Enhancing Rab7 Activity by Inhibiting TBC1D5 Expression Improves Mitophagy in Alzheimer's Disease Models.

Background: Mitochondrial dysfunction exists in Alzheimer's disease (AD) brain, and damaged mitochondria need to be removed by mitophagy. Small GTPase Rab7 regulates the fusion of mitochondria and lysosome, while TBC1D5 inhibits Rab7 activation. However, it is not clear whether the regulation of Rab7 activity by TBC1D5 can improve mitophagy and inhibit AD progression. Objective: To investigate the role of TBC1D5 in mitophagy and its regulatory mechanism for Rab7, and whether activation of mitophagy can inhibit the progression of AD. Methods: Mitophagy was determined by western blot and immunofluorescence. The morphology and quantity of mitochondria were tracked by TEM. pCMV-Mito-AT1.03 was employed to detect the cellular ATP. Amyloid-ß secreted by AD cells was detected by ELISA. Co-immunoprecipitation was used to investigate the binding partner of the target protein. Golgi-cox staining was applied to observe neuronal morphology of mice. The Morris water maze test and Y-maze were performed to assess spatial learning and memory, and the open field test was measured to evaluate motor function and anxiety-like phenotype of experimental animals. Results: Mitochondrial morphology was impaired in AD models, and TBC1D5 was highly expressed. Knocking down TBC1D5 increased the expression of active Rab7, promoted the fusion of lysosome and autophagosome, thus improving mitophagy, and improved the morphology of hippocampal neurons and the impaired behavior in AD mice. Conclusions: Knocking down TBC1D5 increased Rab7 activity and promoted the fusion of autophagosome and lysosome. Our study provided insights into the mechanisms that bring new possibilities for AD therapy targeting mitophagy.

Association of in situ thrombus within the patent foramen ovale and patients with migraine: A prospective cohort study.

Background: Patent foramen ovale (PFO) is associated with migraine; however, the mechanism of PFO-associated migraine is not well known; additionally, percutaneous closure is controversial. This study aimed to investigate in situ thrombi within the PFO and explore the possible predictors of the effectiveness of PFO closure in migraineurs. Methods: This prospective cohort study included 48 asymptomatic patients and 92 migraineurs with PFO. Optical coherence tomography (OCT) was used to evaluate the PFO microstructure. Only migraineurs underwent percutaneous closure. Migraineurs were divided into two cohorts based on the presence of a thrombus within the PFO. The symptoms were assessed at the 12-month follow-up visit. Predictors were evaluated employing multivariate logistic regression and receiver operating characteristic curve analyses. Results: In situ thrombi within PFO were identified in 69 migraineurs and in two asymptomatic patients (76.7 % vs. 4.3 %; P < 0.001). Additionally, endocardial irregularity, discontinuity, low signal, and spasm were found in 59 (65.6 %), 15 (16.7 %), 13 (14.4 %), and six (6.7 %) patients, respectively, in the migraine group. In situ thrombus was associated with migraine risk (OR 49.03; 95%CI 8.52-282.18; P < 0.001). At the 12-month follow-up of the migraineur cohort, the primary endpoint, a 50 % reduction in migraine frequency after closure (with or without thrombus in PFO) was met (85.3 % vs. 25.0 %; P < 0.001). In situ thrombus was associated with migraine relief (OR 6.75; 95%CI 1.28-35.56; P = 0.024). Conclusions: In situ thrombus and abnormal endocardium within PFOs were common in migraineurs, and in situ thrombus was a risk factor for migraine. Percutaneous closure was more effective in migraineurs with thrombi within the PFO. OCT imaging improved the understanding of pathogenic PFOs and may be helpful in selecting suitable migraineurs for PFO closure.

Mathematical modeling of multi-component aerosol droplet evaporation and growth in indoor environments.

