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Abstract Background Despite centuries of traditional use of silymarin for hepatoprotection, current randomized controlled trial (RCT) studies on the effectiveness of silymarin in managing metabolic dysfunction-associated steatotic liver disease (MASLD) are limited and inconclusive, particularly when it is administered alone. The low bioavailability of silymarin highlights the possible influence of gut microbiota on the effectiveness of silymarin; however, no human studies have investigated this aspect. Objective To determine the potential efficacy of silymarin in improving MASLD indicators and to investigate the underlying mechanisms related to gut microbiota. Method In this 24-week randomized, double-blind, placebo-controlled trial, 83 patients with MASLD were randomized to either placebo (n = 41) or silymarin (103.2 mg/d, n = 42). At 0, 12, and 24 weeks, liver stiffness and hepatic steatosis were assessed using FibroScan, and blood samples were gathered for biochemical detection, while faecal samples were collected at 0 and 24 weeks for 16S rRNA sequencing. Results Silymarin supplementation significantly reduced liver stiffness (LSM, -0.21 ± 0.17 vs. 0.41 ± 0.17, P = 0.015) and serum levels of γ-glutamyl transpeptidase (GGT, -8.21 ± 3.01 vs. 1.23 ± 3.16, P = 0.042) and ApoB (-0.02 ± 0.03 vs. 0.07 ± 0.03, P = 0.023) but had no significant effect on the controlled attenuation parameter (CAP), other biochemical indicators (aminotransferases, total bilirubin, glucose and lipid parameters, hsCRP, SOD, and UA), physical measurements (DBP, SBP, BMI, WHR, BF%, and BMR), or APRI and FIB-4 indices. Gut microbiota analysis revealed increased species diversity and enrichment of Oscillospiraceae in the silymarin group. Conclusion These findings suggest that silymarin supplementation could improve liver stiffness in MASLD patients, possibly by modulating the gut microbiota. Trial registration The trial was registered at the Chinese Clinical Trial Registry (ChiCTR2200059043).

Objective In the central Yunnan region, the geological structure is complex and karst formations are prevalent. Sudden water gushing and attenuation of spring flow are among the most difficult problems in tunnel construction. The Mengkuanggou karst water system exhibits a high degree of karst conduitization, with significant differences between karst fissures and karst conduits. Methods This study employs the MODFLOW-CFPv2 dual medium numerical model to simulate the karst water system of Mengkuanggou, providing a detailed description of karst pipeline and diversion tunnel to understand the influence of tunnel construction on groundwater flow and spring flow. Results The results show that (1) The MODFLOW-CFPv2 model can describe the complex geological structure of karst areas, and simulate the dynamic characteristics of the groundwater level and the response characteristics of karst spring flow in the study area. (2) Under the condition of strong discharge, the water inflow per unit length of the tunnel is 164 m3/d·m, with a stable water inflow of 69 m3/d·m, while the Mengkuanggou karst spring flow shows a significant downwards trend. During the simulation period, the average spring flow decreased from 1 578 L/s under natural conditions to 1 098 L/s, an overall decrease of 30.4%, and the peak flow rate decreased from 2 133 L/s to 1 375 L/s, a decrease of 35.5%. The construction of strong discharge conditions will have a significant impact on tunnel construction and the groundwater environment. Under the condition of limited discharge, the maximum water inflow of the tunnel is 39 m3/d·m, and the stable water inflow is 24 m3/d·m. The water inflow of the tunnel is significantly reduced, and the downwards trend of the karst spring flow in Mengkuanggou is also improved to a certain extent. During the simulation period, the average spring flow is reduced to 1 284 L/s, a reduction of 18.6%, and the peak flow is reduced to 1 617 L/s, a decrease of 22.1%. Conclusion The MODFLOW-CFPv2 dual-medium model used in this study accurately describes highly heterogeneous karst water systems with pipelines, karst caves and fissures in karst areas. It can be used to quantitatively evaluate the karst water of Mengkuanggou during Xianglushan Tunnel construction.

