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Abstract A bio-inspired strategy has recently been developed for camouflaging nanocarriers with biomembranes, such as natural cell membranes or subcellular structure-derived membranes. This strategy endows cloaked nanomaterials with improved interfacial properties, superior cell targeting, immune evasion potential, and prolonged duration of systemic circulation. Here, we summarize recent advances in the production and application of exosomal membrane-coated nanomaterials. The structure, properties, and manner in which exosomes communicate with cells are first reviewed. This is followed by a discussion of the types of exosomes and their fabrication methods. We then discuss the applications of biomimetic exosomes and membrane-cloaked nanocarriers in tissue engineering, regenerative medicine, imaging, and the treatment of neurodegenerative diseases. Finally, we appraise the current challenges associated with the clinical translation of biomimetic exosomal membrane-surface-engineered nanovehicles and evaluate the future of this technology.

Abstract Fungi and bacteria afflict humans with innumerous pathogen-related infections and ailments. Most of the commonly employed microbicidal agents target commensal and pathogenic microorganisms without discrimination. To distinguish and fight the pathogenic species out of the microflora, novel antimicrobials have been developed that selectively target specific bacteria and fungi. The cell wall features and antimicrobial mechanisms that these microorganisms involved in are highlighted in the present review. This is followed by reviewing the design of antimicrobials that selectively combat a specific community of microbes including Gram-positive and Gram-negative bacterial strains as well as fungi. Finally, recent advances in the antimicrobial immunomodulation strategy that enables treating microorganism infections with high specificity are reviewed. These basic tenets will enable the avid reader to design novel approaches and compounds for antibacterial and antifungal applications.

Abstract Solanum lyratum is one of the temperate plants, broadly distributed in Korea, China, Japan, India, and South-East Asia and well-documented in those oriental ethnic medicine systems for curing cancers, jaundice, edema, gonorrhea, cholecystitis, phlogosis, rheumatoid arthritis, etc. This review systematically summarized the research progress on S. lyratum respecting the botany, traditional uses, phytochemistry, pharmacology, and toxicology to increase people's in-depth understanding of this plant, by data retrieval in a series of online or off-line electronic databases as far as we can reach. Steroidal saponins and alkaloids, terpenoids, nitrogenous compounds, and flavonoid compounds are the main chemical constituents in S. lyratum. Among them, steroidal alkaloids and saponins are the major active ingredients ever found in S. lyratum, exerting activities of anti-cancer, anti-inflammation, anti-microbial, anti-allergy, and anti-oxidation in vivo or in vitro. As a result, S. lyratum has been frequently prescribed for the abovementioned therapeutic purposes, and there are substantial traditional and modern shreds of evidence of its use. Graphical Abstract

Due to the worldwide epidemic of allergic disease and a cure nowhere in sight, there is a crucial need to explore its pathophysiological mechanisms. As allergic disease has been associated with gut dysbiosis, we searched for a possible mechanism from the perspective of the molecular interface between host and microbiota with concurrent metabolomics and microbiome composition analysis. Sprague-Dawley rats were injected with Artemisia pollen extract to stimulate a hyper reaction to pollen. This hyper reaction decreased the circulation of valine, isoleucine, aspartate, glutamate, glutamine, indole-propionate (IPA), and myo-inositol, and reduced short-chain fatty acids (SCFAs) in feces. Several beneficial genera belonging to Ruminococcaceae, Lachnospiraceae, and Clostridiales declined in the model group, whereas Helicobacter and Akkermansia were only expressed in the model group. Furthermore, the expression of intestinal claudin-3 and liver fatty acid binding protein was downregulated in the model group and associated with metabolic changes and bacteria. Our results suggest that alterations in amino acids as well as their derivatives (especially valine, and IPA which is the reductive product of tryptophan), SCFAs, and the gut microbiome (specifically Akkermansia and Helicobacter) may disrupt the intestinal barrier function by inhibiting the expression of claudin proteins and affecting the mucus layer, which further results in hay fever.