Multi-component droplets from daily activities and production processes severely degrade indoor air quality. Their health hazards and removal efficiency depend on size and composition, significantly affected by evaporation and growth. The phase transition process is complex, involving a broad spectrum of droplet sizes with diverse heat and mass transfer characteristics. Components within the droplets experience simultaneous phase transitions at differing rates and mass transfer directions. This study aims to refine the existing evaporation model of single-component droplets in continuous flows by theoretically integrating the effects of varying droplet sizes and multiple components. A multi-component droplet evaporation/growth model that spans the entire range of droplet sizes has been developed, and predictions have been made based on this model. Utilizing MATLAB, this model accurately predicts the indoor dynamics of multi-component droplets, with deviations under 16 % from experiments. It improves accuracy by over 25 % across droplet sizes via dimensionless transfer coefficients and boosts precision by over 24 % for multi-component droplets with zero-diffusion transport. The radius of the droplet after phase change can reach 8.42 × 10-6 m and remains suspended in the air for an extended period. This study establishes a solid theoretical foundation for accurately predicting the indoor distribution of multi-component droplets.

Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

OBJECTIVE: To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). METHODS AND RESULTS: Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S1-S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100 nM) (n = 15) greatly steepened the restitution curves (Smax > 1) (p < .01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p < .05) and decreased the thresholds of the VA and APD alternans (p < .01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (Smax < 1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p < .05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. CONCLUSION: PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx.

Long-term outcomes in patients with bicuspid valve stenosis and aortic dilation undergoing transcatheter valve implantation.

BACKGROUND: To date, whether ascending aorta dilation (AAD) should be considered a contraindication for transcatheter aortic valve replacement (TAVR) remains a topic of debate.. OBJECTIVE: The study investigated the clinical outcome of TAVR in patients with bicuspid aortic valve stenosis (BAV-AS) complicated by AAD. METHODS: We included patients with BAV-AS who underwent TAVR between 2012 and 2019. We collected patient perioperative clinical data., tracked clinical outcomes for over four years post-TAVR, and obtained echocardiography images one year postoperatively. The Kaplan-Meier method was employed for analyzing both unadjusted and adjusted survival data, which was compared using the log-rank test. COX regression and nomograms were used to assess the impact of AAD on post-TAVR clinical outcomes in patients with aortic stenosis (AS), with all-cause mortality as the primary clinical endpoint. RESULTS: A total of 111 BAV patients were included in this study. Long-term follow-up showed an increased mortality risk in patients with BAV-AAD (adjusted Kaplan-Meier analysis: P = .02/0.001). Cox correlation analysis indicated that age (OR = 1.137; P = .034), AAD (OR = 3.51; P = .038), and postoperative left ventricular pressure (LVSP) (OR: 0.959; P = .044) were predictive factors for mortality more than four years after TAVR in patients with BAV. The area under the curve of the Nomogram predicting long-term survival for the training set of patients based on the above metrics was 0.845 (95% CI: 0.696-0.994). Short-term cardiac ultrasound follow-up showed a more rapid rate of AA expansion (0.29 [0-0.34] vs. -1 [-3.3-1] mm/month, P = .001) and a smaller proportion of AA diameter reduction (7.1% vs. 53.7%, P = .001) in patients who died. CONCLUSIONS: Patients with BAV-AAD-AS treated with TAVR have an increased risk of long-term mortality, and clinical prediction models, including AAD age and postoperative LVSP, may predict long-term patient survival. CONDENSED ABSTRACT: The study investigated the clinical outcome of transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (BAV-AS) complicated by ascending aorta dilation (AAD). Patients with BAV-AAD-AS treated with TAVR have an increased risk of long-term mortality. AAD, age and postoperative LVSP, may predict long-term patient survival. Short-term cardiac ultrasound follow-up showed a more rapid rate of AA expansion and a smaller proportion of AA diameter reduction in patients who died. A high postoperative AAD expansion rate may indicate an adverse clinical outcome. Surgery regimens for tolerable BAV-AADs and can be considered as a treatment option.

Transcatheter Closure of Atrial Septal Defects with Absent Aortic Rim and the Predictors of Right Atrial Reverse Remodeling: 5 Years Experience in China.

