Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains unclear.Our study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)analyses.Methods:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES 2017-2018.Subsequently,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and NAFLD.The primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and NAFLD.Sensitivity analyses were adopted to confirm the robustness of the results.Results:A total of 3144 participants were enrolled for our observational study in NHANES.Weighted multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with NAFLD.Moreover,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and NAFLD.Similar results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and NAFLD.The sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

Causal Relationship Between Gut Microbiota and Liver Cirrhosis:16S rRNA Sequencing and Mendelian Randomization Analyses

Background and Aims:Accumulating evidence highlights the association between the gut microbiota and liver cirrhosis.However,the role of the gut microbiota in liver cirrhosis remains unclear.Methods:We first assessed the differences in the composition of the bacterial community between CCl4-induced liver cirrhosis and control mice using 16S rRNA sequencing.We then performed a two-sample Mendelian randomization(MR)analysis to reveal the underlying causal relationship between the gut microbiota and liver cirrhosis.Causal relationships were analyzed using primary inverse variance weighting(IVW)and other supplemental MR methods.Furthermore,fecal samples from liver cirrhosis patients and healthy controls were collected to validate the results of the MR analysis.Results:Analysis of 16S rRNA sequencing indicated significant differences in gut microbiota composition between the cirrhosis and control groups.IVW analyses suggested that Alphaproteobacteria,Bacillales,NB1n,Rhodospirillales,Dorea,Lachnospiraceae,and Rhodospirillaceae were positively correlated with the risk of liver cirrhosis,whereas Butyricicoccus,Hungatella,Marvinbryantia,and Lactobacillaceae displayed the opposite effects.However,the weighted median and MR-PRESSO estimates further showed that only Butyricicoccus and Marvinbryantia presented stable negative associations with liver cirrhosis.No significant heterogeneity or horizontal pleiotropy was observed in the sensitivity analysis.Furthermore,the result of 16S rRNA sequencing also showed that healthy controls had a higher relative abundance of Butyricicoccus and Marvinbryantia than liver cirrhosis patients.Conclusions:Our study provides new causal evidence for the link between gut microbiota and liver cirrhosis,which may contribute to the discovery of novel strategies to prevent liver cirrhosis.

Insights into thermodynamic performance of a hypersonic precooled air-breathing engine with a complicated multi-branch closed cycle

An advanced precooled airbreathing engine with a closed Brayton cycle is a promising solution for high-speed propulsion,of which the Synergetic Air Breathing Rocket Engine(SABRE)is a representative configuration.The performance of the latest SABRE-4 cycle was analyzed in this paper.Firstly,a relatively complete engine performance model that considers the characteristics of turbomachinery and heat exchangers was developed.Then,Sobol’global sensitivity analysis of key performance parameters was carried out to identify the most influential design variables.Optimal specific impulses under different target specific thrusts were obtained by particle swarm optimization,of which the thermodynamic parameters corresponding to a specific thrust of 1.12 kN·s·kg^(-1)and a specific impulse of 3163 s were chosen as the design values.Four different control laws were analyzed in contrast,and the charge control method had the strongest ability of thrust regulation as well as maintaining a favorable specific impulse performance.Finally,working characteristics under the charge control and over a typical flight envelope were calculated,in which the average value of the maximum specific impulse was as high as 5315 s.This study would help to deepen the understanding of SABRE-4 thermodynamic characteristics and other precooled airbreathing engine cycles with similar layouts.

Mitochondrial dysfunction: A promising therapeutic target for liver diseases

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy,which is mainly produced by the mitochondria.Liver tissues of pa-tients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mito-chondrial lesions,mitochondrial DNA damage,disturbed mitochondrial dynamics,and compromised ATP production.Overproduction of mitochondrial reactive oxygen species in-duces oxidative damage to mitochondrial proteins and mitochondrial DNA,decreases mito-chondrial membrane potential,triggers hepatocyte inflammation,and promotes programmed cell death,all of which impair liver function.Mitochondrial DNA may be a poten-tial novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B virus.We herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases,such as hepatocellular carcinoma,viral hepatitis,drug-induced liver injury,alcoholic liver disease,and non-alcoholic fatty liver disease.This review also discusses mito-chondrion-centric therapies for treating liver diseases.

Uncertainty analysis of measured geometric variations in turbine blades and impact on aerodynamic performance

Inevitable geometric variations significantly affect the performance of turbines or even that of entire engines;thus,it is necessary to determine their actual characteristics and accurately estimate their impact on performance.In this study,based on 1781 measured profiles of a typical turbine blade,the statistical characteristics of the geometric variations and the uncertainty impact are analyzed,and some commonly used uncertainty modelling methods based on Principal-Component Analysis(PCA)are verified.The geometric variations are found to be evident,asymmetric,and non-uniform,and the non-normality of the random distributions is non-negligible.The performance is notably affected,which is manifested as an overall offset,a notable scattering,and significant deterioration in several extreme cases.Additionally,it is demonstrated that the PCA reconstruction model is effective in characterizing major uncertainty characteristics of the geometric variations and their impact on the performance with almost the first 10 PCA modes.Based on a reasonable profile error and mean geometric deviation,the Gaussian assumption and stochasticprocess-based model are also found to be effective in predicting the mean values and standard deviations of the performance variations.However,they fail to predict the probability of some extreme cases with high loss.Finally,a Chi-square-based correction model is proposed to compensate for this deficiency.The present work can provide a useful reference for uncertainty analysis of the impact of geometric variations,and the corresponding uncertainty design of turbine blades.

IGF2-NR4A2 Signaling Regulates Macrophage Subtypes to Attenuate Liver Cirrhosis

Background and Aims:Liver cirrhosis can lead to liver failure and eventually death.Macrophages are the main contributors to cirrhosis and have a bidirectional role in regulating matrix deposition and degradation.Macrophage-based cell therapy has been developed as an alternative to liver transplantation.However,there is insufficient evidence regarding its safety and efficacy.In this study,we aimed to explore the effect of combining insulin-like growth factor 2(IGF2)with bone marrow-derived macrophages(BMDMs)to treat mice with liver cirrhosis.Methods:We assessed liver inflammation,fibrosis regression,liver function,and liver regeneration in mice with CCl4-induced cirrhosis and treated with BMDM only or IGF2+BMDM.We performed in vitro experiments in which activated hepatic stellate cells(HSCs)were co-cultured with macrophages in the presence or absence of IGF2.The polarity of macrophages and the degree of inhibition of HSCs were examined.The effect of IGF2 on macrophages was also verified by the overexpression of IGF2.Results:Combining IGF2 with BMDM reduced liver inflammation and fibrosis and increased hepatocyte proliferation.Combining IGF2 with BMDM was more effective than using BMDM alone.In vitro experiments demonstrated that IGF2 inhibited HSCs activation by upregulating NR4A2 to promote the anti-inflammatory macrophages phenotype.IGF2 also increased the synthesis of matrix metalloproteinases(MMPs)by macrophages,which may explain why administering IGF2 combined with BMDM was more effective than administering BMDM only.Conclusions:Our study provides a theoretical basis for the future use of BMDM-based cell therapy to treat liver cirrhosis.