Candidate pathway analysis of surfactant proteins identifies CTSH and SFTA2 that influences lung cancer risk.

Pulmonary surfactant is a lipoprotein synthesized and secreted by alveolar type II cells in lung. We evaluated the associations between 200,139 single nucleotide polymorphisms (SNPs) of 40 surfactant-related genes and lung cancer risk using genotyped data from two independent lung cancer genome-wide association studies. Discovery data included 18,082 cases and 13,780 controls of European ancestry. Replication data included 1,914 cases and 3,065 controls of European descent. Using multivariate logistic regression, we found novel SNPs in surfactant-related genes CTSH [rs34577742 C > T, odds ratio (OR) = 0.90, 95% confidence interval (CI) = 0.89-0.93, P = 7.64 × 10-9] and SFTA2 (rs3095153 G > A, OR = 1.16, 95% CI = 1.10-1.21, P = 1.27 × 10-9) associated with overall lung cancer in the discovery data and validated in an independent replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.80-0.96, P = 5.76 × 10-3) and SFTA2 (rs3095153 G > A, OR = 1.14, 95% CI = 1.01-1.28, P = 3.25 × 10-2). Among ever smokers, we found SNPs in CTSH (rs34577742 C > T, OR = 0.89, 95% CI = 0.85-0.92, P = 1.94 × 10-7) and SFTA2 (rs3095152 G > A, OR = 1.20, 95% CI = 1.14-1.27, P = 4.25 × 10-11) associated with overall lung cancer in the discovery data and validated in the replication data-CTSH (rs34577742 C > T, OR = 0.88, 95% CI = 0.79-0.97, P = 1.64 × 10-2) and SFTA2 (rs3095152 G > A, OR = 1.15, 95% CI = 1.01-1.30, P = 3.81 × 10-2). Subsequent transcriptome-wide association study using expression weights from a lung expression quantitative trait loci study revealed genes most strongly associated with lung cancer are CTSH (PTWAS = 2.44 × 10-4) and SFTA2 (PTWAS = 2.32 × 10-6).

TRAF2 decrease promotes the TGF-ß-mTORC1 signal in MAFLD-HCC through enhancing AXIN1-mediated Smad7 degradation.

According to recent research, metabolic-associated fatty liver disease (MAFLD) has emerged as an important underlying etiology of hepatocellular carcinoma (HCC). However, the molecular mechanism of MAFLD-HCC is still unclear. Tumor necrosis factor receptor-associated factor 2 (TRAF2) is the key molecule to mediate the signal of inflammatory NF-κB pathway. This study aims to investigate the potential dysregulation of TRAF2 and its biological function in MAFLD-HCC. Huh7 TRAF2-/- demonstrated increased tumor formation ability compared to huh7 TRAF2+/+ when stimulated with transforming growth factor-ß (TGF-ß). The decisive role of TGF-ß in the development of MAFLD-HCC was confirmed through the specific depletion of TGF-ß receptor II gene in the hepatocytes (Tgfbr2ΔHep) of mice. In TRAF2-/- cells treated with TGF-ß, both the glycolysis rate and lipid synthesis were enhanced. We proved the signal of the mechanistic target of rapamycin complex 1 (mTORC1) could be activated in the presence of TGF-ß, and was enhanced in TRAF2-/- cells. The coimmunoprecipitation (co-IP) experiments revealed that TRAF2 fortified the Smurf2-mediated ubiquitination degradation of AXIN1. Hence, TRAF2 depletion resulted in increased Smad7 degradation induced by AXIN1, thus promoting the TGF-ß signal. We also discovered that PLX-4720 could bind with AXIN1 and restrained the tumor proliferation of TRAF2-/- in mice fed with high-fat diet (HFD). Our findings indicate that TRAF2 plays a significant role in the pathogenesis of MAFLD-HCC. The reduction of TRAF2 expression leads to the enhancement of the TGF-ß-mTORC1 pathway by facilitating AXIN1-mediated Smad7 degradation.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Genome-wide chromatin contacts of super-enhancer-associated lncRNA identify LINC01013 as a regulator of fibrosis in the aortic valve.

