Proteomic biomarkers for noninvasive left atrial appendage thrombus prediction in patients with atrial fibrillation.

INTRODUCTION: The CHA2DS2-VASc score, used to assess the risk of left atrial appendage thrombus (LAAT) formation in patients with atrial fibrillation (AF), has limited predictive value. Moreover, transesophageal echocardiography imaging, the gold standard diagnostic method to identify thrombi, is semi-invasive. Consequently, there is a need for alternative and noninvasive diagnostic methods for LAAT risk assessment. METHODS: Deep proteomic analysis was conducted in plasma samples from 8 patients with nonvalvular AF, divided into thrombus and control groups (4 patients in each group) based on the presence or absence of LAAT. Biomarkers associated with LAAT were validated using an enzyme-linked immunosorbent assay in a cohort of 179 patients with available clinical, transthoracic, and transesophageal echocardiography data. Predictive models were developed to assess the improvement in LAAT identification. RESULTS: The LAAT group had higher CHA2DS2-VASc scores, larger LA diameter, and lower LAA flow velocities. Deep proteomic analysis identified 30 differentially expressed proteins, including myosin light chain 4, prenylcysteine oxidase 1 (PCYOX1), and decorin as potential diagnostic biomarkers of LAAT. The model showed that PCYOX1 and decorin provided an area under the curve (AUC) of 0.970 for LAAT prediction compared with 0.672 in a model including the CHA2DS2-VASc score and LAA cauliflower morphology. The incremental value of proteomic biomarkers for LAAT in patients with nonvalvular AF was further confirmed with the net reclassification improvement and integrated discrimination improvement indices. CONCLUSIONS: Protein levels of PCYOX1 and decorin improve the predictive performance for LAAT in patients with nonvalvular AF.

Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging.

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL.

Polysaccharide-Based Micro/Nanomotors for Active Ingredient Delivery in Food.

Micro/nanomotors (MNMs) are miniature devices that can generate energy through chemical reactions or physical processes, utilizing this energy for movement. By virtue of their small size, self-propulsion, precise positioning within a small range, and ability to access microenvironments, MNMs have been applied in various fields including sensing, biomedical applications, and pollutant adsorption. However, the development of food-grade MNMs and their application in food delivery systems have been scarcely reported. Currently, there are various issues with the decomposition, oxidation, or inability to maintain the activity of some nutrients or bioactive substances, such as the limited application of curcumin (Cur) in food. Compared to traditional delivery systems, MNMs can adjust the transport speed and direction as needed, effectively protecting bioactive substances during delivery and achieving efficient transportation. Therefore, this study utilizes polysaccharides as the substrate, employing a simple, rapid, and pollution-free template method to prepare polysaccharide-based microtubes (PMTs) and polysaccharide-based micro/nanomotors (PMNMs). PMNMs can achieve multifunctional propulsion by modifying ferrosoferric oxide (Fe3O4), platinum (Pt), and glucose oxidase (GOx). Fe-PMNMs and Pt-PMNMs exhibit excellent photothermal conversion performance, showing promise for applications in photothermal therapy. Moreover, PMNMs can effectively deliver curcumin, achieving the effective delivery of nutrients and exerting the anti-inflammatory performance of the system.

Intensive Versus Standard Blood Pressure Management after Endovascular Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

