Isolation and Diverse Reactivity of an Unsymmetrical 1,2-Bis(silylene)-Stabilized Pentacarbonyl Chromium(0) Species.

The construction of the unsymmetrical 1,2-bis(silylene) pentacarbonyl chromium(0) complex 1 was achieved through the reaction of chlorosilylene with half an equivalent of K2Cr(CO)5. X-ray diffraction analysis of 1 confirms the formation of the Si-Si bond and the coordination of one of the silicon atoms to the Cr center. Density functional theory (DFT) calculations disclose that highest occupied molecular orbital (HOMO) mainly corresponds to the lone pair of electrons on the silicon atom and the σ-bonding interaction between two Si atoms. Based on its unique electronic structure, its diverse reactivity toward the transition metal compounds and small molecules was investigated in detail. The reactions of 1 with Fe2(CO)9 or CuCl yielded the 1,2-bis(silylene)-stabilized heterobimetallic complex 2 or oxidized product 3, respectively. Additionally, treatments of 1 with selenium, CO2, or Me3SiN3 led to the formation of the corresponding selenium-, oxo-, and nitrogen-bridged complexes 4-7. All compounds were characterized by multinuclear NMR spectroscopy and X-ray crystallography.

A Bifunctional Lactoferrin-Derived Amyloid Coating Prevents Bacterial Adhesion and Occludes Dentinal Tubules via Deep Remineralization.

Dentin hypersensitivity (DH) manifests as sharp and uncomfortable pain due to the exposure of dentinal tubules (DTs) following the erosion of tooth enamel. Desensitizing agents commonly used in clinical practice have limitations such as limited depth of penetration, slow remineralization and no antimicrobial properties. To alleviate these challenges, our study designed a lactoferrin-derived amyloid nanofilm (PTLF nanofilm) inspired by the saliva-acquired membrane (SAP). The nanofilm utilises Tris(2-carboxyethyl)phosphine (TCEP) to disrupt the disulfide bonds of lactoferrin (LF) under physiological conditions. The PTLF nanofilm modifies surfaces across various substrates and effectively prevents the early and stable adhesion of cariogenic bacteria, such as Streptococcus mutans and Lactobacillus acidophilus. Simultaneously, it adheres rapidly and securely to demineralized dentin surfaces, facilitating in-situ remineralization of HAP through a simple immersion process. This leads to the formation of a remineralized layer resembling natural dentin, with an occlusion depth of dentinal tubules exceeding 80 µm after three days. The in vivo and vitro results confirm that the PTLF nanofilm possesses good biocompatibility and its ability to exert simultaneous antimicrobial effects and dentin remineralization. Accordingly, this innovative bifunctional PTLF amyloid coating offers promising prospects for the management of DH-related conditions. STATEMENT OF SIGNIFICANCE: We design a simple, fast, inexpensive, and easy-to-process PTLF nanofilm for nearly any material surface or shape. The PTLF nanofilm modifies surfaces across various substrates and effectively prevents the adhesion of cariogenic bacteria, such as Streptococcus mutans and Lactobacillus acidophilus. The abundant functional groups on the surface of PTLF nanofilm facilitate bioactive hydroxyapatite (HAP) formation and maintain stability at the HAP remineralization interface.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor.

BACKGROUND: Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome (ARDS) patients. Mesenchymal stromal cell-derived microvesicles (MSC-MVs) have been shown to exert antifibrotic effects in lung diseases. AIM: To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models. METHODS: MSC-MVs with low hepatocyte growth factor (HGF) expression (siHGF-MSC-MVs) were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model. Following intubation, respiratory mechanics-related indicators were measured via an experimental small animal lung function tester. Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging. Immunohistochemical, western blotting, ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators. RESULTS: The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice. Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores. However, low expression of HGF (siHGF-MSC-MVs) significantly inhibited the effects of MSC-MVs (P < 0.05). Compared with the ARDS pulmonary fibrosis group, the MSC-MVs group exhibited suppressed expression of type I collagen antigen, type III collagen antigen, and the proteins transforming growth factor-ß and α-smooth muscle actin, whereas the siHGF-MVs group exhibited significantly increased expression of these proteins. In addition, pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group, and the effects of the MSC-MVs were significantly inhibited by low HGF expression (all P < 0.05). CONCLUSION: MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

Knowledge-aware Multisite Adaptive Graph Transformer for Brain Disorder Diagnosis.

