Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Proteomic analysis reveals key differences in pro-stromal corneal tissue between highly myopic males and females.

Background and purpose: Nowadays, myopia has become a highly prevalent disease globally, especially in East Asia. Epidemiological studies have found that there may be sex differences in the occurrence and progression of myopia, with females having a higher incidence of myopia and higher risk of myopia progression. The purpose of this study was to explore the sex differences in myopic cornea using corneal stroma removed by small incision lenticule extraction (SMILE) surgery. Methods: The corneal stroma of females with high myopia (FH) and males with high myopia (MH) were subjected to proteomic assays. Proteomic-related data were statistically analyzed using software such as MaxQuan, KAAS, Proteome Discovery, etc. The total number of proteins in the cornea and the proteins specifically expressed in the two groups were counted, and the differentially expressed proteins in the two groups were identified by expression fold change >2 and p-value <0.05, and volcano plots were constructed, and functional enrichment analysis, subcellular organelle analysis, and molecular interaction were implemented. Results: Ten samples from each group were analyzed. Twenty-seven proteins were down-regulated and 27 proteins were up-regulated in the FH group, of which 23 proteins were up-regulated in the range of 2-10-fold and 4 proteins were up-regulated in the range of >10-fold. Comparative proteomic analysis of the cornea of male and female patients with high myopia revealed that the expression of corneal extracellular matrix and collagen I, III, V, and VIII-associated proteins were increased in the cornea of female patients, and the transforming growth factor-ß (TGF-ß)/Smad pathway was an important pathway obtained by functional analysis. Conclusion: Comparative proteomic analysis of cornea from male and female patients with high myopia revealed increased expression of proteins related to extracellular matrix and collagen I, III, V, and VIII in female patients, and the TGF-ß/Smad pathway was an important pathway obtained from the functional analysis, suggesting that extracellular matrix remodeling and collagen fiber synthesis may be more active in the cornea of female patients.

Causal Association Between Atopic Dermatitis and Keratoconus: A Mendelian Randomization Study.

Purpose: Although many studies have indicated that atopic dermatitis (AD) could contribute to the risk of keratoconus (KC), the causality between AD and KC remains controversial. This study aimed to explore the potential causal associations between AD and KC. Methods: Instrumental variables for both exposures and outcomes were obtained from large-scale genome-wide association study summary statistics from previous meta-analyses. Mendelian randomization (MR) was applied to infer causal associations between AD and KC. Our main analyses were conducted by inverse-variance weighted (IVW) method multiplicative random effect model, complemented with additional five models and sensitivity analyses. Reverse MR analysis was applied to determine the direction of the causal association between AD and KC. Results: Both IVW and weighted median methods revealed a causal effect of AD on KC (IVW odds ratio [OR], 1.475; P = 4.16 × 10-4; weighted median OR, 1.351; P = 7.65 × 10-3). The weighted mode, simple mode, and MR Egger methods demonstrated consistent direction of causality. Evidence from all sensitivity analyses further supported these associations. Reverse MR analyses did not suggest causal effects of KC on AD. Conclusions: This study supported a significant causal effect of AD on KC, and reverse MR analysis proved that the causal association was unilateral. Translational Relevance: This study provides valid evidence that regular ophthalmic examinations are recommended for patients with AD to detect and prevent KC at an early stage.

Cockroach Blaptica dubia biodegrades polystyrene plastics: Insights for superior ability, microbiome and host genes.