Background The purpose of this study was to explore the feasibility, safety and efficacy of iodine-125 seed implantation in the treatment of dysphagia of advanced esophageal cancer. Methods We retrospectively analyzed patients with advanced esophageal cancer who underwent EUS-guided iodine-125 seed implantation or conventional chemoradiotherapy in our hospital. The propensity score match was used to reduce the baseline differences. Results A total of 127 patients were enrolled, 17 patients received EUS-guided iodine 125 seed implantation (Group A), 31 patients received radiotherapy (Group B), 38 patients received chemotherapy (Group C) and 41 patients received chemotherapy combined with radiotherapy (Group D). At half month postoperatively, the dysphagia remission rate in Group A (100%) was better than that in Groups B (39.3%), C (20%), D (15.8%), respectively, in the original cohort ( P < 0.01); At 1 month postoperatively, the dysphagia remission rate in Group A (86.7%) was better than that in Group B (57.1%) ( P > 0.05), Group C (25.7%) ( P < 0.05) and Group D (34.2%) ( P < 0.05), respectively, in the original cohort. There was no statistically significant difference in median overall survival (OS) between Group A (16 months) and Group B (37 months) ( P = 0.149), and between Group A (16months) and Group C (16 months) ( P = 0.918) in the original cohort. The mean OS of Group D (54 months) was better than that of Group A (20 months) in the original cohort ( P = 0.031). The incidences of grade ≥2 myelosuppression in Groups B, C, and D were 12.9%, 28.9%, and 43.9%, respectively; the incidence of grade ≥2 gastrointestinal adverse events in Groups B, C, and D were 12.9%, 15.8%, 12.2%, respectively. No serious adverse events were found in Group A. The radiation dose around the patient was reduced to a safe range after the distance from the implantation site was more than 1 m (4.2 ± 2.6 μSv/h) or with lead clothing (0.1 ± 0.07 μSv/h). Conclusions Compared with conventional radiotherapy or chemotherapy alone, iodine-125 seed implantation might improve dysphagia more quickly and safely, further clinical data is needed to verify whether it could effectively prolong the OS of patients.

ObjectivesTo propose a deep learning-based classification framework, which can carry out patient-level benign and malignant tumors classification according to the patient’s multi-plane images and clinical information.MethodsA total of 430 cases of spinal tumor, including axial and sagittal plane images by MRI, of which 297 cases for training (14072 images), and 133 cases for testing (6161 images) were included. Based on the bipartite graph and attention learning, this study proposed a multi-plane attention learning framework, BgNet, for benign and malignant tumor diagnosis. In a bipartite graph structure, the tumor area in each plane is used as the vertex of the graph, and the matching between different planes is used as the edge of the graph. The tumor areas from different plane images are spliced at the input layer. And based on the convolutional neural network ResNet and visual attention learning model Swin-Transformer, this study proposed a feature fusion model named ResNetST for combining both global and local information to extract the correlation features of multiple planes. The proposed BgNet consists of five modules including a multi-plane fusion module based on the bipartite graph, input layer fusion module, feature layer fusion module, decision layer fusion module, and output module. These modules are respectively used for multi-level fusion of patient multi-plane image data to realize the comprehensive diagnosis of benign and malignant tumors at the patient level.ResultsThe accuracy (ACC: 79.7%) of the proposed BgNet with multi-plane was higher than that with a single plane, and higher than or equal to the four doctors’ ACC (D1: 70.7%, p=0.219; D2: 54.1%, p

Circulating tumour cells can be useful for monitoring disease progression but how they survive in the circulatory system is unclear. Here, the authors use single-cell sequencing of circulating tumour cells from multiple vascular sites in liver cancer patients and identify genes that may help the cells survive.

Abstract Under adverse conditions, such as sustained or chronic hyperglycemia or hyperlipidemia, ROS (reactive oxygen species) or/and ER-stress (endoplasmic reticulum stress) will be induced in pancreatic β cells. ROS or ER-stress damages β-cells even leads to apoptosis. Previously we found ROS or ER-stress resulted in JNK activation in β cells and overexpressing NR4A1 in MIN6 cells reduced JNK activation via modulating cbl-b expression and subsequent degrading the upstream JNK kinase (MKK4). To search other possible mechanisms, we found the mRNA level and protein level of MKP7 (a phosphatase for phospho-JNK) were dramatic reduced in pancreatic β cells in the islets from NR4A1 KO mice compared with that from wild type mice. To confirm what we found in animals, we applied pancreatic β cells (MIN6 cells) and found that the expression of MKP7 was increased in NR4A1-overexpression MIN6 cells. We further found that knocking down the expression of MKP7 increased the p-JNK level in pancreatic β cells upon treatment with TG or H2O2. After that, we figured out that NR4A1 did enhance the transactivation of the MKP7 promoter by physical association with two putative binding sites. In sum, NR4A1 attenuates JNK phosphorylation incurred by ER-stress or ROS partially via enhancing MKP7 expression, potentially decreases pancreatic β cell apoptosis induced by ROS or ER-stress. Our finding provides a clue for diabetes prevention.