Calcific aortic valve disease (CAVD) is characterized by a fibrocalcific process. The regulatory mechanisms that drive the fibrotic response in the aortic valve (AV) are poorly understood. Long noncoding RNAs derived from super-enhancers (lncRNA-SE) control gene expression and cell fate. Herein, multidimensional profiling including chromatin immunoprecipitation and sequencing, transposase-accessible chromatin sequencing, genome-wide 3D chromatin contacts of enhancer-promoter identified LINC01013 as an overexpressed lncRNA-SE during CAVD. LINC01013 is within a loop anchor, which has contact with the promoter of CCN2 (CTGF) located at ~180 kb upstream. Investigation showed that LINC01013 acts as a decoy factor for the negative transcription elongation factor E (NELF-E), whereby it controls the expression of CCN2. LINC01013-CCN2 is part of a transforming growth factor beta 1 (TGFB1) network and exerts a control over fibrogenesis. These findings illustrate a novel mechanism whereby a dysregulated lncRNA-SE controls, through a looping process, the expression of CCN2 and fibrogenesis of the AV.

A Test to Comprehensively Capture the Known Genetic Component of Familial Pulmonary Fibrosis.

The recent European Respiratory Society statement on familial pulmonary fibrosis supports the need for genetic testing in the care of patients and their relatives. However, no solution (i.e., a concrete test) was provided to implement genetic testing in daily practice. Herein, we tabulated and standardized the nomenclature of 128 genetic variants in 20 genes implicated in adult-onset pulmonary fibrosis. The objective was to develop a laboratory-developed test (LDT) on the basis of standard Sanger sequencing to capture all known familial pulmonary fibrosis-associated variants. Targeted DNA fragments were amplified using harmonized PCR conditions to perform the LDT in a single 96-well plate. The new genetic test was evaluated in 62 sporadic cases of idiopathic pulmonary fibrosis. As expected in this population, we observed a low yield of disease-causing mutations. More important, 100% of targeted variants by the LDT were successfully evaluated. Furthermore, four variants of uncertain significance with in silico-predicted deleterious scores were identified in three patients, suggesting novel pathogenic variants in genes known to cause idiopathic pulmonary fibrosis. Finally, the MUC5B promoter variant rs35705950 was strongly enriched in these patients with a minor allele frequency of 41.1% compared with 10.6% in a matched population-based cohort (n = 29,060), leading to an estimation that this variant may explain up to 35% of the population-attributable risk. This LDT provides a solution for rapid clinical translation. Technical laboratory details are provided so that specialized pulmonary centers can implement the LDT in house to expedite the clinical recommendations of expert panels.

Nonlinear association between atherogenic index of plasma and type 2 diabetes mellitus in overweight and obesity patients: evidence from Chinese medical examination data.

BACKGROUND: The atherogenic index of plasma (AIP) is closely associated with the onset of diabetes, with obesity being a significant risk factor for type 2 diabetes mellitus (T2DM). However, the association between the AIP and T2DM in overweight and obese populations has been infrequently studied. Therefore, this study aimed to explore this association in overweight and obese individuals with T2DM. METHODS: This cross-sectional analysis utilized data from 40,633 participants with a body mass index (BMI) ≥ 24 kg/m2 who were screened from January 2018 to December 2023 at Henan Provincial People's Hospital. Participants were categorized into groups of overweight and obese individuals with and without diabetes according to the T2DM criteria. The AIP, our dependent variable, was calculated using the formula log10 [(TG mol/L)/HDL-C (mol/L)]. We investigated the association between the AIP and T2DM in overweight and obese individuals using multivariate logistic regression, subgroup analysis, generalized additive models, smoothed curve fitting, and threshold effect analysis. Additionally, mediation analysis evaluated the role of inflammatory cells in AIP-related T2DM. RESULTS: Overweight and obese patients with T2DM exhibited higher AIP levels than those without diabetes. After adjusting for confounders, our results indicated a significant association between the AIP and the risk of T2DM in overweight and obese individuals (odds ratio (OR) = 5.17, 95% confidence interval (CI) 4.69-5.69). Notably, participants with a high baseline AIP (Q4 group) had a significantly greater risk of T2DM than those in the Q1 group, with an OR of 3.18 (95% CI 2.94-3.45). Subgroup analysis revealed that the association between the AIP and T2DM decreased with increasing age (interaction P < 0.001). In overweight and obese populations, the association between AIP and T2DM risk displayed a J-shaped nonlinear pattern, with AIP > - 0.07 indicating a significant increase in T2DM risk. Various inflammatory cells, including neutrophils, leukocytes, and monocytes, mediated 4.66%, 4.16%, and 1.93% of the associations, respectively. CONCLUSION: In overweight and obese individuals, the AIP was independently associated with T2DM, exhibiting a nonlinear association. Additionally, the association between the AIP and T2DM decreased with advancing age. Multiple types of inflammatory cells mediate this association.