The report demonstrated that a member of cockroach family, Blaptica dubia (Blattodea: Blaberidae) biodegraded commercial polystyrene (PS) plastics with Mn of 20.3 kDa and Mw of 284.9 kDa. The cockroaches digested up to 46.6 % of ingested PS within 24 h. The biodegradation was confirmed by the 13C isotopic shift of the residual PS in feces versus pristine PS (Δ Î´13C of 2.28 ‰), reduction of molecular weight and formation of oxidative functional groups in the residual PS. Further tests found that B.dubia cockroaches degraded all eight high purity PS microplastics with low to ultra-high molecular weights (MW) at 0.88, 1.20, 3.92, 9.55, 62.5, 90.9, 524.0, and 1040 kDa, respectively, with superior biodegradation ability. PS depolymerization/biodegradation pattern was MW-dependent. Ingestion of PS shifted gut microbial communities and elevated abundances of plastic-degrading bacterial genes. Genomic, transcriptomic and metabolite analyses indicated that both gut microbes and cockroach host contributed to digestive enzymatic degradation. PS plastic diet promoted a highly cooperative model of gut digestive system. Weighted gene co-expression network analysis revealed different PS degradation patterns with distinct MW profiles in B. dubia. These results have provided strong evidences of plastic-degrading ability of cockroaches or Blaberidae family and new understanding of insect and their microbe mediated biodegradation of plastics.

Water-Driven Surface Lattice Oxygen Activation in MnO2 for Promoted Low-Temperature NH3-SCR.

Water is ubiquitous in various heterogeneous catalytic reactions, where it can be easily adsorbed, chemically dissociated, and diffused on catalyst surfaces, inevitably influencing the catalytic process. However, the specific role of water in these reactions remains unclear. In this study, we innovatively propose that H2O-driven surface lattice oxygen activation in γ-MnO2 significantly enhances low-temperature NH3-SCR. The proton from water dissociation activates the surface lattice oxygen in γ-MnO2, giving rise to a doubling of catalytic activity (achieving 90% NO conversion at 100 °C) and remarkable stability. Comprehensive in situ characterizations and calculations reveal that spontaneous proton diffusion to the surface lattice oxygen reduces the orbital overlap between the protonated oxygen atom and its neighboring Mn atom. Consequently, the Mn-O bond is weakened and the surface lattice oxygen is effectively activated to provide excess oxygen vacancies available for converting O2 into O2-. Therefore, the redox property of Mn-H is improved, leading to enhanced NH3 oxidation-dehydrogenation and NO oxidation processes, which are crucial for low-temperature NH3-SCR. This work provides a deeper understanding and fresh perspectives on the water promotion mechanism in low-temperature NOx elimination.

4d-2p-4f Gradient Orbital Coupling Enables Tandem Catalysis for Simultaneous Abatement of N2O and CO on Atomically Dispersed Rh/CeO2 Catalyst.

N2O and CO coexist in various industrial and mobile sources. The synergistic reaction of N2O and CO to generate N2 and CO2 has garnered significant research interest, but it remains extremely challenging. Herein, we constructed an atomically dispersed Rh-supported CeO2 catalyst with asymmetric Rh-O-Ce sites through gradient Rh 4d-O 2p-Ce 4f orbital coupling. This design effectively regulates the 4f electron states of Ce and promotes the electron filling of the O 3π* antibonding orbital to facilitate N-O bond cleavage. Near-ambient-pressure X-ray photoelectron spectroscopy (NAP-XPS) reveals that CO reacts with the surface-adsorbed O* generated by N2O decomposition through self-tandem catalysis, accelerating the rate-limiting step in N2O decomposition and activating the synergistic reaction of N2O and CO at temperatures as low as 115 °C. This work can guide the development of high-performance catalysts using the strategy of high-order orbital hybridization combined with the tandem concept to achieve versatile catalytic applications.

Effects of plastic aging on biodegradation of polystyrene by Tenebrio molitor larvae: Insights into gut microbiome and bacterial metabolism.