Prospective clinical studies on blood pressure (BP) management targets after endovascular therapy (EVT) for acute ischemic stroke (AIS) have recently been published. Our objective was to assess the impact on clinical outcomes of BP management guided by established systolic BP (SBP) targets within the first 24 hours after successful EVT. Four randomized controlled trials (RCTs) including 1556 participants across 5 SBP target settings identified from 5 databases up to September 6, 2023 were included in this systematic review and meta-analysis. All the intensive SBP target groups in these RCTs were combined to facilitate head-to-head comparisons. Patients receiving intensive SBP management had lower risk of 90-day functional independence as assessed by the modified Rankin scale score (relative risk [RR], 0.81; 95% confidence interval [CI], 0.72 to 0.91; I2, 12%), excellent outcomes (RR,0.86; 95% CI, 0.75 to 0.99; I2, 7%), favorable outcomes (RR, 0.85; 95% CI, 0.78 to 0.92; I2, 0%), and quality of life (standardized mean difference, -0.22; 95% CI, -0.35 to -0.10; I2,0%). There were no differences in the probability of any intracerebral hemorrhage (RR, 1.04; 95% CI, 0.92 to 1.19; I2,0%), symptomatic intracerebral hemorrhage (RR, 1.10; 95% CI, 0.76 to 1.60; I2, 0%), stroke-related death (RR, 1.16; 95% CI, 0.80 to 1.68; I2, 0%), or parenchymal hematoma (RR, 1.71; 95% CI, 0.74 to 3.98; I2, 47%) between SBP targets. This meta-analysis provides evidence from RCTs suggesting that intensive SBP control (target<160 mm Hg) may be detrimental to clinical outcomes in AIS patients with successful reperfusion after EVT.

KDGene: knowledge graph completion for disease gene prediction using interactional tensor decomposition.

The accurate identification of disease-associated genes is crucial for understanding the molecular mechanisms underlying various diseases. Most current methods focus on constructing biological networks and utilizing machine learning, particularly deep learning, to identify disease genes. However, these methods overlook complex relations among entities in biological knowledge graphs. Such information has been successfully applied in other areas of life science research, demonstrating their effectiveness. Knowledge graph embedding methods can learn the semantic information of different relations within the knowledge graphs. Nonetheless, the performance of existing representation learning techniques, when applied to domain-specific biological data, remains suboptimal. To solve these problems, we construct a biological knowledge graph centered on diseases and genes, and develop an end-to-end knowledge graph completion framework for disease gene prediction using interactional tensor decomposition named KDGene. KDGene incorporates an interaction module that bridges entity and relation embeddings within tensor decomposition, aiming to improve the representation of semantically similar concepts in specific domains and enhance the ability to accurately predict disease genes. Experimental results show that KDGene significantly outperforms state-of-the-art algorithms, whether existing disease gene prediction methods or knowledge graph embedding methods for general domains. Moreover, the comprehensive biological analysis of the predicted results further validates KDGene's capability to accurately identify new candidate genes. This work proposes a scalable knowledge graph completion framework to identify disease candidate genes, from which the results are promising to provide valuable references for further wet experiments. Data and source codes are available at https://github.com/2020MEAI/KDGene.

Fish arginase constrains excessive production of nitric oxide and limits mitochondrial damage during Aeromonas hydrophila infection.

Bacteria-enhanced inducible nitric oxide synthase (iNOS) overproduces nitric oxide (NO) leading to mitochondrial and cellular damage. In mammals, arginase (ARG), the enzyme consuming the same substrate l-arginine with iNOS, was believed to inhibit iNOS activity by competing the substrate. But in fish, this conception has been widely challenged. In this study, the gene expression using real-time quantitative PCR (RT-qPCR) technology showed that when stimulated by Aeromonas hydrophila (A. hydrophila), grass carp (gc) iNOS was up-regulated in head kidney monocytes/macrophages (M0/MФ), and its changes were not detected in the whole tissue of liver or spleen, showing a high degree of cell-specific expression pattern. At the same time, gcARG2 had a high basal expression in tissues and was up-regulated by A. hydrophila stimulation. Next, phthalaldehyde-primaquine reaction was first used in the determination of intracellular urea in fish cells. It was found that the induced gcARG2 led to an increase in the intracellular urea content. Moreover, urea and NO production in M0/MФ were increased in a substrate dose-dependent manner from 30 to 100 µM of l-arginine and reached the highest yield at 300 and 3000 µM of l-arginine, respectively. Furthermore, head kidney M0/MФ was cultured in RPMI1640 medium containing physiological concentration (500 µM) of l-arginine to evaluate the effect of ARG. Under A. hydrophila stimulation, treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) showed that inhibition of arginase could further enhance the NO production stimulated by A. hydrophila. This in turn led to a cumulation in peroxynitrite (ONOO-) content and an injury of the mitochondrial membrane potential. Our study showed for the first time that fish ARG in head kidney M0/MФ can limit excessive production of NO and harmful products by iNOS to maintain mitochondrial and cellular homeostasis.

