Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology, cognition, and behavior in APP/PS1 mice.

JOURNAL/nrgr/04.03/01300535-202502000-00030/figure1/v/2024-05-28T214302Z/r/image-tiff In patients with Alzheimer's disease, gamma-glutamyl transferase 5 (GGT5) expression has been observed to be downregulated in cerebrovascular endothelial cells. However, the functional role of GGT5 in the development of Alzheimer's disease remains unclear. This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer's disease, as well as the underlying mechanism. We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer's disease (Aß1-42-treated hCMEC/D3 and bEnd.3 cells), as well as in the APP/PS1 mouse model. Additionally, injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits. Interestingly, increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-ß in the brains of APP/PS1 mice. This effect may be attributable to inhibition of the expression of ß-site APP cleaving enzyme 1, which is mediated by nuclear factor-kappa B. Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer's disease pathogenesis, and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice. These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer's disease.

Efficacy of pulpotomy for permanent teeth with carious pulp exposure: A systematic review and meta-analysis of randomized controlled trials.

This meta-analysis aims to assess the success rate of pulpotomy in the treatment of permanent teeth with carious pulp exposure and to compare the efficacy of different capping materials. Randomized controlled trials were searched in PubMed, EMBASE, Web of Science, Clinicaltrial.gov, and Cochrane Library until August 31, 2023. The pooled success rate was estimated in the overall population and in subgroups. Additional analyses comparing different capping materials using odds ratio (OR) and 95% confidence interval (95%CI) were performed. The certainty of evidence was graded using the GRADE approach. A total of 25 randomized trials with an average follow-up duration ≥ 12 months were finally included. The overall success rate of pulpotomy was 86.7% (95%CI: 82.0-90.7%). The success rate was not significantly affected by root development, pulpotomy type, and follow-up duration. Teeth with irreversible pulpitis had a relatively lower success rate than teeth with normal pulp or reversible pulpitis (82.4% [95%CI: 74.6-89.0%] vs 92.0% [95%CI: 87.9-95.4%], P = 0.013). Directly compared to conventional calcium hydroxide, mineral trioxide aggregate (88.2% vs 79.1%, OR = 2.41, 95%CI: 1.28-4.51, P = 0.006) and Biodentine (97.5% vs 82.9%, OR = 6.03, 95%CI: 0.97-37.6, P = 0.054) had higher successful rates. No significant difference between MTA and other biomaterials was found. The results were graded as very low to low certainty of evidence. In conclusion, pulpotomy is an effective treatment of permanent teeth with carious pulp exposure. Mineral trioxide aggregate and Biodentine can be recommended with more favorable outcomes as capping materials.

A comprehensive review of sustainable solutions for reusing wind turbine blade waste materials.

By 2050, approximately 43 million tons of wind-turbine blade (WTB) waste materials will have accumulated, emphasizing the critical importance of effective waste management strategies for WTBs at the end of their life cycle to ensure sustainability. Comparing current WTB waste management methods, reuse emerges as a highly-sustainable method that can also serve as a sustainable solution to environmental challenges, including global warming and natural resource depletion associated with civil engineering activities. This paper presents a comprehensive review of sustainable solutions for reusing WTB waste materials in civil engineering applications. Repurposing WTB waste materials as structural elements in housing, urban furniture, recreational facilities, and slow-traffic infrastructure can be a viable option. WTB waste can also be utilized in powder, fiber, and aggregate forms as an eco-friendly material for construction and pavement (e.g., mortar, concrete, asphalt) to replace cement and natural resource aggregates while meeting necessary strength and performance standards. Through a detailed analysis of reusing WTB waste materials, economic and environmental challenges are also discussed. According to the findings, the properties of mortar, concrete, and asphalt can be affected by the type, shape, and content of fibers, polymers, and impurities present in the blades, as well as the cutting direction. Furthermore, while reuse is considered a sustainable end-of-life (EoL) option for WTB waste management from both economic and environmental perspectives, further research is required to fully understand the environmental consequences of this method.

Six-Cyclic Crown Ether-Type Pillar[5]arene: Enhanced Binding Ability to Bispyridinium Derivatives.