Plastics aging reduces resistance to microbial degradation. Plastivore Tenebrio molitor rapidly biodegrades polystyrene (PS, size: < 80 µm), but the effects of aging on PS biodegradation by T. molitor remain uncharacterized. This study examined PS biodegradation over 24 days following three pre-treatments: freezing with UV exposure (PS1), UV exposure (PS2), and freezing (PS3), compared to pristine PS (PSv) microplastic. The pretreatments deteriorated PS polymers, resulting in slightly higher specific PS consumption (602.8, 586.1, 566.7, and 563.9 mg PS·100 larvae-1·d-1, respectively) and mass reduction rates (49.6 %, 49.5 %, 49.2 %, and 48.7 %, respectively) in PS1, PS2, and PS3 compared to PSv. Improved biodegradation correlated with reduced molecular weights and the formation of oxidized functional groups. Larvae fed more aged PS exhibited greater gut microbial diversity, with microbial community and metabolic pathways shaped by PS aging, as supported by co-occurrence network analysis. These findings indicated that the aging treatments enhanced PS biodegradation by only limited extent but impacted greater on gut microbiome and bacterial metabolic genes, indicating that the T. molitor host have highly predominant capability to digest PS plastics and alters gut microbiome to adapt the PS polymers fed to them.

Intra-Individual Reproducibility of Automated Abdominal Organ Segmentation-Performance of TotalSegmentator Compared to Human Readers and an Independent nnU-Net Model.

The purpose of this study is to assess segmentation reproducibility of artificial intelligence-based algorithm, TotalSegmentator, across 34 anatomical structures using multiphasic abdominal CT scans comparing unenhanced, arterial, and portal venous phases in the same patients. A total of 1252 multiphasic abdominal CT scans acquired at our institution between January 1, 2012, and December 31, 2022, were retrospectively included. TotalSegmentator was used to derive volumetric measurements of 34 abdominal organs and structures from the total of 3756 CT series. Reproducibility was evaluated across three contrast phases per CT and compared to two human readers and an independent nnU-Net trained on the BTCV dataset. Relative deviation in segmented volumes and absolute volume deviations (AVD) were reported. Volume deviation within 5% was considered reproducible. Thus, non-inferiority testing was conducted using a 5% margin. Twenty-nine out of 34 structures had volume deviations within 5% and were considered reproducible. Volume deviations for the adrenal glands, gallbladder, spleen, and duodenum were above 5%. Highest reproducibility was observed for bones (- 0.58% [95% CI: - 0.58, - 0.57]) and muscles (- 0.33% [- 0.35, - 0.32]). Among abdominal organs, volume deviation was 1.67% (1.60, 1.74). TotalSegmentator outperformed the reproducibility of the nnU-Net trained on the BTCV dataset with an AVD of 6.50% (6.41, 6.59) vs. 10.03% (9.86, 10.20; p < 0.0001), most notably in cases with pathologic findings. Similarly, TotalSegmentator's AVD between different contrast phases was superior compared to the interreader AVD for the same contrast phase (p = 0.036). TotalSegmentator demonstrated high intra-individual reproducibility for most abdominal structures in multiphasic abdominal CT scans. Although reproducibility was lower in pathologic cases, it outperforms both human readers and a nnU-Net trained on the BTCV dataset.

Anthraquinones-based photocatalysis: A comprehensive review.

In recent years, there has been significant interest in photocatalytic technologies utilizing semiconductors and photosensitizers responsive to solar light, owing to their potential for energy and environmental applications. Current efforts are focused on enhancing existing photocatalysts and developing new ones tailored for environmental uses. Anthraquinones (AQs) serve as redox-active electron transfer mediators and photochemically active organic photosensitizers, effectively addressing common issues such as low light utilization and carrier separation efficiency found in conventional semiconductors. AQs offer advantages such as abundant raw materials, controlled preparation, excellent electron transfer capabilities, and photosensitivity, with applications spanning the energy, medical, and environmental sectors. Despite their utility, comprehensive reviews on AQs-based photocatalytic systems in environmental contexts are lacking. In this review, we thoroughly describe the photochemical properties of AQs and their potential applications in photocatalysis, particularly in addressing key environmental challenges like clean energy production, antibacterial action, and pollutant degradation. However, AQs face limitations in practical photocatalytic applications due to their low electrical conductivity and solubility-related secondary contamination. To mitigate these issues, the design and synthesis of graphene-immobilized AQs are highlighted as a solution to enhance practical photocatalytic applications. Additionally, future research directions are proposed to deepen the understanding of AQs' theoretical mechanisms and to provide practical applications for wastewater treatment. This review aims to facilitate mechanistic studies and practical applications of AQs-based photocatalytic technologies and to improve understanding of these technologies.