Brain disorder diagnosis via resting-state functional magnetic resonance imaging (rs-fMRI) is usually limited due to the complex imaging features and sample size. For brain disorder diagnosis, the graph convolutional network (GCN) has achieved remarkable success by capturing interactions between individuals and the population. However, there are mainly three limitations: 1) The previous GCN approaches consider the non-imaging information in edge construction but ignore the sensitivity differences of features to non-imaging information. 2) The previous GCN approaches solely focus on establishing interactions between subjects (i.e., individuals and the population), disregarding the essential relationship between features. 3) Multisite data increase the sample size to help classifier training, but the inter-site heterogeneity limits the performance to some extent. This paper proposes a knowledge-aware multisite adaptive graph Transformer to address the above problems. First, we evaluate the sensitivity of features to each piece of non-imaging information, and then construct feature-sensitive and feature-insensitive subgraphs. Second, after fusing the above subgraphs, we integrate a Transformer module to capture the intrinsic relationship between features. Third, we design a domain adaptive GCN using multiple loss function terms to relieve data heterogeneity and to produce the final classification results. Last, the proposed framework is validated on two brain disorder diagnostic tasks. Experimental results show that the proposed framework can achieve state-of-the-art performance.

Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease.

Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14 G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aß affinity greatly inhibited Aß oligomerization/fibrillation, and interrupted Aß interaction with neuron/microglia by reducing neuronal mitochondrial Aß deposition and promoting microglial phagocytosis of Aß. In 3× Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.

Vulnerability extraction and prediction method based on improved information gain algorithm.

More and more attention has been paid to computer security, and its vulnerabilities urgently need more sensitive solutions. Due to the incomplete data of most vulnerability libraries, it is difficult to obtain pre-permission and post-permission of vulnerabilities, and construct vulnerability exploitation chains, so it cannot to respond to vulnerabilities in time. Therefore, a vulnerability extraction and prediction method based on improved information gain algorithm is proposed. Considering the accuracy and response speed of deep neural network, deep neural network is adopted as the basic framework. The Dropout method effectively reduces overfitting in the case of incomplete data, thus improving the ability to extract and predict vulnerabilities. These experiments confirmed that the excellent F1 and Recall of the improved method reached 0.972 and 0.968, respectively. Compared to the function fingerprints vulnerability detection method and K-nearest neighbor algorithm, the convergence is better. Its response time is 0.12 seconds, which is excellent. To ensure the reliability and validity of the proposed method in the face of missing data, the reliability and validity of Mask test are verified. The false negative rate was 0.3% and the false positive rate was 0.6%. The prediction accuracy of this method for existing permissions reached 97.9%, and it can adapt to the development of permissions more actively, so as to deal with practical challenges. In this way, companies can detect and discover vulnerabilities earlier. In security repair, this method can effectively improve the repair speed and reduce the response time. The prediction accuracy of post-existence permission reaches 96.8%, indicating that this method can significantly improve the speed and efficiency of vulnerability response, and strengthen the understanding and construction of vulnerability exploitation chain. The prediction of the posterior permission can reduce the attack surface of the vulnerability, thus reducing the risk of breach, speeding up the detection of the vulnerability, and ensuring the timely implementation of security measures. This model can be applied to public network security and application security scenarios in the field of computer security, as well as personal computer security and enterprise cloud server security. In addition, the model can also be used to analyze attack paths and security gaps after security accidents. However, the prediction of post-permissions is susceptible to dynamic environments and relies heavily on the updated guidance of security policy rules. This method can improve the accuracy of vulnerability extraction and prediction, quickly identify and respond to security vulnerabilities, shorten the window period of vulnerability exploitation, effectively reduce security risks, and improve the overall network security defense capability. Through the application of this model, the occurrence frequency of security vulnerability time is reduced effectively, and the repair time of vulnerability is shortened.

Nanoengineered Injectable Hydrogel: An Advanced Radioprotective Barrier with Magnetic Hyperthermia Synergy.

