Genetic causal relationship between multiple immune cell phenotypes and Parkinson's disease: a two sample bidirectional Mendelian randomization study.

BACKGROUND: The exact etiology of Parkinson's disease (PD), a degenerative disease of the central nervous system, is unclear. It is currently believed that its main pathological basis is a decrease in dopamine concentration in the striatum of the brain. Although many researchers have previously focused on the critical role of the immune response in PD, there has been a lack of valid genetic evidence for a causal association between specific immune cell traits and phenotypes and PD. METHODS: We employed Mendelian randomisation (MR) as an analytical method to effectively assess genetic associations between exposure and outcome. Based on the largest genome-wide association study (GWAS) data to date, causal associations between multiple immune cell phenotypes and PD were validly assessed by using single nucleotide polymorphisms (SNPs), which are randomly assigned and not subject to any causality. RESULTS: By testing 731 immune cell phenotypes and their association with PD, the results of IVW analysis suggested that some phenotypes were considered to have a causal effect on PD(P＜0.05) . In addition, PD could have an effect on certain immunophenotypes located on Myeloid cell panel, Monocyte panel, the specific immunophenotypic results and statistical analysis values are shown in the text. The results of sensitivity analyses suggested that none of them observed the presence of horizontal pleiotropy. CONCLUSION: Our study identified a close link between immune cells and PD, and the results of this study provide ideas for the study of the immune mechanism of PD and the exploration of effective therapeutic means.

Exploring the common mechanism of vascular dementia and inflammatory bowel disease: a bioinformatics-based study.

Objective: Emerging evidence has shown that gut diseases can regulate the development and function of the immune, metabolic, and nervous systems through dynamic bidirectional communication on the brain-gut axis. However, the specific mechanism of intestinal diseases and vascular dementia (VD) remains unclear. We designed this study especially, to further clarify the connection between VD and inflammatory bowel disease (IBD) from bioinformatics analyses. Methods: We downloaded Gene expression profiles for VD (GSE122063) and IBD (GSE47908, GSE179285) from the Gene Expression Omnibus (GEO) database. Then individual Gene Set Enrichment Analysis (GSEA) was used to confirm the connection between the two diseases respectively. The common differentially expressed genes (coDEGs) were identified, and the STRING database together with Cytoscape software were used to construct protein-protein interaction (PPI) network and core functional modules. We identified the hub genes by using the Cytohubba plugin. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were applied to identify pathways of coDEGs and hub genes. Subsequently, receiver operating characteristic (ROC) analysis was used to identify the diagnostic ability of these hub genes, and a training dataset was used to verify the expression levels of the hub genes. An alternative single-sample gene set enrichment (ssGSEA) algorithm was used to analyze immune cell infiltration between coDEGs and immune cells. Finally, the correlation between hub genes and immune cells was analyzed. Results: We screened 167 coDEGs. The main articles of coDEGs enrichment analysis focused on immune function. 8 shared hub genes were identified, including PTPRC, ITGB2, CYBB, IL1B, TLR2, CASP1, IL10RA, and BTK. The functional categories of hub genes enrichment analysis were mainly involved in the regulation of immune function and neuroinflammatory response. Compared to the healthy controls, abnormal infiltration of immune cells was found in VD and IBD. We also found the correlation between 8 shared hub genes and immune cells. Conclusions: This study suggests that IBD may be a new risk factor for VD. The 8 hub genes may predict the IBD complicated with VD. Immune-related coDEGS may be related to their association, which requires further research to prove.

Effect of high-frequency repetitive transcranial magnetic stimulation on cognitive impairment in WD patients based on inverse probability weighting of propensity scores.