CCTA-Derived Fat Attenuation Index Predict Future Percutaneous Coronary Intervention.

OBJECTIVES: This study aims to investigate the differences in plaque characteristics and fat attenuation index (FAI) between in patients who received revascularization versus those who did not receive revascularization and examine whether the machine-learning (ML) based model constructed by plaque characteristics and FAI can predict revascularization. MATERIALS & METHODS: This study was a post hoc analysis of a prospective single-center registry of sequential patients undergoing CCTA, referred from inpatient and emergency department settings (n = 261, 63 years ± 8; 188 men). The primary outcome was revascularization by percutaneous coronary revascularization. The CTA images were analyzed by experienced radiologists using a dedicated workstation in a blinded fashion. The ML-based model was automatically computed. RESULTS: The study cohort consisted of 261 subjects. Revascularization was performed in 105 subjects. Patients receiving revascularization had higher FAI value (67.35±5.49 Hu vs -80.10±7.75 Hu, p < 0.001) as well as higher plaque length, calcified, lipid and fibrous plaque burden and volume. When FAI was incorporated into a ML risk model based on plaque characteristics to predict revascularization, the area under the curve increased from 0.84 (95% CI: 0.68-0.99) to 0.95 (95% CI: 0.88-1.00). CONCLUSION: ML-algorithms based on FAI and characteristics could help improve the prediction of future revascularization and identify patients likely to receive revascularization. ADVANCES IN KNOWLEDGE: Pre-procedural FAI could help guide revascularization in symptomatic CAD patients.

Gastric metastasis of small cell lung carcinoma: Three case reports and review of literature.

BACKGROUND: Small cell lung carcinoma (SCLC) is highly susceptible to metastasis in the early stages of the disease. However, the stomach is an uncommon site of metastasis in SCLC, and only a few cases of this type of metastasis have been reported. Therefore, SCLC gastric metastases have not been systematically characterized and are easily missed and misdiagnosed. CASE SUMMARY: We report three cases of gastric metastasis from SCLC in this article. The first patient presented primarily with cough, hemoptysis, and epigastric fullness. The other two patients presented primarily with abdominal discomfort, epigastric distension, and pain. All patients underwent gastroscopy and imaging examinations. Meanwhile, the immunohistochemical results of the lesions in three patients were suggestive of small cell carcinoma. Finally, the three patients were diagnosed with gastric metastasis of SCLC through a comprehensive analysis. The three patients did not receive appropriate treatment and died within a short time. CONCLUSION: Here, we focused on summarizing the characteristics of gastric metastasis of SCLC to enhance clinicians' understanding of this disease.

Whole transcriptome sequencing revealed the gene regulatory network of hypoxic response in yak Sertoli cells.

Yaks live in the Qinghai-Tibet Plateau for a long time where oxygen is scarce, but can ensure the smooth development of testis and spermatogenesis. The key lies in the functional regulation of the Sertoli cells under hypoxia. In this study, we sequenced yak Sertoli cells cultured in normal oxygen concentration (Normoxia) and treated with low oxygen concentration (Hypoxia) by whole transcriptomics, and screened out 194 differentially expressed mRNAs (DEmRNAs), 934 differentially expressed LncRNAs (DELncRNAs) and 129 differentially expressed miRNAs (DEmiRNAs). GO and KEGG analysis showed that these differential genes were mainly concentrated in PI3K-AKT, MAPK, RAS, and other signaling pathways, and were associated with glucose metabolism, tight junction, steroid hormone synthesis, cell fusion, and immunity of yak Sertoli cells. We constructed the gene interaction network of yak Sertoli cells in hypoxia and screened out the relationship pairs related to glucose metabolism and tight junction. The results suggested that the changes in energy metabolism, tight junction, and immune regulation of yak Sertoli cells under hypoxia might provide favorable conditions for spermatogenesis. This study provides data for further study on the role of non-coding RNA in testis development and spermatogenesis of yak.