INTRODUCTION: Atrial septal defect (ASD) is one of the most common congenital heart malformations. Although not recommended, a significant proportion of patients with aortic root defects receive ASD closure, some of whom have improved right ventricular function. The study aimed to investigate the safety of interventional therapy in ASD patients with complete aortic rim deficiency and explore the predictors of right atrial (RA) non-reverse remodeling. METHODS: 1,011 patients with ASD who underwent transcatheter closure in the Department of Cardiology, Zhongshan Hospital, affiliated to Fudan University from June 2017 to June 2023 were enrolled in the study. They were divided into a complete aortic rim deficiency group and without absent aortic rim group. Furthermore, patients who had an enlarged RA in the absent aortic rim group were divided into two subgroups according to whether their RA remodeling was reversed post-procedure. Multivariate logistic regression was used to determine the predictors of RA reverse remodeling. RESULTS: During the 1-year follow-up, no major operative complications occurred in all patients with the absence of an aortic rim and a normal edge. After the operation, the right heart remodeling was significantly reversed, multivariate logistic regression analysis was performed, and it was found that no coronary heart disease before an operation, lower plasma creatinine level, and larger RA and RV dimensions were the predictive factors for the reverse of RA remodeling after treatment. CONCLUSION: Transcatheter closure of ASD with complete aortic rim deficiency is safe and feasible. For patients without coronary heart disease, the lower the creatinine value and the lower the tricuspid regurgitation before an operation, the more improvement of RA remodeling after the operation.

Associations between Life's Essential 8 and abdominal aortic calcification among US Adults: a cross-sectional study.

BACKGROUND: Cardiovascular health (CVH) and abdominal aortic calcification (AAC) are closely linked to cardiovascular disease (CVD) and related mortality. However, the relationship between CVH metrics via Life's Essential 8 (LE8) and AAC remains unexplored. METHODS: The study analyzed data from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) cohort, which included adults aged 40 or above. The research used the LE8 algorithm to evaluate CVH. Semi-quantitative AAC-24 scoring techniques were employed to assess AAC, categorized into no calcification, mild to moderate calcification, and severe calcification. RESULTS: The primary analysis involved 2,478 participants. Following adjustments for multiple factors, the LE8 score exhibited a significant association with ACC risk (Mild-moderate ACC: 0.87, 95% CI: 0.81,0.93; Severe ACC: 0.77, 95% CI: 0.69,0.87, all P < 0.001), indicating an almost linear dose-response relationship. Compared to the low CVH group, the moderate CVH group showed lower odds ratios (OR) for mild-moderate and severe calcification (OR = 0.78, 95% CI: 0.61-0.99, P = 0.041; OR = 0.68, 95% CI: 0.46-0.99, P = 0.047, respectively). Moreover, the high CVH group demonstrated even lower ORs for mild-moderate and severe calcification (OR = 0.46, 95% CI: 0.31, 0.69, P < 0.001; OR = 0.29, 95% CI: 0.14, 0.59, P = 0.001, respectively). Interactions were found between chronic kidney disease (CKD) condition, history of CVD, marital status and CVH metrics to ACC. Participants without CKD exhibited a more pronounced negative association between the CVH metric and both mild-moderate and severe ACC. Those lacking a history of CVD, and never married/widowed/divorced/separated showed a stronger negative association between the CVH metric and severe ACC. CONCLUSIONS: The novel CVH metrics demonstrated an inverse correlation with the risk of AAC. These findings suggest that embracing improved CVH levels may assist in alleviating the burden of ACC.

Predicting Elimination of Small-Molecule Drug Half-Life in Pharmacokinetics Using Ensemble and Consensus Machine Learning Methods.

Half-life is a significant pharmacokinetic parameter included in the excretion phase of absorption, distribution, metabolism, and excretion. It is one of the key factors for the successful marketing of drug candidates. Therefore, predicting half-life is of great significance in drug design. In this study, we employed eXtreme Gradient Boosting (XGboost), randomForest (RF), gradient boosting machine (GBM), and supporting vector machine (SVM) to build quantitative structure-activity relationship (QSAR) models on 3512 compounds and evaluated model performance by using root-mean-square error (RMSE), R2, and mean absolute error (MAE) metrics and interpreted features by SHapley Additive exPlanation (SHAP). Furthermore, we developed consensus models through integrating four individual models and validated their performance using a Y-randomization test and applicability domain analysis. Finally, matched molecular pair analysis was used to extract the transformation rules. Our results revealed that XGboost outperformed other individual models (RMSE = 0.176, R2 = 0.845, MAE = 0.141). The consensus model integrating all four models continued to enhance prediction performance (RMSE = 0.172, R2 = 0.856, MAE = 0.138). We evaluated the reliability, robustness, and generalization ability via Y-randomization test and applicability domain analysis. Meanwhile, we utilized SHAP to interpret features and employed matched molecular pair analysis to extract chemical transformation rules that provide suggestions for optimizing drug structure. In conclusion, we believe that the consensus model developed in this study serve as a reliable tool to evaluate half-life in drug discovery, and the chemical transformation rules concluded in this study could provide valuable suggestions in drug discovery.