Z-scheme heterojunction composed of Fe-doped g-C3N4 and Bi2MoO6 for photo-fenton degradation of antibiotics over a wide pH range: Activity and toxicity assessment.

In photo-Fenton technology, the narrower pH range limits its practical application for antibiotic wastewater remediation. Therefore, in this study, a Z-scheme heterojunction photo-Fenton catalyst was constructed by Fe-doped graphite-phase carbon nitride in combination with bismuth molybdate for the degradation of typical antibiotics. Fe doping can shorten the band gap and increase visible-light absorption. Simultaneously, the constructed Z-scheme heterojunction provides a better charge transfer pathway for the photo-Fenton reaction. Within 30 min, Fe3CN/BMO-3 removed 95.54% of tetracycline hydrochloride (TC), and its remarkable performance was the higher Fe3+/Fe2+ conversion efficiency through the decomposition of H2O2. The Fe3CN/BMO-3 catalyst showed remarkable photo-Fenton degradation performance in a wide pH range (3.0-11.0), and it also had good stability in the treatment of TC wastewater. Furthermore, the order of action of the active species was h+ > ·O2- > 1O2 > ·OH, and the toxicity assessment suggested that Fe3CN/BMO-3 was effective in reducing the biotoxicity of TC. The catalyst proved to be an economically feasible and applicable material for antibiotic photo-Fenton degradation, and this study provides another perspective on the application of elemental doping and constructed heterojunction photo-Fenton technology for antibiotic water environmental remediation.

Determining optimal range of reduction rates for nitrogen fertilization based on responses of vegetable yield and nitrogen losses to reduced nitrogen fertilizer application.

Vegetable production is commonly accompanied by high nitrogen fertilizer rates but low nitrogen use efficiency in China. Reduced fertilization has been frequently recommended in existing studies as an efficient measurement to avoid large amount of nutrient loss and subsequent nonpoint source pollution. However, the reported responses of vegetable yield and nitrogen losses to reduced fertilization rates varied in a large range, which has resulted into large uncertainties in the potential benefits of those recommended reduction rates. Thus, we constructed the relationship between responses of nitrogen losses and vegetable yield to reduced nitrogen fertilization rates to determine the optimal range of reduction rates for nitrogen fertilization in a proportional form based on data reported in literatures across China's mainland, and evaluated the roles of greenhouse, managing options, and vegetable species on the responses. The relationships were constructed separately for 4 subregions: Northern arid and semiarid, loess plateau regions (NSL), Temperate monsoon zone (TMZ), Southeast monsoon zone (SMZ), Southwest zone (SWZ). The optimal nitrogen fertilizer reduction range for the TMZ, SMZ and SWZ were 51 % to 67 %, 40 % to 66 % and 54 % to 80 %, respectively and no reduction for NSL. Vegetable yields were not be sacrificed when fertilizations were reduced within the optimal ranges. Greenhouse and managing options showed no significant effect on the responses of both vegetable yield and nitrogen losses by the optimal reduction range but vegetable species played a relatively important role on the responses of vegetable yield. This indicated that the optimal reduction rates can be effective on reducing nitrogen loss in both open-field and greenhouse conditions across China's mainland without extra managing options. Therefore, the optimal reduction rates can still serve as a good starting point for making regional plans of nitrogen reduction that help balancing the chasing of high vegetable yield and low nitrogen loss.