Despite its effectiveness in eradicating cancer cells, current tumor radiotherapy often causes irreversible damage to the surrounding healthy tissues. To address this issue and enhance therapeutic outcomes, we developed a multifunctional injectable hydrogel that integrates electromagnetic shielding and magnetothermal effects. This innovation aims to improve the efficacy of brachytherapy while protecting adjacent normal tissues. Recognizing the limitations of existing hydrogel materials in terms of stretchability, durability, and single functionality, we engineered a composite hydrogel by self-assembling nickel nanoparticles on the surface of liquid metal particles and embedding them into an injectable hydrogel matrix. The resulting composite material demonstrates superior electromagnetic interference shielding performance (74.89 dB) and a rapid magnetothermal heating rate (10.9 °C/min), significantly enhancing its in vivo applicability. The experimental results confirm that this innovative nanocomposite hydrogel effectively attenuates electromagnetic waves during brachytherapy, thereby protecting normal tissues surrounding the tumor and enhancing radiotherapy efficacy through magnetothermal therapy. This study advances the safety and effectiveness of cancer treatments and provides new insights into the development of multifunctional biomedical materials, promoting the innovative application of nanotechnology in the medical field.

Ginsenoside Rg3 Restores Mitochondrial Cardiolipin Homeostasis via GRB2 to Prevent Parkinson's Disease.

Regulating cardiolipin to maintain mitochondrial homeostasis is a promising strategy for addressing Parkinson's disease (PD). Through a comprehensive screening and validation process involving multiple models, ginsenoside Rg3 (Rg3) as a compound capable of enhancing cardiolipin levels is identified. This augmentation in cardiolipin levels fosters mitochondrial homeostasis by bolstering mitochondrial unfolded protein response, promoting mitophagy, and enhancing mitochondrial oxidative phosphorylation. Consequently, this cascade enhances the survival of tyrosine hydroxylase positive (TH+) dopaminergic neurons, leading to an amelioration in motor performance within PD mouse models. Using limited proteolysis-small-molecule mapping combined with molecular docking analysis, it has confirmed Growth Factor Receptor-Bound Protein 2 (GRB2) as a molecular target for Rg3. Furthermore, these investigations reveal that Rg3 facilitates the interaction between GRB2 and TRKA (Neurotrophic Tyrosine Kinase, Receptor, Type 1), thus promotes EVI1 (Ecotropic Virus Integration Site 1 Protein Homolog) phosphorylation by ERK, subsequently increases CRLS1 (Cardiolipin Synthase 1) gene expression and boosts cardiolipin synthesis. The absence of GRB2 or CRLS1 significantly attenuates the beneficial effects of Rg3 on PD symptoms. Finally, Tenofovir Disoproxil Fumarate (TDF) that also promotes the binding between GRB2 and TRKA is further identified. The identified compounds, Rg3 and TDF, exhibit promising potential for the prevention of PD by bolstering cardiolipin expression and reinstating mitochondrial homeostasis.

Bio-inspired Adaptive and Responsive Protein-based Materials.

In nature, the inherent adaptability and responsiveness of proteins play a crucial role in the survival and reproduction of organisms, enabling them to adjust to ever-changing environments. A comprehensive understanding of protein structure and function is essential for unraveling the complex biological adaptive processes, providing new insights for the design of protein-based materials in advanced fields. Recently, materials derived from proteins with specific properties and functions have been engineered. These protein-based materials, distinguished by their engineered adaptability and responsiveness, range from the nanoscale to the macroscale through meticulous control of protein structure. First, the review introduces the natural adaptability and responsiveness of proteins in organisms, encompassing biological adhesion and the responses of organisms to light, magnetic fields, and temperature. Next, it discusses the achievements in protein-engineered adaptability and adhesion through protein assembly and nanotechnology, emphasizing precise control over protein bioactivity. Finally, the review briefly addresses the application of protein engineering techniques and the self-assembly capabilities of proteins to achieve responsiveness in protein-based materials to humidity, light, magnetism, temperature, and other factors. We hope this review will foster a multidimensional understanding of protein adaptability and responsiveness, thereby advancing the interdisciplinary integration of biomedical science, materials science, and biotechnology.