Association of the triglyceride-glucose index with all-cause and cardiovascular mortality in patients with cardiometabolic syndrome: a national cohort study.

OBJECTIVE: This study aimed to evaluate the association of triglyceride-glucose (TyG) index with all-cause and cardiovascular mortality risk among patients with cardiometabolic syndrome (CMS). METHODS: We performed a cohort study of 5754 individuals with CMS from the 2001-2018 National Health and Nutrition Examination Survey. The TyG index was calculated as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Multivariate Cox proportional hazards regression models assessed the associations between TyG index and mortality . Non-linear correlations and threshold effects were explored using restricted cubic splines and a two-piecewise Cox proportional hazards model. RESULTS: Over a median follow-up of 107 months, 1201 all-cause deaths occurred, including 398 cardiovascular disease-related deaths. The multivariate Cox proportional hazards regression model showed a positive association between the TyG index and all-cause and cardiovascular mortality. Each one-unit increase in the TyG index was associated with a 16% risk increase in all-cause mortality (HR: 1.16, 95% CI 1.03, 1.31, P = 0.017) and a 39% risk increase in cardiovascular mortality (HR: 1.39, 95% CI 1.14, 1.71, P = 0.001) after adjusting for confounders. The restricted cubic splines revealed a U-shaped association between the TyG index and all-cause (P for nonlinear < 0.001) and cardiovascular mortality (P for nonlinear = 0.044), identifying threshold values (all-cause mortality: 9.104; cardiovascular mortality: 8.758). A TyG index below these thresholds displayed a negative association with all-cause mortality (HR: 0.58, 95% CI 0.38, 0.90, P = 0.015) but not with cardiovascular mortality (HR: 0.39, 95% CI 0.12, 1.27, P = 0.119). Conversely, a TyG index exceeding these thresholds was positively associated with all-cause and cardiovascular mortality (HR: 1.35, 95% CI 1.17, 1.55, P < 0.001; HR: 1.54, 95% CI 1.25, 1.90, P < 0.001, respectively). Notably, a higher TyG index (≥ threshold values) was significantly associated with increased mortality only among individuals aged under 55 compared to those with a lower TyG index (< threshold values). CONCLUSIONS: The TyG index demonstrated a U-shaped correlation with all-cause and cardiovascular mortality in individuals with CMS. The thresholds of 9.104 and 8.758 for all-cause and cardiovascular mortality, respectively, may be used as intervention targets to reduce the risk of premature death and cardiovascular disease.

Three-century climate variations recovered from Lake Heilongtan in southwest China and potential Anthropogenic evidences.

Under increasing influences of human activities on earth surface system, the concept of Anthropocene has been proposed and widely investigated to represent such a human-dominated geological epoch. To acquire further details about the Anthropocene, investigations on high-resolution continuous records are essentially necessary, especially for regions under notable human impacts. Here, a continuous sediment record covering the past three centuries was collected from Lake Heilongtan, a closed basin lake located in the Hengduan Mountains, in southwest China. High-resolution sedimentary proxies were examined to reconstruct past climate and environment changes, including grain size distribution, geochemical element composition, and organic matter content. The results indicated that water levels were relatively higher under generally warm and wet conditions between 1717 and 1800 CE, while a decline in regional moisture after 1800 CE caused serious shrinkage of the lake level. Comparisons with regional paleoclimate records revealed that solar activity played a significant role in promoting climate variations in southwest China. After 1910 CE, the sedimentary proxies revealed an out-of-phase with regional climate changes, especially the progressive increase after 1950 CE. With the expansion of regional population, the intensified human activities have possibly affected the catchment erosion and sedimentation processes, accounting for the deviation from natural climate changes. Accordingly, the reconstructed sedimentation history in Lake Heilongtan experienced a possible transition from natural-driven to human-dominant status during the past three centuries, revealing potential evidence for the Anthropocene in southwest China.