The impact of contrast retention on thrombus formation risks in patients with atrial fibrillation: A numerical study.

Background: Contrast retention (CR) is an important predictor of left atrial appendage thrombus (LAAT) and stroke in patients with non-valvular atrial fibrillation (AF). We sought to explore the underlying mechanisms of CR using computational fluid dynamic (CFD) simulations. Methods: A total of 12 patients with AF who underwent both cardiac computed tomography angiography (CTA) and transesophageal echocardiography (TEE) before left atrial appendage occlusion (LAAO) were included in the study. The patients were allocated into the CR group or non-CR group based on left atrial appendage (LAA) angiography. Patient-specific models were reconstructed to evaluate time-averaged wall shear stress (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and endothelial cell activation potential (ECAP). Additionally, the incidence of thrombosis was predicted using residence time (RT) at different time-points. Results: TAWSS was lower [median (Interquartile Range) 0.27 (0.19-0.47) vs 1.35 (0.92-1.79), p < 0.001] in LAA compared to left atrium. In contrast, RRT [1438 (409.70-13869) vs 2.23 (1.81-3.14), p < 0.001] and ECAP [122.70 (30.01-625.70) vs 0.19 (0.16-0.27), p < 0.001)] was higher in the LAA. The patients in the CR group had significantly higher RRT [(mean ± SD) 16274 ± 11797 vs 639.70 ± 595.20, p = 0.009] and ECAP [610.80 ± 365.30 vs 54.26 ± 54.38, p = 0.004] in the LAA compared to the non-CR group. Additionally, patients with CR had a wider range of thrombus-prone regions [0.44(0.27-0.66)% vs 0.05(0.03-0.27)%, p = 0.009] at the end of the 15th cardiac cycle. Conclusions: These findings suggest that CR might be an indicator of high-risk thrombus formation in the LAA. And CT-based CFD simulation may be a feasible substitute for the evaluation of LAA thrombotic risk in patients with AF, especially in patients with CR.

Oxymatrine alleviates high-fat diet/streptozotocin-induced non-alcoholic fatty liver disease in C57BL/6 J mice by modulating oxidative stress, inflammation and fibrosis.

Non-alcoholic fatty liver disease (NAFLD) represents a complex complication of type 2 diabetes mellitus (T2DM). Oxymatrine (OMT) is an alkaloid extracted from Sophora flavescens with broad pharmacological effects. However, there is currently a lack of research on OMT in the field of NAFLD. The present study aimed to explore the effects and underlying mechanisms of oxymatrine in treating T2DM with NAFLD. The T2DM mice model was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6 J mice. Animals were randomly divided into four groups (n = 8): Control group, DC group, OMT-L group (45 mg/kg i.g.), and OMT-H group (90 mg/kg, i.g.). The drug was administered once a day for 8 weeks. In addition, HepG2 hepatocytes were incubated with palmitic acid (PA) to establish a fatty liver cell model. Treated with OMT, the body weight and fasting blood glucose (FBG) of DC mice were reduced and the liver organ coefficient was significantly optimized. Meanwhile, OMT markedly enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and also reduced malondialdehyde (MDA) levels. These biochemical alterations were accompanied by noticeable improvements in liver histopathology. Furthermore, OMT down-regulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1ß (IL-1ß), transforming growth factor-ß1 (TGF-ß1) and collagen I significantly, highlighting its potential in modulating inflammatory and fibrotic pathways. In conclusion, OMT improved liver impairment effectively in diabetic mice by suppressing oxidative stress, inflammation and fibrosis. These results suggest that OMT may represent a novel therapy for NAFLD with diabetes.

Prediction of pathological complete response in locally advanced head and neck squamous cell carcinoma treated with neoadjuvant chemo-immunotherapy using volumetric multisequence MRI histogram analysis.