The Forchheimer equation is one of the basic equations widely used in non-Darcy seepage. The determination of coefficients A and B in the equation has always been a hotspot and difficulty in the field of porous media seepage. Different studies have proposed various empirical formulas for the coefficients A and B from seepage experiments. However, there are few studies evaluating the applicability of each empirical formula under homogeneous condition and heterogeneous with mixed particle size. In this study, to provide basic information for selecting the empirical formula of the Forchheimer equation under different porous media conditions, the normalized objective function (NOF) and linear regression method are used to evaluate the applicability of the empirical formula of the Forchheimer equation, on the basis of the seepage resistance experiment. The results show that: for homogeneous porous media, Sidiropoulou’s formula has a good prediction effect on hydraulic gradient. For the porous media mixed two kinds of particle size, the mass ratio and size factors of the mixed particle size should be considered based on the average particle size. The prediction effect of the Macdonald formula is slightly affected by the mass ratio and the mixed particle size; while the predicted hydraulic gradient from the Kadlecan and Knight formula is relatively stable. As to the porous media mixed five kinds of particle size, the predictive effect of using d60 as the characteristic particle size is fine.The Kadlecan and Knight formula is suitable to predict coefficient A, and the Ergun formula is effective to predict coefficient B. This study can provide a basis for selecting the Forchheimer equation for seepage of homogeneous and heterogeneous loose sand and gravel porous media in engineering.

Nattokinase (NK) and red yeast rice (RYR) are both indicated for their potential in cardiovascular disease prevention and management, but their combined effects especially in coronary artery disease (CAD) are scarcely examined. This 90-day randomized, double-blind trial aims to investigate the effect of NK and RYR supplementations on cardiometabolic parameters in patients with stable CAD. 178 CAD patients were randomized to four groups: NK + RYR, NK, RYR, and placebo. No adverse effects due to the interventions were reported. In comparisons across groups, NK + RYR showed the maximum effect in reducing triglyceride (−0.39 mmol), total cholesterol (−0.66 mmol/L), diastolic blood pressure (−7.39 mmHg), and increase in high-density lipoprotein cholesterol (0.195 mmol/L) than other groups (all p for multiple groups comparison

Background: Managing refractory epilepsy presents a significant a substantial clinical challenge. Deep brain stimulation (DBS) has emerged as a promising avenue for addressing refractory epilepsy. However, the optimal stimulation targets and effective parameters of DBS to reduce seizures remian unidentified. Objectives: This study endeavors to scrutinize the therapeutic potential of DBS within the zona incerta (ZI) across diverse seizure models and elucidate the associated underlying mechanisms. Methods: We evaluated the therapeutic potential of DBS with different frequencies in the ZI on kainic acid (KA)-induced TLE model or M1-cortical seizures model, pilocarpine-induced M1-cortical seizure models, and KA-induced epilepsy model. Further, employing calcium fiber photometry combined with cell-specific ablation, we sought to clarified the causal role of ZI GABAergic neurons in mediating the therapeutic effects of DBS. Results: Our findings reveal that DBS in the ZI alleviated the severity of seizure activities in the KA-induced TLE model. Meanwhile, DBS attenuated seizure activities in KA- or pilocarpine-induced M1-cortical seizure model. In addition, DBS exerts a mitigating influence on KA induced epilepsy model. DBS in the ZI showed anti-seizure effects at low frequency spectrum, with 5 Hz exhibiting optimal efficacy. The low-frequency DBS significantly increased the calcium activities of ZI GABAergic neurons. Furthermore, selective ablation of ZI GABAergic neurons with taCasp3 blocked the anti-seizure effect of low-frequency DBS, indicating the anti-seizure effect of DBS is mediated by the activation of ZI GABAergic neurons. Conclusion: Our results demonstrate that low-frequency DBS in the ZI attenuates seizure via driving GABAergic neuronal activity. This suggests that the ZI represents a potential DBS target for treating both hippocampal and cortical seizure through the activation of GABAergic neurons, thereby holding therapeutic significance for seizure treatment.

The consumption of probiotics has been extensively employed for the management or prevention of gastrointestinal disorders by modifying the gut microbiota and changing metabolites. Nevertheless, the probiotic-mediated regulation of host metabolism through the metabolism of bile acids (BAs) remains inadequately comprehended. The gut-liver axis has received more attention in recent years due to its association with BA metabolism. The objective of this research was to examine the changes in BAs and gut microbiota using an in vitro fermentation model. The metabolism and regulation of gut microbiota by commercial probiotics complex containing various species such as Lactobacillus, Bifidobacterium, and Streptococcus were investigated. The findings indicated that the probiotic strains had produced diverse metabolic profiles of BAs. The probiotics mixture demonstrated the greatest capacity for Bile salt hydrolase (BSH) deconjugation and 7α-dehydroxylation, leading to a significant elevation in the concentrations of Chenodeoxycholic acid, Deoxycholic acidcholic acid, and hyocholic acid in humans. In addition, the probiotic mixtures have the potential to regulate the microbiome of the human intestines, resulting in a reduction of isobutyric acid, isovaleric acid, hydrogen sulfide, and ammonia. The probiotics complex intervention group showed a significant increase in the quantities of Lactobacillus and Bifidobacterium strains, in comparison to the control group. Hence, the use of probiotics complex to alter gut bacteria and enhance the conversion of BAs could be a promising approach to mitigate metabolic disorders in individuals.

