Synaptotagmin-3 interactions with GluA2 mediate brain damage and impair functional recovery in stroke.

Synaptotagmin III (Syt3) is a Ca2+-dependent membrane-traffic protein that is highly concentrated in synaptic plasma membranes and affects synaptic plasticity by regulating post-synaptic receptor endocytosis. Here, we show that Syt3 is upregulated in the penumbra after ischemia/reperfusion (I/R) injury. Knockdown of Syt3 protects against I/R injury, promotes recovery of motor function, and inhibits cognitive decline. Overexpression of Syt3 exerts the opposite effects. Mechanistically, I/R injury augments Syt3-GluA2 interactions, decreases GluA2 surface expression, and promotes the formation of Ca2+-permeable AMPA receptors (CP-AMPARs). Using a CP-AMPAR antagonist or dissociating the Syt3-GluA2 complex via TAT-GluA2-3Y peptide promotes recovery from neurological impairments and improves cognitive function. Furthermore, Syt3 knockout mice are resistant to cerebral ischemia because they show high-level expression of surface GluA2 and low-level expression of CP-AMPARs after I/R. Our results indicate that Syt3-GluA2 interactions, which regulate the formation of CP-AMPARs, may be a therapeutic target for ischemic insults.

Down-regulation and clinical significance of Sorbin and SH3 domain-containing protein 1 in bladder cancer tissues.

Bladder cancer (BC) is a common cancer worldwide with a high prevalence. This study was conducted to elucidate the expression and clinical significance of Sorbin and SH3 domain-containing protein 1 (SORBS1) in BC as well as to explore its molecular mechanism in BC tumourigenesis. RNA-sequencing data, microarray, and Immunohistochemistry (IHC) were applied to elucidated the SORBS1 expression at multiple levels. After that, the relationship between tumour-immune infiltration and SORBS1 was also explored. Finally, SORBS1-related genes in BC were identified to perform functional enrichment analyses. The expression integration revealed that the comprehensive expression of SORBS1 at the mRNA level was -1.02 and that at the protein level was -3.73, based on 12 platforms, including 1221 BC and 187 non-BC samples. SORBS1 was negatively correlated with tumour purity (correlation = -0.342, p < 0.001) and positively correlated with macrophage (correlation = 0.358, p < 0.001). The results of enrichment analyses revealed that the most significant biological pathways of SORBS1-related genes were epithelial-mesenchymal transition. SORBS1 was significantly down-regulated in BC and may play a role as tumour suppressor. This study provides new directions and biomarkers for future BC diagnosis.

Lung protective effects of dietary malate esters derivatives from Bletilla striata against SiO2 nanoparticles through activation of Nrf2 pathway.

Objective: To study the protective activities of the dietary malate esters derivatives of Bletilla striata against SiO2 nanoparticles-induced A549 cell lines and its mechanism action. Methods: The components were isolated and elucidated by spectroscopic methods such as 1D NMR and 2D NMR. And MTT assays was used to tested these components on the A549 cell survival rates and ROS or proteins levels were detected by Western blotting. Results: A new glucosyloxybenzyl 2-isobutylmalate (a malate ester derivative), along with 31 known compounds were isolated and identified from n-BuOH extract of EtOH extract of B. striata. Among them, compounds 3, 4, 11, 12 and 13 possessed noteworthy proliferative effects for damaged cells, with ED50 of 14.0, 13.1, 3.7, 11.6 and 11.5 µmol/L, respectively, compared to positive control resveratrol (ED50, 14.7 µmol/L). Militarine (8) prominently inhibited the intracellular ROS level, and increased the expression of Nrf2 and its downstream genes (HO-1 and γ-GCSc). Furthermore, Nrf2 activation mediates the interventional effects of compound 8 against SiO2 nanoparticles (nm SiO2)-induced lung injury. Moreover, treatment with compound 8 significantly reduced lung inflammation and oxidative stress in nm SiO2-instilled mice. Molecular docking experiment suggested that 8 bound stably to the HO-1 protein by hydrogen bond interactions. Conclusion: The dietary malate esters derivatives of B. striata could significantly increase the viability of nm SiO2-induced A549 cells and decrease the finer particles-induced cell damages. Militarine is especially promising compound for chemoprevention of lung cancer induced by nm SiO2 through activation of Nrf2 pathway.

