A cohort study of self-perception of ageing and all-cause mortality among older adults in China: a multiple mediators analysis.

BACKGROUND: Positive self-perception of aging (SPA) is a well-known predictor of longevity, while how and to what extent SPA is linked with all-cause mortality among older adults is still unclear. This study aims to elucidate the relationship between positive SPA and all-cause mortality and its potential mediators among Chinese older adults. METHODS: This is a 20-year dynamic cohort study conducted among 22,957 older adults aged ≥ 65 years old from a nationally representative sample. Positive SPA was measured using a validated 7-item scale. Potential mediators including health behaviors and social participation were collected using a self-reported questionnaire. Cox proportional hazards regression models were conducted to examine the association between positive SPA and all-cause mortality. A mediation analysis was conducted to determine whether health behaviors and social participation mediated the association between SPA and all-cause mortality. RESULTS: Throughout follow-up (median [interquartile range], 46 [21-84] months), all-cause mortality was 87.4%. Compared with older adults with the lowest quartile positive SPA, hazard ratio(HR) of all-cause mortality among older adults with the second, third, and fourth quartile of positive SPA was 0.96(95%CI:0.93-1.00), 0.93(95%CI:0.90-0.99), and 0.92(95%CI:0.87-0.96) respectively after controlling for all potential mediators and covariates. The mediation analysis showed that regular daily vegetable intake, physical activity, and high social participation explained 41.1-48.5% of the variance in the association between positive SPA and all-cause mortality. CONCLUSIONS: In this cohort study, we found that high positive SPA was associated with decreased all-cause mortality directly, and indirectly through healthy lifestyle behaviors and social participation. These findings suggest that interventions targeted at promoting or maintaining positive SPA may contribute to healthy ageing among older adults in China.

Effect of Chemical Composition on the Thermoplastic Formability and Nanoindentation of Ti-Based Bulk Metallic Glasses.

A series of Ti41Zr25Be34-xNix (x = 4, 6, 8, 10 at.%) and Ti41Zr25Be34-xCux (x = 4, 6, 8 at.%) bulk metallic glasses were investigated to examine the influence of Ni and Cu content on the viscosity, thermoplastic formability, and nanoindentation of Ti-based bulk metallic glasses. The results demonstrate that Ti41Zr25Be30Ni4 and Ti41Zr25Be26Cu8 amorphous alloys have superior thermoplastic formability among the Ti41Zr25Be34-xNix and Ti41Zr25Be34-xCux amorphous alloys due to their low viscosity in the supercooled liquid region and wider supercooled liquid region. The hardness and modulus exhibit obvious variations with increasing Ni and Cu content in Ti-based bulk metallic glasses, which can be attributed to alterations in atomic density. Optimal amounts of Ni and Cu in Ti-based bulk metallic glasses enhance thermoplastic formability and mechanical properties. The influence of Ni and Cu content on the hardness of Ti-based bulk metallic glasses is discussed from the perspective of the mean atomic distance.

The relationship between epicardial adipose tissue volume on coronary computed tomography angiography and idiopathic ventricular tachycardia: a propensity score matching case-control study in Chinese population.