A six-cyclic crown ether-type pillar[5]arene was synthesized, and the five ethylene oxide loops were located outside the cavity and not affected by temperature changes which was confirmed by variable-temperature NMR experiment in DMSO-d6 and CDCl3 and 2D 1H-1H NOESY experiment in CDCl3. The six-cyclic pillar[5]-crown also showed greater binding ability of host-guest with bis(pyridinium) derivatives than conventional alkoxy pillar[5]arenes that illustrated through 1H NMR titration spectroscopic experiment in acetone-d6/CDCl3 (1:1) and UV-vis titration experiments in CHCl3 at room temperature. The five benzocrown ethers at the periphery were able to bind metal cations by 1H NMR titration spectroscopic experiment in CD2Cl2/methanol-d4(9:1).

New insight into the spatiotemporal distribution and ecological risk assessment of endocrine-disrupting chemicals in the Minjiang and Tuojiang rivers: perspective of watershed landscape patterns.

This study evaluated the pollution characteristics, spatiotemporal distribution, and ecological risks of eight endocrine-disrupting chemicals (EDCs) in the Minjiang and Tuojiang rivers. Utilizing 3S technology (ArcGIS, remote sensing, GPS) and Fragstats, the research calculated eight landscape pattern indices related to land use types along the Minjiang river and established correlations between landscape factors and EDC distribution through stepwise multiple regression. The results indicated that bisphenol A (BPA) and nonylphenol (NP) were the most concerning EDCs, with detection frequencies of 97-100% and peak concentrations up to 63.35 ng L-1, primarily located in the middle and lower reaches of the Minjiang river and the upper reaches of the Tuojiang river. There was a significant correlation between the spatial distribution of pollutants and landscape patterns, where increased fragmentation, a higher number of patches, and complex patch shapes within a 10-kilometer buffer zone were associated with elevated levels of river pollution. By integrating four classical mathematical models to fit curves for acute and chronic toxicity data of BPA and NP, the findings suggested that BPA posed a higher ecological risk. This interdisciplinary research provided essential theoretical insights for investigating river pollution and its influencing factors, offering a new perspective on simultaneous river pollution control, urban functional zoning, and adjustment of watershed landscape spatial patterns from an urban planning standpoint.

Umbilical cord mesenchymal stem cell exosomes alleviate necrotizing enterocolitis in neonatal mice by regulating intestinal epithelial cells autophagy.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease that affects premature infants. Although mounting evidence supports the therapeutic effect of exosomes on NEC, the underlying mechanisms remain unclear. AIM: To investigate the mechanisms underlying the regulation of inflammatory response and intestinal barrier function by umbilical cord mesenchymal stem cell (UCMSCs) exosomes, as well as their potential in alleviating NEC in neonatal mice. METHODS: NEC was induced in 5-d-old C57BL/6 pups through hypoxia and gavage feeding of formula containing lipopolysaccharide (LPS), after which the mice received human UCMSC exosomes (hUCMSC-exos). The control mice were allowed to breastfeed with their dams. Ileal tissues were collected from the mice and analyzed by histopathology and immunoblotting. Colon tissues were collected from NEC neonates and analyzed by immunofluorescence. Molecular biology and cell culture approaches were employed to study the related mechanisms in intestinal epithelial cells. RESULTS: We found that autophagy is overactivated in intestinal epithelial cells during NEC, resulting in reduced expression of tight junction proteins and an increased inflammatory response. The ability of hUCMSC-exos to ameliorate NEC in a mouse model was dependent on decreased intestinal autophagy. We also showed that hUCMSC-exos alleviate the inflammatory response and increase migration ability in intestinal epithelial cells induced by LPS. CONCLUSION: These results contribute to a better understanding of the protective mechanisms of hUCMSC-exos against NEC and provide a new theoretical and experimental foundation for NEC treatment. These findings also enhance our understanding of the role of the autophagy mechanism in NEC, offering potential avenues for identifying new therapeutic targets.

Synergistic effect of additional anlotinib and immunotherapy as second-line or later-line treatment in pancreatic cancer: A retrospective cohort study.