Association between high-density lipoprotein cholesterol and lumbar bone mineral density in Chinese: a large cross-sectional study.

BACKGROUND: The association between lipid and bone metabolism, particularly the role of high-density lipoprotein cholesterol (HDL-C) in regulating bone mineral density (BMD), is of significant interest. Despite numerous studies, findings on this relationship remain inconclusive, especially since evidence from large, sexually diverse Chinese populations is sparse. This study, therefore, investigates the correlation between HDL-C and lumbar BMD in people of different genders using extensive population-based data from physical examinations conducted in China. METHODS: Data from a cross-sectional survey involving 20,351 individuals aged > = 20 years drawn from medical records of health check-ups at the Health Management Centre of the Henan Provincial People's Hospital formed the basis of this study. The primary objective was to determine the correlation between HDL-C levels and lumbar BMD across genders. The analysis methodology included demographic data analysis, one-way ANOVA, subgroup analyses, multifactorial regression equations, smoothed curve fitting, and threshold and saturation effect analyses. RESULTS: Multifactorial regression analysis revealed a significant inverse relationship between HDL-C levels and lumbar BMD in both sexes, controlling for potential confounders (Male: ß = -8.77, 95% CI -11.65 to -5.88, P < 0.001; Female: ß = -4.77, 95% CI -8.63 to -0.90, P = 0.015). Subgroup and threshold saturation effect analyses indicated a stronger association in males, showing that increased HDL-C correlates with reduced lumbar BMD irrespective of age and body mass index (BMI). The most significant effect was observed in males with BMI > 28 kg/m2 and HDL-C > 1.45 mmol/L and in females with a BMI between 24 and 28 kg/m2. CONCLUSION: Elevated HDL-C is associated with decreased bone mass, particularly in obese males. These findings indicate that individuals with high HDL-C levels should receive careful clinical monitoring to mitigate osteoporosis risk. TRIAL REGISTRATION: The research protocol received ethics approval from the Ethics Committee at Beijing Jishuitan Hospital, in conformity with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are a contribution of the China Health Quantitative CT Big Data Research team, registered at clinicaltrials.gov (code: NCT03699228).

Interpretable-ADMET: a web service for ADMET prediction and optimization based on deep neural representation.

MOTIVATION: In the process of discovery and optimization of lead compounds, it is difficult for non-expert pharmacologists to intuitively determine the contribution of substructure to a particular property of a molecule. RESULTS: In this work, we develop a user-friendly web service, named interpretable-absorption, distribution, metabolism, excretion and toxicity (ADMET), which predict 59 ADMET-associated properties using 90 qualitative classification models and 28 quantitative regression models based on graph convolutional neural network and graph attention network algorithms. In interpretable-ADMET, there are 250 729 entries associated with 59 kinds of ADMET-associated properties for 80 167 chemical compounds. In addition to making predictions, interpretable-ADMET provides interpretation models based on gradient-weighted class activation map for identifying the substructure, which is important to the particular property. Interpretable-ADMET also provides an optimize module to automatically generate a set of novel virtual candidates based on matched molecular pair rules. We believe that interpretable-ADMET could serve as a useful tool for lead optimization in drug discovery. AVAILABILITY AND IMPLEMENTATION: Interpretable-ADMET is available at http://cadd.pharmacy.nankai.edu.cn/interpretableadmet/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The role of NADPH oxidase 1 in alcohol-induced oxidative stress injury of intestinal epithelial cells.

