Graphene Oxide/Black Phosphorus Functionalized Collagen Scaffolds with Enhanced Near-Infrared Controlled In Situ Biomineralization for Promoting Infectious Bone Defect Repair through PI3K/Akt Pathway.

Infectious bone defects resulting from surgery, infection, or trauma are a prevalent clinical issue. Current treatments commonly used include systemic antibiotics and autografts or allografts. Nevertheless, therapies come with various disadvantages, including multidrug-resistant bacteria, complications arising from the donor site, and immune rejection, which makes artificial implants desirable. However, artificial implants can fail due to bacterial infections and inadequate bone fusion after implantation. Thus, the development of multifunctional bone substitutes that are biocompatible, antibacterial, osteoconductive, and osteoinductive would be of great clinical importance. This study designs and prepares 2D graphene oxide (GO) and black phosphorus (BP) reinforced porous collagen (Col) scaffolds as a viable strategy for treating infectious bone defects. The fabricated Col-GO@BP scaffold exhibited an efficient photothermal antibacterial effect under near-infrared (NIR) irradiation. A further benefit of the NIR-controlled degradation of BP was to promote biomineralization by phosphorus-driven and calcium-extracted phosphorus in situ. The abundant functional groups in GO could synergistically capture the ions and enhance the in situ biomineralization. The Col-GO@BP scaffold facilitated osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSC) by leveraging its mild photothermal effect and biomineralization process, which upregulated heat shock proteins (HSPs) and activated PI3K/Akt pathways. Additionally, systematic in vivo experiments demonstrated that the Col-GO@BP scaffold obviously promotes infectious bone repair through admirable photothermal antibacterial performance and enhanced vascularization. As a result of this study, we provide new insights into the photothermal activity of GO@BP nanosheets, their degradation, and a new biological application for them.

VAE-WACGAN: An Improved Data Augmentation Method Based on VAEGAN for Intrusion Detection.

To address the class imbalance issue in network intrusion detection, which degrades performance of intrusion detection models, this paper proposes a novel generative model called VAE-WACGAN to generate minority class samples and balance the dataset. This model extends the Variational Autoencoder Generative Adversarial Network (VAEGAN) by integrating key features from the Auxiliary Classifier Generative Adversarial Network (ACGAN) and the Wasserstein Generative Adversarial Network with Gradient Penalty (WGAN-GP). These enhancements significantly improve both the quality of generated samples and the stability of the training process. By utilizing the VAE-WACGAN model to oversample anomalous data, more realistic synthetic anomalies that closely mirror the actual network traffic distribution can be generated. This approach effectively balances the network traffic dataset and enhances the overall performance of the intrusion detection model. Experimental validation was conducted using two widely utilized intrusion detection datasets, UNSW-NB15 and CIC-IDS2017. The results demonstrate that the VAE-WACGAN method effectively enhances the performance metrics of the intrusion detection model. Furthermore, the VAE-WACGAN-based intrusion detection approach surpasses several other advanced methods, underscoring its effectiveness in tackling network security challenges.

Engineering Ag-Decorated Graphene Oxide Nano-Photothermal Platforms with Enhanced Antibacterial Properties for Promoting Infectious Wound Healing.

Introduction: Graphene oxide (GO) nanoparticles have emerged as a compelling photothermal agent (PHTA) in the realm of photothermal antibacterial therapy, owing to their cost-effectiveness, facile synthesis, and remarkable photostability. Nevertheless, the therapeutic efficacy of GO nanoparticles is commonly hindered by their inherent drawback of low photothermal conversion efficiency (PCE). Methods: Herein, we engineer the Ag/GO-GelMA platform by growing the Ag on the surface of GO and encapsulating the Ag/GO nanoparticles into the GelMA hydrogels. Results: The resulting Ag/GO-GelMA platform demonstrates a significantly enhanced PCE (47.6%), surpassing that of pure GO (11.8%) by more than fourfold. As expected, the Ag/GO-GelMA platform, which was designed to integrate the benefits of Ag/GO nanoparticles (high PCE) and hydrogel (slowly releasing Ag+ to exert an inherent antibacterial effect), has been shown to exhibit exceptional antibacterial efficacy. Furthermore, transcriptome analyses demonstrated that the Ag/GO-GelMA platform could significantly down-regulate pathways linked to inflammation (the MAPK and PI3K-Akt pathways) and had the ability to promote cell migration. Discussion: Taken together, this study presents the design of a potent photothermal antibacterial platform (Ag/GO-GelMA) aimed at enhancing the healing of infectious wounds. The platform utilizes a handy method to enhance the PCE of GO, thereby making notable progress in the utilization of GO nano-PHTAs.