Objective The Kuncheng Tunnel of the Central Yunnan Water Diversion Project crosses the Heilongtan and Bailongtan areas, the major headwater regions in the Chenggong District of Kunming City. Methods Tunnel water inrush may seriously threaten the safety of the urban water supply. In this paper, based on hydrodynamic data and hydrochemical data during tunnel construction, the characteristics of the karst water system, the origin of the springs, and the impact of tunnel construction were analysed. Then, a three-dimensional groundwater flow model for the Heilongtan-Bailongtan Section was developed and calibrated to simulate and predict groundwater level changes during the construction of the Kuncheng Tunnel, and the water environment effect of tunnel construction was evaluated. Results The results show that both the Heilongtan and Bailongtan springs are mainly recharged by the same karst P1q+m aquifer. However, controlled by aquitard P1d and the Hunshuitang fault downstream of the Sanjiacun Depression, the two springs actually belong to two relatively independent karst water systems. In addition, the excavation of the Kuncheng Tunnel has changed the regional groundwater flow field and cut off the flow of Bailongtan, while it has negligible impact on Heilongtan. Conclusion This study discusses the genetic relationship of karst spring, and quantitatively analyzes the impact of tunnel excavation on water environment, which has reference significance for preventing water inrush in tunnel construction.

Silymarin, salvianolic acids B, and puerarin were considered healthy food agents with tremendous potential to ameliorate non-alcoholic fatty liver disease (NAFLD). However, the mechanisms by which they interact with gut microbiota to exert benefits are largely unknown. After 8 weeks of NAFLD modeling, C57BL/6J mice were randomly divided into five groups and fed a normal diet, high-fat diet (HFD), or HFD supplemented with a medium or high dose of Silybum marianum extract contained silymarin or polyherbal extract contained silymarin, salvianolic acids B, and puerarin for 16 weeks, respectively. The untargeted metabolomics and 16S rRNA sequencing were used for molecular mechanisms exploration. The intervention of silymarin and polyherbal extract significantly improved liver steatosis and recovered liver function in the mice, accompanied by an increase in probiotics like Akkermansia and Blautia, and suppressed Clostridium, which related to changes in the bile acids profile in feces and serum. Fecal microbiome transplantation confirmed that this alteration of microbiota and its metabolites were responsible for the improvement in NAFLD. The present study substantiated that alterations of the gut microbiota upon silymarin and polyherbal extract intervention have beneficial effects on HFD-induced hepatic steatosis and suggested the pivotal role of gut microbiota and its metabolites in the amelioration of NAFLD.

Abstract Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE.

ObjectiveIntermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis.MethodsIn this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples.ResultsOur results showed that IER longitudinally reduced the activity of obese-related brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes.ConclusionsThere was dynamical alteration of BGM axis (the communication of E. coli with specific brain regions) during the weight loss under the IER.

ABSTRACTDietary fibers/probiotics may relieve constipation via optimizing gut microbiome, yet with limited trial-based evidences. We aimed to evaluate the effects of formulas with dietary fibers or probiotics on functional constipation symptoms, and to identify modulations of gut microbiota of relevance. We conducted a 4-week double-blinded randomized placebo-controlled trial in 250 adults with functional constipation. Intervention: A: polydextrose; B: psyllium husk; C: wheat bran + psyllium husk; D: Bifidobacterium animalis subsp. lactis HN019 + Lacticaseibacillus rhamnosus HN001; Placebo: maltodextrin. Oligosaccharides were also included in group A to D. 16S rRNA sequencing was used to assess the gut microbiota at weeks 0, 2, and 4. A total of 242 participants completed the study. No time-by-group effect was observed for bowel movement frequency (BMF), Bristol stool scale score (BSS), and degree of defecation straining (DDS), while BSS showed mean increases of 0.95–1.05 in group A to D (all P