Background: Hepatolenticular degeneration [Wilson disease (WD)] is an autosomal recessive metabolic disease characterized by copper metabolism disorder. Cognitive impairment is a key neuropsychiatric symptom of WD. At present, there is no effective treatment for WD-related cognitive impairment. Methods: In this study, high-frequency repetitive transcranial magnetic stimulation (rTMS) was used to treat WD-related cognitive impairment, and inverse probability weighting of propensity scores was used to correct for confounding factors. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Auditory Verbal Learning Test (AVLT), Boston Naming Test (BNT), Clock Drawing Test (CDT) and Trail Making Test (TMT) were used to evaluate overall cognition and specific cognitive domains. Results: The MMSE, MoCA and CDT scores after treatment were significantly different from those before treatment (MMSE: before adjustment: OR = 1.404, 95% CI: 1.271-1.537; after adjustment: OR = 1.381, 95% CI: 1.265-1.497, p < 0.001; MoCA: before adjustment: OR = 1.306, 95% CI: 1.122-1.490; after adjustment: OR = 1.286, 95% CI: 1.104; AVLT: OR = 1.161, 95% CI: 1.074-1.248; after adjustment: OR = 1.145, 95% CI: 1.068-1.222, p < 0.05; CDT: OR = 1.524, 95% CI: 1.303-1.745; after adjustment: OR = 1.518, 95% CI: 1.294-1.742, p < 0.001). The BNT and TMT scores after adjustment were not significantly different from those before adjustment (BNT: before adjustment: OR = 1.048, 95% CI: 0.877-1.219; after adjustment: OR = 1.026, 95% CI: 0.863-1.189, p > 0.05; TMT: before adjustment: OR = 0.816, 95% CI: 1.122-1.490; after adjustment: OR = 0.791, 95% CI: 0.406-1.176, p > 0.05). Conclusion: High-frequency rTMS can effectively improve cognitive impairment, especially memory and visuospatial ability, in WD patients. The incidence of side effects is low, and the safety is good.

Exploration of TCM syndrome types of the material basis and risk prediction of Wilson disease liver fibrosis based on 1H NMR metabolomics.

Wilson disease (WD) is an autosomal recessive disorder characterized by abnormal copper metabolism. The accumulation of copper in the liver can progress to liver fibrosis and, ultimately, cirrhosis, which is a primary cause of death in WD patients. Metabonomic technology offers an effective approach to investigate the traditional Chinese medicine (TCM) syndrome types of WD-related liver fibrosis by monitoring the alterations in small molecule metabolites within the body. In this study, we employed 1H-Nuclear Magnetic Resonance (1H NMR) metabonomics to assess the metabolic profiles associated with five TCM syndrome types of WD-related liver fibrosis and analyzed the diagnostic and predictive capabilities of various metabolites. The study found a variety of metabolites, each with varying levels of diagnostic and predictive capabilities. Furthermore, the discerned differential metabolic pathways were primarily associated with various pathways involving carbohydrate metabolism, amino acid metabolism, and lipid metabolism. This study has identified various characteristic metabolic markers and pathways associated with different TCM syndromes of liver fibrosis in WD, providing a substantial foundation for investigating the mechanisms underlying these TCM syndromes.

Application of flipped classroom teaching method based on ADDIE concept in clinical teaching for neurology residents.