Multiparametric MRI-Based Deep Learning Radiomics Model for Assessing 5-Year Recurrence Risk in Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Accurately assessing 5-year recurrence rates is crucial for managing non-muscle-invasive bladder carcinoma (NMIBC). However, the European Organization for Research and Treatment of Cancer (EORTC) model exhibits poor performance. PURPOSE: To investigate whether integrating multiparametric MRI (mp-MRI) with clinical factors improves NMIBC 5-year recurrence risk assessment. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-one patients (median age, 65 years; age range, 54-73 years; 27 females) underwent mp-MRI between 2011 and 2017, and received ≥5-year follow-ups. They were divided into a training cohort (N = 115) and validation/testing cohorts (N = 38 in each). Recurrence rates were 23.5% (27/115) in the training cohort and 23.7% (9/38) in both validation and testing cohorts. FIELD STRENGTH/SEQUENCE: 3-T, fast spin echo T2-weighted imaging (T2WI), single-shot echo planar diffusion-weighted imaging (DWI), and volumetric spoiled gradient echo dynamic contrast-enhanced (DCE) sequences. ASSESSMENT: Radiomics and deep learning (DL) features were extracted from the combined region of interest (cROI) including intratumoral and peritumoral areas on mp-MRI. Four models were developed, including clinical, cROI-based radiomics, DL, and clinical-radiomics-DL (CRDL) models. STATISTICAL TESTS: Student's t-tests, DeLong's tests with Bonferroni correction, receiver operating characteristics with the area under the curves (AUCs), Cox proportional hazard analyses, Kaplan-Meier plots, SHapley Additive ExPlanations (SHAP) values, and Akaike information criterion for clinical usefulness. A P-value <0.05 was considered statistically significant. RESULTS: The cROI-based CRDL model showed superior performance (AUC 0.909; 95% CI: 0.792-0.985) compared to other models in the testing cohort for assessing 5-year recurrence in NMIBC. It achieved the highest Harrell's concordance index (0.804; 95% CI: 0.749-0.859) for estimating recurrence-free survival. SHAP analysis further highlighted the substantial role (22%) of the radiomics features in NMIBC recurrence assessment. DATA CONCLUSION: Integrating cROI-based radiomics and DL features from preoperative mp-MRI with clinical factors could improve 5-year recurrence risk assessment in NMIBC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Molybdenum and Vanadium-Codoped Cobalt Carbonate Nanosheets Deposited on Nickel Foam as a High-Efficient Bifunctional Catalyst for Overall Alkaline Water Splitting.

To address issues of global energy sustainability, it is essential to develop highly efficient bifunctional transition metal-based electrocatalysts to accelerate the kinetics of both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Herein, the heterogeneous molybdenum and vanadium codoped cobalt carbonate nanosheets loaded on nickel foam (VMoCoCOx@NF) are fabricated by facile hydrothermal deposition. Firstly, the mole ratio of V/Mo/Co in the composite is optimized by response surface methodology (RSM). When the optimized composite serves as a bifunctional catalyst, the water-splitting current density achieves 10 mA cm-2 and 100 mA cm-2 at cell voltages of 1.54 V and 1.61 V in a 1.0 M KOH electrolyte with robust stability. Furthermore, characterization is carried out using field emission scanning electron microscopy-energy dispersive spectroscopy (FESEM-EDS), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Density functional theory (DFT) calculations reveal that the fabricated VMoCoCOx@NF catalyst synergistically decreases the Gibbs free energy of hydrogen and oxygen-containing intermediates, thus accelerating OER/HER catalytic kinetics. Benefiting from the concerted advantages of porous NF substrates and clustered VMoCoCOx nanosheets, the fabricated catalyst exhibits superior electrocatalytic performance. This work presents a novel approach to developing transition metal catalysts for overall water splitting.

Comparison of clinical characteristics and surgical outcomes in non-vasectomized epididymal obstructive azoospermia patients with or without concurrent vas-deferens obstruction.