Nonalcoholic steatohepatitis (NASH) represents an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD). The activation of the NOD-like receptor protein 3 (NLRP3) inflammasome triggers pyroptosis, thus propelling the progression from simple steatosis to NASH. Silibinin, a hepatoprotective compound derived from milk thistle, exerts diverse hepatoprotective effects. However, the direct impact of silibinin on NLRP3 inflammasome activation and its ability to mitigate pyroptosis remain uncertain. To address this, we utilized an in vitro model of NASH, employing HepG2 cells treated with deoxycholic acid (DCA) and free fatty acids. Subsequently, we treated these model cells with silibinin for 24 h. Our findings demonstrated that, although there were no significant changes in cellular lipid content, silibinin effectively ameliorated hepatocyte injuries. Silibinin treatment inhibited the activation of the NLRP3 inflammasome and suppressed DCA-induced pyroptosis. Additionally, molecular docking analysis revealed that silibinin exhibited a binding affinity to components of the NLRP3 inflammasome similar to that of MCC950, a selective NLRP3 inhibitor. These results suggest that silibinin may alleviate inflammation in DCA-exposed HepG2 cells by mitigating pyroptosis, possibly through its binding affinity and inhibition of the NLRP3 inflammasome. Overall, our study indicates that silibinin holds promise as a therapeutic agent for NASH by modulating pyroptosis and inhibiting NLRP3 inflammasome activation.

Abstract This commentary highlights a research article published recently in Cell Stem Cell “Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy”. Generally, Lentini et al. reveal a strategy to fulfill in vivo glia-to-neuron reprogramming, which is a potential disease-modifying strategy for treatment of intractable seizures. Here, we describe exciting research advances in the treatment of intractable seizures based on this research article, summarizing its key findings, emphasizing its importance and providing further discussions. Further, issues worthy of further investigations are also postulated so that clinic translation can be better achieved.

Epilepsy, one of the most common neurological disorders, often is not well controlled by current pharmacological and surgical treatments. Sensory neuromodulation, including multi-sensory stimulation, auditory stimulation, olfactory stimulation, is a kind of novel noninvasive mind-body intervention and receives continued attention as complementary safe treatment of epilepsy. In this review, we summarize the recent advances of sensory neuromodulation, including enriched environment therapy, music therapy, olfactory therapy, other mind-body interventions, for the treatment of epilepsy based on the evidence from both clinical and preclinical studies. We also discuss their possible anti-epileptic mechanisms on neural circuit level and propose perspectives on possible research directions for future studies.

IntroductionArabinoxylan (AX) is a versatile polysaccharide that shows various effects in modulating gut microbiota and health. The influence of arabinoxylan carbohydrate structural feature and feruloylation on fermentability and the effect of modulation of gut microbiota of AX was not clear.MethodsArabinoxylans from rice bran and corn bran (RAX and CAX), and their deferulyolated counterpart dRAX and dCAX were fermented using an in vitro fermentation model. Structural information was determined based on monosaccharide composition. Gas production of fermentation products, SCFAs production, pH change, and microbiota change were measured.ResultsRAX and dRAX posessed lower A/X ratio compared with CAX and dCAX. The gas and total SCFAs production were lower in RAX and dRAX, and the butyrate production were higher in RAX and dRAX compared with CAX and dCAX. Butyrate production was lower at dRAX compared to RAX. On the other hand, butyrate production was higher in dCAX than in CAX. The microbiota shift were different for the four fibers.DiscussionThe AXs from rice have a higher A/X ratio than the AXs from maize, suggesting more branching and a more complex side chain. The structural difference was crucial for the difference in fermentation pattern. Different Bacteroides species are responsible for the utilization of rice AXs and corn AXs. Although feruloylation had a minor effect on the overall fermentation pattern, it significantly affected butyrate production and alpha diversity. dRAX promoted less butyrate than RAX, which is associated with a significantly lower amount of Faecalibacterium prausnitzi. dCAX promoted more butyrate than CAX, which may be associated with a lower amount of Bacteroides ovatus and a higher amount of Blautia in dCAX compared to CAX. The effects of feruloylation on the fermentation pattern and the resulted microbiota shift of AX varied depending on the carbohydrate structure.

IntroductionAutism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly representing impaired social communication. The etiology of ASD includes genetic and environmental risk factors. Rodent models containing ASD risk gene mutations or environmental risk factors, such as exposure to maternal inflammation, show abnormal behavior. Although zebrafish conserves many important brain structures of humans and has sophisticated and fine behaviors in social interaction, it is unknown whether the social behaviors of their offspring would be impaired due to exposure to maternal inflammation.MethodsWe exposed zebrafish to maternal immune activation (MIA) by injection with polyinosinic:polycytidylic acid [poly(I:C)], and screened their behaviors through social behavioral tests such as social preference and shoaling behavior tests. We compared phenotypes resulted from different ways of poly(I:C) exposure. RNA sequencing was performed to explore the differential expression genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein–protein interaction (PPI) network analysis was performed with the detected DEGs to find the concentrated pathways. Finally, we knocked out the fatty acid-binding protein 2 (fabp2), a key node of the concentrated PPI network, to find its rescues on the altered social behavior.ResultsWe reported here that MIA offspring born to mothers injected with poly(I:C) exhibited impaired social approach and social cohesion that mimicked human ASD phenotypes. Both maternal exposure and direct embryo exposure to poly(I:C) resulted in activations of the innate immune system through toll-like receptors 3 and 4. RNA-sequencing results from MIA brain tissues illustrated that the numbers of overexpressed genes were significantly more than that of underexpressed genes. GO and KEGG analyses found that MIA-induced DEGs were mainly concentrated in complement and coagulation cascade pathways. PPI network analyses suggested that villin-1 (vil1) pathway might play a key role in MIA-induced ASD. Knockout of fabp2 in F0 zebrafish rescued the social behavior deficits in MIA offspring.ConclusionsOverall, our work established an ASD model with assessable behavior phenotype in zebrafish and provided key insights into environmental risk factor in ASD etiology and the influence of fabp2 gene on ASD-like behavior.