Background: Large epicardial adipose tissue (EAT) volume is associated with the incidence of premature ventricular beats. The relationship between EAT volume and idiopathic ventricular tachycardia (IVT) is not yet clear. We aimed to investigate the effect of EAT volume on the risk of IVT. Methods: This is a retrospective consecutive case-control study from January 2020 to September 2022. IVT patients (n=81) and control patients (n=162) undergoing coronary computed tomography angiography (CCTA) were retrospectively recruited. The patients in the control group were all hospitalized patients for different reasons, such as chest tightness, shortness of breath, chest pain, and so on. Demographic parameters and clinical characteristics of each individual were collected from the patient's medical records. We selected evaluation criteria for the conduct of a 1:1 propensity score (PS)-adjusted analysis. Multivariable logistic analysis was used to investigate risk factors for IVT. Furthermore, the impact of EAT volume on cardiac repolarization indices was assessed in IVT patients. Results: Patients with IVT had a larger EAT volume than control group patients in the unadjusted cohort. Variables with P<0.10 in the univariable analysis and important factors were included in the multivariable analysis model, including body mass index (BMI), left ventricular ejection fraction (LVEF), early peak/artial peak (E/A) ratios <1, EAT attenuation, and EAT volume (per increase 10 mL). The multivariable logistic analysis found that EAT volume [per increase 10 mL, odds ratio (OR): 1.29, 95% confidence interval (CI): 1.17-1.41, P<0.001] was an independent risk factor for IVT. EAT volume (per increase 10 mL, OR: 1.43, 95% CI: 1.25-1.64, P<0.001) independent effect was demonstrated in the PS adjusted cohort (n=57 in both groups). The area under the curve of EAT volume to predict the risk of IVT patients in the PS adjusted cohort was 0.859. The sensitivity and specificity were 86.0%, and 75.4%, respectively. Furthermore, A large EAT volume of IVT patients had a longer time in Tp-e, and Tp-e/QTc, compared with low EAT volume. Conclusions: Patients with IVT had increased EAT volume compared to control subjects. Our study revealed that large EAT volume is associated with an extended repolarization process in IVT patients. These insights are essential for understanding the mechanisms linking EAT with IVT.

AMBRA1 promotes intestinal inflammation by antagonizing PP4R1/PP4c mediated IKK dephosphorylation in an autophagy-independent manner.

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.

Non-insulin-based insulin resistance indexes in predicting atrial fibrillation recurrence following ablation: a retrospective study.

BACKGROUND: Insulin resistance (IR) is involved in the pathophysiological processes of arrhythmias. Increasing evidence suggests triglyceride and glucose (TyG) index, metabolic score for insulin resistance (METS-IR), triglyceride glucose-body mass index (TyG-BMI), and triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio are simple and reliable surrogates for IR. Although they have been associated with atrial fibrillation (AF), evidence supporting this is limited. Here, this is the first study to investigate the association between TyG-BMI index and AF recurrence following radiofrequency catheter ablation (RFCA). The performance of the four non-insulin-based IR indexes in predicting AF recurrence after ablation was explored. METHODS: A total of 2242 AF patients who underwent a de novo RFCA between June 2018 to January 2022 at two hospitals in China were included in this retrospective study. The predictive values of IR indexes for AF recurrence after ablation were assessed. RESULTS: During 1-year follow-up, 31.7% of patients experienced AF recurrence. The multivariable analysis revealed that TyG index, METS-IR, and TyG-BMI index were independent risk factors for AF recurrence. Restricted cubic spline analysis revealed a connection between METS-IR, TyG-BMI index, and AF recurrence (P < 0.001). Furthermore, incorporating the METS-IR or TyG-BMI index to the basic risk model with fully adjusted factors considerably enhanced the forecast of AF recurrence, as demonstrated by the C-statistic, continuous net reclassification improvement, and integrated discrimination improvement. CONCLUSIONS: TyG index, METS-IR, and TyG-BMI index were independently associated with AF recurrence following ablation. Among the four non-insulin-based IR indexes, TyG-BMI had the highest predictive value, followed by METS-IR.

PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcomes and therapeutic resistance.