Regulation of Nrf2/A20/eEF1A2 Axis by Ginsenoside Rb1: A Key Pathway in Alleviating Cerebral Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIRI) is a prevalent neurological disorder, characterized by the oxidative stress and inflammatory response induced during the ischemia-reperfusion process, leading to significant damage to brain cells. Ginsenoside Rb1, a natural medicinal ingredient, possesses potential neuroprotective effects. This study aims to investigate the mechanism of action of ginsenoside Rb1 in CIRI and its protective effects on brain injury. METHODS: We utilized a mouse CIRI model and randomly divided the mice into control group, CIRI group, and ginsenoside Rb1 treatment group. The effects of Rb1 on brain tissue damage, apoptosis, expression of inflammatory factors, and pyroptotic cell numbers in CIRI mice were observed through triphenyl tetrazolium chloride (TTC) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, real-time reverse transcription polymerase chain reaction (qRT-PCR), and electron microscopy. In a cell model, the regulatory effect of Rb1 on oxygen-glucose deprivation/reperfusion (OGD/R)-induced HT22 cell pyroptosis via the nuclear respiratoty factor 2/tumor necrosis factor-α (TNF-α)-induced Protein 3 (TNFAIP3, aka A20)/eukaryotic translation elongation factor 1A2 (Nrf2/A20/eEF1A2) axis was detected using Western blot and TUNEL staining. Additionally, the impact of Nrf2 inhibitor ML385 and eEF1A2 overexpression on the neuroprotective effect of Rb1 was assessed. Using the comprehensive experimental methods mentioned above, the neuroprotective mechanism of Rb1 in CIRI was thoroughly evaluated. RESULTS: Our findings demonstrate that treatment with ginsenoside Rb1 alleviated behavioral deficits induced by CIRI and reduced pathological damage in brain tissue. Furthermore, ginsenoside Rb1 treatment notably decreased oxidative stress and the inflammatory response induced by CIRI, leading to lower levels of inflammatory factors (p < 0.05). Further experimental results indicated that ginsenoside Rb1 promoted antioxidant and anti-inflammatory responses by regulating the activity of the Nrf2/A20/eEF1A2 axis. Additionally, ginsenoside Rb1 inhibited the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, thereby reducing the release of inflammatory factors and the occurrence of cell apoptosis. CONCLUSION: Our study results suggest that ginsenoside Rb1 exerts neuroprotective effects and alleviates brain injury induced by CIRI by regulating the Nrf2/A20/eEF1A2 axis and inhibiting the activation of the NLRP3 inflammasome. These findings provide new treatment insights for CIRI and support ginsenoside Rb1's development as a therapeutic drug. However, despite the promising nature of our findings, further research is required to validate these discoveries and explore the feasibility and safety of ginsenoside Rb1 in clinical applications. We hope that our study can provide new directions and strategies for the treatment and prevention of CIRI, contributing to the development of neuroprotective drugs.

Gene editing by SSB/CRISPR-Cas9 ribonucleoprotein in bacteria.

The application of CRISPR-Cas9 ribonucleoprotein (RNP) for gene editing is commonly used in plants and animals, but its application in bacteria has not been reported. In this study, we employed DNA single-strand binding protein (SSB) to construct an SSB/CRISPR-Cas9 RNP-editing system for non-homologous recombination and homologous recombination gene editing of the upp gene in bacteria. The RNP targeting the upp gene, along with SSB, was introduced into the protoplasts of Escherichia coli, Pseudomonas, and Bacillus subtilis. Transformants were obtained on plates containing 5-fluorouracil (5-FU) with gene editing efficiencies (percentage of transformants relative to the number of protoplasts) of 9.75 %, 5.02 %, and 8.37 %, respectively, and sequencing analysis confirmed 100 % non-homologous recombination. When RNP, SSB, and a 100-nucleotide single-stranded oligodeoxynucleotide (ssODN) donor were introduced into the protoplasts of these bacteria, transformants were obtained with editing efficiencies of 45.11 %, 30.13 %, and 27.18 %, respectively, and sequencing confirmed 100 % homologous recombination knockout of the upp gene. Additionally, introducing RNP, SSB, and a 100 base-pair double-stranded oligodeoxynucleotide (dsODN) donor containing a tetracycline resistance gene (tetR-dsODN) resulted in transformants on 5-FU plates with editing efficiencies of 35.94 %, 22.46 %, and 19.08 %, respectively, with sequencing confirming 100 % homologous recombination replacement of the upp gene with tetR. These results demonstrate that the SSB/CRISPR-Cas9 RNP system can efficiently, simply, and rapidly edit bacterial genomes without the need for plasmids. This study is the first to report the use of RNP-based gene editing in bacteria.