Background: Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of a second-line or later-line treatment strategy. We aimed to analyze the efficacy and safety of additional anlotinib, specifically anlotinib in combination with immunotherapy, in patients with PDAC who have failed first-line therapy. Methods: Patients with pathological diagnosis of PDAC were additionally treated with anlotinib, and some patients were treated with anti-PD-1 agents at the same time, which could be retrospectively analyzed. The efficacy and safety of additional anlotinib were evaluated. Results: A total of 23 patients were included. In patients treated with additional anlotinib, the overall median progression-free survival (PFS) was 1.8 months and the median overall survival (OS) was 6.3 months, regardless of anti-PD-1 agents. Among patients receiving additional anlotinib in combination with anti-PD-1 agents, median PFS and OS were 1.8 and 6.5 months, respectively. Adverse events (AEs) were observed in 16 patients (69.6%). In patients treated with additional anlotinib, the majority of AEs were grade 1-3. Univariate analysis revealed that patients with baseline red blood cell distribution width (RDW) <14% treated with additional anlotinib plus anti-PD-1 agents had significantly longer OS than patients with baseline RDW ≥14% (p = 0.025). Patients with additional anlotinib plus anti-PD-1 agents as second-line therapy had a longer OS than those treated as later-line therapy (p = 0.012). Multivariate analysis showed that baseline RDW was the only independent risk factor for OS (p = 0.042). Conclusion: The combination of anlotinib and immunotherapy represents an effective add-on therapy with tolerable AEs as second- or later-line therapy in patients with PDAC, particularly in patients with baseline RDW <14%.

An efficient and high-water-content enzymatic esterification method for the synthesis of ß-sitosterol conjugated linoleate via a sodium citrate-based three-liquid-phase system.

Three-liquid-phase systems (TLPSs) are novel interfacial enzymatic reaction systems that have been successfully applied in many valuable reactions. However, these systems are suitable only for hydrolysis reactions and not for more widely used esterification reactions. Surprisingly, our recent research revealed that two water-insoluble substrates (ß-sitosterol and conjugated linoleic acid) could be rapidly esterified in this system. The initial rate of the esterification reaction in the TLPS based on sodium citrate was enhanced by approximately 10-fold relative to that in a traditional water/n-hexane system. The special emulsion structure (S/W1/W2 emulsion) formed may be vital because it not only provides a larger reaction interface but also spontaneously generates a middle phase that might regulate water activity to facilitate esterification. Furthermore, the lipase-enriched phase could be reused at least 8 times without significant loss of catalytic efficiency. Therefore, this TLPS is an ideal enzymatic esterification platform for ester synthesis because it is efficient, convenient to use, and cost-effective.

Assessment of cardiorespiratory fitness in Chinese patients with early to mid-stage Parkinson's disease.

Introduction In recent years, exercise has been increasingly recognised as an effective and promising non-pharmacological intervention to improve physical function in patients with Parkinson's disease (PD). Cardiorespiratory fitness (CRF) is an objective measure of a person's ability to perform aerobic exercise. Therefore, it is necessary to evaluate the CRF of patients with PD.However, the CRF of Chinese patients with PD is deficient.This study is to evaluate cardiorespiratory fitness in patients with early to mid-stage PD by cardiopulmonary exercise test(CPET) on a stationary cycle ergometer; Methods:To compare the differences in each index of the CPET between the two groups of subjects; general data such as disease duration, medication use and exercise habits were also collected.Results:1)Finally, 36 PD patients and 12 healthy controls successfully completed the CPET without any adverse events.2)The V'O2peak, Metspeak, RERpeak, MVVpeak, Wpeak, HRpeak, HRpeak/pre,percentage of HRR-1 min decay > 12 bpm,SBPpeak in the PD group were lower than those in the control group(p < 0.05,each). Detailed data:V'O2peak(15.7 ± 4.5vs21.5 ± 3.6ml/kg/min,p < 0.01),Metspeak(4.5 ± 1.3 vs 6.1 ± 1.0,p < 0.01),RERpeak(1.04 ± 0.10 vs 1.15 ± 0.10,p = 0.001),MVVpeak(37.22 ± 11.58 vs 53.00 ± 16.85L/min,p = 0.009),Wpeak(49.17 ± 29.72vs49.17 ± 29.72W,p < 0.01),HRpeak(111.08 ± 16.67 vs111.08 ± 16.67bpm,p < 0.01),HRpeak/pre(71.19 ± 10.06 vs96.00 ± 21.13,p = 0.002),percentage of HRR-1min decay > 12bpm(33.3% vs 100%,p < 0.01),SBP(155.81 ± 31.83 vs 175.83 ± 17.84mmHg,p = 0.01).3)Divided PD patients into high V'O2peak group(V'O2peak ≥ 15 mL/kg/min) and low V'O2peak group(V'O2peak < 15 mL/kg/min). The age of patients, Hoehn-Yahr grade and incidence of symptom fluctuation in high V'O2peak group were lower(p < 0.05,respectively),percentage of males and percentage of HRR-1 min decay > 12 bpm were higher(p < 0.05,respectively);p < 0.05 is considered a statistically significant difference.Detailed data:age of patients(61.05 ± 6.93vs68.57 ± 7.99years,p = 0.005),Hoehn-Yahr grade(1.75 ± 0.48 vs 2.18 ± 0.64,p = 0.028),incidence of symptom fluctuation(59.1 vs 92.9%,p = 0.03),percentage of males(77.7 vs 42.9%,p = 0.041),percentage of HRR-1 min decay > 12 bpm(50 vs 7.1%,p = 0.008). Conclusions:CPET were safe to perform and the cardiorespiratory fitness is significantly reduced in patients with early and middle stage Parkinson's disease.Patients with PD presented blunted HR and SBP responses to exercise test. Females, older age, fluctuating symptoms, high H-Y staging, and higher ADL may be associated with lower oxygen uptake.

Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study.

BACKGROUND: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of prenatally diagnosed developmental malformation. This study aimed to assess the relationship between maternal diseases and CAKUT in offspring. METHODS: This retrospective study enrolled all pregnant women registered from January 2020 to December 2022 at one medical center. Medical information on maternal noncommunicable diseases, including obesity, hypertension, diabetes mellitus, kidney disease, hyperthyroidism, hypothyroidism, psychiatric disease, epilepsy, cancer, and autoimmune disease was collected. Based on the records of ultrasound scanning during the third trimester, the diagnosis was classified as isolated urinary tract dilation (UTD) or kidney anomalies. Multivariate logistic regression was performed to establish models to predict antenatal CAKUT. RESULTS: Among the 19,656 pregnant women, perinatal ultrasound detected suspicious CAKUT in 114 (5.8/1000) fetuses, comprising 89 cases with isolated UTD and 25 cases with kidney anomalies. The risk of antenatal CAKUT was increased in the fetuses of mothers who experienced gestational diabetes, thyroid dysfunction, neuropsychiatric disease, anemia, ovarian and uterine disorders. A prediction model for isolated UTD was developed utilizing four confounding factors, namely gestational diabetes, gestational hypertension, maternal thyroid dysfunction, and hepatic disease. Similarly, a separate prediction model for kidney anomalies was established based on four distinct confounding factors, namely maternal thyroid dysfunction, gestational diabetes, disorders of ovarian/uterine, and kidney disease. CONCLUSIONS: Isolated UTD and kidney anomalies were associated with different maternal diseases. The results may inform the clinical management of pregnancy and highlight potential differences in the genesis of various subtypes of CAKUT.

Application of Emerging Teaching Models in Dental Education: A Systematic Review and Meta-Analysis.

INTRODUCTION AND AIMS: As an experimental teaching method, emerging learning methods including problem-based learning (PBL), case-based learning, team-based learning and flipped classroom (FC) have been widely applied in dental education. This study aims to evaluate the effect of these teaching methods on dental education performance compared to traditional lecture-based learning (LBL). METHODS: The search was carried out in April 2024 in PubMed, EMBASE, Web of Science, and Cochrane Library. All randomized controlled trials were included and the methodological quality assessment was based on the guidelines described in the Cochrane Handbook for Systematic Reviews, followed by a meta-analysis using Stata 14.0 software. Using standard mean deviation (SMD) and 95% confidence interval (95% CI) to determine the effectiveness of emerging teaching methods and LBL in all dental disciplines. Meta-regression was used to analyse sources of heterogeneity. Sensitivity analysis was performed to determine the stability, and Begg's analysis was used to determine whether there is publication bias. RESULTS: A total of 29 randomized controlled trials including 3502 students were included. The results indicate that emerging educational methods have a significantly positive effect on achieving higher scores (SMD = 0.48, 95% CI = 0.34-0.62, P < .001), whether it was theoretical scores (SMD = 0.52, 95% CI = 0.32-0.72, P < .001) or skill scores (SMD = 0.45, 95% CI = 0.15-0.76, P < .001). Compared to LBL, PBL (SMD = 0.33, 95% CI = 0.01-0.65, P = .045) and FC (SMD = 0.50, 95% CI = 0.31-0.69, P < .001) can both significantly improve students' academic performance. CONCLUSION: Compared to LBL, emerging educational methods (PBL, case-based learning, and FC) have significantly improved the learning effectiveness of dental students. These emerging educational methods can be advocated and popularized as routine teaching methods. CLINICAL RELEVANCE: This study is the first meta-analysis of the effects of emerging teaching methods in dental education which shows great impact of emerging teaching methods on students' development.