Novel machine-learning prediction tools for overall survival of patients with chondrosarcoma: Based on recursive partitioning analysis.

BACKGROUND: Chondrosarcoma (CHS), a bone malignancy, poses a significant challenge due to its heterogeneous nature and resistance to conventional treatments. There is a clear need for advanced prognostic instruments that can integrate multiple prognostic factors to deliver personalized survival predictions for individual patients. This study aimed to develop a novel prediction tool based on recursive partitioning analysis (RPA) to improve the estimation of overall survival for patients with CHS. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database were analyzed, including demographic, clinical, and treatment details of patients diagnosed between 2000 and 2018. Using C5.0 algorithm, decision trees were created to predict survival probabilities at 12, 24, 60, and 120 months. The performance of the models was assessed through confusion scatter plot, accuracy rate, receiver operator characteristic (ROC) curve, and area under ROC curve (AUC). RESULTS: The study identified tumor histology, surgery, age, visceral (brain/liver/lung) metastasis, chemotherapy, tumor grade, and sex as critical predictors. Decision trees revealed distinct patterns for survival prediction at each time point. The models showed high accuracy (82.40%-89.09% in training group, and 82.16%-88.74% in test group) and discriminatory power (AUC: 0.806-0.894 in training group, and 0.808-0.882 in test group) in both training and testing datasets. An interactive web-based shiny APP (URL: https://yangxg1209.shinyapps.io/chondrosarcoma_survival_prediction/) was developed, simplifying the survival prediction process for clinicians. CONCLUSIONS: This study successfully employed RPA to develop a user-friendly tool for personalized survival predictions in CHS. The decision tree models demonstrated robust predictive capabilities, with the interactive application facilitating clinical decision-making. Future prospective studies are recommended to validate these findings and further refine the predictive model.

The Combined Use of Cinnamaldehyde and Vitamin C Is Beneficial for Better Carcass Character and Intestinal Health of Broilers.

The use of cinnamaldehyde and Vitamin C can improve immunity and intestinal health. A two-way factorial design was employed to investigate the main and interactive effects of cinnamaldehyde and vitamin C on the growth, carcass, and intestinal health of broiler chickens. A total of 288 one-day-old female Arbor Acres broiler chicks were randomly distributed among four treatment groups, consisting of six replicate cages with 12 birds each. Four treatments were basal diet or control (CON), supplemental cinnamaldehyde (CA) 300 g/ton (g/t), vitamin C (VC) 300 g/t, and cinnamaldehyde 300 g/t, and vitamin C 300 g/t (CA + VC), respectively. The results showed that supplemental CA did not affect the growth performance or slaughter performance of broilers at 21 days (d), 42 days (d), and 1-42 days (d); however, it could improve intestinal barrier function at 42 d of age and reduce the mRNA expression of inflammatory factors in the intestine at 21 d and 42 d of age. Supplemental VC showed a trend towards increasing body weight gain (BWG) at 21 d (p = 0.094), increased breast muscle rate (at 21-d 5.33%, p < 0.05 and at 42-d 7.09%, p = 0.097), and decreased the abdominal fat (23.43%, p < 0.05) and drip loss (20.68%, p < 0.05) at 42-d. Moreover, VC improves intestinal morphology and intestinal barrier function and maintains a balanced immune response. The blend of CA and VC significantly upregulated the mRNA expression of myeloid differentiation factor 88 (MyD-88) in the intestine at 21 d of age, the mRNA expression of catalase (CAT), Occludin, Claudin-1, Mucin-2, nuclear factor-kappa B (NF-κB) and toll-like receptor 4 (TLR-4) in the intestine at 42 d of age (p < 0.01), and downregulated the mRNA expression of interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α) in the intestine at 21-d and 42-d of age, and interleukin-1 beta (IL-1ß) mRNA in intestine at 42 d of age (p < 0.01). This study suggested that the combination of CA and VC had the potential to regulate intestinal health and result in better carcass character of broilers.