Dyslipidemia, a condition implying high cardiovascular risks, has been widely studied on its potential nutrition interventions, including functional foods. This study aims to examine the effect of nattokinase monascus supplements (NMSs) on cardiovascular biomarkers and carotid intima-media thickness (CIMT) in patients with dyslipidemia. A total of 113 eligible subjects were randomly assigned to receive either NMSs or a placebo (55 and 58, respectively). After a 120-day intervention, there were significant mean absolute changes in total cholesterol (TC), low-density cholesterol (LDL-C), non-high-density cholesterol (non-HDL-C), and low-density cholesterol to high-density cholesterol ratio (LDL-C to HDL-C ratio), with values of −0.52 (95% CI: −0.51 to −0.54) mmol/L, −0.43 (95% CI: −0.45 to −0.41) mmol/L, −0.52 (95% CI: −0.52 to −0.52) mmol/L, and −0.29 (95% CI: −0.30 to −0.28) mmol/L, respectively, between the two groups. However, no significant differences were found in triglycerides (TGs), high-density cholesterol (HDL-C), and CIMT. Furthermore, the results for lipids and CIMT remained essentially unchanged after adjusting for various confounding factors using the analysis of covariance model. There were no significant differences in coagulation, liver function, renal function, or other indicators. No intervention-related adverse events, such as mouth ulcers, drooling, and stomach pain, were reported. The study results demonstrate that NMSs can ameliorate lipid levels (TC, LDL-C, non-HDL-C, and the LDL-C to HDL-C ratio) without the occurrence of adverse events. However, it did not significantly affect serum TG, HDL-C, and CIMT.

Diabetes mellitus is one of the most critical global health concerns, with a fast-growing prevalence. The incidence of diabetic vascular complications is also rapidly increasing, exacerbating the burden on individuals with diabetes and the consumption of public medical resources. Despite the overall improvements in the prevention, diagnosis, and treatment of diabetic microvascular complications in recent years, safe and effective alternative or adjunctive therapies are urgently needed. The mechanisms underlying diabetic vascular complications are complex, with hyperglycemia-induced oxidative stress and inflammation being the leading causes. Therefore, glycemic control, antioxidation, and anti-inflammation are considered the main targets for the treatment of diabetes and its vascular comorbidities. Vaccinium L. (Ericaceae) is a genus of plants enriched with polyphenolic compounds in their leaves and fruits. Vaccinium and its extracts have demonstrated good bioactivity in reducing blood glucose, oxidative stress, and inflammation, making them excellent candidates for the management of diabetes and diabetic vascular complications. Here, we review recent preclinical and clinical studies on the potential effect of Vaccinium on ameliorating diabetes and diabetic complications, particularly diabetic kidney disease and diabetic retinopathy.

Non-homologous end joining (cNHEJ) is a major pathway to repair double-strand breaks (DSBs) in DNA. Several core cNHEJ are involved in the progress of the repair such as KU70 and 80, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Artemis, X-ray repair cross-complementing protein 4 (XRCC4), DNA ligase IV, and XRCC4-like factor (XLF). Recent studies have added a number of new proteins during cNHEJ. One of the newly identified proteins is Paralogue of XRCC4 and XLF (PAXX), which acts as a scaffold that is required to stabilize the KU70/80 heterodimer at DSBs sites and promotes the assembly and/or stability of the cNHEJ machinery. PAXX plays an essential role in lymphocyte development in XLF-deficient background, while XLF/PAXX double-deficient mouse embryo died before birth. Emerging evidence also shows a connection between the expression levels of PAXX and cancer development in human patients, indicating a prognosis role of the protein. This review will summarize and discuss the function of PAXX in DSBs repair and its potential role in cancer development.

Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine at multiple phases of atherosclerosis in animals, but human studies are few and inconsistent. The aim of this study is to investigate the association of serum MCP-1 with all-cause and cardiovascular disease (CVD) mortality among coronary artery disease (CAD) patients and determine whether this biomarker can add secondary prognostic value to standard risk predictors.MCP-1 was measured at baseline in 1411 CAD patients who were 40-85 years of age. Cox proportional hazards regression models were used to estimate the association of MCP-1 levels with death risk.During a median follow-up of 3.3 years, 117 deaths were recorded, 88 of which were due to CVD. The multivariable-adjusted hazard ratios across tertiles of MCP-1 were 1.51 (95% confidence intervals [CI] 0.89-2.58), 1.00, and 2.11 (95% CI 1.31-3.40) for all-cause mortality, and 1.50 (95% CI 0.80-2.81), 1.00, and 2.21 (95% CI 1.27-3.87) for CVD mortality. The addition of serum MCP-1 to the fully adjusted model increased the C-index by 0.009 (p

Previous studies suggested that dietary fatty acids could affect blood lipids by interacting with genetic variations in fatty acid desaturase 1 (FADS1). However, little is known about their direct effects on coronary artery disease (CAD). The aim of this study was to evaluate whether dietary n-3 long-chain polyunsaturated fatty acids (LCPUFAs)-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could modulate the effect of FADS1 rs174547 polymorphism on CAD.FADS1 single-nucleotide polymorphisms rs174547 genotypes were measured in 440 CAD patients and 838 healthy controls. Dietary EPA and DHA intakes were assessed with a validated quantitative frequency food questionnaire. The association between FADS1 rs174547 and CAD was estimated using logistic regression under both dominant and additive genetic models. The interactions between rs174547 polymorphism and LCPUFAs were analyzed by using multiple logistic regression and the "genotype × n-3 LCPUFAs" interaction term was included into the model.We found that the minor T allele of FADS1 rs174547 increased CAD risk (OR = 1.36, 95%CIs 1.03-1.80), and observed significant interaction between rs174547 and dietary EPA intakes on CAD (P-interaction = 0.028). The T-allele was only associated with higher CAD risk among individuals with lower dietary EPA intakes, but not in those with higher EPA intakes. Similarly, significant interaction was also observed between rs174547 and dietary DHA intakes on CAD (P-interaction = 0.020).Dietary n-3 LCPUFA intakes could modulate the association between FADS1 rs174547 polymorphism and CAD. High dietary n-3 LCPUFA intakes could negate the unfavorable effect of genetic variation in FADS1 on CAD in middle-aged and elderly Chinese population.

Objectives. To evaluate whether serum interleukin-6 (IL-6) is associated with increased risk of mortality in coronary artery disease (CAD) patients. Methods. We performed a prospective cohort study of 718 CAD patients from the Guangzhou Cardiovascular Disease Cohort (GCDC) study. Multivariable-adjusted Cox proportional hazards regression analyses were used to examine the association between serum IL-6 with all-cause and cardiovascular mortality. Results. During the 1663 person-years of followup, the cumulative all-cause mortality and cardiovascular mortality were 6.5% (n=47) and 3.3% (n=24), respectively. The mean length of followup was 2.32±0.81 years. In the multivariable analyses, a one-SD increment in log-transformed serum IL-6 was positively associated with an increased risk of all-cause and cardiovascular mortality, with hazard ratios (HR) of 2.93 (95% CI, 2.11–4.08) and 2.04 (95% CI, 1.34–3.68) within the patients combined and 2.98 (95% CI, 2.12–4.18) and 3.10 (95% CI, 1.98–4.85) within males, respectively. Patients in the highest serum IL-6 tertile versus the lowest tertile were at higher risk of all-cause and cardiovascular mortality, with HR of 17.12 (95% CI 3.11–71.76) and 8.68 (95% CI, 1.88–37.51), respectively. Conclusions. In hospitalized patients with CAD, serum IL-6 is significantly associated with all-cause and cardiovascular mortality.

Background. Cardiometabolic risk factors significantly accelerate the progression of coronary artery disease (CAD); however, whether CAD patients in South China are aware of the prevalence of these risk factors is not clear yet. Methods. The study consisted of 2312 in-admission CAD patients from 2008 to 2011 in South China. Disease history including hypertension, dyslipidemia, and diabetes was relied on patients' self-reported records. Physical and clinical examinations were tested to assess the real prevalence of the cardiometabolic risk factors. Results. 57.9% of CAD patients had more than 3 cardiometabolic risk factors in terms of the metabolic syndrome. The self-known and real prevalence of hypertension, diabetes, and dyslipidemia were 56.6%, 28.3%, and 25.1% and 91.3%, 40.9%, and 92.0%, respectively. The awareness rates were 64.4%, 66.3%, and 28.5% for hypertension, diabetes, and dyslipidemia. The prevalence of cardiometabolic risk factors was significantly different among gender and among disease status. Conclusions. Most CAD patients in South China had more than three cardiometabolic risk factors. However, the awareness rate of cardiometabolic diseases was low, especially for dyslipidemia. Strategies of routine physical examination programs are needed for the early detection and treatment of cardiometabolic risk factors in order to prevent CAD progression and prognosis.

