Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy.

Distinct metabolic programs, either energy-consuming anabolism or energy-generating catabolism, were required for different biological functions. Macrophages can adopt different immune phenotypes in response to various cues and exhibit anti- or pro-inflammatory properties relying on catabolic pathways associated with oxidative phosphorylation (OXPHOS) or glycolysis. Spermidine, a natural polyamine, has been reported to regulate inflammation through inducing anti-inflammatory (M2) macrophages. However, the underlying mechanisms remain elusive. We show here that the M2-polarization induced by spermidine is mediated by mitochondrial reactive oxygen species (mtROS). The levels of mitochondrial superoxide and H2O2 were markedly elevated by spermidine. Mechanistically, mtROS were found to activate AMP-activated protein kinase (AMPK), which in turn enhanced mitochondrial function. Furthermore, hypoxia-inducible factor-1α (Hif-1α) was upregulated by the AMPK activation and mtROS and was required for the expression of anti-inflammatory genes and induction of autophagy. Consistent with previous report that autophagy is required for the M2 polarization, we found that the M2 polarization induced by spermidine was also mediated by increased autophagy. The macrophages treated with spermidine in vitro were found to ameliorate Dextran Sulfate Sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. Thus, spermidine can elicit an anti-inflammatory program driven by mtROS-dependent AMPK activation, Hif-1α stabilization and autophagy induction in macrophages. Our studies revealed a critical role of mtROS in shaping macrophages into M2-like phenotype and provided novel information for management of inflammatory disease by spermidine

Genome-Wide Association Study of Lung Adenocarcinoma in East Asia and Comparison With a European Population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Effects of Astragaloside IV on the SDF-1/CXCR4 Expression in Atherosclerosis of apoE−/− Mice Induced by Hyperlipaemia

Astragaloside IV (AsIV) is the major effective component extracted from the Chinese herb Astragalus membranaceus, which has been widely used to treat cardiovascular disease. Recent studies have shown that AsIV can potentially protect the arteries from atherosclerosis; however the mechanisms underneath are unknown. The aim of this study was to investigate the effects of AsIV on blood lipids, CD40-CD40L signal system, and SDF-1/CXCR4 biological axis in high-fat diet apoE−/− mice and reveal the molecular mechanisms of AsIV against atherosclerosis. Here, we showed that AsIV alleviated the extent of atherosclerosis in aorta of apoE−/− mice. And AsIV can significantly downregulate PAC-1, CD40L, and CXCR4 expression on platelet surface in blood of high-fat diet apoE−/− mice. AsIV also can significantly downregulate mRNA and protein level of SDF-1 and CXCR4 in thoracic aorta. Consistent with aorta CXCR4 expression, CXCR4 in bone marrow-derived endothelial progenitor cell (EPC) was also reduced. Meanwhile biochemical analysis showed that AsIV could downregulate TG, TC, and LDL-C levels and upregulate HDL-C level in blood of high-fat diet apoE−/− mice. We concluded that the protective effects of AsIV in atherosclerosis injury may be related to regulating blood lipids, CD40-CD40L system, and SDF-1/CXCR4 biological axis. SDF-1/CXCR4 biological axis is probably one of the main targets of intervening atherosclerosis

Effect of aspirin on blood pressure in hypertensive patients: a systematic review and meta-analysis

Abstract Introduction Aspirin is widely used for secondary prevention in patients with hypertension. However, previous studies mainly focused on the preventive effects of aspirin, and there has been a lack of reliable evidence on whether taking aspirin affects blood pressure This study aimed to investigate whether aspirin would affect the blood pressure in patients with hypertension. Methods PubMed, Cochrane database, Embase, Scopus and Medline databases were searched until September 2023. For continuous variables (e.g., blood pressure reduction), the mean difference (MD) was selected as the effect magnitude indices. We used the Cochrane Collaboration’s Risk of Bias tool to assess the risk of bias. Result A total of five studies were included, comprising 20,312 patients. We found that aspirin did not affect SBP (MD = -0.78, 95% CI: − 2.41, 0.84). A similar result was found for DBP (MD = -0.86, 95% CI: − 2.14, 0.42). Conclusion This study showed no significant difference in blood pressure between the aspirin and control groups, suggesting that aspirin does not affect blood pressure

A Model of Multi-Finger Coordination in Keystroke Movement

In multi-finger coordinated keystroke actions by professional pianists, movements are precisely regulated by multiple motor neural centers, exhibiting a certain degree of coordination in finger motions. This coordination enhances the flexibility and efficiency of professional pianists’ keystrokes. Research on the coordination of keystrokes in professional pianists is of great significance for guiding the movements of piano beginners and the motion planning of exoskeleton robots, among other fields. Currently, research on the coordination of multi-finger piano keystroke actions is still in its infancy. Scholars primarily focus on phenomenological analysis and theoretical description, which lack accurate and practical modeling methods. Considering that the tendon of the ring finger is closely connected to adjacent fingers, resulting in limited flexibility in its movement, this study concentrates on coordinated keystrokes involving the middle and ring fingers. A motion measurement platform is constructed, and Leap Motion is used to collect data from 12 professional pianists. A universal model applicable to multiple individuals for multi-finger coordination in keystroke actions based on the backpropagation (BP) neural network is proposed, which is optimized using a genetic algorithm (GA) and a sparrow search algorithm (SSA). The angular rotation of the ring finger’s MCP joint is selected as the model output, while the individual difference information and the angular data of the middle finger’s MCP joint serve as inputs. The individual difference information used in this study includes ring finger length, middle finger length, and years of piano training. The results indicate that the proposed SSA-BP neural network-based model demonstrates superior predictive accuracy, with a root mean square error of 4.8328°. Based on this model, the keystroke motion of the ring finger’s MCP joint can be accurately predicted from the middle finger’s keystroke motion information, offering an evaluative method and scientific guidance for the training of multi-finger coordinated keystrokes in piano learners