Lasso-Cox interpretable model of AFP-negative hepatocellular carcinoma.

BACKGROUND: In AFP-negative hepatocellular carcinoma patients, markers for predicting tumor progression or prognosis are limited. Therefore, our objective is to establish an optimal predicet model for this subset of patients, utilizing interpretable methods to enhance the accuracy of HCC prognosis prediction. METHODS: We recruited a total of 508 AFP-negative HCC patients in this study, modeling with randomly divided training set and validated with validation set. At the same time, 86 patients treated in different time periods were used as internal validation. After comparing the cox model with the random forest model based on Lasso regression, we have chosen the former to build our model. This model has been interpreted with SHAP values and validated using ROC, DCA. Additionally, we have reconfirmed the model's effectiveness by employing an internal validation set of independent periods. Subsequently, we have established a risk stratification system. RESULTS: The AUC values of the Lasso-Cox model at 1, 2, and 3 years were 0.807, 0.846, and 0.803, and the AUC values of the Lasso-RSF model at 1, 2, and 3 years were 0.783, 0.829, and 0.776. Lasso-Cox model was finally used to predict the prognosis of AFP-negative HCC patients in this study. And BCLC stage, gamma-glutamyl transferase (GGT), diameter of tumor, lung metastases (LM), albumin (ALB), alkaline phosphatase (ALP), and the number of tumors were included in the model. The validation set and the separate internal validation set both indicate that the model is stable and accurate. Using risk factors to establish risk stratification, we observed that the survival time of the low-risk group, the middle-risk group, and the high-risk group decreased gradually, with significant differences among the three groups. CONCLUSION: The Lasso-Cox model based on AFP-negative HCC showed good predictive performance for liver cancer. SHAP explained the model for further clinical application.

The Combination of Gefitinib and Acetaminophen Exacerbates Hepatotoxicity via ROS-Mediated Apoptosis.

Gefitinib is the well-tolerated first-line treatment of non-small cell lung cancer. As it need for analgesics during oncology treatment, particularly in the context ofthe coronavirus disease, where patients are more susceptible to contract high fever and sore throat. This has increased the likelihood of taking both gefitinib and antipyretic analgesic acetaminophen (APAP). Given that gefitinib and APAP overdose can predispose patients to liver injury or even acute liver failure, there is a risk of severe hepatotoxicity when these two drugs are used concomitantly. However, little is known regarding their safety at therapeutic doses. This study simulated the administration of gefitinib and APAP at clinically relevant doses in an animal model and confirmed that gefitinib in combination with APAP exhibited additional hepatotoxicity. We found that gefitinib plus APAP significantly exacerbated cell death, whereas each drug by itself had little or minor effect on hepatocyte survival. Mechanistically, combination of gefitinib and APAP induces hepatocyte death via the apoptotic pathway obviously. Reactive oxygen species (ROS) generation and DNA damage accumulation are involved in hepatocyte apoptosis. Gefitinib plus APAP also promotes the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated the antioxidant factor, Nuclear factor erythroid 2-related factor 2 (Nrf2), by inhibiting p62 expression. Taken together, this study revealed the potential ROS-mediated apoptosis-dependent hepatotoxicity effect of the combination of gefitinib and APAP, in which the p62/Keap1/Nrf2 signaling pathway participates and plays an important regulatory role.

Role of dynamin-related protein 1-dependent mitochondrial fission in drug-induced toxicity.