BACKGROUND: As an important medical personnel training system in China, standardized residency training plays an important role in enriching residents' clinical experience, improving their ability to communicate with patients and their clinical expertise. The difficulty of teaching neurology lies in the fact that there are many types of diseases, complicated conditions, and strong specialisation, which puts higher requirements on residents' independent learning ability, the cultivation of critical thinking, and the learning effect. Based on the concept of ADDIE (Analysis-Design-Development-Implementation-Evaluation), this study combines the theory and clinical practice of flipped classroom teaching method to evaluate the teaching effect, so as to provide a basis and reference for the implementation of flipped classroom in the future of neurology residency training teaching. METHODS: The participants of the study were 90 neurology residents in standardised training in our hospital in the classes of 2019 and 2020. A total of 90 residents were divided into a control group and an observation group of 45 cases each using the random number table method. The control group used traditional teaching methods, including problem based learning (PBL), case-based learning (CBL), and lecture-based learning (LBL). The observation group adopted the flipped classroom teaching method based on the ADDIE teaching concept. A unified assessment of the learning outcomes of the residents was conducted before they left the department in the fourth week, including the assessment of theoretical and skill knowledge, the assessment of independent learning ability, the assessment of critical thinking ability, and the assessment of clinical practice ability. Finally, the overall quality of teaching was assessed. RESULTS: The theoretical and clinical skills assessment scores achieved by the observation group were significantly higher than those of the control group, and the results were statistically significant (P < 0.001). The scores of independent learning ability and critical thinking ability of the observation group were better than those of the control group, showing statistically significant differences (P < 0.001). The observation group was better than the control group in all indicators in terms of Mini-Cex score (P < 0.05). In addition, the observation group had better teaching quality compared to the control group (P < 0.001). CONCLUSION: Based on the concept of ADDIE combined with flipped classroom teaching method can effectively improve the teaching effect of standardized training of neurology residents, and had a positive effect on the improvement of residents' autonomous learning ability, critical thinking ability, theoretical knowledge and clinical comprehensive ability.

Spread of antibiotic resistance genes in drinking water reservoirs: Insights from a deep metagenomic study using a curated database.

The exploration of antibiotic resistance genes (ARGs) in drinking water reservoirs is an emerging field. Using a curated database, we enhanced the ARG detection and conducted a comprehensive analysis using 2.2 Tb of deep metagenomic sequencing data to determine the distribution of ARGs across 16 drinking water reservoirs and associated environments. Our findings reveal a greater diversity of ARGs in sediments than in water, underscoring the importance of extensive background surveys. Crucial ARG carriers-specifically Acinetobacter, Pseudomonas, and Mycobacterium were identified in drinking water reservoirs. Extensive analysis of the data uncovered a considerable concern for drinking water safety, particularly in regions reliant on river sources. Mobile genetic elements have been found to contribute markedly to the propagation of ARGs. The results of this research suggest that the establishment of drinking water reservoirs for supplying raw water may be an effective strategy for alleviating the spread of water-mediated ARGs.

Genetic causal role of body mass index in multiple neurological diseases.

Body mass index (BMI) is a crucial health indicator for obesity. With the progression of socio-economic status and alterations in lifestyle, an increasing number of global populations are at risk of obesity. Given the complexity and severity of neurological diseases, early identification of risk factors is vital for the diagnosis and prognosis of such diseases. In this study, we employed Mendelian randomization (MR) analysis utilizing the most comprehensive genome-wide association study (GWAS) data to date. We selected single nucleotide polymorphisms (SNPs) that are unaffected by confounding factors and reverse causality as instrumental variables. These variables were used to evaluate the genetic and causal relationships between Body Mass Index (BMI) and various neurological diseases, including Parkinson's Disease (PD), Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), Ischemic Stroke (IS), and Epilepsy (EP). The Inverse Variance Weighted (IVW) analysis indicated that there was no significant causal relationship between Body Mass Index (BMI) indicators and PD (P-value = 0.511), AD (P-value = 0.076), ALS (P-value = 0.641), EP (P-value = 0.380). However, a causal relationship was found between BMI indicators and MS (P-value = 0.035), and IS (P-value = 0.000), with the BMI index positively correlated with the risk of both diseases. The Cochran's Q test for MR-IVW showed no heterogeneity in the MR analysis results between the BMI index and the neurological diseases (P > 0.05). The Egger intercept test for pleiotropy revealed no horizontal pleiotropy detected in any of the neurological diseases studied (P > 0.05). It was found that there was no causal relationship between BMI and PD, AD, ALS, EP, and a genetic causal association with MS, and IS. Meanwhile, the increase in BMI can lead to a higher risk of MS and IS, which reveals the critical role of obesity as a risk factor for specific neurological diseases in the pathogenesis of the diseases.