Alcohol-mediated reactive oxygen species (ROS) play a vital role in intestinal barrier injury. However, the mechanism of ROS accumulation in enterocytes needs to be explored further. In our study, we found that chronic-binge ethanol-fed mice had increased levels of gut oxidative stress and high intestinal permeability. The transcription profiles of the colonic epithelial cells showed that the level of NADPH oxidase 1 (NOX1) was significantly elevated in alcohol-exposed mice compared with isocaloric-exposed mice. In vitro, NOX1 silencing alleviated ROS accumulation and the apoptosis of human colonic epithelial cells (NCM460), while NOX1 overexpression accelerated oxidative stress injury of NCM460 cells. Propionic acid was reduced in the gut of chronic-binge ethanol-fed mice, compared with isocaloric-fed mice, as observed through untargeted metabolomic analysis. Supplementation with propionate relieved ethanol-induced liver and intestinal barrier injuries and reduced the level of ROS accumulation and apoptosis of ethanol-induced colonic epithelial cells. Propionate alleviating NOX1 induced ROS injury of colonic epithelial cells, independent of G protein-coupled receptors. Propionate significantly inhibited histone deacetylase 2 (HDAC2) expressions both in ethanol-exposed colonic epithelial cells and TNF-α-treated NCM460. Chromatin immunoprecipitation (ChIP) assays showed that propionate suppressed the NOX1 expression by regulating histone acetylation in the gene promoter region. In conclusion, NOX1 induces oxidative stress injury of colonic epithelial cells in alcohol-related liver disease. Propionate, which can act as an endogenous HDAC2 inhibitor, can decrease levels of apoptosis of intestinal epithelial cells caused by oxidative stress.

Association between total cholesterol and lumbar bone density in Chinese: a study of physical examination data from 2018 to 2023.

BACKGROUND: The impact of total cholesterol (TC) on lumbar bone mineral density (BMD) is a topic of interest. However, empirical evidence on this association from demographic surveys conducted in China is lacking. Therefore, this study aimed to examine the relationship between serum TC and lumbar BMD in a sample of 20,544 Chinese adults between the ages of 20 and 80 years over a period of 5 years, from February 2018 to February 2023. Thus, we investigated the effect of serum TC level on lumbar BMD and its relationship with bone reduction in a Chinese adult population. METHODS: This cross-sectional study used data obtained from the Department of Health Management at Henan Provincial People's Hospital between February 2018 and February 2023. The aim of this study was to examine the correlation between serum TC and lumbar BMD in individuals of different sexes. The research methodology encompassed population description, analysis of stratification, single-factor and multiple-equation regression analyses, smooth curve fitting, and analysis of threshold and saturation effects. The R and EmpowerStats software packages were used for statistical analysis. RESULTS: After adjusting for confounding variables, a multiple linear regression model revealed a significant correlation between TC and lumbar BMD in men. In subgroup analysis, serum TC was found to have a positive association with lumbar BMD in men, specifically those aged 45 years or older, with a body mass index (BMI) ranging from 24 to 28 kg/m2. A U-shaped correlation arose between serum TC and lumbar BMD was detected in women of different ages and BMI, the inflection point was 4.27 mmol/L for women aged ≥ 45 years and 4.35 mmol/L for women with a BMI of ≥ 28 kg/m2. CONCLUSION: In this study, Chinese adults aged 20-80 years displayed different effects of serum TC on lumbar BMD in sex-specific populations. Therefore, monitoring BMI and serum TC levels in women of different ages could prevent osteoporosis and osteopenia. TRIAL REGISTRATION: The research protocol was approved by the Ethics Committee of Beijing Jishuitan Hospital, in accordance with the Declaration of Helsinki guidelines (No. 2015-12-02). These data are part of the China Health Quantitative CT Big Data Research team, which has been registered at clinicaltrials.gov (code: NCT03699228).

The HSP90 inhibitor 17-DMAG alleviates primary biliary cholangitis via cholangiocyte necroptosis prevention.