BACKGROUND: The tumor microenvironment (TME) plays a vital role in tumor progression through intricate molecular interactions. Cancer-associated fibroblasts (CAFs), notably those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are instrumental in this context and correlate with unfavorable outcomes in colorectal cancer (CRC). While several transcription factors influence TME, the exact regulator causing CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) stands out, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 is debated due to inconsistent study findings. METHODS: Using the ULCAN portal, we noted an elevated PROX1 level in advanced colon adenocarcinoma, linking to a poor prognosis. Assays determined the impact of PROX1 overexpression on CRC cell properties, while co-culture experiments spotlighted the PROX1-CAF relationship. Molecular expressions were validated by qRT-PCR and Western blots, with in vivo studies further solidifying the observations. RESULTS: Our study emphasized the connection between PROX1 and α-SMA in CAFs. Elevated PROX1 in CRC samples correlated with increased α-SMA in tumors. PROX1 modulation influenced the behavior of specific CRC cells, with its overexpression fostering invasiveness. Kaplan-Meier evaluations demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or with α-SMA, emerges as a CRC prognostic marker. Co-culture and animal experiments further highlighted this relationship. CONCLUSION: PROX1 appears crucial in modulating CRC behavior and therapeutic resistance within the TME by influencing CAFs, signifying the combined PROX1/α-SMA gene as a potential CRC prognostic marker. The concept of developing inhibitors targeting this gene set emerges as a prospective therapeutic strategy. However, this study is bound by limitations, including potential challenges in clinical translation, a focused exploration on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposition.

A novel causative role of imbalanced kynurenine pathway in ulcerative colitis: Upregulation of KMO and KYNU promotes intestinal inflammation.

The kynurenine pathway (KP) is the principal metabolic route for the essential amino acid tryptophan (TRP). Recent advances have highlighted a pivotal role for several KP metabolites in inflammatory diseases, including ulcerative colitis (UC). However, the alterations of KP enzymes and their functional impact in UC remain poorly defined. Here, we focused on kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which serve as critical branching enzymes in the KP. We observed that dextran sodium sulfate (DSS)-induced colitis mice exhibited disturbed TRP metabolism along with KMO and KYNU upregulated. In patients with active UC, both the expression of KMO and KYNU were positively correlated with inflammatory factors TNF-α and IL-1ß. Pharmacological blockade of KMO or genetic silencing of KYNU suppressed IL-1ß-triggered proinflammatory cytokines expression in intestinal epithelial cells. Furthermore, blockage of KMO by selective inhibitor Ro 61-8048 alleviated the symptoms of DSS-induced colitis in mice, accompanied by an expanded NAD+ pool and redox balance restoration. The protective role of Ro 61-8048 may be partly due to its effect on KP regulation, particularly in enhancing kynurenic acid production. In summary, our study provides new evidence for the proinflammatory property of KMO and KYNU in intestinal inflammation, hinting at a promising therapeutic approach in UC through targeting these enzymes.

A small-scale external quality assessment for PCR detection of group B streptococcus in China.

BACKGROUND: Group B streptococcus (GBS) is considered a leading cause of maternal and infant morbidity and mortality. Molecular diagnosis is a routinely used approach for GBS screening to protect pregnant women and prevent early-onset GBS neonatal disease. The objective of this study was to identify issues and guarantee the dependability of GBS molecular diagnosis by an external quality assessment (EQA) scheme. METHODS: The EQA panel comprised eight samples spiked with 10-fold dilutions of GBS suspension (20-2,000,000 copies/mL), and 2 negative control samples. The panels were coded randomly and distributed to participating laboratories for GBS detection. RESULTS: In total, 44 participating laboratories submitted results with eight commercial GBS PCR assays and one in-house assay. Among them, 36 obtained an acceptable or higher performance score, while 8 required improvement. Among the 440 results returned, 62 (14.1 %) were incorrect, including 5 false positives and 57 false negatives. CONCLUSIONS: Our small-scale EQA showed that most participating laboratories have reliable diagnostic capacities for GBS PCR detection. Nonetheless, further improvements in the detection performance of some laboratories are required, particularly with low-concentration samples. Our survey also reinforces the use of EQA as an essential tool to evaluate the overall proficiency of clinical laboratories.

Relationship Between Epicardial Adipose Tissue Volume and Recurrence After Ablation in Premature Ventricular Complexes.