BACKGROUND: Microsurgical vasoepididymostomy is an effective surgical method for treating epididymal obstructive azoospermia but the surgical outcomes can be affected in some non-vasectomized epididymal obstructive azoospermia patients with concurrent vas-deferens obstruction. This study aimed to explore the clinical characteristics and surgical outcomes in non-vasectomized epididymal obstructive azoospermia patients with versus without concurrent vas-deferens obstruction. STUDY DESIGN: Retrospective study. OBJECTIVE: To explore the clinical characteristics and surgical outcomes in non-vasectomized epididymal obstructive azoospermia patients with versus without concurrent vas-deferens obstruction, aiming to identify predictive factors for concurrent vas-deferens obstruction and evaluate the efficacy of microsurgical vasoepididymostomy in patients with epididymal obstructive azoospermia and concurrent short-segment vas-deferens obstruction. MATERIALS AND METHODS: A retrospective analysis of 225 epididymal obstructive azoospermia cases was conducted at the First Affiliated Hospital of Fujian Medical University from November 2016 to March 2023. All patients underwent a comprehensive preoperative evaluation. During surgery, the vas deferens were assessed to determine the presence and extent of obstruction. Depending on the obstruction length, either a standard microsurgical vasoepididymostomy was performed, or the obstructed segment was resected followed by microsurgical vasoepididymostomy. If the remaining length post-resection was insufficient for anastomosis, the procedure was discontinued. Data on patient clinical characteristics, operative findings, and outcomes were collected and analyzed. Logistic regression was used to identify predictive factors for concurrent vas-deferens obstruction, and comparative analysis assessed patency and pregnancy rates between patients with and without concurrent vas-deferens obstruction. RESULTS: Of the 225 patients in the study, 77 (34.22%) presented with epididymal obstructive azoospermia and concurrent vas-deferens obstruction. Logistic regression analysis revealed that "the history of epididymitis" was a significant predictive factor for epididymal obstructive azoospermia patients with concurrent vas-deferens obstruction (odds ratio = 9.06, p < 0.001). The average length of vas deferens obstruction amenable to microsurgical vasoepididymostomy post-resection was 1.31 ± 0.54 cm (range from 0.50 to 2.50 cm). In contrast, cases unsuitable for microsurgical vasoepididymostomy presented an average obstruction length of 15.26 ± 5.79 cm (p < 0.001). The patency rates were 82.17% in epididymal obstructive azoospermia patients without concurrent vas-deferens obstruction and 74.14% in those with concurrent vas-deferens obstruction. The pregnancy rates followed a similar trend, at 34.11% and 34.48%, respectively. These differences were not statistically significant (p > 0.05 for both). However, epididymal obstructive azoospermia patients with vas-deferens obstruction exhibited a decreased likelihood of bilateral microsurgical vasoepididymostomy (p < 0.001). DISCUSSION AND CONCLUSION: Our study identifies a noticeable occurrence of concurrent vas-deferens obstruction in non-vasectomized epididymal obstructive azoospermia patients, with approximately one-third of the cases (34.22%) exhibiting vas-deferens obstruction during surgical interventions. Notably, a small fraction (6.67%) of these individuals chose not to proceed with any microsurgical vasoepididymostomy, even on one side, due to the extensive length of the obstruction. Through logistic analysis, we have demonstrated that "the history of epididymitis" is a critical predictive factor for the presence of vas-deferens obstruction, underscoring its significance in preoperative evaluations. Furthermore, our research confirms that microsurgical vasoepididymostomy is still an effective treatment for epididymal obstructive azoospermia patients with concurrent short-segment vas-deferens obstruction, achieving significant patency and favorable pregnancy rates compared to those patients without vas-deferens obstruction. These insights are pivotal for enhancing surgical strategies and improving fertility outcomes in this patient cohort.

Factors affecting patency time and semen quality in a single-armed microsurgical vasoepididymostomy.