Cholangiocyte death accompanied by the progression of primary biliary cholangitis (PBC) has not yet been thoroughly investigated. Thus, we are aimed to explore the role of HSP90 and a potential treatment strategy in cholangiocyte necroptosis. First, we detected the expression of HSP90 and necroptotic markers in liver tissues from patients and mice with PBC by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR). Then, the HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), was administered by intraperitoneal injection to evaluate its therapeutic effect for PBC by IHC, real-time PCR, and western blotting. Human intrahepatic bile duct epithelial cells (HIBECs) were induced to necroptosis by toxic bile acid and lipopolysaccharide (LPS) treatment, and evaluated via Cell Counting Kit-8 and flow cytometry assays. Additionally, 17-DMAG, cycloheximide, and a proteasome inhibitor were used to evaluate the role of HSP90 in cholangiocyte necroptosis. We found that the expression of HSP90 was elevated in the cholangiocytes of patients and mice with PBC, along with higher expressions of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3, mixed lineage kinase domain-like protein (MLKL), and phosphorylated-MLKL (p-MLKL). Proinflammatory cytokines and antibody levels of the E2 subunit of pyruvate dehydrogenase complex decreased after treatment with 17-DMAG in PBC mice. Meanwhile, RIPK1, RIPK3, phosphorylated-RIPK3, MLKL, and p-MLKL protein expressions decreased with 17-DMAG treatment. In vitro, 17-DMAG and necrostatin-1 prevented glycochenodeoxycholic acid and LPS-induced necroptosis of HIBECs. Immunoprecipitation and high-performance liquid chromatography-mass spectrometry analysis showed that RIPK1 combined with HSP90. Additionally, the 17-DMAG treatment reduced the RIPK1 half-life. Overall, 17-DMAG might be a potential therapeutic agent for PBC via cholangiocyte necroptosis prevention by accelerating RIPK1 degradation.

Synthesis and antimicrobial activity of the hybrid molecules between amoxicillin and derivatives of benzoic acid.

Due to the increasing problem of bacterial resistance worldwide, the demand for new antibiotics is becoming increasingly urgent. We wished to: (a) prepare hybrid molecules by linking different pharmacophores by chemical bonds; (b) investigate the antib acterial activity of these hybrids using drug-sensitive and drug-resistant pathogens in vitro and vivo. A series of hybrid molecules with a diester structure were designed and synthesized that linked amoxicillin and derivatives of benzoic acid via a methylene bridge. Synthesized compounds were evaluated for activities against Gram-positive bacteria (Staphylococcus aureus American Type Culture Collection [ATCC] 29213, ATCC 11632; methicillin-resistant S. aureus [MRSA] 11; Escherichia coli ATCC 25922) and Gram-negative bacteria (Salmonella LS677, GD836, GD828, GD3625) by microdilution of broth. Synthesized compounds showed good activity against Gram-positive and Gram-negative bacteria in vitro. In particular, amoxicillin-p-nitrobenzoic acid (6d) showed good activity against Salmonella species and had better activity against methicillin-resistant S. aureus (minimum inhibitory concentration [MIC] = 64 µg/ml) than the reference drug, amoxicillin (MIC = 128 µg/ml). Amoxicillin-p-methoxybenzoic acid (6b) had the best antibacterial activity in vivo (ED50 = 13.2496 µg/ml). The hybrid molecules of amoxicillin and derivatives of benzoic acid synthesized based on a diester structure can improve the activity of amoxicillin against Salmonella species and even improve the activity against MRSA.

Transcriptome-wide association study reveals candidate causal genes for lung cancer.

We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome-wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never- and ever-smokers). We performed replication analysis using lung data from the Genotype-Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever-smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E-99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E-6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3-adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E-5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.

Enhanced Chemisorption and Catalytic Effects toward Polysulfides by Modulating Hollow Nanoarchitectures for Long-Life Lithium-Sulfur Batteries.

Hollow nanostructures with intricate interior and catalytic effects hold great promise for the construction of advanced lithium-sulfur batteries. Herein, a double-shelled hollow polyhedron with inlaid cobalt nanoparticles encapsulated by nitrogen-doped carbon (Co/NC) nanodots (Co-NC@Co9 S8 /NPC) is reported, which is acquired by using imidazolium-based ionic-polymer-encapsulated zeolitic imidazolate framework-67 as a core-shelled precursor. The Co/NC nanodots promote redox kinetics and chemical adsorbability toward polysulfides, while the interconnected double shells serve as a nanoscale electrochemical reaction chamber, which effectively suppresses the polysulfide shuttling and accelerates ion/electron transport. Benefiting from structural engineering and reaction kinetics modulation, the Co-NC@Co9 S8 /NPC-S electrode exhibits high cycling stability with a low capacity decay of 0.011% per cycle within 2000 cycles at 2 C. The electrode still shows high rate performance and cyclability over 500 cycles even in the case of high sulfur loading of 4.5 mg cm-2 and 75 wt% sulfur content. This work provides one type of new hollow nanoarchitecture for the development of advanced Li-S batteries and other energy storage systems.

Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1-Dependent Manner in Mice.

Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in-depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A-stimulated genes (Creg), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of Creg in hepatic I/R remains largely unknown. A genetic engineering technique was used to explore the function of Creg in hepatic I/R injury. Hepatocyte-specific Creg knockout (CregΔHep ) and transgenic mice were generated and subjected to hepatic I/R injury, as were the controls. Creg in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from CregΔHep that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo. Moreover, further molecular experiments showed that Creg suppressed mitogen-activated protein kinase (MAPK) signaling by inhibiting TAK1 (TGF-ß-activated kinase 1) phosphorylation. Inhibiting TAK1 by 5Z-7-ox or mutating the TAK1-binding domain of Creg abolished the protective role of Creg indicating that Creg binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion: These data demonstrate that Creg prevents hepatocytes from liver I/R injury. The Creg-TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury.

Relationship between expression of XRCC1 and tumor proliferation, migration, invasion, and angiogenesis in glioma.

Recently, XRCC1 polymorphisms were reported to be associated with glioma in Chinese population. However, only a few studies reported on the XRCC1 expression, and cancer progression. In this study, we investigated whether XRCC1 plays a role in glioma pathogenesis. Using the tissue microarray technology, we found that XRCC1 expression is significantly decreased in glioma compared with tumor adjacent normal brain tissue (P < 0.01, χ2 test) and reduced XRCC1 staining was associated with WHO stages (P < 0.05, χ2 test). The mRNA and protein levels of XRCC1 were significantly downregulated in human primary glioma tissues (P < 0.001, χ2 test). We also found that XRCC1 was significantly decreased in glioma cell lines compared to normal human astrocytes (P < 0.01, χ2 test). Overexpression of XRCC1 dramatically reduced the proliferation and caused cessation of cell cycle. The reduced cell proliferation is due to G1 phase arrest as cyclin D1 is diminished whereas p16 is upregulated. We further demonstrated that XRCC1 overexpression suppressed the glioma cell migration and invasion abilities by targeting MMP-2. In addition, we also found that overexpression of XRCC1 sharply inhibited angiogenesis, which correlated with down-regulation of VEGF. The data indicate that XRCC1 may be a tumor suppressor involved in the progression of glioma.

Self-regulating positive emotion networks by feedback of multiple emotional brain states using real-time fMRI.

Disordered emotion regulation may affect work efficiency, induce social disharmony, and even cause psychiatric diseases. Despite recent neurocomputing advances, whether positive and negative emotion networks can be voluntarily modulated is still unknown. In the present study, we addressed this question through multivariate voxel pattern analysis and real-time functional MRI neurofeedback (rtfMRI-nf). During a sustained emotion regulation task, participants' emotional states (positive or negative) were given to them as feedback. Participants were able to increase the percentage of positive emotional states, enhancing emotion regulation network activities. Participants showed an improvement on the positive subscale of positive and negative affect scale that came close to significance. Furthermore, the activation of several emotion-related brain regions, including insula, amygdala, anterior cingulate cortex, and dorsomedial prefrontal cortex, was also increased during rtfMRI-nf training. These findings suggest that humans are able to voluntarily modulate positive emotion networks, leading to exciting applications in the treatment of various neurological and psychiatric disorders.

Fission cross-section measurements for the 238U(n,f)97m+gNb, 238U(n,f)133gTe and 238U(n,f)130gSb reactions induced by D-T neutrons.