Molecular subtypes of breast cancer are important references to personalized clinical treatment. For cost and labor savings, only one of the patient’s paraffin blocks is usually selected for subsequent immunohistochemistry (IHC) to obtain molecular subtypes. Inevitable block sampling error is risky due to the tumor heterogeneity and could result in a delay in treatment. Molecular subtype prediction from conventional H&E pathological whole slide images (WSI) using the AI method is useful and critical to assist pathologists to pre-screen proper paraffin block for IHC. It is a challenging task since only WSI-level labels of molecular subtypes from IHC can be obtained without detailed local region information. Gigapixel WSIs are divided into a huge amount of patches to be computationally feasible for deep learning, while with coarse slide-level labels, patch-based methods may suffer from abundant noise patches, such as folds, overstained regions, or non-tumor tissues. A weakly supervised learning framework based on discriminative patch selection and multi-instance learning was proposed for breast cancer molecular subtype prediction from H&E WSIs. Firstly, co-teaching strategy using two networks was adopted to learn molecular subtype representations and filter out some noise patches. Then, a balanced sampling strategy was used to handle the imbalance in subtypes in the dataset. In addition, a noise patch filtering algorithm that used local outlier factor based on cluster centers was proposed to further select discriminative patches. Finally, a loss function integrating local patch with global slide constraint information was used to fine-tune MIL framework on obtained discriminative patches and further improve the prediction performance of molecular subtyping. The experimental results confirmed the effectiveness of the proposed AI method and our models outperformed even senior pathologists, which has the potential to assist pathologists to pre-screen paraffin blocks for IHC in clinic.

Abstract Background The number of patients receiving anaesthesia is increasing, but the impact of general anaesthesia on the patient's immune system remains unclear. The aim of the present study is to investigate dynamics of systemic immune cell responses to anaesthesia during perioperative period at a single‐cell solution. Methods The peripheral blood mononuclear cells (PBMCs) and clinical phenomes were harvested and recorded 1 day before anaesthesia and operation, just after anaesthesia (0 h), and 24 and 48 h after anaesthesia. Single‐cell sequencing of PBMCs was performed with 10× genomics. Subsequently, data analysis was performed with R packages: Seurat, clusterProfiler and CellPhoneDB. Results We found that the cluster of CD56+ NK cells changed at 0 h and the cluster of monocytes increased at 24 and 48 h after anaesthesia. The characteristic genes of CD56+ NK cells were mainly enriched in the Jak‐STAT signalling pathway and in cell adhesion molecules (24 h) and carbon metabolism (48 h). The communication between CD14+ monocytes and other cells decreased substantially 0 and 48 h after operation. The number of plasma cells enriched in protein export in men was substantially higher than that in women, although the total number in patients decreased 24 h after operation. CD14+ monocytes dominated that cell‐cell communications appeared in females, while CD8+ NKT cells dominated that cell‐cell communications appeared in male. The number of plasma cells increased substantially in patients with major surgical trauma, with enrichments of pentose phosphate pathway. The communications between plasma cells with other cells varied between surgical severities and anaesthetic forms. The intravenous anaesthesia caused major alterations of cell types, including CD14+ monocytes, plasmas cells and MAIT cells, as compared with inhalation anaesthesia. Conclusion We initially reported the roles of perioperative anaesthesia/surgery in temporal phenomes of circulating immune cells at a single‐cell solution. Thus, the protection against immune cell changes would benefit the recovery from anaesthesia/surgery.