Bioinformatics analysis and verification of key candidate genes influencing the pathogenesis of chronic rhinosinusitis with nasal polyps.

OBJECTIVES: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a prominent public health issue. Furthermore, the prognosis of eosinophilic CRSwNP is poor, with a high recurrence rate. The underlying molecular mechanisms of eosinophilic CRSwNP remain unclear. Therefore, in this study, we sought to determine the crucial genes underlying eosinophil infiltration in eosinophilic CRSwNP pathogenesis. METHODS: We used the Gene Expression Omnibus database (GEO) (GSE36830 and GSE23552 datasets) to mine gene expression profiles of CRSwNP patients and normal subjects. Differentially expressed genes (DEGs) between normal and CRSwNP tissues were identified and subjected to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses. Co-expression networks were established using a weighted gene co-expression network analysis (WGCNA) and single-sample gene set enrichment analysis (GSEA). Protein-protein interaction networks were developed to detect functional protein modules. Based on the common DEGs, candidate miRNAs and related lncRNAs were predicted using the mirTarBase and StarBase databases. Finally, we generated immune cell subtypes of CRSwNP. RESULTS: A total of 146 DEGs were identified. Of these, 131 genes were upregulated, whereas 15 were downregulated. GO analysis indicated that DEGs primarily participated in leukocyte chemotaxis and migration as well as cell chemotaxis. KEGG pathway analysis suggested that DEGs participated in the interactions between cytokines and viral proteins, osteoclast differentiation, and cytokine-cytokine receptor interactions. Real-time quantitative polymerase chain reaction analysis showed that Complement C5a Receptor 1 (C5AR1), C-C Motif Chemokine Receptor 3 (CCR3), Complement C3a Receptor 1 (C3AR1), and C-C Motif Chemokine Ligand 13 (CCL13) expression levels were significantly upregulated in nasal polyps, whereas C-C Motif Chemokine Ligand 4 (CCL4) expression levels were significantly downregulated. CONCLUSIONS: The candidate genes identified in this study may influence the activation and accumulation of eosinophils, cell chemotaxis, and inflammatory responses, thereby potentially representing molecular targets for future studies of CRSwNP.

Chinese Experts Consensus and Practice Guideline on Discoid Lateral Meniscus.

Discoid lateral meniscus (DLM) is the most common congenital variant of the lateral meniscus, which is prone to degeneration and lesions, and often leads to knee osteoarthritis. At present, there is no consensus on the clinical practice of DLM, and this expert consensus and practice guidelines on DLM was developed and approved by Chinese Society of Sports Medicine according to the Delphi method. Among 32 statements drafted, 14 statements were excluded for redundant information, and 18 statements achieved consensus. This expert consensus focused on the definition, epidemiology, etiology, classification, clinical manifestations, diagnosis, treatment, prognosis, and rehabilitation of DLM. Restoring the normal shape, retaining appropriate width and thickness, and ensuring the stability of the remnant meniscus is critical to sustaining the physiological function of the meniscus and preserving the knee. The partial meniscectomy with or without repair should be the first-line treatment when possible, given that the clinical and radiological long-term outcomes of total or subtotal meniscectomy are worse.

PECTIN METHYLESTERASE INHIBITOR18 functions in stomatal dynamics and stomatal dimension.