Distribution and response of electroactive microorganisms to freshwater river pollution.

Electroactive microorganisms (EAMs) play a vital role in biogeochemical cycles by facilitating extracellular electron transfer. They demonstrate remarkable adaptability to river sediments that are characterized by pollution and poor water quality, significantly contributing to the sustainability of river ecosystems. However, the distribution and diversity of EAMs remain poorly understood. In this study, 16S rRNA gene high-throughput sequencing and real-time fluorescence quantitative PCR were used to assess EAMs in 160 samples collected from eight rivers within the Pearl River Delta of Southern China. The results indicated that specialized EAMs communities in polluted sediments exhibited variations in response to water quality and sediment depth. Compared to clean sediment, polluted sediments showed a 4.5% increase in the relative abundances of EAMs communities (59 genera), with 45- and 17-times higher abundances of Geobacter and cable bacteria. Additionally, the abundance of cable bacteria decreased with increasing sediment depth in polluted sediments, while the abundance of L. varians GY32 exhibited an opposite trend. Finally, the abundances of Geobacter, cable bacteria, and L. varians GY32 were positively correlated with the abundance of filamentous microorganisms (FMs) across all samples, with stronger interactions in polluted sediments. These findings suggest that EAMs demonstrate heightened sensitivity to polluted environments, particularly at the genus (species) level, and exhibit strong adaptability to conditions characterized by high levels of acid volatile sulfide, low dissolved oxygen, and elevated nitrate nitrogen. Therefore, environmental factors could be manipulated to optimize the growth and efficiency of EAMs for environmental engineering and natural restoration applications.

Multimodal ischemic stroke recurrence prediction model based on the capsule neural network and support vector machine.

Ischemic stroke (IS) has a high recurrence rate. Machine learning (ML) models have been developed based on single-modal biochemical tests, and imaging data have been used to predict stroke recurrence. However, the prediction accuracy of these models is not sufficiently high. Therefore, this study aimed to collect biochemical detection and magnetic resonance imaging (MRI) data to establish a dataset and propose a high-performance heterogeneous multimodal IS recurrence prediction model based on deep learning. This is a retrospective cohort study. Data were retrospectively collected from 634 IS patients in Zhuhai, China, a 12-month follow-up was conducted to determine stroke recurrence. We propose the ischemic stroke multi-group learning (ISGL) model, an integrated model for predicting the recurrence risk of multimodal IS in patients, based on a capsule neural network and a linear support vector machine (SVM). Two capsule neural network prediction models based on T1 and T2 signals in the MRI data and a SVM prediction model based on biochemical test data were established. Finally, a vote was conducted on the final judgment of the integrated model. The ISGL model was compared with 6 classical ML and deep learning models: k-nearest neighbors, SVM, logistic regression, random forest, eXtreme Gradient Boosting, and visual geometry group. The results revealed that the accuracy, specificity, sensitivity and the area under the curve of the ISGL model were 95%, 96%, 94%, and 95%, respectively. Among the comparison models, the visual geometry group method exhibited the best performance, but it much lower than those of the ISGL model. Analysis of the importance of biochemical test data revealed that low-density lipoprotein, smoking, and heart disease history were the positively correlated factors, and total cholesterol, high-density lipoprotein, and diabetes were and the negatively correlated factors. This study proposes the ISGL model can be used simultaneously with MRI and biochemical data to predict IS recurrence. This combination resulted in higher rate of performance than that of the other ML models. Additionally, this study found related risk factors affected recurrence, which can be used to intervene in high-risk patients' recurrence as early as possible and promote the development of secondary prevention of stroke.