PURPOSE: This study aimed to develop a multisequence MRI-based volumetric histogram metrics model for predicting pathological complete response (pCR) in advanced head and neck squamous cell carcinoma (HNSCC) patients undergoing neoadjuvant chemo-immunotherapy (NCIT) and compare its predictive performance with AJCC staging and RECIST 1.1 criteria. METHODS: Twenty-four patients with locally advanced HNSCC from a prospective phase II trial were enrolled for analysis. All patients underwent pre- and post-NCIT MRI examinations from which whole-tumor histogram features were extracted, including T1WI, T2WI, enhanced T1WI (T1Gd), diffusion-weighted imaging (DWI) sequences, and their corresponding apparent diffusion coefficient (ADC) maps. The pathological results divided the patients into pathological complete response (pCR) and non-pCR (N-pCR) groups. Delta features were calculated as the percentage change in histogram features from pre- to post-treatment. After data reduction and feature selection, logistic regression was used to build prediction models. ROC analysis was performed to assess the diagnostic performance. RESULTS: Eleven of 24 patients achieved pCR. Pre_T2_original_firstorder_Minimum, Post_ADC_original_firstorder_MeanAbsoluteDeviation, and Delta_T1Gd_original_firstorder_Skewness were associated with achieving pCR after NCIT. The Combined_Model demonstrated the best predictive performance (AUC 0.95), outperforming AJCC staging (AUC 0.52) and RECIST 1.1 (AUC 0.72). The Pre_Model (AUC 0.83) or Post-Model (AUC 0.83) had a better predictive ability than AJCC staging. CONCLUSION: Multisequence MRI-based volumetric histogram analysis can non-invasively predict the pCR status of HNSCC patients undergoing NCIT. The use of histogram features extracted from pre- and post-treatment MRI exhibits promising predictive performance and offers a novel quantitative assessment method for evaluating pCR in HNSCC patients receiving NCIT.

Association of lymphocyte subsets with the efficacy and prognosis of PD­1 inhibitor therapy in advanced gastric cancer: results from a monocentric retrospective study.

PURPOSE: This retrospective study aimed to investigate the changes in peripheral blood lymphocyte subsets before and after immunotherapy in patients with advanced gastric cancer and their relationship n with the therapeutic efficacy and clinical prognosis. METHODS: Peripheral blood lymphocyte subsets, including CD4 + T cells, CD8 + T cells, CD4+/CD8 + ratio, NK cells, Treg cells, and B cells, were collected from 195 patients with advanced gastric cancer who were admitted to the First Hospital of Shanxi Medical University with immunotherapy from January 2020 to October 2021, at the time of diagnosis of advanced gastric cancer, before immunotherapy and after 3 cycles of immunotherapy. T-tests were used to examine the factors influencing the patients' peripheral blood lymphocyte subsets and the changes after immunotherapy. To examine the relationship between lymphocyte subsets and treatment outcomes, ROC curves were plotted using a logistic regression. Kaplan-Meier curve was drawn, and the Log Rank test was carried out to compare the differences in PFS between the different groups. Cox proportional hazards regression model was used to analyze the factors affecting PFS after calibration of other variables. RESULTS: The proportion of peripheral blood lymphocyte subsets in patients with advanced gastric cancer was affected by age and PD-L1 level. Compared to the baseline, the treatment effective group had higher proportions of CD4 + T cells, a higher CD4+/CD8 + ratio, NK cells and Treg cells, and lower proportions of CD8 + T cells and B cells in the peripheral blood after three cycles of immunotherapy. In the treatment-naive group, there were no significant differences in the lymphocyte subsets. With cut-off values of 30.60% and 18.00%, baseline CD4 + T cell and NK cell ratios were independent predictors of immunotherapy efficacy and PFS. Treg cell ratio, gender, PD-L1 levels, and MMR status all predicted PFS independently. CONCLUSION: The proportion of peripheral blood lymphocyte subsets was modified in patients who responded to PD-1 inhibitors. Different lymphocyte subpopulation levels can be used as biomarkers to predict immunotherapy efficacy and clinical prognosis in patients with advanced gastric cancer.