Pectin methylesterification in guard cell (GC) walls plays an important role in stomatal development and stomatal response to external stimuli, and pectin methylesterase inhibitors (PMEIs) modulate pectin methylesterification by inhibition of pectin methylesterase (PME). However, the function of PMEIs has not been reported in stomata. Here, we report the role of Arabidopsis (Arabidopsis thaliana) PECTIN METHYLESTERASE INHIBITOR18 in stomatal dynamic responses to environmental changes. PMEI18 mutation increased pectin demethylesterification and reduced pectin degradation, resulting in increased stomatal pore size, impaired stomatal dynamics, and hypersensitivity to drought stresses. In contrast, overexpression of PMEI18 reduced pectin demethylesterification and increased pectin degradation, causing more rapid stomatal dynamics. PMEI18 interacted with PME31 in plants, and in vitro enzymatic assays demonstrated that PMEI18 directly inhibits the PME activity of PME31 on pectins. Genetic interaction analyses suggested that PMEI18 modulates stomatal dynamics mainly though inhibition of PME31 on pectin methylesterification in cell walls. Our results provide insight into the molecular mechanism of the PMEI18-PME31 module in stomatal dynamics and highlight the role of PMEI18 and PME31 in stomatal dynamics through modulation of pectin methylesterification and distribution in GC walls.

Comparison of a full and partial choice set design in a labeled discrete choice experiment.

Labeled discrete choice experiments (DCEs) commonly present all alternatives using a full choice set design (FCSD), which could impose a high cognitive burden on respondents. In the setting of employment preferences, this study explored if a partial choice set design (PCSD) reduced cognitive burden whilst maintaining convergent validity compared with a FCSD. Respondents' preferences between the two designs were investigated. In the experimental design, labeled utility functions were rewritten into a single generic utility function using label dummy variables to generate an efficient PCSD with 3 alternatives shown in each choice task (out of 6). The DCE was embedded in a nationwide survey of 790 Australian pharmacy degree holders where respondents were presented with both a block of FCSD and PCSD tasks in random order. The PCSD's impact on error variances was investigated using a heteroscedastic conditional logit model. The convergent validity of PCSD was based on the equality of willingness-to-forgo-expected-salary estimates from Willingness-to-pay-space mixed logit models. A nested logit model was used combined with respondents' qualitative responses to understand respondents' design preferences. We show a promising future use of PCSD by providing evidence that PCSD can reduce cognitive burden while satisfying convergent validity compared to FCSD.

Data-driven subgroups of prediabetes and the associations with outcomes in Chinese adults.

Prediabetes and its pathophysiology remain important issues. We aimed to examine the cluster characteristics of prediabetes and explore their associations with developing diabetes and its complications based on 12 variables representing body fat, glycemic measures, pancreatic ß cell function, insulin resistance, blood lipids, and liver enzymes. A total of 55,777 individuals with prediabetes from the China Cardiometabolic Disease and Cancer Cohort (4C) were classified at baseline into six clusters. During a median of 3.1 years of follow-up, significant differences in the risks of diabetes and its complications between clusters were observed. The odds ratios of diabetes stepwisely increase from cluster 1 to cluster 6. Clusters 1, 4, and 6 have increased chronic kidney diseases risks, while the prediabetes in cluster 4, characterized by obesity and insulin resistance, confers higher risks of cardiovascular diseases compared with others. This subcategorization has potential value in developing more precise strategies for targeted prediabetes prevention and treatment.

High-Entropy Solid-State Na-Ion Conductor for Stable Sodium-Metal Batteries.

Solid-state sodium-metal batteries (SSBs) hold great promise for their merits in low-cost, high energy density, and safety. However, developing solid electrolyte (SE) materials for SSBs with high performance is still a great challenge. Here, we successfully synthesizehigh-entropy Na4.9Sm0.3Y0.2Gd0.2La0.1Al0.1Zr0.1Si4O12 atcomparatively low sintering temperature of 950 °C with high room-temperature ionic conductivity of 6.7×10-4 S cm-1 and a low activation energy of 0.22 eV. More importantly, the Na symmetric cells using high-entropy SE show a high critical current density of 0.6 mA cm-2, outstanding rate performance with fairly flat potential profiles at 0.5 mA cm-2 and steady cycling over 700 h under 0.1 mA cm-2. Solid-state Na3V2(PO4)3||high-entropy SE||Na batteries are further assembled manifesting a desirable cycling stability with almost no capacity decay after 600 cycles and high Columbic efficiency over 99.9%. The findings presented opportunities forthe design of high-entropy Na-ion conductors toward the development of SSBs.