Abnormal M1 polarization of placental macrophage induced by IL-15/STAT5 activation in VVC may lead to adverse pregnancy outcomes.

Pregnant women with vulvovaginal candidiasis (VVC) may experience adverse pregnancy outcomes such as premature delivery, intrauterine infection, abortion, and neonatal infection. Therefore, finding new treatments for VVC in pregnancy is a public health priority. We aimed to study the adverse consequences of Candida albicans (C. albicans) vaginal infection in pregnant mice and explore the mechanisms by which C. albicans affects macrophages. Our findings contribute to the development of new approaches to treat VVC during pregnancy. We established an animal model of vaginal infection by C. albicans in pregnant mice and observed adverse pregnancy outcomes such as decreased body weight, reduced implantation number, and increased abortion rates. Additionally, we infected mouse macrophage line RAW264.7 cells with C. albicans and established a cell model. We employed RT-qPCR, Western blot, and immunofluorescence staining to verify the changes in the IL-15/STAT5 signaling pathway and the role it played on the M1 polarization of C. albicans-infected macrophages at both the gene and protein levels. Our results indicate that the adverse pregnancy outcomes in VVC may be linked to changes in the IL-15/STAT5 pathway induced by C. albicans, which could impact macrophage M1 polarization.

Construction of a prognostic model for colorectal adenocarcinoma based on Zn transport-related genes identified by single-cell sequencing and weighted co-expression network analysis.

Background: Colorectal cancer (CRC) is one of the most prevalent malignancies and the third most lethal cancer globally. The most reported histological subtype of CRC is colon adenocarcinoma (COAD). The zinc transport pathway is critically involved in various tumors, and its anti-tumor effect may be through improving immune function. However, the Zn transport pathway in COAD has not been reported. Methods: The determination of Zn transport-related genes in COAD was carried out through single-cell analysis of the GSE 161277 obtained from the GEO dataset. Subsequently, a weighted co-expression network analysis of the TCGA cohort was performed. Then, the prognostic model was conducted utilizing univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Functional enrichment, immune microenvironment, and survival analyses were also carried out. Consensus clustering analysis was utilized to verify the validity of the prognostic model and explore the immune microenvironment. Ultimately, cell experiments, including CCK-8,transwell and scratch assays, were performed to identify the function of LRRC59 in COAD. Results: According to the Zn transport-related prognostic model, the individuals with COAD in TCGA and GEO databases were classified into high- and low-risk groups. The group with low risk had a comparatively more favorable prognosis. Two groups had significant variations in the immune infiltration, MHC, and the expression of genes related to the immune checkpoint. The cell experiments indicated that the proliferation, migration, and invasion of the HCT-116, DLD-1, and RKO cell lines were considerably increased after LRRC59 knockdown. It proved that LRRC59 was indeed a protective factor for COAD. Conclusion: A prognostic model for COAD was developed using zinc transport-related genes. This model can efficiently assess the immune microenvironment and prognosis of individuals with COAD. Subsequently, the function of LRRC59 in COAD was validated via cell experiments, highlighting its potential as a biomarker.

Emission and purification of evaporated-condensed oil droplets affected by condensation nuclei during machining.

Fine oil droplets emitted by evaporation-condensation during machining are typical indoor air contaminants. Airborne particles can act as condensation nuclei, facilitating the condensation of oil vapor. The physical properties of these resultant droplets significantly affect their purification efficiency. Herein, this study aimed to elucidate the emission characteristics of oil droplets formed by evaporation-condensation affected by condensation nuclei and the purification efficiency of intense field dielectric (IFD) technology for the droplets under varying airflow velocities. Results show that the removal of condensation nuclei can effectively reduce the mass of evaporated-condensed oil droplets, and the increment in the mass of oil droplets reached 1.7 times the increment in the mass of condensation nuclei. It was more effective to reduce the mass of oil droplets by removing large condensation nuclei and decreasing the amount of evaporated soluble oil, as compared to removing smaller condensation nuclei or using straight oil. Condensation nuclei mainly contributed to the generation of oil droplets below 5 µm. For droplet diameters of 0.3-5.0 µm and airflow velocities of 0.5-2.0 m/s, the purification efficiency was within the 84-96% range. The purification efficiency of the IFD purifier for oil droplets could be improved either by increasing the size of the oil droplets or by reducing the airflow velocity.