A Fair Contribution Measurement Method for Federated Learning.

Federated learning is an effective approach for preserving data privacy and security, enabling machine learning to occur in a distributed environment and promoting its development. However, an urgent problem that needs to be addressed is how to encourage active client participation in federated learning. The Shapley value, a classical concept in cooperative game theory, has been utilized for data valuation in machine learning services. Nevertheless, existing numerical evaluation schemes based on the Shapley value are impractical, as they necessitate additional model training, leading to increased communication overhead. Moreover, participants' data may exhibit Non-IID characteristics, posing a significant challenge to evaluating participant contributions. Non-IID data have greatly affected the accuracy of the global model, weakened the marginal effect of the participants, and led to the underestimated contribution measurement results of the participants. Current work often overlooks the impact of heterogeneity on model aggregation. This paper presents a fair federated learning contribution measurement scheme that addresses the need for additional model computations. By introducing a novel aggregation weight, it enhances the accuracy of the contribution measurement. Experiments on the MNIST and Fashion MNIST dataset show that the proposed method can accurately compute the contributions of participants. Compared to existing baseline algorithms, the model accuracy is significantly improved, with a similar time cost.

Causality of Helicobacter pylori infection on eosinophilic esophagitis and potential pathogenesis: a Mendelian randomization study.

Background: Observational studies have indicated a possible connection between Helicobacter pylori (H. pylori) infection and eosinophilic esophagitis (EoE), but their causal relationship has yet to be established. To investigate the causal associations between H. pylori infection and EoE, we performed a Mendelian randomization (MR) analysis. Methods: Firstly, we conducted both univariable and multivariable Mendelian randomization (MR) analyses. Furthermore, a two-step MR was carried out to ascertain the potential underlying pathways of these associations, particularly the involvement of inflammatory cytokines. We employed the inverse-variance weighted (IVW) method as the main analysis in our MR study. To enhance the credibility of the results, we also conducted several sensitivity analyses. Results: Our study demonstrated a noteworthy correlation between genetically predicted anti-H. pylori IgG antibody levels and a reduced risk of EoE (OR=0.325, 95% CI=0.165-0.643, P value=0.004, adj p value=0.009). No significant causal associations were detected between other H. pylori antibodies and EoE in our study. When it comes to multivariable MR analysis controlling for education attainment, household income, and deprivation individually, the independent causal impact of anti-H. pylori IgG on EoE persisted. Surprisingly, the two-step MR analysis indicated that inflammatory factors (IL-4, IL-5, IL-13, IL-17, and IFN-γ) did not appear to mediate the protective effect of H. pylori infection against EoE. Conclusion: Findings suggested that among the range of H. pylori-related antibodies, anti-H. pylori IgG antibody is the sole causal factor associated with protection against EoE. Certain inflammatory factors may not be involved in mediating this association. These findings make a significant contribution to advancing our understanding of the pathogenesis of EoE and its evolving etiology.

Enhanced physiochemical, antibacterial, and hemostatic performance of collagen-quaternized chitosan-graphene oxide sponges for promoting infectious wound healing.