ABSTRACT: Although microsurgical vasoepididymostomy (MVE) is an effective treatment for epididymal obstructive azoospermia, some patients may experience delayed patency or suboptimal semen parameters after patency. However, research into patency time, semen quality postpatency, and associated influencing factors remains limited. This study aimed to address these issues by evaluating 181 patients who underwent at least one-sided MVE employing asingle-armed longitudinal intussusception vasoepididymostomy technique, with a follow-up period of over 12 months for 150 patients. The overall patency rate was 75.3%, with 86.0% of patients achieving patency within 6 months following MVE. Unexpectedly, factors such as age, history of epididymitis, duration of surgery, side of anastomosis, sperm motility in epididymal fluid, and the site of anastomosis showed no correlation with patency time. Nonetheless, our univariate and multivariate linear regression analysis indicated that only the site of anastomosis was positively correlated with and could independently predict postoperative total motile sperm count. Therefore, the site of anastomosis might serve as a predictor for optimal postoperative semen quality following the MVE procedure.

Multi-objective evolutionary optimization for hardware-aware neural network pruning.

Neural network pruning is a popular approach to reducing the computational complexity of deep neural networks. In recent years, as growing evidence shows that conventional network pruning methods employ inappropriate proxy metrics, and as new types of hardware become increasingly available, hardware-aware network pruning that incorporates hardware characteristics in the loop of network pruning has gained growing attention. Both network accuracy and hardware efficiency (latency, memory consumption, etc.) are critical objectives to the success of network pruning, but the conflict between the multiple objectives makes it impossible to find a single optimal solution. Previous studies mostly convert the hardware-aware network pruning to optimization problems with a single objective. In this paper, we propose to solve the hardware-aware network pruning problem with Multi-Objective Evolutionary Algorithms (MOEAs). Specifically, we formulate the problem as a multi-objective optimization problem, and propose a novel memetic MOEA, namely HAMP, that combines an efficient portfolio-based selection and a surrogate-assisted local search, to solve it. Empirical studies demonstrate the potential of MOEAs in providing simultaneously a set of alternative solutions and the superiority of HAMP compared to the state-of-the-art hardware-aware network pruning method.

Curcumin for gastric cancer: Mechanism prediction via network pharmacology, docking, and in vitro experiments.

BACKGROUND: Curcumin originates from the natural herb turmeric, and its antitumor effects have been known about for a long time. However, the mechanism by which curcumin affects gastric cancer (GC) has not been elucidated. AIM: To elucidate the potential mechanisms of curcumin in the treatment of GC. METHODS: Network pharmacological approaches were used to perform network analysis of Curcumin. We first analyzed Lipinski's Rule of Five for the use of Curcumin. Curcumin latent targets were predicted using the PharmMapper, SwissTargetPrediction and DrugBank network databases. GC disease targets were mined through the GeneCard, OMIM, DrugBank and TTD network databases. Then, GO enrichment, KEGG enrichment, protein-protein interaction (PPI), and overall survival analyses were performed. The results were further verified through molecular docking, differential expression analysis and cell experiments. RESULTS: We identified a total of 48 curcumin-related genes with 31 overlapping GC-related targets. The intersection targets between curcumin and GC have been enriched in 81 GO biological processes and 22 significant pathways. Following PPI analysis, 6 hub targets were identified, namely, estrogen receptor 1 (ESR1), epidermal growth factor receptor (EGFR), cytochrome P450 family 3 subfamily A member 4 (CYP3A4), mitogen-activated protein kinase 14 (MAPK14), cytochrome P450 family 1 subfamily A member 2 (CYP1A2), and cytochrome p450 family 2 subfamily B member 6 (CYP2B6). These factors are correlated with decreased survival rates among patients diagnosed with GC. Molecular docking analysis further substantiated the strong binding interactions between Curcumin and the hub target genes. The experimental findings demonstrated that curcumin not only effectively inhibits the growth of BGC-823 cells but also suppresses their proliferation. mRNA levels of hub targets CYP3A4, MAPK14, CYP1A2, and CYP2B6 in BGC-823 cells were significantly increased in each dose group. CONCLUSION: Curcumin can play an anti-GC role through a variety of targets, pathways and biological processes.

TRIM21-mediated ubiquitination of SQSTM1/p62 abolishes its Ser403 phosphorylation and enhances palmitic acid cytotoxicity.