Enhanced Photocatalytic Nitrogen Reduction via Bismuth Nanoparticle-Decorating ZnCdS Solid Solution.

The construction of photocatalysts with a surface plasmon resonance effect (SPR) has been demonstrated as a highly effective strategy for enhancing photocatalytic efficiency. In this paper, we synthesized a catalyst with bismuth metal loaded on ZnCdS nanospheres for an efficient photocatalytic nitrogen reduction reaction (PNRR). The SPR effect induced by Bi nanoparticles under light excitation significantly promoted the ammonia production efficiency of the photocatalyst. Under air ambient conditions with lactic acid as the sacrificial agent, the photocatalytic NH4+ yield of 3% Bi@ZnCdS was 58.93 µmol·g-1·h-1, which exhibited an approximately 7.7 times that of the pure phase ZnCdS. The experimental characterization results demonstrate that the incorporation of metallic bismuth enhances the light absorption capacity of the catalyst and improves the separation efficiency of the photogenerated carriers. Theoretical calculations proved that Bi NPs provide more photogenerated electrons to convert N2 to NH3 for solid-solution ZnCdS. This work presents a novel concept for the development of advanced plasma nanomaterials to enhance the photocatalytic nitrogen fixation reaction.

Anesthesia on Clinical Outcomes in an Extended Time Window During Endovascular Stroke Therapy: Exploratory Analysis of the ANGEL-ACT Registry.

OBJECTIVE: Data on the impact of different anesthesia methods on clinical outcomes in patients with acute ischemic stroke undergoing endovascular therapy (EVT) in extended windows are limited. This study compared clinical outcomes in patients with stroke having general anesthesia (GA), conscious sedation (CS), or local anesthesia (LA) during EVT in extended (>6 h) time windows. METHODS: We conducted an exploratory analysis of data from the ANGEL-ACT registry. The primary outcome was the modified Rankin Scale (mRS) score at 90 days. Secondary outcomes included the proportions of patients with mRS scores of 0 to 1, 0 to 2, and 0 to 3, and safety outcomes were any intracranial hemorrhage (ICH), symptomatic ICH, or mortality within 90 days. Multivariate analyses, inverse probability of treatment weighting, and coarsened exact matching were used to adjust for indication bias. RESULTS: A total of 646 patients were included in the analysis (GA,280; CS, 103; LA, 263). Patients having LA during EVT were more likely to have a favorable mRS score (adjusted odds ratio [aOR]: 1.75; 95% CI: 1.28 to 2.40) and a lower incidence of symptomatic ICH (aOR: 0.33; 95% CI: 0.14 to 0.76) than those having GA group. Similarly, CS was associated with greater odds of favorable 90-day mRS scores compared with GA (aOR: 1.69; 95% CI: 1.11 to 2.56). Posterior circulation stroke was overrepresented in the GA group (29.6%) and may be a reason for the worse outcomes in the GA group. CONCLUSIONS: Patients who received LA or CS had better neurological outcomes than those who received GA within extended time windows in a real-world setting.

Ammonia Synthesis via Electrocatalytic Nitrate Reduction Using NiCoO2 Nanoarrays on a Copper Foam.

Ammonia (NH3) plays a vital role in industrial and agricultural development. The electrocatalytic nitrate reduction reaction (eNO3RR) is an effective method to produce NH3 under environmental conditions but also requires considerably active and selective electrocatalysts. Herein, a copper foam was used as a conductive substrate for the electrode materials. Specifically, a Co metal-organic framework (Co-MOF) was in situ grown on the copper foam, etched, and calcined to form NiCoO2@Cu nanosheets, which were used as cathode electrodes for the eNO3RR. In 0.1 M Na2SO4 with 0.1 M NaNO3 electrolyte, NiCoO2@Cu nanosheets realized an NH3 yield of 5940.73 µg h-1 cm-2 at -0.9 V vs reversible hydrogen electrode (RHE), with a Faradaic efficiency of 94.2% at -0.7 V vs RHE. After 33 h of the catalytic reaction, the selectivity of NH3-N increased to 99.7%. The excellent electrocatalytic performance of NiCoO2@Cu nanosheets was attributed to the apparent synergistic effect between the Ni atoms and the Co atoms of bimetallic materials. This study shows that the Ni doping of NiCoO2@Cu nanosheets effectively facilitated the adsorption of NO3- on NiCoO2@Cu, and it promoted the eNO3RR.