DNAJA3 regulates B cell development and immune function.

BACKGROUND: DnaJ homolog subfamily A member 3 (DNAJA3), also known as the tumorous imaginal disc (Tid1), is shown to be crucial in T cell development. DNAJA3 functions as a tumor suppressor implicated in lymphocyte development and survival. However, the role of DNAJA3 in B cell development and immune function remains unknown. In this study, we utilized a mouse model of B cell-specific DNAJA3 knockout (CD19-Cre/+; DNAJA3flx/flx) to investigate the physiological function of DNAJA3 in B cell development and immune function. METHODS: We characterized B cell populations in various developmental stages and examined mitochondrial content and function between control and DNAJA3 KO using flow cytometry analysis. DNAJA3 and OXPHOS protein complexes in sorted B cells between mice groups were compared using immunoblot techniques. The activity of B cell blastogenesis in splenocytes was measured by performing CFSE and MTT assays. Furthermore, immunoglobulin production was detected using the ELISA method. RESULTS: DNAJA3 deficiency decreases from pro B cells to immature B cells. The overall B220+ population in the bone marrow and secondary immune organs also decreased. B cell subpopulations B1 (B1b) and B2 significantly decrease. The B cell blastogenesis activity and immunoglobulin production decreased in DNAJA3 KO mice. Mechanistically, DNAJA3 deficiency significantly increases dysfunctional mitochondria activity and decreases mitochondrial mass, membrane potential, and mitochondria respiratory complex proteins. These factors could have influenced B cell differentiation during development, differentiation to antibody-secreting cells, and immune activation. CONCLUSION: Overall, our study provides supportive evidence for the role of DNAJA3 in B cell development and function.

Mitochondrial damage-induced abnormal glucose metabolism with ageing in the hippocampus of APP/PS1 mice.

INTRODUCTION: Accumulation of ß-amyloid (Aß) in neurons of patients with Alzheimer's disease (AD) inhibits the activity of key enzymes in mitochondrial metabolic pathways, triggering mitochondrial dysfunction, which plays an important role in the onset and development of AD. Mitophagy is a process whereby dysfunctional or damaged mitochondria are removed from the cell. Aberrant mitochondrial metabolism may hinder mitophagy, promote autophagosome accumulation, and lead to neuronal death. OBJECTIVES: The aim of this experiment is to explore the mechanism of neuronal mitochondria damage in the hippocampus of different age APP/PS1 double transgenic AD mice, and to explore the related metabolites and metabolic pathways for further understanding of the pathogenesis, so as to provide new ideas and strategies for the treatment of AD. METHODS: In this study, 24 APP/PS1(APPswe/PSEN1dE9) mice were divided into 3, 6, 9, and 12-month-old groups, and 6-month-old wild-type C57BL/6 mice were as controls. The Morris water maze test was used to evaluate learning and memory. Levels of Aß were detected by immunohistochemistry. Electron microscopy was used to observe mitochondrial damage and autophagosome accumulation. Western blot was for measuring LC3, P62, PINK1, Parkin, Miro1, and Tom 20 protein expression levels. Gas chromatography coupled with mass spectrometry was used to screen differentially abundant metabolites. RESULTS: The results showed that with the increase of age in APP/PS1 mice, cognitive impairment, hippocampal neuron mitochondrial damage, and autophagosome accumulation all increased. Furthermore, enhanced mitophagy and impaired mitochondrial clearance leading to metabolic abnormalities were observed with ageing in APP/PS1 mouse hippocampus. Especially, abnormal accumulation of succinic acid and citric acid in the Krebs cycle was observed. CONCLUSION: This study investigated the abnormal glucose metabolism associated with age-related damage to mitochondria in the hippocampus of APP/PS1 mice. These findings provide new insights into the pathogenesis of AD.