Long-chain free fatty acids (FFAs) accumulation and oxidative toxicity is a major cause for several pathological conditions. The mechanisms underlying FFA cytotoxicity remain elusive. Here we show that palmitic acid (PA), the most abundant FFA in the circulation, induces S403 phosphorylation of SQSTM1/p62 (sequestosome 1) and its aggregation, which sequesters KEAP1 and activates the non-canonical SQSTM1-KEAP1-NFE2L2 antioxidant pathway. The PA-induced SQSTM1 S403 phosphorylation and aggregation are dependent on SQSTM1 K7-D69 hydrogen bond formation and dimerization in the Phox and Bem1 (PB1) domain, which facilitates the recruitment of TBK1 that phosphorylates SQSTM1 S403. The ubiquitin E3 ligase TRIM21 ubiquitinates SQSTM1 at the K7 residue and abolishes the PB1 dimerization, S403 phosphorylation, and SQSTM1 aggregation. TRIM21 is oxidized at C92, C111, and C114 to form disulfide bonds that lead to its oligomerization and decreased E3 activity. Mutagenizing the three C residues to S (3CS) abolishes TRIM21 oligomerization and increases its E3 activity. TRIM21 ablation leads to decreased SQSTM1 K7 ubiquitination, hence elevated SQSTM1 S403 phosphorylation and aggregation, which confers protection against PA-induced oxidative stress and cytotoxicity. Therefore, TRIM21 is a negative regulator of SQSTM1 phosphorylation, aggregation, and the antioxidant sequestration function. TRIM21 is oxidized to reduce its E3 activity that helps enhance the SQSTM1-KEAP1-NFE2L2 antioxidant pathway. Inhibition of TRIM21 May be a viable strategy to protect tissues from lipotoxicity resulting from long-chain FFAs.Abbreviations: ER: endoplasmic reticulum; FFA: free fatty acid; HMOX1/HO-1: heme oxygenase 1; IB: immunoblotting; IF: immunofluorescence; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; MASH: metabolic dysfunction-associated steatohepatitis; MEF: mouse embryonic fibroblast; NFE2L2/Nrf2: NFE2 like BZIP transcription factor 2; PA: palmitic acid; PB1: Phox and Bem 1; ROS: reactive oxygen species; SLD: steatotic liver disease; SQSTM1: sequestosome 1; TBK1: TANK-binding kinase 1; TRIM21: tripartite motif containing 21.

Spatial immune landscapes of SARS-CoV-2 gastrointestinal infection: macrophages contribute to local tissue inflammation and gastrointestinal symptoms.

Background: In some patients, persistent gastrointestinal symptoms like abdominal pain, nausea, and diarrhea occur as part of long COVID-19 syndrome following acute respiratory symptoms caused by SARS-CoV-2. However, the characteristics of immune cells in the gastrointestinal tract of COVID-19 patients and their association with these symptoms remain unclear. Methodology: Data were collected from 95 COVID-19 patients. Among this cohort, 11 patients who exhibited gastrointestinal symptoms and underwent gastroscopy were selected. Using imaging mass cytometry, the gastrointestinal tissues of these patients were thoroughly analyzed to identify immune cell subgroups and investigate their spatial distribution. Results: Significant acute inflammatory responses were found in the gastrointestinal tissues, particularly in the duodenum, of COVID-19 patients. These alterations included an increase in the levels of CD68+ macrophages and CD3+CD4+ T-cells, which was more pronounced in tissues with nucleocapsid protein (NP). The amount of CD68+ macrophages positively correlates with the number of CD3+CD4+ T-cells (R = 0.783, p < 0.001), additionally, spatial neighborhood analysis uncovered decreased interactions between CD68+ macrophages and multiple immune cells were noted in NP-positive tissues. Furthermore, weighted gene coexpression network analysis was employed to extract gene signatures related to clinical features and immune responses from the RNA-seq data derived from gastrointestinal tissues from COVID-19 patients, and we validated that the MEgreen module shown positive correlation with clinical parameter (i.e., Total bilirubin, ALT, AST) and macrophages (R = 0.84, p = 0.001), but negatively correlated with CD4+ T cells (R = -0.62, p = 0.004). By contrast, the MEblue module was inversely associated with macrophages and positively related with CD4+ T cells. Gene function enrichment analyses revealed that the MEgreen module is closely associated with biological processes such as immune response activation, signal transduction, and chemotaxis regulation, indicating its role in the gastrointestinal inflammatory response. Conclusion: The findings of this study highlight the role of specific immune cell groups in the gastrointestinal inflammatory response in COVID-19 patients. Gene coexpression network analysis further emphasized the importance of the gene modules in gastrointestinal immune responses, providing potential molecular targets for the treatment of COVID-19-related gastrointestinal symptoms.