High dietary intake of β-cryptoxanthin (BCX, an oxygenated provitamin A carotenoid) is associated with a lower risk of lung disease in smokers. BCX can be cleaved by β-carotene-15,15′-oxygenase (BCO1) and β-carotene-9′,10′-oxygenase (BCO2) to produce retinol and apo-10′-carotenoids. We investigated whether BCX has protective effects against cigarette smoke (CS)-induced lung injury, dependent or independent of BCO1/BCO2 and their metabolites. Both BCO1−/−/BCO2−/− double knockout mice (DKO) and wild type (WT) littermates were supplemented with BCX 14 days and then exposed to CS for an additional 14 days. CS exposure significantly induced macrophage and neutrophil infiltration in the lung tissues of mice, regardless of genotypes, compared to the non-exposed littermates. BCX treatment significantly inhibited CS-induced inflammatory cell infiltration, hyperplasia in the bronchial epithelium, and enlarged alveolar airspaces in both WT and DKO mice, regardless of sex. The protective effects of BCX were associated with lower expression of IL-6, TNF-α, and matrix metalloproteinases-2 and -9. BCX treatment led to a significant increase in hepatic BCX levels in DKO mice, but not in WT mice, which had significant increase in hepatic retinol concentration. No apo-10′-carotenoids were detected in any of the groups. In vitro BCX, at comparable doses of 3-OH-β-apo-10′-carotenal, was effective at inhibiting the lipopolysaccharide-induced inflammatory response in a human bronchial epithelial cell line. These data indicate that BCX can serve as an effective protective agent against CS-induced lung lesions in the absence of carotenoid cleavage enzymes.

Background: Healthy dietary patterns are related to better cognitive health in aging populations. While levels of individual nutrients in neural tissues are individually associated with cognitive function, the investigation of nutrient patterns in human brain tissue has not been conducted.Methods: Brain tissues were acquired from frontal and temporal cortices of 47 centenarians from the Georgia Centenarian Study. Fat-soluble nutrients (carotenoids, vitamins A, E, K, and fatty acids [FA]) were measured and averaged from the two brain regions. Nutrient patterns were constructed using principal component analysis. Cognitive composite scores were constructed from cognitive assessment from the time point closest to death. Dementia status was rated by Global Deterioration Scale (GDS). Pearson's correlation coefficients between NP scores and cognitive composite scores were calculated controlling for sex, education, hypertension, diabetes, and APOE ε4 allele.Result: Among non-demented subjects (GDS = 1–3, n = 23), a nutrient pattern higher in carotenoids was consistently associated with better performance on global cognition (r = 0.38, p = 0.070), memory (r = 0.38, p = 0.073), language (r = 0.42, p = 0.046), and lower depression (r = −0.40, p = 0.090). The findings were confirmed with univariate analysis.Conclusion: Both multivariate and univariate analyses demonstrate that brain nutrient pattern explained mainly by carotenoid concentrations is correlated with cognitive function among subjects who had no dementia. Investigation of their synergistic roles on the prevention of age-related cognitive impairment remains to be performed.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and chronic, excessive alcohol consumption is responsible for 32%–45% of all the liver cancer cases in the United States. Avoidance of chronic or excessive alcohol intake is the best protection against alcohol-related liver injury; however, the social presence and addictive power of alcohol are strong. Induction of the cytochrome P450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. The review will overview the prevention of ALD and HCC through dietary tomato rich in lycopene as an effective intervention strategy and the crucial role of CYP2E1 induction as a molecular target. The review also indicates a need for caution among individuals consuming both alcohol and high dose lycopene as a dietary supplement. Keywords: Tomato, Lycopene, Alcoholic liver disease, Liver cancer, CYP2E1

Objective: Allergic airway diseases (AADs) are a group of heterogeneous disease mediated by T-helper type 2 (Th2) immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. Data Sources: Articles referred in this review were collected from the database of PubMed published in English up to January 2018. Study Selection: We had done a literature search using the following terms “allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte”. Related original or review articles were included and carefully analyzed. Results: It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP), are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. Conclusions: In view of the redundancy of cytokines and “united airway” theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2LKO) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2LKO hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy.

Network traffic prediction was an important problem of network management and network congestion control.In order to solve this problem,a network traffic prediction method based on chaos theory and improved echo state net-work was proposed.Firstly,network traffic sample with differe time scale were analyzed by 0-1 test algorithm for chaos and maximum Lyapunov exponent,the calculation results show that the network traff has chaotic characteristics in different time scale.The phase space reconstruction technique was introduced for the prediction of network traffic,the delay time was determined through the C-C method,the embedding dimension was determined through the G-P algo-rithm.Network traffic time series was processed with phase space reconstruction,the multi-step prediction of network traffic was achieved by an improved echo state network.In order to improve the prediction precision,the key dynamic reservoir and prediction parameters of echo state network were optimized by an improved harmony search algorithm.Through the simulation on public and actual network traffic data,the results verify the proposed prediction method has higher prediction accuracy and smaller prediction error.