Bacteria-infected wound healing has attracted widespread attention in biomedical engineering. Wound dressing is a potential strategy for repairing infectious wounds. However, the development of wound dressing with appropriate physiochemical, antibacterial, and hemostatic properties, remains challenging. Hence, there is a motivation to develop new synthetic dressings to improve bacteria-infected wound healing. Here, we fabricate a biocompatible sponge through the covalent crosslinking of collagen (Col), quaternized chitosan (QCS), and graphene oxide (GO). The resulting Col-QCS-GO sponge shows an elastic modulus of 1.93-fold higher than Col sponge due to enhanced crosslinking degree by GO incorporation. Moreover, the fabricated Col-QCS-GO sponge shows favorable porosity (84.30 ± 3.12 %), water absorption / retention (2658.0 ± 113.4 % / 1114.0 ± 65.7 %), and hemostasis capacities (blood loss <50.0 mg). Furthermore, the antibacterial property of the Col-QCS-GO sponge under near-infrared (NIR) irradiation is significantly enhanced (the inhibition rates are 99.9 % for S. aureus and 99.9 % for E. coli) due to the inherent antibacterial properties of QCS and the photothermal antibacterial capabilities of GO. Finally, the Col-QCS-GO+NIR sponge exhibits the lowest percentage of wound area (9.05 ± 1.42 %) at day 14 compared to the control group (31.61 ± 1.76 %). This study provides new insights for developing innovative sponges for bacteria-infected wound healing.

Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.

BACKGROUND: The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens. METHODS: The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history. RESULTS: Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits. CONCLUSION: For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.

Development and validation of a novel risk classification tool for predicting long length of stay in NICU blood transfusion infants.

Newborns are as the primary recipients of blood transfusions. There is a possibility of an association between blood transfusion and unfavorable outcomes. Such complications not only imperil the lives of newborns but also cause long hospitalization. Our objective is to explore the predictor variables that may lead to extended hospital stays in neonatal intensive care unit (NICU) patients who have undergone blood transfusions and develop a predictive nomogram. A retrospective review of 539 neonates who underwent blood transfusion was conducted using median and interquartile ranges to describe their length of stay (LOS). Neonates with LOS above the 75th percentile (P75) were categorized as having a long LOS. The Least Absolute Shrinkage and Selection Operator (LASSO) regression method was employed to screen variables and construct a risk model for long LOS. A multiple logistic regression prediction model was then constructed using the selected variables from the LASSO regression model. The significance of the prediction model was evaluated by calculating the area under the ROC curve (AUC) and assessing the confidence interval around the AUC. The calibration curve is used to further validate the model's calibration and predictability. The model's clinical effectiveness was assessed through decision curve analysis. To evaluate the generalizability of the model, fivefold cross-validation was employed. Internal validation of the models was performed using bootstrap validation. Among the 539 infants who received blood transfusions, 398 infants (P75) had a length of stay (LOS) within the normal range of 34 days, according to the interquartile range. However, 141 infants (P75) experienced long LOS beyond the normal range. The predictive model included six variables: gestational age (GA) (< 28 weeks), birth weight (BW) (< 1000 g), type of respiratory support, umbilical venous catheter (UVC), sepsis, and resuscitation frequency. The area under the receiver operating characteristic (ROC) curve (AUC) for the training set was 0.851 (95% CI 0.805-0.891), and for the validation set, it was 0.859 (95% CI 0.789-0.920). Fivefold cross-validation indicates that the model has good generalization ability. The calibration curve demonstrated a strong correlation between the predicted risk and the observed actual risk, indicating good consistency. When the intervention threshold was set at 2%, the decision curve analysis indicated that the model had greater clinical utility. The results of our study have led to the development of a novel nomogram that can assist clinicians in predicting the probability of long hospitalization in blood transfused infants with reasonable accuracy. Our findings indicate that GA (< 28 weeks), BW(< 1000 g), type of respiratory support, UVC, sepsis, and resuscitation frequency are associated with a higher likelihood of extended hospital stays among newborns who have received blood transfusions.

3D-printed PCL framework assembling ECM-inspired multi-layer mineralized GO-Col-HAp microscaffold for in situ mandibular bone regeneration.