BACKGROUND: Epicardial adipose tissue (EAT) is recognized as a clinical diagnostic marker for cardiometabolic disease. Thicker EAT may be associated with recurrence of ventricular tachycardia after ablation. The association between EAT volume and recurrence of premature ventricular complexes (PVC) following ablation has not been clarified. We investigated the association between EAT volume and PVC recurrence following radiofrequency catheter ablation.Methods and Results: This retrospective study included 401 patients with PVC undergoing catheter ablation with preprocedural non-contrast computed tomography between 2017 and 2022. The impact of EAT volume in predicting PVC recurrence after ablation was analyzed. The mean (±SD) age of patients was 50.2±13.3 years. Multivariable Cox analysis revealed that a large EAT volume was an independent predictor of PVC recurrence after ablation during a median follow-up of 16.3 months. Kaplan-Meier analysis showed a difference in postablation PVC recurrence between the 2 groups dichotomized around the EAT volume cut-off. The risk of recurrence increased with increasing EAT volume according to restricted cubic spline regression. Furthermore, PVC originating from epicardial locations had larger EAT volumes than those originating from the right ventricular outflow tract. CONCLUSIONS: A large EAT volume was independently associated with PVC recurrence following ablation. Patients with PVC originating from epicardial sites had large EAT volumes. EAT volume may help stratify patients according to their risk of PVC recurrence after ablation.

High-fructose corn syrup aggravates colitis via microbiota dysbiosis-mediated Th17/Treg imbalance.

Dietary fructose is widely used in beverages, processed foods, and Western diets as food additives, and is closely related to the increased prevalence of multiple diseases, including inflammatory bowel disease (IBD). However, the detailed mechanism by which high fructose disrupts intestinal homeostasis remains elusive. The present study showed that high-fructose corn syrup (HFCS) administration exacerbated intestinal inflammation and deteriorated barrier integrity. Several in vivo experimental models were utilized to verify the importance of gut microbiota and immune cells in HFCS-mediated dextran sulfate sodium (DSS)-induced colitis. In addition, untargeted metabolomics analysis revealed the imbalance between primary bile acids (PBAs) and secondary bile acids (SBAs) in feces. Hence, high fructose was speculated to modulate gut microbiota community and reduced the relative abundance of Clostridium and Clostridium scindens at genus and species level respectively, followed by a decrease in SBAs, especially isoalloLCA, thereby affecting Th17/Treg cells equilibrium and promoting intestinal inflammation. These findings provide novel insights into the crosstalk between gut flora, bile acids, and mucosal immunity, and highlight potential strategies for precise treatment of IBD.

The relationship between frequent premature ventricular complexes and epicardial adipose tissue volume.

Background: Epicardial adipose tissue (EAT) is related to atrial fibrillation. The association between EAT volume and premature ventricular complexes (PVCs) remains unclear. Our study aimed to investigate the effect of EAT volume on the risk of frequent PVCs and burden levels of PVCs. Methods: This observational study retrospectively recruited consecutive patients who had consultation between 2019 and 2021 at the First Affiliated Hospital of Zhengzhou University. Frequent PVC patients (n = 402) and control patients (n = 402) undergoing non-contrast computed tomography (CT) were enrolled. We selected evaluation criteria for the conduct of a 1:1 propensity score matching (PSM) analysis. Multivariable logistic analysis was used to investigate factors related to frequent PVCs. Furthermore, the determinants of EAT volume and the burden levels of PVCs were evaluated. Results: Patients with PVCs had a significantly larger EAT volume than control patients. EAT volume was significantly larger in male PVC patients with BMI ≥24 kg/m2, diabetes mellitus, and E/A ratio <1. EAT volume was independently associated with PVCs. Moreover, the larger EAT volume was an independent predictor for the high burden level of PVCs. We revealed that the risk of high PVC burden level was increased with the rising of EAT volume by restricted cubic splines. Conclusions: EAT volume was larger in frequent PVC patients than in control patients, regardless of other confounding factors. A large EAT volume was independently associated with high burden levels of PVCs. EAT volume may be a new mechanism to explain the pathogenesis of PVCs.