Multimerization of TREM2 is impaired by Alzheimer's disease-associated variants.

INTRODUCTION: The immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) is among the strongest genetic risk factors for Alzheimer's disease (AD) and is a therapeutic target. TREM2 multimers have been identified in crystallography and implicated in the efficacy of antibody therapeutics; however, the molecular basis for TREM2 multimerization remains poorly understood. METHODS: We used molecular dynamics simulations and binding energy analysis to determine the effects of AD-associated variants on TREM2 multimerization and validated with experimental results. RESULTS: TREM2 trimers remained stably bound, driven primarily by salt bridge between residues D87 and R76 at the interface of TREM2 units. This salt bridge was disrupted by the AD-associated variants R47H and R98W and nearly ablated by the D87N variant. This decreased binding among TREM2 multimers was validated with co-immunoprecipitation assays. DISCUSSION: This study uncovers a molecular basis for TREM2 forming stable trimers and unveils a novel mechanism by which TREM2 variants may increase AD risk by disrupting TREM2 oligomerization to impair TREM2 normal function. HIGHLIGHTS: Triggering receptor expressed on myeloid cells 2 (TREM2) multimerization could regulate TREM2 activation and function. D87-R76 salt bridges at the interface of TREM2 units drive the formation of stable TREM2 dimers and trimers. Alzheimer's disease (AD)-associated R47H and R98W variants disrupt the D87-R76 salt bridge. The AD-associated D87N variant leads to complete loss of the D87-R76 salt bridge.

Expanding the Structural Diversity of Tubulin-Targeting Agents: Development of Highly Potent Benzimidazoles for Treating Fungal Diseases.

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1H-benzo[d]imidazole (A25) exhibited optimal antifungal activity against Sclerotinia sclerotiorum (S. s.), affording an excellent half-maximal effective concentration (EC50) of 0.158 µg/mL, which was higher than that of the reference agent carbendazim (EC50 = 0.594 µg/mL). Pot experiments revealed that compound A25 (200 µg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A25 and ß-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

Polymyxins: recent advances and challenges.

Antibiotic resistance is a pressing global health challenge, and polymyxins have emerged as the last line of defense against multidrug-resistant Gram-negative (MDR-GRN) bacterial infections. Despite the longstanding utility of colistin, the complexities surrounding polymyxins in terms of resistance mechanisms and pharmacological properties warrant critical attention. This review consolidates current literature, focusing on polymyxins antibacterial mechanisms, resistance pathways, and innovative strategies to mitigate resistance. We are also investigating the pharmacokinetics of polymyxins to elucidate factors that influence their in vivo behavior. A comprehensive understanding of these aspects is pivotal for developing next-generation antimicrobials and optimizing therapeutic regimens. We underscore the urgent need for advancing research on polymyxins to ensure their continued efficacy against formidable bacterial challenges.

A Multi-State Model Study of the Disability-Free Life Expectancy Among Older Adults with Chronic Multimorbidity Based on CHARLS - China, 2011-2020.

What is already known about this topic?: Chronic disease multimorbidity is prevalent among older Chinese people, seriously affecting their well-being and quality of life. What is added by this report?: This study estimated the impact of multimorbidity on the risk of health state transitions and health expectancy among older adults in China. It used population-representative, long-term longitudinal data and multi-state Markov modeling along with microsimulation methods. What are the implications for public health practice?: The study results suggest that the Chinese government should strengthen the prevention and management of multimorbidity and accelerate the transition from chronic disease management to multimorbidity management.