Integrating transcriptomics and metabolomics to analyze the defense response of Morus notabilis to mulberry ring rot disease.

Introduction: The mulberry industry has thrived in China for millennia, offering significant ecological and economic benefits. However, the prevalence of mulberry ring rot disease poses a serious threat to the quality and yield of mulberry leaves. Methods: In this study, we employed a combination of transcriptomic and metabolomic analyses to elucidate the changes occurring at the transcriptional and metabolic levels in Morus notabilis in response to this disease infestation. Key metabolites identified were further validated through in vitro inhibition experiments. Results: The findings revealed significant enrichment in Kyoto Encyclopedia of Genes and Genomes pathways, particularly those related to flavonoid biosynthesis. Notably, naringenin, kaempferol, and quercetin emerged as pivotal players in M. notabilis' defense mechanism against this disease pathogen. The upregulation of synthase genes, including chalcone synthase, flavanone-3-hydroxylase, and flavonol synthase, suggested their crucial roles as structural genes in this process. In vitro inhibition experiments demonstrated that kaempferol and quercetin exhibited broad inhibitory properties, while salicylic acid and methyl jasmonate demonstrated efficient inhibitory effects. Discussion: This study underscores the significance of the flavonoid biosynthesis pathway in M. notabilis' defense response against mulberry ring rot disease, offering a theoretical foundation for disease control measures.

Evidence for genetic causality between iron homeostasis and Parkinson's disease: A two-sample Mendelian randomization study.

BACKGROUND: Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence. METHODS: We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors. RESULTS: By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ ß = - 0.524; 95%cl=-0.046 to -0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (ß=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (ß=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (ß=-0.387; 95%Cl=-1.179-0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (ß=-0.142; 95%Cl=-0.197-0.481; P=0.414), TSAT (ß=-0.316; 95%Cl=-0.861-0.229; P=0.255), and ferritin (ß=-0.101; 95%Cl=--0.987 to -0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test. CONCLUSION: Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.

Interfacial π-p Electron Coupling Prompts Hydrogen Evolution Reaction Activity in Acidic Electrolyte.

The thermodynamically stable 2H-phase MoS2 is a brilliant material toward hydrogen evolution reaction (HER) owing to its excellent Gibbs free energy of hydrogen adsorption. Nevertheless, the poor intrinsic properties of 2H-MoS2 limit its electrocatalytic performances toward HER. In this work, graphitic carbon nitride covalently bridging 2H-MoS2 (MoS2/GCN) is proposed to construct robust HER electrocatalysts. The strong π-p electron coupling between the delocalized π electrons of GCN and the localized p electrons of S atoms sufficiently expose active sites and accelerate the reaction kinetics. To be specific, MoS2/GCN exhibits remarkable HER activity (160 mV at 10 mA·cm-2) and long-term durability. Importantly, MoS2/GCN also provides great potential for industrial application. Density functional theory (DFT) calculations disclose that the π-p electron coupling at the MoS2/GCN interface regulates the electronic structure of S atoms, consequently providing enhanced HER performance. This work presents a feasible pathway to develop advanced electrocatalysts for energy conversions.

Improving on mapping long-term surface water with a novel framework based on the Landsat imagery series.