Astrocytes form extensive intercellular networks through gap junctions to support both biochemical and electrical coupling between adjacent cells. ATP-sensitive K(+) (K(ATP)) channels couple cell metabolic state to membrane excitability and are enriched in glial cells. Activation of astrocytic mitochondrial K(ATP) (mitoK(ATP)) channel regulates certain astrocytic functions. However, less is known about its impact on electrical coupling between directly coupled astrocytes ex vivo. By using dual patch clamp recording, we found that activation of mitoK(ATP) channel increased the electrical coupling ratio in brain slices. The electrical coupling ratio started to increase 3 min after exposure to Diazoxide, a mitoK(ATP) channel activator, peaked at 5 min, and maintained its level with little adaptation until the end of the 10-min treatment. Blocking the mitoK(ATP) channel with 5-hydroxydecanoate, inhibited electrical coupling immediately, and by 10-min, the ratio dropped by 71% of the initial level. Activation of mitoK(ATP) channel also decreased the latency time of the transjunctional currents by 50%. The increase in the coupling ratio resulting from the activation of the mitoK(ATP) channel in a single astrocyte was further potentiated by the concurrent inhibiting of the channel on the recipient astrocyte. Furthermore, Meclofenamic acid, a gap-junction inhibitor which completely blocked the tracer coupling, hardly reversed the impact of mitoK(ATP) channel's activation on electrical coupling (by 7%). The level of mitochondrial Connexin43, a gap junctional subunit, significantly increased by 70% in astrocytes after 10-min Diazoxide treatment. Phospho-ERK signals were detected in Connexin43 immunoprecipitates in the Diazoxide-treated astrocytes, but not untreated control samples. Finally, inhibiting ERK could attenuate the effects of Diazoxide on electrical coupling by 61%. These findings demonstrate that activation of astrocytic mitoK(ATP) channel upregulates electrical coupling between hippocampal astrocytes ex vivo. In addition, this effect is mainly via up-regulation of the Connexin43-constituted gap junction coupling by an ERK-dependent mechanism in the mitochondria.

Objective: Intermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis. Methods: In this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples. Results: Our results showed that IER longitudinally reduced the activity of obeserelated brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes. Conclusions: There was dynamical alteration of BGM axis (the communication of E. coli with specific brain regions) during the weight loss under the IER. [ABSTRACT FROM AUTHOR]

The 10 vol% ZrMgMo3O12/2024Al composites were fabricated using the powder metallurgy process and consolidation via vacuum hot pressing. The effects of the ball milling process and solution treatment time on the composites’ microstructure, Vickers hardness, and compressive properties were studied. Increasing the ball milling speed and extending the ball milling duration reduce the size of ZrMgMo3O12 particles, resulting in a more uniform dispersion within the aluminum matrix. Extending the solution treatment duration facilitates the dissolution of more primary Al2Cu phase into the aluminum matrix reducing the presence of coarse primary Al2Cu phase and increasing the number of fine Al2Cu precipitates formed during the aging process. The results indicated that an appropriate increase in ball milling speed, extension of ball milling duration, and solution treatment time can enhance the Vickers hardness and room temperature compressive strength of the composites. Specifically, the composites processed with a ball milling speed of 350 rpm for 6 h, a solid solution treatment at 495 °C for 24 h, and an aging treatment at 190 °C for 8 h exhibited a Vickers hardness of 277 HV and a compressive yield strength of 687 MPa, along with a compressive strain of 7.8 %.