Edwardsiella piscicida causes iron storage disorders by an autophagy pathway in fish monocytes/macrophages.

Edwardsiella piscicida (E. piscicida) is a gram-negative pathogen that survives in intracellular environment. Currently, the interplay between E. piscicida and host cells has not been completely explored. In this study, we found that E. piscicida disturbed iron homeostasis in grass carp monocytes/macrophages to maintain its own growth. Further investigation revealed the bacteria induced an increase of intracellular iron, which was subjected to the degradation of ferritin. Moreover, the autophagy inhibitor impeded the degradation of ferritin and increase of intracellular iron in E. piscicida-infected monocytes/macrophages, implying possible involvement of autophagy response in the process of E. piscicida-broken iron homeostasis. Along this line, confocal microscopy observed that E. piscicida elicited the colocalization of ferritin with LC3-positive autophagosome in the monocytes/macrophages, indicating that E. piscicida mediated the degradation of ferritin possibly through the autophagic pathway. These results deepened our understanding of the interaction between E. piscicida and fish cells, hinting that the disruption of iron homeostasis was an important factor for pathogenicity of E. piscicida. They also indicated that autophagy was a possible mechanism governing intracellular iron metabolism in response to E. piscicida infection and might offer a new avenue for anti-E. piscicida strategies in the future.

Solvent-Exchange Triggered Solidification of Peptide/POM Coacervates for Enhancing the On-Site Underwater Adhesion.

Peptide-based biomimetic underwater adhesives are emerging candidates for understanding the adhesion mechanism of natural proteins secreted by sessile organisms. However, there is a grand challenge in the functional recapitulation of the on-site interfacial spreading, adhesion and spontaneous solidification of native proteins in water using peptide adhesives without applied compressing pressure. Here, a solvent-exchange strategy was utilized to exert the underwater injection, on-site spreading, adhesion and sequential solidification of a series of peptide/polyoxometalate coacervates. The coacervates were first prepared in a mixed solution of water and organic solvents by rationally suppressing the non-covalent interactions. After switching to a water environment, the solvent exchange between bulk water and the organic solvent embedded in the matrix of the peptide/polyoxometalate coacervates recovered the hydrophobic effect by increasing the dielectric constant, resulting in a phase transition from soft coacervates to hard solid with enhanced bulk cohesion and thus compelling underwater adhesive performance. The key to this approach is the introduction of suitable organic solvents, which facilitate the control of the intermolecular interactions and the cross-linking density of the peptide/polyoxometalate adhesives in the course of solidification under the water line. The solvent-exchange method displays fascinating universality and compatibility with different peptide segments.

Identification of Cancer Stem Cell-related Gene by Single-cell and Machine Learning Predicts Immune Status, Chemotherapy Drug, and Prognosis in Lung Adenocarcinoma.