BACKGROUND: In recent years, natural bone extracellular matrix (ECM)-inspired materials have found widespread application as scaffolds for bone tissue engineering. However, the challenge of creating scaffolds that mimic natural bone ECM's mechanical strength and hierarchical nano-micro-macro structures remains. The purposes of this study were to introduce an innovative bone ECM-inspired scaffold that integrates a 3D-printed framework with hydroxyapatite (HAp) mineralized graphene oxide-collagen (GO-Col) microscaffolds and find its application in the repair of mandibular bone defects. METHODS: Initially, a 3D-printed polycaprolactone (PCL) scaffold was designed with cubic disks and square pores to mimic the macrostructure of bone ECM. Subsequently, we developed multi-layer mineralized GO-Col-HAp microscaffolds (MLM GCH) to simulate natural bone ECM's nano- and microstructural features. Systematic in vitro and in vivo experiments were introduced to evaluate the ECM-inspired structure of the scaffold and to explore its effect on cell proliferation and its ability to repair rat bone defects. RESULTS: The resultant MLM GCH/PCL composite scaffolds exhibited robust mechanical strength and ample assembly space. Moreover, the ECM-inspired MLM GCH microscaffolds displayed favorable attributes such as water absorption and retention and demonstrated promising cell adsorption, proliferation, and osteogenic differentiation in vitro. The MLM GCH/PCL composite scaffolds exhibited successful bone regeneration within mandibular bone defects in vivo. CONCLUSIONS: This study presents a well-conceived strategy for fabricating ECM-inspired scaffolds by integrating 3D-printed PCL frameworks with multilayer mineralized porous microscaffolds, enhancing cell proliferation, osteogenic differentiation, and bone regeneration. This construction approach holds the potential for extension to various other biomaterial types.

Mamestra brassicae Multiple Nucleopolyhedroviruses Prevents Pupation of Helicoverpa armigera by Regulating Juvenile Hormone Titer.

Baculovirus infection can prevent the pupation of insects. Juvenile hormone (JH) plays a vital role in regulating insect molting and metamorphosis. However, the molecular mechanism of baculovirus preventing the pupation of larvae by regulating the Juvenile hormone (JH) pathway is still unclear. In this study, we found that the Mamestra brassicae multiple nucleopolyhedroviruses (MbMNPV) infection prolonged the larval stage of fourth instar Helicoverpa armigera (H. armigera) by 0.52 d and caused an increase in JH titer. To identify the genes that contribute to the JH increase in H. armigera-MbMNPV interaction, we analyzed mRNA expression profiles of the fat bodies of H. armigera infected by MbMNPV. A total of 3637 differentially expressed mRNAs (DE-mRNAs) were filtered out through RNA-seq analysis. These DE-mRNAs were mainly enriched in Spliceosome, Ribosome biogenesis in eukaryotes, Aminoacyl-tRNA biosynthesis, Mismatch repair, and RNA degradation signaling pathway, which are related to the virus infection. Real-time PCR was used to verify the RNA sequencing results. To find out which genes caused the increase in JH titer, we analyzed all the DE-mRNAs in the transcriptome and found that the JHE and JHEH genes, which were related to JH degradation pathway, were down-regulated. JHE and JHEH genes in the larvae of MbMNPV-infected group were significantly down-regulated compared with the control group by RT-qPCR. We further proved that the JH is degraded by JHE in H. armigera larvae by RNAi, ELISA, RT-qPCR and bioassay, while the hydrolysis of JH by JHEH in H. armigera larvae can almost be ignored. Knocking down of HaJHE promoted the expression of the JH receptor gene Met and the downstream gene Kr-h1, and the replication of MbMNPV. This study clarified that JH is mainly degraded by JHE in H. armigera larvae. The MbMNPV infection of H. armigera larvae leads to the increase of JH titer by inhibiting the expression of JHE. The increase in JH titer promotes the expression of the JH receptor gene Met and the downstream gene Kr-h1, which prevents the pupation of H. armigera, and promotes MbMNPV replication. This study provides new insights into H. armigera and MbMNPV interaction mechanisms.

Tailored gelatin methacryloyl-based hydrogel with near-infrared responsive delivery of Qiai essential oils boosting reactive oxygen species scavenging, antimicrobial, and anti-inflammatory activities for diabetic wound healing.

The management of diabetic wounds poses a substantial economic and medical burden for diabetic patients. Oxidative stress and persistent bacterial infections are considered to be the primary factors. Qiai essential oil (QEO) exhibits various pharmacological characteristics, including inflammatory-reducing, antibacterial, and antioxidant properties. Nevertheless, the hydrophobic nature and propensity for explosive release of this substance present constraints on its potential for future applications. Here, we developed a stimulus-responsive hydrogel to overcome the multiple limitations of QEO-based wound dressings. The QEO was encapsulated within graphene oxide (GO) through repeated extrusion using an extruder. Subsequently, QEO@GO nanoparticles were incorporated into a Gelatin-methacryloyl (GelMA) hydrogel. The QEO@GO-GelMA hydrogel demonstrated controlled release ablation, photothermal antibacterial effects, and contact ablation against two representative bacterial strains. It effectively reduced reactive oxygen species (ROS) generation, promoted angiogenesis, and decreased levels of the pro-inflammatory cytokine interleukin-6 (IL-6), thereby accelerating the healing process of diabetic wounds. In addition, in vitro and in vivo tests provided further evidence of the favorable biocompatibility of this multifunctional hydrogel dressing. Overall, the QEO@GO-GelMA hydrogel provides numerous benefits, encompassing antimicrobial properties, ROS-scavenging abilities, anti-inflammatory effects, and the capacity to expedite diabetic wound healing. These attributes make it an optimal choice for diabetic wound management.