Role of inflammation in neurological damage and regeneration following spinal cord injury and its therapeutic implications.

Spinal cord injury (SCI) is an incurable trauma that frequently results in partial or complete loss of motor and sensory function. Massive neurons are damaged after the initial mechanical insult. Secondary injuries, which are triggered by immunological and inflammatory responses, also result in neuronal loss and axon retraction. This results in defects in the neural circuit and a deficiency in the processing of information. Although inflammatory responses are necessary for spinal cord recovery, conflicting evidence of their contributions to specific biological processes have made it difficult to define the specific role of inflammation in SCI. This review summarizes our understanding of the complex role of inflammation in neural circuit events following SCI, such as cell death, axon regeneration and neural remodeling. We also review the drugs that regulate immune responses and inflammation in the treatment of SCI and discuss the roles of these drugs in the modulation of neural circuits. Finally, we provide evidence about the critical role of inflammation in facilitating spinal cord neural circuit regeneration in zebrafish, an animal model with robust regenerative capacity, to provide insights into the regeneration of the mammalian central nervous system.

Do intravitreal anti-vascular endothelial growth factor agents lead to renal adverse events? A pharmacovigilance real-world study.

Purpose: Intravitreal vascular endothelial growth factor (VEGF) blockade is essential in many macular edema diseases treatment. However, intravitreal VEGF treatment has been reported to lead to deteriorated proteinuria and renal function. This study aimed to explore the relationship between renal adverse events (AEs) and the intravitreal use of VEGF inhibitors. Method: In the FDA's Adverse Event Reporting System (FAERS) database, we searched for renal AEs of patients receiving various anti-VEGF drugs. We performed statistics on renal AEs in patients treated with Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab (from January 2004 to September 2022) using disproportionate and Bayesian analysis. We also investigated the time to onset, fatality, and hospitalization rates of renal AEs. Results: We identified 80 reports. Renal AEs were most frequently associated with Ranibizumab (46.25%) and Aflibercept (42.50%). However, the association between intravitreal anti-VEGFs and renal AEs was insignificant since the reporting odds ratio of Aflibercept, Bevacizumab, Ranibizumab, and Brolucizumab were 0.23 (0.16, 0.32), 0.24 (0.11, 0.49), 0.37 (0.27, 0.51) and 0.15 (0.04, 0.61), respectively. The median time to renal AEs onsets was 37.5 (interquartile range 11.0-107.3) days. The hospitalization and fatality rates in patients who developed renal AEs were 40.24 and 9.76%, respectively. Conclusion: There are no clear signals for the risk of renal AEs following various intravitreal anti-VEGF drugs based on FARES data.

Perception and Practice of Bariatric Surgery and Reproductive Health in Women: a Cross-sectional Study of Chinese Bariatric Surgeons.

BACKGROUND AND PURPOSE: Western studies have explored bariatric surgeons concerning their views on bariatric surgery (BS) and reproductive health, but Asian data were lacking. The aim of this study was to explore the perception and practice of bariatric surgeons on the reproductive health of female patients who underwent BS in China to better guide clinical practice and improve clinical outcomes. METHOD: An online questionnaire of 31 questions developed by bariatric surgeons was collected by sending to one online communication group (WeChat group) whose members are Chinese bariatric surgeons. RESULT: A total of 87 bariatric surgeons from mainland China were surveyed. Almost all (97.7%, 85/87) surgeons considered the reproductive health conversation for women who underwent BS to be important or very important. Only 1/4 of surgeons routinely discuss reproductive health-related issues with patients, and only 56% of doctors always ask patients for postoperative contraception. Less than 20% of bariatric surgeons have full knowledge of postoperative contraception, and nearly 40% of them believe that gynecologists should be responsible for providing contraception. More than 35% of bariatric surgeons have never been involved in the co-management of pregnancy in patients with a history of BS. CONCLUSION: Although most bariatric surgeons are aware of the importance of female reproductive health, there is a large gap in the perception and clinical practice of bariatric surgeons in terms of reproductive health. It is necessary to further strengthen the education of bariatric surgeons and enhance multidisciplinary cooperation with gynecology, obstetrics, and other disciplines to bring better clinical outcomes.