Introduction: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly representing impaired social communication. The etiology of ASD includes genetic and environmental risk factors. Rodent models containing ASD risk gene mutations or environmental risk factors, such as exposure to maternal inflammation, show abnormal behavior. Although zebrafish conserves many important brain structures of humans and has sophisticated and fine behaviors in social interaction, it is unknown whether the social behaviors of their offspring would be impaired due to exposure to maternal inflammation. Methods: We exposed zebrafish to maternal immune activation (MIA) by injection with polyinosinic:polycytidylic acid [poly(I:C)], and screened their behaviors through social behavioral tests such as social preference and shoaling behavior tests. We compared phenotypes resulted from different ways of poly(I:C) exposure. RNA sequencing was performed to explore the differential expression genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis was performed with the detected DEGs to find the concentrated pathways. Finally, we knocked out the fatty acid-binding protein 2 (fabp2), a key node of the concentrated PPI network, to find its rescues on the altered social behavior. Results: We reported here that MIA offspring born to mothers injected with poly(I:C) exhibited impaired social approach and social cohesion that mimicked human ASD phenotypes. Both maternal exposure and direct embryo exposure to poly(I:C) resulted in activations of the innate immune system through toll-like receptors 3 and 4. RNA-sequencing results from MIA brain tissues illustrated that the numbers of overexpressed genes were significantly more than that of underexpressed genes. GO and KEGG analyses found that MIA-induced DEGs were mainly concentrated in complement and coagulation cascade pathways. PPI network analyses suggested that villin-1 (vil1) pathway might play a key role in MIA-induced ASD. Knockout of fabp2 in F0 zebrafish rescued the social behavior deficits in MIA offspring. Conclusions: Overall, our work established an ASD model with assessable behavior phenotype in zebrafish and provided key insights into environmental risk factor in ASD etiology and the influence of fabp2 gene on ASD-like behavior. [ABSTRACT FROM AUTHOR]

Negative thermal expansion (NTE) ceramics Sm0.85Zn0.15MnO3 (SZMO) and ZrMgMo3O12 (ZMMO) were selected to prepare Sm0.85Zn0.15MnO3-ZrMgMo3O12/Al-20Si (SZMO-ZMMO/Al-20Si) composites using ball milling and vacuum heating-press sintering processes in this study. The synergistic effect of the SZMO and ZMMO NTE ceramic reinforcements on the microstructure, mechanical properties, and coefficient of thermal expansion (CTE) of the composites was investigated. The results show that the processes of ball milling and sintering did not induce the decomposition of SZMO or ZMMO NTE ceramic reinforcements, nor did they promote a reaction between the Al-20Si matrix and SZMO or ZMMO NTE ceramic reinforcements. However, the excessive addition of SZMO and ZMMO NTE ceramics led to their aggregation within the composite. Adding a small amount of SZMO in combination with ZMMO effectively increased hardness and yield strength while reducing CTE in the Al-20Si alloy. The improvement in strength was primarily provided by SZMO, while the inhibition effect on CTE was primarily provided by ZMMO. An evaluation parameter denoted as α was proposed to evaluate the synergy effects of SZMO and ZMMO NTE ceramic reinforcements on the mechanical properties and CTE of the composites. Based on this parameter, among all composites fabricated, adding 2.5 vol% SZMO NTE ceramic and 10 vol% ZMMO NTE ceramic resulted in an optimal balance between CTE and strength for these composites with a compressive yield strength of 349.72 MPa and a CTE of 12.55 × 10−6/K, representing a significant increase in yield strength by 79.20% compared to that of Al-20Si alloy along with a notable reduction in CTE by 26.44%.

NbxCu0.3Cr2Fe2Ni3Mn2 (x = 0, 0.2, and 0.4; named Nb0, Nb0.2, and Nb0.4, respectively) high-entropy alloys (HEAs) were prepared using arc melting process. The effect of Nb content on the microstructure and corrosion behavior of HEAs in HNO3 solution was studied. Nb0 and Nb0.2 alloys are composed of a single FCC phase, whereas Nb0.4 alloy is composed of FCC + Laves phase. In 10% and 30% HNO3 solutions, the immersion corrosion rate and potentiodynamic polarization corrosion rate of the HEAs showed a trend of first increasing and then decreasing with the increase in Nb content. After 30 days of immersion corrosion, Nb0.4 alloy exhibited the lowest average corrosion rate in 10% and 30% HNO3 solutions, with values of 4.6 × 10−3 and 2.8 × 10−3 mm/yr, respectively. Potentiodynamic polarization corrosion showed that Nb0.4 alloy also had the lowest corrosion current density and average corrosion rate in 10% and 30% HNO3 solutions, with values of 1.74 × 10−5, 5.56 × 10−6 A/cm2 and 0.18, 0.06 mm/yr, respectively. In addition, The Rpo of Nb0.4 alloy are 91 times and 8737 times higher than those of Nb0 alloy, respectively, and has the largest relative thickness of the passivation film. Therefore, Nb0.4 alloy exhibited the best resistance to HNO3 corrosion, mainly because adding Nb reduced the segregation of Cu, thereby weakening the corrosion effect of the primary battery. Meanwhile, Nb could play a stabilizing role in the passivation film of the alloy. The formation of corrosion-resistant Laves phase also correspondingly improved the HNO3 corrosion resistance of the alloy.