Baohuoside I suppresses the NLRP3 inflammasome activation via targeting GPER to fight against Parkinson's disease.

BACKGROUND: Accumulating evidence indicates the crucial role of microglia-mediated inflammation and the NLR family pyrin domain containing 3 (NLRP3) inflammasome-mediated pyroptosis in the pathogenesis of Parkinson's disease (PD). Baohuoside I, a natural flavonoid extracted from Herba Epimedii, has been shown to possess anti-inflammatory effects, but its potential neuroprotective effects and mechanism against PD have not been documented. STUDY DESIGN AND METHODS: The anti-inflammatory effects of Baohuoside I were evaluated by LPS-induced BV2 cells or primary microglia isolated from wide type or G protein-coupled estrogen receptor (GPER) gene knockout mice. The underlying mechanism related to GPER-mediated NLRP3 inflammasome inhibition was further explored using LPS-induced GPER+/+ or GPER-/- mouse models of PD. The neuroprotective effects of Baohuoside I were detected through western blot analysis, real-time PCR, molecular docking, mouse behavioral tests, immunofluorescence, and immunohistochemistry. RESULTS: Baohuoside I significantly alleviated LPS-induced neuroinflammation by inhibiting the activation of NF-κB signal and the increase of pyroptosis levels as evidenced by the downregulated expression of pyroptosis-related proteins (NLRP3, ASC, pro-Caspase-1, IL-1ß) in microglia cells. Intragastric administration of Baohuoside I protected against LPS-induced motor dysfunction and loss of dopaminergic neurons, reduced pro-inflammatory cytokines expressions, and inhibited microglial (Iba-1) and astrocyte (GFAP) activation in the nigrostriatal pathway in LPS-induced mouse model of PD. Pretreatment with GPER antagonist G15 in microglia cells or GPER gene deletion in mice significantly blocked the inhibitory effects of Baohuoside I on LPS-induced neuroinflammation and activation of the NLRP3/ASC/Caspase-1 pathway. Molecular docking further indicated that Baohuoside I might bind to GPER directly with a binding energy of -10.4 kcal/mol. CONCLUSION: Baohuoside I provides neuroprotective effects against PD by inhibiting the activation of the NF-κB signal and NLRP3/ASC/Caspase-1 pathway. The molecular target for its anti-inflammatory effects is proved to be GPER in the PD mouse model. Baohuoside I may be a valuable anti-neuroinflammatory agent and a drug with well-defined target for the treatment of PD.

Correlation analysis of hypertension, traditional Chinese medicine constitution, and LPL gene polymorphism in the elderly in communities in Shanghai.

BACKGROUND: Research on the genetic mechanisms of hypertension has been a hot topic in the cardiovascular field. OBJECTIVE: To study the correlation between senile hypertension and traditional Chinese medicine (TCM) constitution and lipoprotein lipase (LPL) gene polymorphism and to provide the theoretical basis for TCM prevention and treatment of hypertension. METHODS: The elderly population in communities in Shanghai (hypertensive: 264 cases; non-hypertensive: 159 cases) was taken as the research object. Essential data and information on TCM constitution were collected. The LPL gene mutation was detected using the second-generation sequencing method. Statistical analysis was performed to clarify the relationship between hypertension and senile hypertension. The correlation of TCM constitution with risk factors and LPL gene polymorphisms was studied. RESULTS: The primary TCM constitutions in the hypertension group were phlegm-dampness constitution (51.52%), yin-deficiency constitution (17.42%), balanced constitution (15.53%), and yin-deficiency (9.43%). Logistic regression analysis showed that the phlegm-dampness constitution (P< 0.05, OR = 2.587) and yin-deficiency constitution (P< 0.01, OR = 2.693) were the risk constitutions of hypertension in the elderly. A total of 37 LPL gene mutation loci (SNP: 22; new discovery: 15) were detected in the LPL gene, and the mutation rates of rs254, rs255, rs3208305, rs316, rs11570891, rs328, rs11570893, and rs13702 were relatively high, which were 26.24%, 26.24%, 16.08%, 14.66%, 13.24%, 12.06%, and 10.64%. In the phlegm-dampness group, the proportion of rs254 CC type, rs255 TT type, and rs13702 TT type in the hypertensive group (77.21%, 77.21%, and 93.38%) was higher than that in the non-hypertensive group (56.41%, 56.41%, and 82.05%), The difference was statistically significant (P< 0.05). CONCLUSION: The phlegm-dampness constitution and yin-deficiency constitution are the risk factors of hypertension in the elderly; in the phlegm-dampness population, rs254 CC type, rs255 TT type, and rs13702 TT type are the risk factors for elderly hypertension.