Two-dimensional viscous numerical simulation of liquid sloshing in rectangular tank with/without baffles and comparison with potential flow solutions

A viscous fluid model based on non-inertial reference system is developed for the problem of liquid sloshing in rectangular tank with/without baffles. The accuracy of the numerical model is validated against available theoretical solutions, experimental data and numerical predictions by linear and nonlinear potential flow models and different Navier–Stokes solvers. The numerical examinations indicate that the dissipative effects have significant influence on the sloshing responses in both non-baffled and baffled tanks. The sloshing responses that are associated with the natural frequencies can be finally damped out due to the physical dissipations, while they are entirely retained in the potential solutions, which accounts for the general over-predictions of sloshing amplitudes by the potential flow theory. The sloshing in baffled tank involves more dissipation due to the stronger vortical flow. The resonant frequency and amplitude are highly dependent on the baffle width and position. The relative sloshing amplitudes around the resonant condition are found to decrease with the excitation amplitude in a power law. The necessity of using viscous fluid model for sloshing predictions is addressed. The extremely long numerical computations have to be carried out in order to obtain convincing stable solutions, especially for the weakly damped sloshing motion

miR-30a-5p promotes glomerular podocyte <?A3B2 tlsb=-0.06w?>apoptosis via DNMT1-mediated hypermethylation under hyperhomocysteinemia<?A3B2 tlsb?>

Abnormal elevation of homocysteine (Hcy) level is closely related to the development and progression of chronic kidney disease (CKD), with the molecular mech2anisms that are not fully elucidated. Given the demonstration that miR-30a-5p is specifically expressed in glomerular podocytes, in the present study we aimed to investigate the role and potential underlying mechanism of miR-30a-5p in glomerular podocyte apoptosis induced by Hcy. We found that elevated Hcy downregulates miR-30a-5p expression in the Cbs+/-- mice and Hcy-treated podocytes, and miR-30a-5p directly targets the 3′-untranslated region (3′-UTR) of the forkhead box A1 (FOXA1) and overexpression of miR-30a-5p inhibits FOXA1 expression. By nMS-PCR and MassARRAY quantitative methylation analysis, we showed the increased DNA methylation level of miR-30a-5p promoter both in vivo and in vitro. Meanwhile, dual-luciferase reporter assay showed that the region between --1400 and --921 bp of miR-30a-5p promoter is a possible regulatory element for its transcription. Mechanistic studies indicated that DNA methyltransferase enzyme 1 (DNMT1) is the key regulator of miR-30a-5p, which in turn enhances miR-30a-5p promoter methylation level and thereby inhibits its expression. Taken together, our results revealed that epigenetic modification of miR-30a-5p is involved in glomerular podocyte injury induced by Hcy, providing a diagnostic marker candidate and novel therapeutic target in CKD induced by Hcy

A combination weighting method for debris flow risk assessment based on t-distribution and linear programming optimization algorithm.

Debris flow risk assessment can provide some reference for debris flow prevention and control projects. In risk assessment, researchers often only focus on the impact of objective or subjective indicators. For this purpose, this paper proposed a weight calculation method based on t-distribution and linear programming optimization algorithm (LPOA). Taking 72 mudslides in Beichuan County as an example, this paper used analytic hierarchy process (AHP), entropy weight method (EWM) and variation coefficient method (VCM) to obtain the initial weights. Based on the initial weights, weight intervals with different confidence levels were obtained by t-distribution. Subsequently, the final weights were obtained by LOPA in the 90% confidence interval. Finally, the final weights were used to calculate the risk score for each debris flow, thus delineating the level of risk for each debris flow. The results showed that this paper's method can avoid overemphasizing the importance of a particular indicator compared to EWM and VCM. In contrast, EWM and VCM ignored the effect of debris flow frequency on debris flow risk. The assessment results showed that the 72 debris flows in Beichuan County were mainly dominated by moderate and light risks. Of these, there were 8 high risk debris flows, 24 medium risk debris flows, and 40 light risk debris flows. The excellent triggering conditions provide favorable conditions for the formation of high-risk debris flows. Slightly and moderate risk debris flows are mainly located on both sides of highways and rivers, still posing a minor threat to Beichuan County. The proposed fusion weighting method effectively avoids the limitations of single weight calculating method. Through comparison and data analysis, the rationality of the proposed method is verified, which can provide some reference for combination weighting method and debris flow risk assessment