Surface water plays a crucial role in the ecological environment and societal development. Remote sensing detection serves as a significant approach to understand the temporal and spatial change in surface water series (SWS) and to directly construct long-term SWS. Limited by various factors such as cloud, cloud shadow, and problematic satellite sensor monitoring, the existent surface water mapping datasets might be short and incomplete due to losing raw information on certain dates. Improved algorithms are desired to increase the completeness and quality of SWS datasets. The present study proposes an automated framework to detect SWS, based on the Google Earth Engine and Landsat satellite imagery. This framework incorporates implementing a raw image filtering algorithm to increase available images, thereby expanding the completeness. It improves OTSU thresholding by replacing anomaly thresholds with the median value, thus enhancing the accuracy of SWS datasets. Gaps caused by Landsat7 ETM + SLC-off are respired with the random forest algorithm and morphological operations. The results show that this novel framework effectively expands the long-term series of SWS for three surface water bodies with distinct geomorphological patterns. The evaluation of confusion matrices suggests the good performance of extracting surface water, with the overall accuracy ranging from 0.96 to 0.97, and user's accuracy between 0.96 and 0.98, producer's accuracy ranging from 0.83 to 0.89, and Matthews correlation coefficient ranging from 0.87 to 0.9 for several spectral water indices (NDWI, MNDWI, ANNDWI, and AWEI). Compared with the Global Reservoirs Surface Area Dynamics (GRSAD) dataset, our constructed datasets promote greater completeness of SWS datasets by 27.01%-91.89% for the selected water bodies. The proposed framework for detecting SWS shows good potential in enlarging and completing long-term global-scale SWS datasets, capable of supporting assessments of surface-water-related environmental management and disaster prevention.

[Response Characteristics of Soil Fungal Community Structure to Long-term Continuous Cropping of Pepper].

This study aimed to clarify the effect of long-term continuous cropping of pepper on soil fungal community structure, reveal the mechanism of continuous cropping obstacles, and provide a theoretical basis for the ecological safety and sustainable development of pepper industry. We took the pepper continuous cropping soil in the vegetable greenhouse planting base of Tongren City as the research object. The diversity and community structure of fungi in farmland soil were analyzed using Illumina MiSeq high-throughput sequencing, the responses of soil physio-chemical properties and fungal community characteristics to long-term continuous pepper cropping were discussed, and the relationships between the characteristics of fungal community structure and environmental factors were determined using CCA and correlation network analysis. The results showed that with the extension of pepper continuous cropping years, the soil pH value and organic matter (OM) content decreased, total phosphorus (TP) and available phosphorus (AP) contents increased, hydrolyzed nitrogen (AN) and available potassium (AK) contents decreased first and then increased, and total nitrogen (TN) and total potassium (TK) contents did not change significantly. Long-term continuous cropping decreased the Chao1 index and observed species index and decreased the Shannon index and Simpson index. The change in continuous cropping years had a significant effect on the relative abundance of soil fungal dominant flora. At the phylum level, the relative abundance of Mortierellomycota decreased with the extension of pepper continuous cropping years, the relative abundance of Ascomycota increased first and then decreased, and the relative abundance of Basidiomycota decreased first and then increased. At the genus level, with the increasing of pepper continuous cropping years, the relative abundance of Fusarium increased, and the relative abundance of Mortierella and Penicillium decreased. In addition, long-term continuous cropping simplified the soil fungal symbiosis network. CCA analysis indicated that pH, OM, TN, AN, AP, and AK were the driving factors of soil fungal community structure, and correlation network analysis showed that pH, OM, TN, TP, TK, AN, AP, and AK were the driving factors of soil fungal community structure, including Fusarium, Lophotrichus, Penicillium, Mortierella, Botryotrichum, Staphylotrichum, Plectosphaerella, and Acremonium. In conclusion, continuous cropping changed the soil physical and chemical properties, affected the diversity and community structure of the soil fungal community, changed the interaction between microorganisms, and destroyed the microecological balance of the soil, which might explain obstacles associated with continuous cropped pepper.

Assessment of sediment transport in Luxiapuqu watershed using RUSLE-TLSD and InSAR techniques: Yarlung Tsangpo River, China.