Superconductivity under pressure in a chromium-based kagome metal.

Superconductivity in a highly correlated kagome system has been theoretically proposed for years (refs. 1-5), yet the experimental realization is hard to achieve6,7. The recently discovered vanadium-based kagome materials8, which exhibit both superconductivity9-11 and charge-density-wave orders12-14, are nonmagnetic8,9 and weakly correlated15,16. Thus these materials are unlikely to host the exotic superconductivity theoretically proposed. Here we report the discovery of a chromium-based kagome metal, CsCr3Sb5, which is contrastingly featured with strong electron correlations, frustrated magnetism and characteristic flat bands close to the Fermi level. Under ambient pressure, this kagome metal undergoes a concurrent structural and magnetic phase transition at 55 K, with a stripe-like 4a0 structural modulation. At high pressure, the phase transition evolves into two transitions, possibly associated with charge-density-wave and antiferromagnetic spin-density-wave orderings. These density-wave-like orders are gradually suppressed with pressure and, remarkably, a superconducting dome emerges at 3.65-8.0 GPa. The maximum of the superconducting transition temperature, Tcmax = 6.4 K, appears when the density-wave-like orders are completely suppressed at 4.2 GPa, and the normal state exhibits a non-Fermi-liquid behaviour, reminiscent of unconventional superconductivity and quantum criticality in iron-based superconductors17,18. Our work offers an unprecedented platform for investigating superconductivity in correlated kagome systems.

Qianggu concentrate: unlocking bone protection power via antioxidative SIRT1/NRF2/HO-1 pathways in type 2 diabetic osteoporosis.

Background: Qianggu Concentrate (QGHJ), a traditional Chinese medicine, is extensively used to treat Type 2 Diabetic Osteoporosis (T2DOP). Despite its widespread use, research on its therapeutic mechanisms within T2DOP is notably scarce. Objective: To explore QGHJ's osteoprotection in T2DOP rats and BMSCs, focusing on the antioxidant activation of SIRT1/NRF2/HO-1 and NRF2 nuclear migration. Methods: QGHJ constituent analysis was performed using UPLC-HRMS. Safety, bone-health efficacy, and glucose metabolic effects in T2DOP rats were evaluated via general condition assessments, biomarker profiling, micro-CT, biomechanics, staining methods, and ELISA, supplemented by RT-qPCR and Western blot. BMSCs' responses to QGHJ under oxidative stress, including viability, apoptosis, and osteogenic differentiation, were determined using CCK-8, flow cytometry, ALP/ARS staining, and molecular techniques. The modulation of the SIRT1/NRF2/HO-1 pathway by QGHJ was explored through oxidative stress biomarkers, immunofluorescence, and Western blot assays. Results: UPLC-HRMS identified flavonoids, monoterpenes, and isoflavones as QGHJ's key compounds. In vivo, QGHJ proved safe and effective for T2DOP rats, enhancing bone mineral density, microenvironment, and biomechanical properties without impairing vital organs. It modulated bone markers PINP, TRACP 5b, RUNX2 and PPARγ, favoring bone anabolism and reduced catabolism, thus optimizing bone integrity. QGHJ also regulated glycemia and mitigated insulin resistance. In vitro, it preserved BMSCs' viability amidst oxidative stress, curbed apoptosis, and fostered osteogenesis with regulated RUNX2/PPARγ expression. Mechanistic insights revealed QGHJ activated the SIRT1/NRF2/HO-1 pathway, augmented NRF2 nuclear translocation, and enhanced the antioxidative response, promoting bone health under stress. Conclusion: In T2DOP rat and BMSCs oxidative stress models, QGHJ's bone protection is anchored in its antioxidative mechanisms via the SIRT1/NRF2/HO-1 pathway activation and NRF2 nuclear translocation.