In this study, we conducted measurements of the independent fission cross-sections of 238U(n, f)97m+gNb, 238U(n, f)133gTe reactions and the cumulative cross section of 238U(n, f)130gSb reactions induced by neutron at energies around 14 MeV, i.e., 14.1 ± 0.3, 14.5 ± 0.3 and 14.7 ± 0.3 MeV. The measurement results were obtained by the neutron activation method in combination with off-line γ-ray spectrometry techniques. The neutron flux was monitored on line by the accompanying α-particle from T(d, n)4He reaction, and the neutron energies were determined by the cross-section ratio of 90Zr(n, 2n)8+gZr to 93Nb(n, 2n)92mNb reactions. The independent fission cross-sections of the fission reactions were obtained by subtracting the influence of precursor nuclei or excited states. The obtained results are as follows: for 238U(n, f)97m+gNb, the independent cross sections are 1.0 ± 0.89, 0.98 ± 0.85 and 0.78 ± 0.70 mb at the specified neutron energy points. For 238U(n, f)133gTe, the independent fission cross-sections are 26.8 ± 2.8, 27.7 ± 2.9 and 20.5 ± 2.3 mb, respectively, at the same neutron energy points. As for 238U(n, f)130gSb, the obtained cumulative fission cross-sections are 5.35 ± 0.58, 5.05 ± 0.53 and 4.03 ± 0.44 mb, respectively, at the specified neutron energy points.

The Compatibility of COFs Cathode and Optimized Electrolyte for Ultra-Long Lifetime Rechargeable Aqueous Zinc-Ion Battery.

Rechargeable aqueous zinc-ion batteries (RAZIBs) are attractive due to their affordability, safety, and eco-friendliness. However, their potential is limited by the lack of high-capacity cathodes and compatible electrolytes needed for reliable performance. Herein, we have presented a compatibility strategy for the development of a durable and long-lasting RAZIBs. The covalent organic frameworks (COFs) based on anthraquinone (DAAQ-COF) is created and utilized as the cathode, with zinc metal serving as the anode. The electrolyte is made up of an aqueous solution containing zinc salts at various concentrations. The COF cathode has been designed to be endowed with a rich array of redox-active groups, enhancing its electrochemical properties. Meanwhile, the electrolyte is formulated using triflate anions, which have exhibited superiority over sulfate anions. This strategy lead to the development of an optimized COF cathode with fast charging capability, high Coulombic efficiency (nearly 100 %) and long-term cyclability (retention rate of nearly 100 % at 1 A g-1 after 10000 cycles). Moreover, through experimental analysis, a co-insertion mechanism involving Zn2+ and H+ in this cathode is discovered for the first time. These findings represent a promising path for the advancement of organic cathode materials in high-performance and sustainable RAZIBs.

A universal plasma metabolites-derived signature predicts cardiovascular disease risk in MAFLD.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD) is a novel concept proposed in 2020, which is more practical for identifying patients with fatty liver disease with high risk of disease progression. Fatty liver is a driver for extrahepatic complications, particularly cardiovascular diseases (CVD). Although the risk of CVD in MAFLD could be predicted by carotid ultrasound test, a very early stage prediction method before the formation of pathological damage is still lacking. METHODS: Stool microbiomes and plasma metabolites were compared across 196 well-characterized participants encompassing normal controls, simple MAFLD patients, MAFLD patients with carotid artery pathological changes, and MAFLD patients with diagnosed coronary artery disease (CAD). 16S rDNA sequencing data and untargeted metabolomic profiles were interrogatively analyzed using differential abundance analysis and random forest (RF) machine learning algorithm to identify discriminatory gut microbiomes and metabolomic. RESULTS: Characteristic microbial changes in MAFLD patients with CVD risk were represented by the increase of Clostridia and Firmicutes-to-Bacteroidetes ratios. Faecalibacterium was negatively correlated with mean-intima-media thickness (IMT), TC, and TG. Megamonas, Bacteroides, Parabacteroides, and Escherichia were positively correlated with the exacerbation of pathological indexes. MAFLD patients with CVD risk were characterized by the decrease of lithocholic acid taurine conjugate, and the increase of ethylvanillin propylene glycol acetal, both of which had close relationship with Ruminococcus and Gemmiger. Biotin l-sulfoxide had positive correlation with mean-IMT, TG, and weight. The general auxin pesticide beta-naphthoxyacetic acid and the food additive glucosyl steviol were both positively correlated with the increase of mean-IMT. The model combining the metabolite signatures with 9 clinical parameters accurately distinguished MAFLD with CVD risk in the proband and validation cohort. It was found that citral was the most important discriminative metabolite marker, which was validated by both in vitro and in vivo experiments. CONCLUSIONS: Simple MAFLD patients and MAFLD patients with CVD risk had divergent gut microbes and plasma metabolites. The predictive model based on metabolites and 9 clinical parameters could effectively discriminate MAFLD patients with CVD risk at a very early stage.