The Yarlung Tsangpo River Basin is characterized by its intricate topography and a significant presence of erosive materials. These often coincide with heavy localized precipitation, resulting in pronounced hydraulic erosion and geological hazards in mountainous regions. To tackle this challenge, we integrated the RUSLE-TLSD (Revised Universal Soil Loss Equation-Transportation-limited sediment delivery) model with InSAR (Interferometric Synthetic Aperture Radar) data, aiming to explore the sediment transport process and pinpoint hazard-prone sites within mountainous small watershed. The RUSLE-TLSD model aids in evaluating multi-year sediment transport dynamics in mountainous zones. And, the InSAR data precisely delineates changes in sediment scouring and siltation at sites vulnerable to hazards. Our research estimates that the potential average soil erosion within the watershed stands at 52.33 t/(hm2 a), with a net soil erosion of 0.69 t/(hm2 a), the sediment transport pathways manifest within the watershed's gullies and channels. Around 4.32% of the watershed area undergoes sedimentation, predominantly at the base of slopes and within channels. Notably, areas (d) and (e) emerge as the most susceptible to disasters within the watershed. Further analysis of the InSAR data highlighted four regions in the typical area (e) from 2017 that are either sedimentation- or erosion-prone, referred to as "hotspots." Among them, R1 exhibits a strong interplay between water and sediment, rendering it highly sensitive to environmental factors. In contrast, R4, characterized by a sharp bend in siltation, remains relatively impervious to external elements. The NDVI (normalized difference vegetation index) stands out as the pivotal determinant influencing sediment transport within the watershed, exerting a pronounced impact on the outlet section, especially in spring. By employing this approach, we gained a deeper understanding of sediment transport mechanisms and potential hazards in small watershed in uninformative mountainous areas. This study furnishes a robust scientific framework beneficial for erosion mitigation and disaster surveillance in mountainous watersheds.

Network pharmacology-based approach to understand the effect and mechanism of chrysophanol against cognitive impairment in Wilson disease.

Wilson disease (WD) is a rare hereditary copper metabolism disorder, wherein cognitive impairment is a common clinical symptom. Chrysophanol (CHR) is an active compound with neuroprotective effects. The study aims to investigate the neuroprotective effect of CHR in WD and attempted to understand the potential mechanisms. Network pharmacology analysis was applied to predict the core target genes of CHR against cognitive impairment in WD. The rats fed with copper-laden diet for 12 weeks, and the effect of CHR on the copper content in liver and 24-h urine, the learning and memory ability, the morphological changes and the apoptosis level of neurons in hippocampal CA1 region, the expression level of Bax, Bcl-2, Cleaved Caspase-3, p-PI3K, PI3K, p-AKT, and AKT proteins were detected. Network pharmacology analysis showed that cell apoptosis and PI3K-AKT signaling pathway might be the main participants in CHR against cognitive impairment in WD. The experiments showed that CHR could reduce the copper content in liver, increase the copper content in 24-h urine, improve the ability of the learning and memory, alleviate the damage and apoptosis level of hippocampal neurons, down-regulate the expression of Bax, Cleaved Caspase-3, and up-regulate the expressions of Bcl-2, p-PI3K/PI3K, p-AKT/AKT. These results suggested that CHR could alleviate cognitive impairment in WD by inhibiting cell apoptosis and triggering the PI3K-AKT signaling pathway.

Ferulic Acid Activates SIRT1-Mediated Ferroptosis Signaling Pathway to Improve Cognition Dysfunction in Wilson's Disease.