Dynamin-related protein 1 (DRP1) is an essential controller of mitochondrial fission whose activity is tightly controlled to ensure balanced mitochondrial dynamics and maintain internal cellular homeostasis. Growing evidence suggests that DRP1-dependent mitochondrial fission plays a role in drug-induced toxicity (DIT). Therefore, understanding the molecular mechanisms underlying DIT and the precise regulation of DRP1 function will inform the development of potential therapeutic treatments for DIT. This review comprehensively summarizes the diverse DITs and their potential mechanism associated with DRP1-dependent mitochondrial fission and discusses in vivo and in vitro model studies of toxicity protection targeting DRP1.

Changes in seminal plasma microecological dynamics and the mechanistic impact of core metabolite hexadecanamide in asthenozoospermia patients.

Asthenozoospermia (AZS) is a prevalent contributor to male infertility, characterized by a substantial decline in sperm motility. In recent years, large-scale studies have explored the interplay between the male reproductive system's microecology and its implications for reproductive health. Nevertheless, the direct association between seminal microecology and male infertility pathogenesis remains inconclusive. This study used 16S rDNA sequencing and multi-omics analysis to conduct a comprehensive investigation of the seminal microbial community and metabolites in AZS patients. Patients were categorized into four distinct groups: Normal, mild AZS (AZS-I), moderate AZS (AZS-II), and severe AZS (AZS-III). Microbiome differential abundance analysis revealed significant differences in microbial composition and metabolite profiles within the seminal plasma of these groups. Subsequently, patients were classified into a control group (Normal and AZS-I) and an AZS group (AZS-II and AZS-III). Correlation and cross-reference analyses identified distinct microbial genera and metabolites. Notably, the AZS group exhibited a reduced abundance of bacterial genera such as Pseudomonas, Serratia, and Methylobacterium-Methylorubrum in seminal plasma, positively correlating with core differential metabolite (hexadecanamide). Conversely, the AZS group displayed an increased abundance of bacterial genera such as Uruburuella, Vibrio, and Pseudoalteromonas, with a negative correlation with core differential metabolite (hexadecanamide). In vitro and in vivo experiments validated that hexadecanamide significantly enhanced sperm motility. Using predictive metabolite-targeting gene analysis and single-cell transcriptome sequencing, we profiled the gene expression of candidate target genes PAOX and CA2. Protein immunoblotting techniques validated the upregulation protein levels of PAOX and CA2 in sperm samples after hexadecanamide treatment, enhancing sperm motility. In conclusion, this study uncovered a significant correlation between six microbial genera in seminal plasma and the content of the metabolite hexadecanamide, which is related to AZS. Hexadecanamide notably enhances sperm motility, suggesting its potential integration into clinical strategies for managing AZS, providing a foundational framework for diagnostic and therapeutic advancements.

Macrophage polarisation and inflammatory mechanisms in atherosclerosis: Implications for prevention and treatment.

Atherosclerosis is a chronic inflammatory disease characterised by plaque accumulation in the arteries. Macrophages are immune cells that are crucial in the development of atherosclerosis. Macrophages can adopt different phenotypes, with the M1 phenotype promoting inflammation while the M2 phenotype counteracting it. This review focuses on the factors that drive the polarisation of M1 macrophages towards a pro-inflammatory phenotype during AS. Additionally, we explored metabolic reprogramming mechanisms and cytokines secretion by M1 macrophages. Hyperlipidaemia is widely recognised as a major risk factor for atherosclerosis. Modified lipoproteins released in the presence of hyperlipidaemia can trigger the release of cytokines and recruit circulating monocytes, which adhere to the damaged endothelium and differentiate into macrophages. Macrophages engulf lipids, leading to the formation of foam cells. As atherosclerosis progresses, foam cells become the necrotic core within the atherosclerotic plaques, destabilising them and triggering ischaemic disease. Furthermore, we discuss recent research focusing on targeting macrophages or inflammatory pathways for preventive or therapeutic purposes. These include statins, PCSK9 inhibitors, and promising nanotargeted drugs. These new developments hold the potential for the prevention and treatment of atherosclerosis and its related complications.

Distance-related functional reorganization predicts motor outcome in stroke patients.