Benefits and Risks of Bariatric Surgery on Women's Reproductive Health: a Narrative Review.

Bariatric surgery (BS) is escalating as the most efficient and endurable therapy for severe obesity. Women's reproductive health is essential to women's quality of life and is receiving increasing attention. However, despite the high prevalence of BS among women, the effect of BS on reproductive health remains underemphasis. The purpose of this narrative review is to provide an overview of BS on women's reproductive health, including their reproductive health before, during, and after pregnancy. Although limited attention has been given, current evidence highlights the substantial implications of bariatric surgery on reproductive health and reminds us of the importance of adopting decision-making conversations about reproductive health before bariatric surgery.

Multi-view feature representation and fusion for drug-drug interactions prediction.

BACKGROUND: Drug-drug interactions (DDIs) prediction is vital for pharmacology and clinical application to avoid adverse drug reactions on patients. It is challenging because DDIs are related to multiple factors, such as genes, drug molecular structure, diseases, biological processes, side effects, etc. It is a crucial technology for Knowledge graph to present multi-relation among entities. Recently some existing graph-based computation models have been proposed for DDIs prediction and get good performance. However, there are still some challenges in the knowledge graph representation, which can extract rich latent features from drug knowledge graph (KG). RESULTS: In this work, we propose a novel multi-view feature representation and fusion (MuFRF) architecture to realize DDIs prediction. It consists of two views of feature representation and a multi-level latent feature fusion. For the feature representation from the graph view and KG view, we use graph isomorphism network to map drug molecular structures and use RotatE to implement the vector representation on bio-medical knowledge graph, respectively. We design concatenate-level and scalar-level strategies in the multi-level latent feature fusion to capture latent features from drug molecular structure information and semantic features from bio-medical KG. And the multi-head attention mechanism achieves the optimization of features on binary and multi-class classification tasks. We evaluate our proposed method based on two open datasets in the experiments. Experiments indicate that MuFRF outperforms the classic and state-of-the-art models. CONCLUSIONS: Our proposed model can fully exploit and integrate the latent feature from the drug molecular structure graph (graph view) and rich bio-medical knowledge graph (KG view). We find that a multi-view feature representation and fusion model can accurately predict DDIs. It may contribute to providing with some guidance for research and validation for discovering novel DDIs.

Eliciting primary healthcare physicians' preferences for job characteristics in rural China: a discrete choice experiment.

INTRODUCTION: The outflow and scarcity of physicians in rural areas can adversely affect universal health coverage and population health outcomes, which are critical concerns in China. This study explored primary healthcare physicians' job preferences using a discrete choice experiment to identify appropriate incentives for retention. METHODS: Eight job characteristics were identified through a literature review and qualitative studies as the attributes relevant to designing the discrete choice experiment, with levels varying between two hypothetical jobs. The data were analysed using conditional logit model, mixed logit model and latent class model. RESULTS: A total of 1781 licensed physicians (including licensed assistant physicians) from township health centres in rural areas were surveyed. Policy simulation suggested that they were sensitive to both monetary and non-monetary policy incentives. As for non-monetary job characteristics, a highly intense doctor-patient relationship, bianzhi (the number of personnel allocated to each employer by the government) and educational opportunities were highly valued by the respondents. The latent class model could identify distinct groups with different job preferences according to their memberships. CONCLUSION: Urban jobs were much preferred to rural ones. However, policy incentives can lend themselves to effective retention strategies. It is also important to tailor policy incentives to different subgroups.