Characteristics of innate, humoral and cellular immunity in children with non-severe SARS-CoV-2 infection.

The symptoms of children infected with SARS-CoV-2 are mainly asymptomatic, mild, moderate, and a few severe cases. To understand the immune response characteristics of children infected with SARS-COV-2 who do not develop severe cases, 82 children infected with the SARS-CoV-2 delta strain were recruited in this study. Our results showed that high levels of IgG, IgM, and neutralization antibodies appeared in children infected with SARS-CoV-2. SARS-CoV-2 induced upregulation of both pro-inflammatory factors including TNF-α and anti-inflammatory factors including IL-4 and IL-13 in the children, even IL-10. The expression of INF-α in infected children also showed a significant increase compared to healthy children. However, IL-6, one of the important inflammatory factors, did not show an increase in infected children. It is worth noting that a large number of chemokines reduced in the SARS-CoV-2-infected children. Subsequently, TCR Repertoire, TCRß bias, and preferential usage were analyzed on data of TCR next-generation sequencing from 8 SARS-CoV-2-infected children and 8 healthy controls. We found a significant decrease in TCR clonal diversity and a significant increase in TCR clonal expansion in SARS-CoV-2-infected children compared to healthy children. The most frequent V and J genes in SARS-CoV-2 children were TRBV28 and TRBJ2-1. The most frequently VßJ gene pairing in SARS-CoV-2 infected children was TRBV20-1-TRBJ2-1. The strong antiviral antibody levels, low expression of key pro-inflammatory factors, significant elevation of anti-inflammatory factors, and downregulation of many chemokines jointly determine that SARS-CoV-2-infected children rarely develop severe cases. Overall, our findings shed a light on the immune response of non-severe children infected with SARS-CoV-2.

Graphene Oxide Functionalized Gelatin Methacryloyl Microgel for Enhanced Biomimetic Mineralization and in situ Bone Repair.

Introduction: The formation of bone-like apatite (Ap) on natural polymers through biomimetic mineralization using simulated body fluid (SBF) can improve osteoconductivity and biocompatibility, while lowering immunological rejection. Nonetheless, the coating efficiency of the bone-like Ap layer on natural polymers requires improvement. Carbonyls (-COOH) and hydroxyls (-OH) are abundant in graphene oxide (GO), which may offer more active sites for biomimetic mineralization and promote the proliferation of rat bone marrow stromal cells (BMSCs). Methods: In this study, gelatin methacryloyl (GelMA) microgels were infused with GO (0, 0.5, 1, and 2 mg/mL) and embedded into microgels in SBF for 1, 7, and 14 days. Systematic in vitro and in vivo experiments were performed to evaluate the structure of the microgel and its effect on cell proliferation and ability to repair bone defects in rats. Results: The resulting GO-GelMA-Ap microgels displayed a porous, interconnected structure with uniformly coated surfaces in bone-like Ap, and the Ca/P ratio of the 1 mg/mL GO-GelMA-Ap group was comparable to that of natural bone tissue. Moreover, the 1 mg/mL GO-GelMA-Ap group exhibited a greater Ap abundance, enhanced proliferation of BMSCs in vitro and increased bone formation in vivo compared to the GelMA-Ap group. Discussion: Overall, this study offers a novel method for incorporating GO into microgels for bone tissue engineering to promote biomimetic mineralization.

Drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.

Oral submucous fibrosis is a chronic, inflammatory and potentially malignant oral disease. Local delivery of triamcinolone to lesion site is a commonly used therapy. The existing methods for local drug delivery include topical administration and submucosal injection. However, in the wet and dynamic oral microenvironment, these methods have drawbacks such as limited drug delivery efficiency and injection pain. Therefore, it is urgently needed to develop an alternative local drug delivery system with high efficiency and painlessness. Inspired by the structure of band-aid, this study proposed a novel double-layered mucoadhesive microneedle patch for transmucosal drug delivery. The patch consisted of a mucoadhesive silk fibroin/tannic acid top-layer and a silk fibroin microneedle under-layer. When applying the annealing condition for the medium content of ß-sheets of silk fibroin, the microneedles in under-layer displayed both superior morphology and mechanical property. The mechanical strength of per needle (0.071N) was sufficient to penetrate the oral mucosa. Sequentially, the gelation efficiency of silk fibroin and tannic acid in top-layer was maximized as the weight ratio of tannic acid to silk fibroin reached 5:1. Moreover, in vitro results demonstrated the double-layered patch possessed undetectable cytotoxicity. The sustained release of triamcinolone was observed from the double-layered patch for at least 7 days. Furthermore, compared with other commercial buccal patches, the double-layered patch exhibited an enhanced wet adhesion strength of 37.74 kPa. In addition, ex vivo mucosal tissue penetration experiment confirmed that the double-layered patch could reach the lamina propria, ensuring effective drug delivery to the lesion site of oral submucous fibrosis. These results illustrate the promising potential of the drug-loaded mucoadhesive microneedle patch for the treatment of oral submucous fibrosis.

D3CARP: a comprehensive platform with multiple-conformation based docking, ligand similarity search and deep learning approaches for target prediction and virtual screening.

Resource- and time-consuming biological experiments are unavoidable in traditional drug discovery, which have directly driven the evolution of various computational algorithms and tools for drug-target interaction (DTI) prediction. For improving the prediction reliability, a comprehensive platform is highly expected as some previously reported webservers are small in scale, single-method, or even out of service. In this study, we integrated the multiple-conformation based docking, 2D/3D ligand similarity search and deep learning approaches to construct a comprehensive webserver, namely D3CARP, for target prediction and virtual screening. Specifically, 9352 conformations with positive control of 1970 targets were used for molecular docking, and approximately 2 million target-ligand pairs were used for 2D/3D ligand similarity search and deep learning. Besides, the positive compounds were added as references, and related diseases of therapeutic targets were annotated for further disease-based DTI study. The accuracies of the molecular docking and deep learning approaches were 0.44 and 0.89, respectively. And the average accuracy of five ligand similarity searches was 0.94. The strengths of D3CARP encompass the support for multiple computational methods, ensemble docking, utilization of positive controls as references, cross-validation of predicted outcomes, diverse disease types, and broad applicability in drug discovery. The D3CARP is freely accessible at https://www.d3pharma.com/D3CARP/index.php.

The Microstructure Evolution and Formation Mechanism of Gradient Nanostructure Prepared on CrCoNi Medium-Entropy Alloy.

An equiatomic CrCoNi medium-entropy alloy was subjected to high-energy shot peening (HESP) to fabricate a gradient nanostructure (GNS) in this work. The microstructures of the GNS samples at different depths within the deformed layer were thoroughly investigated. The microstructure exhibited a transformation from unstressed coarse grains to deformed coarse grains, followed by the formation of ultrafine grains, and ultimately reaching a final nanocrystalline structure with a uniform size of approximately 50 nm. Detailed structural analysis indicated that the deformation process was primarily influenced by the interaction between dislocations and deformation twins, which was attributed to the low stacking fault energy (SFE) of the alloy. The nanocrystalline mechanism was divided into three stages. In the coarse-grained deformation stage, the dislocation band divided twin/matrix lamellae into sub-segments, and the cross twin divided coarse grains into ultrafine grains simultaneously. In the ultrafine grain deformation stage, dislocations were arranged around the deformation twins in order to break the twins to form incoherent boundaries, destroying the coherent relationship between the twin and matrix. Finally, in the nanocrystalline deformation stage, the nanocrystalline structure was further divided into smaller segments to accommodate additional strains through the interaction between dislocations and twins.