Composite dietary antioxidant index was negatively associated with the prevalence of diabetes independent of cardiovascular diseases.

AIM: The association between composite dietary antioxidant index (CDAI) and diabetes remains unknown. Our study was to investigate the association of CDAI with diabetes. METHODS: A total of 11,956 participants were enrolled from the National Health and Nutrition Examination Surveys (NHANES). The CDAI was calculated from the intake of six dietary antioxidants. Multivariable logistic regressions were performed to explore the associations between CDAI and the prevalence of diabetes and glycemic index. Non-linear associations were explored using restricted cubic splines. RESULTS: In the multivariate logistic regression model, the odds ratio (95% confidence interval) of CDAI associating with obesity was 0.98 (0.97-1.00; p = 0.033). Compared with the lowest quartile, the highest quartile was related to 0.84-fold risk of diabetes (0.71-0.99; p = 0.035). However, CDAI was not independently associated with fasting glucose and hemoglobin A1c. CONCLUSION: CDAI was negatively associated with diabetes and the relationship was independent of other traditional risk factors.

Impact of pericoronary adipose tissue attenuation on recurrence after radiofrequency catheter ablation for atrial fibrillation.

BACKGROUND: Inflammation plays a vital role in the occurrence and progression of atrial fibrillation (AF). The association between pericoronary adipose tissue attenuation (PCATA) and AF recurrence following ablation has not been fully clarified. HYPOTHESIS: We aimed to evaluate the association between PCATA and AF recurrence after radiofrequency catheter ablation (RFCA). METHODS: Patients who underwent the first RFCA for AF and performed coronary computed tomography angiography before ablation between 2018 and 2021 were enrolled. The predictive values of PCATA for AF recurrence after ablation were investigated. The area under curve (AUC), relative integrated discrimination improvement (IDI), and categorical free net reclassification improvement (NRI) were used to assess the discrimination ability of different models for AF recurrence. RESULTS: During 1-year follow-up, 34.1% patients experienced AF recurrence. The multivariable analysis model revealed that PCATA of the right coronary artery (RCA) was an independent risk factor for AF recurrence. Patients with a high level of RCA-PCATA had a high risk of recurrence, after adjusting for other risk factors by restricted cubic splines. The performance in predicting AF recurrence was significantly improved by adding the marker of RCA-PCATA to the clinical model (AUC: 0.724 vs. 0.686, p = .024), with a relative IDI of 0.043 (p = .006) and continuous NRI of 0.521 (p < .001). CONCLUSIONS: PCATA of RCA was independently associated with AF recurrence after ablation. PCATA may be helpful for risk classification for AF ablation patients.

Comparison of Cold-Sprayed Coatings of Copper-Based Composite Deposited on AZ31B Magnesium Alloy and 6061 T6 Aluminum Alloy Substrates.

Copper-coated graphite and copper mixture powders were deposited on AZ31B magnesium alloy and 6061 T6 aluminum alloy substrates under different process parameters by a solid-state cold spray technique. The microstructure of the copper-coated graphite and copper composite coatings was visually examined using photographs taken with an optical microscope and a scanning electron microscope. The surface roughness of the coatings was investigated with a 3D profilometer. The thickness of the coatings was determined through the analysis of the microstructure images, while the adhesion of the coatings was characterized using the scratch test method. The results indicate that the surface roughness of the coatings sprayed on the two different substrates gradually decreases as gas temperature and gas pressure increase. Additionally, the thickness and adhesion of the coatings deposited on the two different substrates both increase with an increase in gas temperature and gas pressure. Comparing the surface roughness, thickness, and adhesion of the coatings deposited on the two different substrates, the surface roughness and adhesion of the coatings on the soft substrate are greater than those of the coatings on the hard substrate, while the thickness of the coatings is not obviously affected by the hardness of the substrate. Furthermore, it is noteworthy that the surface roughness, thickness, and adhesion of the copper-coated graphite and copper composite coatings sprayed on the two different substrates exhibit a distinct linear relationship with particle velocity.