BACKGROUND: Analyzing distance-dependent functional connectivity density (FCD) yields valuable insights into patterns of brain activity. Nevertheless, whether alterations of FCD in non-acute stroke patients are associated with the anatomical distance between brain regions remains unclear. This study aimed to explore the distance-related functional reorganization in non-acute stroke patients following left and right hemisphere subcortical lesions, and its relationship with clinical assessments. METHODS: In this study, we used resting-state fMRI to calculate distance-dependent (i.e., short- and long-range) FCD in 25 left subcortical stroke (LSS) patients, 22 right subcortical stroke (RSS) patients, and 39 well-matched healthy controls (HCs). Then, we compared FCD differences among the three groups and assessed the correlation between FCD alterations and paralyzed motor function using linear regression analysis. RESULTS: Our findings demonstrated that the left inferior frontal gyrus displayed distance-independent FCD changes, while the bilateral supplementary motor area, cerebellum, and left middle occipital gyrus exhibited distance-dependent FCD alterations in two patient subgroups compared with HCs. Furthermore, we observed a positive correlation between increased FCD in the bilateral supplementary motor area and the motor function of lower limbs, and a negative correlation between increased FCD in the left inferior frontal gyrus and the motor function of both upper and lower limbs across all stroke patients. These associations were validated by using a longitudinal dataset. CONCLUSIONS: The FCD in the cerebral and cerebellar cortices shows distance-related changes in non-acute stroke patients with motor dysfunction, which may serve as potential biomarkers for predicting motor outcomes after stroke. These findings enhance our comprehension of the neurobiological mechanisms driving non-acute stroke. TRIAL REGISTRATION: All data used in the present study were obtained from a research trial registered with the ClinicalTrials.gov database (NCT05648552, registered 05 December 2022, starting from 01 January 2022).

Quorum-Sensing Signal DSF Inhibits the Proliferation of Intestinal Pathogenic Bacteria and Alleviates Inflammatory Response to Suppress DSS-Induced Colitis in Zebrafish.

The imbalance of gut microbiota is an important factor leading to inflammatory bowel disease (IBD). Diffusible signal factor (DSF) is a novel quorum-sensing signal that regulates bacterial growth, metabolism, pathogenicity, and host immune response. This study aimed to explore the therapeutic effect and underlying mechanisms of DSF in a zebrafish colitis model induced by sodium dextran sulfate (DSS). The results showed that intake of DSF can significantly improve intestinal symptoms in the zebrafish colitis model, including ameliorating the shortening of the intestine, reducing the increase in the goblet cell number, and restoring intestinal pathological damage. DSF inhibited the upregulation of inflammation-related genes and promoted the expression of claudin1 and occludin1 to protect the tightness of intestinal tissue. The gut microbiome analysis demonstrated that DSF treatment helped the gut microbiota of the zebrafish colitis model recover to normal at the phylum and genus levels, especially in terms of pathogenic bacteria; DSF treatment downregulated the relative abundance of Aeromonas hydrophila and Staphylococcus aureus, and it was confirmed in microbiological experiments that DSF could effectively inhibit the colonization and infection of these two pathogens in the intestine. This study suggests that DSF can alleviate colitis by inhibiting the proliferation of intestinal pathogens and inflammatory responses in the intestine. Therefore, DSF has the potential to become a dietary supplement that assists in the antibiotic and nutritional treatment of IBD.

Fatigue Analysis of Composite Bolted Joints under Random and Constant Amplitude Fatigue Loadings.

This paper attempts to analyze the random fatigue life and failure modes of joints using two calculation methods. Three kinds of tests were carried out, which were the static test, constant amplitude fatigue test and the random fatigue test, and four kinds of joints were designed. After the static test, the joint was subjected to a constant amplitude fatigue test by selecting different percentages of load according to the static strength. In order to predict the random fatigue life more precisely, two calculation methods were carried out, which were the linear cumulative damage method and the equivalent loading finite element method. Based on the linear cumulative damage hypothesis, the fatigue life of the joint was established as a function of the load amplitude, and then, the random life prediction was calculated by the amplitude distribution of the random loading. Another method was the equivalent loading method, which was to obtain the equivalent constant amplitude fatigue loading of the random loading spectrum. The finite element model was established based on the stiffness and strength degradation rule. The equivalent random life and fatigue failure modes of the joint were modeled. The two life prediction methods show good agreement with the fatigue experimental result, and all prediction results were included in a scatter band of the factor of 2.