Background: Group 2 innate lymphoid cells (ILC2s) are regarded as a novel population of lineage-negative cells that induce innate Type 2 responses by producing the critical Th2-type cytokines interleukin (IL)-5 and IL-13. ILC2s as key players in the development of allergic rhinitis (AR) have been proved, however, the effect of subcutaneous immunotherapy (SCIT) with dermatophagoides pteronyssinus extract (Der p-SCIT) on ILC2s in AR patients is not clear. This study aimed to investigate the response of ILC2s of peripheral blood in house dust mites (HDM)-sensitized Chinese patients with AR who received SCIT with Der P extract. Methods: Seven healthy controls without symptoms of AR who had negative reactions to any of the allergens from skin-prick testing, nine patients diagnosed with persistent AR according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, and 24 AR patients who received Der p-SCIT for 1.0–3.5 years were recruited for the study. ILC2s in the peripheral blood were evaluated using flow cytometry. The severity of their symptoms of all participants was rated based on the Total 5 symptom score. Results: Among 40 participants, 9 AR patients were assigned to the untreated group, 24 AR patients receiving Der p-SCIT were assigned to the immunotherapy group, and 7 healthy controls without symptoms of AR were assigned to healthy control group. The mean Total 5 symptom score of immunotherapy group was significantly lower than that of untreated group (4.3 ± 1.4 vs. 10.1 ± 2.5, P< 0.001). Similarly, the levels of ILC2s in the peripheral blood of immunotherapy group were significantly reduced compared with that in untreated group (P < 0.001), but were not significantly different from healthy controls (P = 0.775). Further subgroup analysis based on the duration of SCIT therapy (1.0–2.0 years [SCIT1-2], 2.0–3.0 years [SCIT2-3], and 3.0–3.5 years [SCIT3-3.5]) showed that the percentage of ILC2s was not significantly different between SCIT1-2, SCIT2-3, and SCIT3-3.5groups (SCIT1-2 vs. SCIT2-3: P = 0.268; SCIT1-2vs. SCIT3-3.5: P = 0.635; and SCIT2-3 vs. SCIT3-3.5: P = 0.787). Conclusions: The present study highlighted the suppression of Der p-SCIT on ILC2s in HDM-AR patients. ILC2s identified in peripheral blood can be used as an effective biomarker for Der p-SCIT.

The identification difficulties for a dual-rate Hammerstein system lie in two aspects. First, the identification model of the system contains the products of the parameters of the nonlinear block and the linear block, and a standard least squares method cannot be directly applied to the model; second, the traditional single-rate discrete-time Hammerstein model cannot be used as the identification model for the dual-rate sampled system. In order to solve these problems, by combining the polynomial transformation technique with the key variable separation technique, this paper converts the Hammerstein system into a dual-rate linear regression model about all parameters (linear-in-parameter model) and proposes a recursive least squares algorithm to estimate the parameters of the dual-rate system. The simulation results verify the effectiveness of the proposed algorithm.

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide. Dietary intervention on adverse cardiac remodeling after MI has significant clinical relevance. Rosemary leaves are a natural product with antioxidant/anti-inflammatory properties, but its effect on morphology and ventricular function after MI is unknown.To determine the effect of the dietary supplementation of rosemary leaves on cardiac remodeling after MI, male Wistar rats were divided into 6 groups after sham procedure or experimental induced MI: 1) Sham group fed standard chow (SR0, n = 23); 2) Sham group fed standard chow supplemented with 0.02% rosemary (R002) (SR002, n = 23); 3) Sham group fed standard chow supplemented with 0.2% rosemary (R02) (SR02, n = 22); 4) group submitted to MI and fed standard chow (IR0, n = 13); 5) group submitted to MI and fed standard chow supplemented with R002 (IR002, n = 8); and 6) group submitted to MI and fed standard chow supplemented with R02 (IR02, n = 9). After 3 months of the treatment, systolic pressure evaluation, echocardiography and euthanasia were performed. Left ventricular samples were evaluated for: fibrosis, cytokine levels, apoptosis, energy metabolism enzymes, and oxidative stress. Rosemary dietary supplementation attenuated cardiac remodeling by improving energy metabolism and decreasing oxidative stress. Rosemary supplementation of 0.02% improved diastolic function and reduced hypertrophy after MI. Regarding rosemary dose, 0.02% and 0.2% for rats are equivalent to 11 mg and 110 mg for humans, respectively.Our findings support further investigations of the rosemary use as adjuvant therapy in adverse cardiac remodeling.