Machine learning radiomics to predict the early recurrence of intrahepatic cholangiocarcinoma after curative resection: A multicentre cohort study.

PURPOSE: Postoperative early recurrence (ER) leads to a poor prognosis for intrahepatic cholangiocarcinoma (ICC). We aimed to develop machine learning (ML) radiomics models to predict ER in ICC after curative resection. METHODS: Patients with ICC undergoing curative surgery from three institutions were retrospectively recruited and assigned to training and external validation cohorts. Preoperative arterial and venous phase contrast-enhanced computed tomography (CECT) images were acquired and segmented. Radiomics features were extracted and ranked through their importance. Univariate and multivariate logistic regression analysis was used to identify clinical characteristics. Various ML algorithms were used to construct radiomics-based models, and the predictive performance was evaluated by receiver operating characteristic curves, calibration curves, and decision curve analysis. RESULTS: 127 patients were included for analysis: 90 patients in the training set and 37 patients in the validation set. Ninety-two patients (72.4%) experienced recurrence, including 71 patients exhibiting ER. Male sex, microvascular invasion, TNM stage, and serum CA19-9 were identified as independent risk factors for ER, with the corresponding clinical model having a poor predictive performance (AUC of 0.685). Fifty-seven differential radiomics features were identified, and the 10 most important features were utilized for modelling. Seven ML radiomics models were developed with a mean AUC of 0.87 ± 0.02, higher than the clinical model. Furthermore, the clinical-radiomics models showed similar predictive performance to the radiomics models (AUC of 0.87 ± 0.03). CONCLUSION: ML radiomics models based on CECT are valuable in predicting ER in ICC.

High-frequency vibration effects on material removal mechanisms in ultrasonic transverse scratching of carbon fiber reinforced plastics.

This paper represented some fundamental investigations on the potential effects of the high-frequency vibration on material removal mechanisms in ultrasonic transverse scratching of carbon fiber reinforced plastics (CFRPs). It was found that the ultrasonic superimposition brought about the evident reduction of the ductile-brittle transition depth of the unidirectional CFRPs. For the scratched groove generated without ultrasonic, the tensile stress and compressive stress caused by the indenter penetration were respectively responsible for the formations of the radial cracks at the leading edges and the central region. Under the combination of the inertia effects induced by the ultrasonic superposition and the skin-core structure of the carbon fibers, the micro-defects situated at the interior of the fibers were nucleated simultaneously, and their propagations caused the formations of the oblique cracks. Incorporated with the strain rate effects of the materials, a fresh theoretical model was proposed to describe the evolution of the mechanical stress during the scratching process. The fiber fragments induced by the oblique cracks were just concentrated on the top surface of the scratched groove, due to the coupling effects of the small penetration depth of the indenter and the express reduction of strain rate.

Ionogels: recent advances in design, material properties and emerging biomedical applications.

Ionic liquid (IL)-based gels (ionogels) have received considerable attention due to their unique advantages in ionic conductivity and their biphasic liquid-solid phase property. In ionogels, the negligibly volatile ionic liquid is retained in the interconnected 3D pore structure. On the basis of these physical features as well as the chemical properties of well-chosen ILs, there is emerging interest in the anti-bacterial and biocompatibility aspects. In this review, the recent achievements of ionogels for biomedical applications are summarized and discussed. Following a brief introduction of the various types of ILs and their key physicochemical and biological properties, the design strategies and fabrication methods of ionogels are presented by means of different confining networks. These sophisticated ionogels with diverse functions, aimed at biomedical applications, are further classified into several active domains, including wearable strain sensors, therapeutic delivery systems, wound healing and biochemical detections. Finally, the challenges and possible strategies for the design of future ionogels by integrating materials science with a biological interface are proposed.