Background: Wilson's disease (WD), an autosomal recessive genetic disease, is characterized by copper metabolism disorder. WD patients may have a series of cognitive deficits in terms of neurological symptoms. Ferroptosis (FPT), a type of programmed cell death, is involved in the pathological progression of various cognitive disorders, and silent information regulator 1 (SIRT1) is considered to be a key factor in FPT. Ferulic acid (FA) is a traditional Chinese medicine monomer, with a remarkable effect in the clinical treatment of cognitive impairment-related disease. However, its intrinsic effect on FPT is still unclear. This study aims to investigate the protective effect of FA on cognitive impairment in animal and cell models of WD, and whether the pharmacological mechanism is related to the SIRT1-mediated FPT signaling pathway. Methods: Copper-loaded WD rats and PC12 cells WD were used as models of cognitive dysfunction in vivo and in vitro, respectively. Morris Water Maze (MWM) was used to evaluate the spatial exploration and memory abilities of rats. HE staining was used to observe neuronal damage in the CA1 region of the rat hippocampus. Immunofluorescence (IF) was used to detect the expression of GPX4 protein. Transmission electron microscopy (TEM) was used to observe the ultrastructure of neurons. The levels of Fe2+, MDA, SOD, GSH, 4HNE, and ROS were detected. Western blot and qRT-PCR were used to detect the protein and mRNA levels of SIRT1, Nrf2, SCL7A11, and GPX4. Results: In the WD copper-loaded model rats, MWM, TEM, and IF results showed that FA could promote the repair of learning and memory function, improve the morphological damage to hippocampal neurons, and maintain mitochondria integrity. In the PC12 cell experiment, the MTT method showed that FA increased the viability of copper-overloaded cell models. Western blot and qRT-PCR results confirmed that FA significantly increased the expression of proteins and mRNA in SIRT1, Nrf2, SCL7A11, and GPX4. In addition, FA reversed the expression of oxidative stress-related indicators, including MDA, SOD, GSH, 4HNE, and ROS. Conclusion: FA alleviates hippocampal neuronal injury by activating SIRT1-mediated FPT, providing a valuable candidate for traditional Chinese medicine monomer for the clinical therapeutics of WD cognitive impairment.

Ru nanoclusters anchored on boron- and nitrogen-doped carbon for a highly efficient hydrogen evolution reaction in alkaline seawater.

Electrochemical seawater splitting is an intriguing strategy for green hydrogen production. Constructing advanced electrocatalysts for the hydrogen evolution reaction (HER) in seawater is extremely demanded for accelerating the sluggish kinetic process. Herein, a Ru nanocluster anchored on boron- and nitrogen-doped carbon (Ru/NBC) catalyst was successfully synthesized for the HER in alkaline/seawater electrolytes. Remarkably, Ru/NBC exhibits outstanding activity and durability, delivering low overpotentials@10 mA cm-2 in 1.0 M KOH (30 mV) and 1.0 M KOH + seawater electrolyte (35 mV), outperforming Pt/C, Ru/NC, Ru/BC and Ru/C. Additionally, Ru/NBC also provides a high specific activity of 0.093 mA cm-2ECSA at an overpotential of 150 mV, which is higher than those of Ru/NC, Ru/BC and Ru/C, respectively. Density functional theory calculation results demonstrate that the Ru-B formed interfacial chemical bond can regulate the electronic structure of Ru active sites of Ru/NBC, which can facilitate the adsorption of water and hydrogen in alkaline media. This work provides a feasible strategy to fabricate outstanding electrocatalysts for the HER in alkaline/alkaline seawater electrolytes.

V-ATPase recruitment to ER exit sites switches COPII-mediated transport to lysosomal degradation.

Endoplasmic reticulum (ER)-phagy is crucial to regulate the function and homeostasis of the ER via lysosomal degradation, but how it is initiated is unclear. Here we discover that Z-AAT, a disease-causing mutant of α1-antitrypsin, induces noncanonical ER-phagy at ER exit sites (ERESs). Accumulation of misfolded Z-AAT at the ERESs impairs coat protein complex II (COPII)-mediated ER-to-Golgi transport and retains V0 subunits that further assemble V-ATPase at the arrested ERESs. V-ATPase subsequently recruits ATG16L1 onto ERESs to mediate in situ lipidation of LC3C. FAM134B-II is then recruited by LC3C via its LIR motif and elicits ER-phagy leading to efficient lysosomal degradation of Z-AAT. Activation of this ER-phagy mediated by the V-ATPase-ATG16L1-LC3C axis (EVAC) is also triggered by blocking ER export. Our findings identify a pathway which switches COPII-mediated transport to lysosomal degradation for ER quality control.