S1PR2/Wnt3a/RhoA/ROCK1/ß-catenin signaling pathway promotes diabetic nephropathy by inducting endothelial mesenchymal transition and impairing endothelial barrier function.

AIMS: Hyperglycemia and hyperlipidemia are key factors in the pathogenesis of diabetic nephropathy (DN), and renal fibrosis is the most common pathway leading to the disease. Endothelial mesenchymal transition (EndMT) is a crucial mechanism for the production of myofibroblasts, and impaired endothelial barrier function is one of the mechanisms for the generation of microalbuminuria in DN. However, the specific mechanisms behind these are not yet clear. MAIN METHODS: Protein expression was detected by immunofluorescence, immunohistochemistry and Western blot. Knocking down or pharmacological inhibition of S1PR2 were used to inhibit Wnt3a, RhoA, ROCK1, ß-catenin, and Snail signaling. Changes in cell function were analyzed by CCK-8 method, cell scratching assay, FITC-dextran permeability assay, and Evans blue staining. KEY FINDINGS: Consistent with increased gene expression of S1PR2 in DN patients and mice with kidney fibrosis disease, S1PR2 expression was significantly increased in glomerular endothelial cells of DN mice and HUVEC cells treated with glucolipids. Knocking down or pharmacological inhibition of S1PR2 significantly decreased the expression of Wnt3a, RhoA, ROCK1, and ß-catenin in endothelial cells. Furthermore, inhibition of S1PR2 in vivo reversed EndMT and endothelial barrier dysfunction in glomerular endothelial cells. Inhibition of S1PR2 and ROCK1 in vitro also reversed EndMT and endothelial barrier dysfunction in endothelial cells. SIGNIFICANCE: Our results suggest that the S1PR2/Wnt3a/RhoA/ROCK1/ß-catenin signaling pathway is involved in the pathogenesis of DN by inducing EndMT and endothelial barrier dysfunction.

Compromised word-level neural tracking in the high-gamma band for children with attention deficit hyperactivity disorder.

Children with attention deficit hyperactivity disorder (ADHD) exhibit pervasive difficulties in speech perception. Given that speech processing involves both acoustic and linguistic stages, it remains unclear which stage of speech processing is impaired in children with ADHD. To investigate this issue, we measured neural tracking of speech at syllable and word levels using electroencephalography (EEG), and evaluated the relationship between neural responses and ADHD symptoms in 6-8 years old children. Twenty-three children participated in the current study, and their ADHD symptoms were assessed with SNAP-IV questionnaires. In the experiment, the children listened to hierarchical speech sequences in which syllables and words were, respectively, repeated at 2.5 and 1.25 Hz. Using frequency domain analyses, reliable neural tracking of syllables and words was observed in both the low-frequency band (<4 Hz) and the high-gamma band (70-160 Hz). However, the neural tracking of words in the high-gamma band showed an anti-correlation with the ADHD symptom scores of the children. These results indicate that ADHD prominently impairs cortical encoding of linguistic information (e.g., words) in speech perception.

Comprehensive analysis of the prognosis, tumor microenvironment, and immunotherapy response of SDHs in colon adenocarcinoma.