Nitric acid oxidation and urea modification of carbon fibres as biofilm carriers.

Carbon fibres (CF) are commonly used as carriers in biofilm-based wastewater treatment. The surface properties of the CF are herein modified using a combination of nitric acid oxidation and urea to optimise the carrier to immobilise bacterial cells. The capacity of the CF carriers to immobilise bacterial cells and activated sludge is evaluated using bacterial cell adhesion and sludge immobilisation tests. The total interaction energy profiles between the CF supports and bacterial cells were calculated according to the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory to explain the mechanism by which these modifications enhance this immobilisation capacity. CF-U has a high capacity for immobilising bacterial cells and activated sludge (3.7 g-sludge/g-CF supports) owing to its low total interaction energy. Nitric acid oxidation reduced the diiodomethane contact angle of CF from 55.1° to 38.5°, which reduced the Lifshitz-van der Waals interaction energy, while urea modification further increased the zeta potential of CF from 12.8 mV to -0.7 mV, thereby reducing the electrostatic interaction energy. Experiments and DLVO theory both determined that a combination of nitric acid oxidation and urea modification significantly enhanced the ability of CF to immobilise microorganisms.

Improved diagnosis of colorectal cancer using combined biomarkers including Fusobacterium nucleatum, fecal occult blood, transferrin, CEA, CA19-9, gender, and age.

BACKGROUND: Conventional blood and stool tests are normally used for early screening of colorectal cancer (CRC) but the accuracy and efficiency remain to be improved. Recent findings suggest Fusobacterium nucleatum to be a biomarker for CRC. This study evaluated the role of F. nucleatum and developed CRC diagnostic models by combining F. nucleatum with fecal occult blood (FOB), transferrin (TRF), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), gender, and age. MATERIALS AND METHODS: Candidates including 71 healthy individuals and 59 CRC patients were recruited. Abundance of F. nucleatum in stool or tissue samples was measured by quantitative real-time PCR. CEA, CA19-9, TRF, and FOB were measured in parallel. These biomarkers together with genders and ages were the seven parameters used to develop CRC diagnostic models. Ten different machine learning algorithms were tested to achieve the best performance. RESULTS: Fecal F. nucleatum abundance was found significantly higher in CRC group compared to healthy group (p = 0.0005). Among the CRC patients, F. nucleatum abundance in tumor tissue was significantly higher than that in paracancerous tissue (p = 0.0087). CRC diagnostic models using different parameters were generated based on Logistic Regression algorithm, which showed good performance. The area under the curve (AUC) score of fecal F. nucleatum as the single diagnostic biomarker was 0.68 while the accuracy was 0.56. The diagnostic performance was obviously improved with the highest AUC (0.93) and accuracy (0.87) achieved when using all the 7 clinical parameters. The combination F. nucleatum + FOB + gender + age had the second highest AUC (0.92) and accuracy (0.85). A more utilitarian model using F. nucleatum + FOB showed relatively high AUC at 0.86 and accuracy at 0.81. CONCLUSIONS: F. nucleatum is valuable for CRC diagnosis. Combination of different clinical parameters could significantly improve CRC diagnostic performance. The combination F. nucleatum + FOB + gender + age may be an effective and noninvasive method for clinical application.

New murine model of alcoholic hepatitis in obesity-induced metabolic-associated fatty liver disease.