AIM: This study aimed to identify the molecular type and prognostic model of lung adenocarcinoma (LUAD) based on cancer stem cell-related genes. Studies have shown that cancer stem cells (CSC) are involved in the development, recurrence, metastasis, and drug resistance of tumors. METHOD: The clinical information and RNA-seq of LUAD were obtained from the TCGA database. scRNA dataset GSE131907 and 5 GSE datasets were downloaded from the GEO database. Molecular subtypes were identified by ConsensusClusterPlus. A CSC-related prognostic signature was then constructed via univariate Cox and LASSO Cox-regression analysis. RESULT: A scRNA-seq GSE131907 dataset was employed to obtain 11 cell clusters, among which, 173 differentially expressed genes in CSC were identified. Moreover, the CSC score and mRNAsi were higher in tumor samples. 18 of 173 genes were survival time-associated genes in both the TCGA-LUDA dataset and the GSE dataset. Next, two molecular subtypes (namely, CSC1 and CSC2) were identified based on 18 survival-related CSC genes with distinct immune profiles and noticeably different prognoses as well as differences in the sensitivity of chemotherapy drugs. 8 genes were used to build a prognostic model in the TCGA-LUAD dataset. High-risk patients faced worse survival than those with a low risk. The robust predictive ability of the risk score was validated by the time-dependent ROC curve revealed as well as the GSE dataset. TIDE analysis showed a higher sensitivity of patients in the low group to immunotherapy. CONCLUSION: This study has revealed the effect of CSC on the heterogeneity of LUAD, and created an 8 genes prognosis model that can be potentially valuable for predicting the prognosis of LUAD and response to immunotherapy.

Grass carp Il-2 promotes neutrophil extracellular traps formation via inducing ROS production and autophagy in vitro.

Interleukin (IL)-2 has been reported to regulate neutrophil functions in humans, mice, pigs and chicken although it is a key regulator of T cells. Consistently, we found that grass carp (Ctenopharyngodon idellus) interleukin-2 (gcIl-2) is capable of modulating the antimicrobial activities of neutrophils via regulating granzyme B- and perforin-like gene expression in our previous study. In the present study, stimulation of gcIl-2 on neutrophil extracellular traps (NETs) formation in grass carp neutrophils was demonstrated by detecting free DNA release, histone H3 citrullination and morphological changes of the cells. Further investigation revealed that reactive oxygen species (ROS) production from NADPH oxidase but not mitochondria was involved in NETosis induced by gcIl-2. Aside from ROS, autophagy was disclosed to be indispensable for NETosis induced by gcIl-2. These converging lines of evidence suggested that fish Il-2 could induce NETs formation via NADPH oxidase-derived ROS- and autophagy-dependent pathways in fish species which is evolutionarily conserved with that in mammals. It is noteworthy that these two pathways did not interplay with each other in Il-2-stimulated NETosis. The mechanisms governing autophagy induced by Il-2 were also explored in the present study, showing that Il-2 modulated the action of high mobility group box 1 (HMGB1) protein to stimulate autophagy, leading to NETs formation in fish neutrophils. These results provided a new insight to the function of Il-2 in fish neutrophils, and a clue about the regulation of NETosis in the lower vertebrates.

Abnormal M1 polarization of placental macrophage induced by IL-15/STAT5 activation in VVC may lead to adverse pregnancy outcomes.

Pregnant women with vulvovaginal candidiasis (VVC) may experience adverse pregnancy outcomes such as premature delivery, intrauterine infection, abortion, and neonatal infection. Therefore, finding new treatments for VVC in pregnancy is a public health priority. We aimed to study the adverse consequences of Candida albicans (C. albicans) vaginal infection in pregnant mice and explore the mechanisms by which C. albicans affects macrophages. Our findings contribute to the development of new approaches to treat VVC during pregnancy. We established an animal model of vaginal infection by C. albicans in pregnant mice and observed adverse pregnancy outcomes such as decreased body weight, reduced implantation number, and increased abortion rates. Additionally, we infected mouse macrophage line RAW264.7 cells with C. albicans and established a cell model. We employed RT-qPCR, Western blot, and immunofluorescence staining to verify the changes in the IL-15/STAT5 signaling pathway and the role it played on the M1 polarization of C. albicans-infected macrophages at both the gene and protein levels. Our results indicate that the adverse pregnancy outcomes in VVC may be linked to changes in the IL-15/STAT5 pathway induced by C. albicans, which could impact macrophage M1 polarization.