Background: Succinate dehydrogenase (SDH), one of the key enzymes in the tricarboxylic acid cycle, is mainly found in the mitochondria. SDH consists of four subunits encoding SDHA, SDHB, SDHC, and SDHD. The biological function of SDH is significantly related to cancer progression. Colorectal cancer (CRC) is one of the most common malignant tumors globally, whose most common histological subtype is colon adenocarcinoma (COAD). However, the correlation between SDH factors and COAD remains unclear. Methods: The data on pan-cancer was obtained from The Cancer Genome Atlas (TCGA) database. Kaplan-Meier survival analysis showed the prognostic ability of SDHs. The cBioPortal database reflected genetic variations of SDHs. The correlation analysis was conducted between SDHs and mitochondrial energy metabolism genes (MMGs) and the protein-protein interaction (PPI) network was built. Consequently, Univariate and Multivariate Cox Regression Analysis on SDHs and other clinical characteristics were conducted. A nomogram was established. The ssGSEA analysis visualized the association between SDHs and immune infiltration. Immunophenoscore (IPS) explored the correlation between SDHs and immunotherapy, and the correlation between SDHs and targeted therapy was investigated through Genomics of Drug Sensitivity in Cancer. Finally, qPCR and immunohistochemistry detected SDHs' expression. Results: After assessing SDHs differential expression in pan-cancer, we found that SDHB, SDHC, and SDHD benefit COAD patients. The cBioPortal database demonstrated that SDHA was the top gene in mutation frequency rank. Correlation analysis mirrored a strong link between SDHs and MMGs. We formulated a nomogram and found that SDHB, SDHC, SDHD, and clinical characteristics correlated with COAD patients' survival. For T helper cells, Th2 cells, and Tem, SDHA, SDHB, SDHC, and SDHD were significantly enriched in the high expression group. Moreover, COAD patients with high SDHA expression were more suitable for immunotherapy. And COAD patients with different SDHs' expression have different sensitivity to targeted drugs. Further verifying the gene and protein expression levels of SDHs, we found that the tissues were consistent with the bioinformatics analysis. Conclusions: Our study analyzed the expression and prognostic value of SDHs in COAD, explored the pathway mechanisms involved, and the immune cell correlations, indicating that SDHs might be biomarkers for COAD patients.

Rapid activation of peroxymonosulfate with iron(â ¢) complex for organic pollutants degradation via a non-radical pathway.

Developing high-performance catalytic systems for eliminating contaminants effectively in water has received a lot of attention. However, the complexity of practical wastewater poses a challenge for degrading organic pollutants. Non-radical active species with strong resistance to interference have shown great advantages in degrading organic pollutants under complex aqueous conditions. Herein, a novel system was constructed by Fe(dpa)Cl2 (FeL, dpa = N, N'-(4-nitro-1,2-phenylene) dipicolinamide) activating peroxymonosulfate (PMS). The mechanism study verified that the FeL/PMS system had high efficiency in producing high-valent iron-oxo and singlet oxygen (1O2) to degrade various organic pollutants. In addition, the chemical bonding between PMS and FeL was elucidated by the density functional theory (DFT) calculations. The FeL/PMS system could remove 96% Reactive Red 195 (RR195) in 2 min, which was much higher than other systems involved in this study. More attractively, the FeL/PMS system demonstrated general resistance to interference from common anions (Cl-, HCO3-, NO3- and SO42-), humic acid (HA) and pH changes and were thus compatible with various natural waters. This work provides a new approach for producing non-radical active species, which is a promising catalytic system for water treatment.

B7-H6 enhances F-actin rearrangement by targeting c-MYC activation to promote medulloblastoma migration and invasion.

Medulloblastoma (MB) is children's most common primary malignant primitive neuro-ectodermal tumor. Group 3 MB showed a higher propensity to metastasis, which is molecularly characterized by c-MYC gene amplification. The activation of c-MYC promotes the remodeling of the F-actin cytoskeleton to enhance metastasis. The B7 homologue 6 (B7-H6) is associated with the manifold essential hallmarks of tumorigenesis. In this study, we will explore whether B7-H6 regulates the reorganization of F-actin by elevating the c-MYC expression to promote metastasis. The Daoy cell line was used to act as the cell model of medulloblastoma. Small interfering RNA and the plasmid were used to downregulate and upregulate the expression of B7-H6 in Daoy cells. Transwell assays with/without the matrigel matrix were used to detect migration and invasion of Daoy cells. Western blots were used to detect the expression of related proteins. Immunofluorescence staining was used to observe the impact of B7-H6 on the c-MYC /F-actin axis. B7-H6 improved migration and invasion in the Daoy cell line. B7-H6 enhanced the rearrangement of F-actin and activated the expression of MMP-9 and MMP-2. B7-H6 promoted the remodeling of F-actin by targeting c-MYC activation to reinforce migration and invasion. B7-H6 acts as a promoter of migration and invasion in medulloblastoma by activating the c-MYC /F-actin axis.