 14.61 (range: 24-96) years. Analyses suggested the model had four factors: social rejection, financial insecurity, internalised shame and social isolation. The model fit statistics of the four-factor SIS were 0.913 for the comparative fit index, 0.902 for the Tucker-Lewis index and 0.088 for root-mean-square error of approximation. Standard estimated factor loadings ranged from 0.509 to 0.836. After controlling for demographic characteristics, the total score of the 23-item SIS predicted depression (odds ratio: 1.087, 95% CI 1.061-1.115; area under the curve: 0.84, 95% CI 0.788-0.892). CONCLUSIONS: The Chinese version of the SIS showed good psychometric properties and can be used to assess the level of perceived stigma experienced by asymptomatic COVID-19 carriers.

The Role of IL-6, IL-10, and TNF-α in Ocular GVHD Following Allogeneic Transplantation.

PURPOSE: To figure out the roles of tear inflammatory cytokines in Ocular graft-versus-host disease (oGVHD) symptoms by analyzing tear cytokine levels and related factors. METHODS: This prospective study involved 27 post-HSCT patients and 19 controls with dry eye disease. Analyses included tear cytokine (IL-6, IL-10, and TNF-α), ocular surface evaluation, and conjunctival impression cell examination. Tear cytokine levels were evaluated in three grades of corneal epithelial lesions. The study also analyzed the correlation between tear cytokine levels and ocular surface parameters. Tear cytokine levels were then used in a Receiver Operating Characteristic (ROC) curve and linear regression model to predict oGVHD related factors. RESULTS: IL-6 has good diagnostic efficacy in oGVHD related dry eye. Elevated levels of tear IL-6 and TNF-α were observed in the group with severe corneal epithelial lesions. IL-6 levels were positively correlated with corneal fluorescein staining (CFS), eyelid margin hyperemia, conjunctival lesions, and meibum secretion. IL-6 showed excellent predictive ability with Area Under the Curve (AUC) values all greater than 0.70 (p < 0.05). IL-10 and TNF-α were negatively correlated with the meibomian gland proportion and conjunctival goblet cell (GC) density, while TNF-α was positively correlated with CFS and eyelid margin hyperemia. CONCLUSION: Dry eye symptoms related to ocular GVHD, can be partly diagnosed and assessed using various tear cytokine level detection methods.

Intrathecal injections of angiotensin IV and oxytocin conjugates induce antihyperalgesia and antiallodynia in both sexes of rats.

Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.

Impact of agricultural activities on the occurrence of N-nitrosamines in an aquatic environment.

N-Nitrosamines, nitroso compounds with strong carcinogenic effects on humans, have been frequently detected in natural waters. In agricultural areas, there is typically a lack of drinking water treatment processes and distribution systems. As a result, residents often consume groundwater as drinking water which may contain N-nitrosamines, necessitating the investigation of the occurrence, sources, and carcinogenic risk of N-nitrosamines within the groundwater of agricultural areas. This study identified eight N-nitrosamines in groundwater and river water in the Jianghan Plain, a famous agricultural region in central China. N-Nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosomorpholine (NMOR), N-nitrosopyrrolidine (NPYR), and N-nitrosodi-n-butylamine (NDBA) were detected in groundwater, with NDMA being the main compound detected (up to 52 ng L-1). Comparable concentrations of these N-nitrosamines were also found in river water. From laboratory experiments, we found a tremendous potential for the formation of N-nitrosamines in groundwater. Principal component analysis and multiple linear regression analysis results showed that the primary sources of N-nitrosamines in groundwater were the uses of nitrogen fertilizers and pesticides carrying specific N-nitrosamines such as NPYR. The average total carcinogenic risk values of detected N-nitrosamines were higher than the acceptable risk level (10-5), suggesting a potential carcinogenic risk of groundwater. Further research is urgently needed to minimize N-nitrosamine levels in the groundwater of agricultural areas, particularly in those where pesticides and fertilizers are heavily used.

EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in non-small cell lung cancer.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.