Metabolic-associated fatty liver disease (MAFLD) and alcoholic hepatitis (AH) are among the most prevalent liver diseases worldwide, and their coexistence is common in clinical practice. However, currently established models of MAFLD-AH coexistence do not fully replicate their pathological characteristics and require sophisticated experimental techniques. Therefore, we aimed to develop an easily replicable model that mimics obesity-induced MAFLD-AH in patients. Our goal was to establish a murine model that replicates MAFLD and AH coexistence, resulting in significant liver injury and inflammation. To this end, we administered a single ethanol gavage dose to ob/ob mice on a chow diet. The administration of a single dose of ethanol led to elevated serum transaminase levels, increased liver steatosis, and apoptosis in ob/ob mice. Furthermore, ethanol binge caused a significant increase in oxidative stress in ob/ob mice, as measured via 4-hydroxynonenal. Importantly, the single dose of ethanol also markedly exacerbated liver neutrophil infiltration and upregulated the hepatic mRNA expression of several chemokines and neutrophil-related proteins, including Cxcl1, Cxcl2, and Lcn2. Whole-liver transcriptomic analysis revealed that ethanol-induced changes in gene expression profile shared similar features with AH and MAFLD. In ob/ob mice, a single dose of ethanol binge caused significant liver injury and neutrophil infiltration. This easy-to-replicate murine model successfully mimics the pathological and clinical features of patients with coexisting MAFLD and AH and closely resembles the transcriptional regulation seen in human disease.

Impact of carotid atherosclerosis on arrhythmia recurrence following atrial fibrillation catheter ablation.

BACKGROUND: It remains unclear whether carotid atherosclerosis (CAS) increases the atrial fibrillation (AF) recurrence rate after ablation. The aim was to assess the association between CAS, defined as carotid intima-media thickness (CIMT) ≥1 mm and or presence of carotid plaques, and AF recurrence rate after ablation. METHODS: We retrospectively collected patients who underwent carotid ultrasonography and AF ablation at the First Affiliated Hospital of Zhengzhou University. The AF recurrence was defined as documented atrial arrhythmias over 30 s on ECG or 24-h Holter monitoring after the first three months blanking period. Cox regression models were used to analyze the risk of AF recurrence. RESULTS: Overall, 385 patients were analyzed (mean age, 60.58±10.98 years old; female, 41.30%; persistent AF, 47.27%). After a follow-up of 1 year, 138 (35.84%) patients experienced recurrence, Kaplan-Meier analysis showed that patients with the presence of carotid plaques, CIMT ≥1 mm, and CAS had a higher risk of recurrence compared with the absence (all log-rank p < .05). In multivariate Cox regression analysis, CAS (HR 2.159, ±95% CI 1.320-3.532, p = .002), carotid plaque (HR 1.815, ±95%CI 1.160-2.841, p = .009), and CIMT ≥1 mm (HR 1.696, ±95%CI 1.192-2.413, p = .003) were independently associated with a higher risk of recurrence. In subgroup analysis, the association of CAS, carotid plaque, and AF recurrence rate was weaker in men than women. CONCLUSION: Carotid atherosclerosis, CIMT ≥1 mm, and carotid plaque were significantly associated with a higher AF recurrence rate after radiofrequency catheter ablation. They were all risk factors for the recurrence of AF.

Design and characterization of a protein fold switching network.

To better understand how amino acid sequence encodes protein structure, we engineered mutational pathways that connect three common folds (3α, ß-grasp, and α/ß-plait). The structures of proteins at high sequence-identity intersections in the pathways (nodes) were determined using NMR spectroscopy and analyzed for stability and function. To generate nodes, the amino acid sequence encoding a smaller fold is embedded in the structure of an ~50% larger fold and a new sequence compatible with two sets of native interactions is designed. This generates protein pairs with a 3α or ß-grasp fold in the smaller form but an α/ß-plait fold in the larger form. Further, embedding smaller antagonistic folds creates critical states in the larger folds such that single amino acid substitutions can switch both their fold and function. The results help explain the underlying ambiguity in the protein folding code and show that new protein structures can evolve via abrupt fold switching.

Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis-associated Th17/Treg imbalance.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis-derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis-related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP-induced bone marrow-derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL-1ß release as well as the protein level of NLRP3, caspase-1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS-induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside-treated foecal bacterium into flora-depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders.