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We study the focusing nonlinear Schrödinger equation with inverse-square potential i ∂ t u + Δ u − a | x | 2 u + | u | p − 1 u = 0 with a > − 1 4 and 3 4 < p − 1 < 4 in three dimensions. In this paper we obtain blow-up and global existence criteria for the solution to ( N L S a ) by the method from Duyckaerts-Roudenko [1], which extend a recent work of Killip-Murphy-Visan-Zheng [2] to above the threshold. [ABSTRACT FROM AUTHOR]

We study the focusing inhomogeneous nonlinear Schrödinger equation with inverse‐square potential i∂tu+Δu−a|x|2u+|x|−b|u|2u=0,$$ i{\partial}_tu&amp;#x0002B;\Delta u-\frac{a}{{\left&amp;#x0007C;x\right&amp;#x0007C;}&amp;#x0005E;2}u&amp;#x0002B;{\left&amp;#x0007C;x\right&amp;#x0007C;}&amp;#x0005E;{-b}{\left&amp;#x0007C;u\right&amp;#x0007C;}&amp;#x0005E;2u&amp;#x0003D;0, $$where a>−14$$ a&gt;-\frac{1}{4} $$ and 0

Introduction: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Methods: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Results: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019.Conclusion: Transbronchial lung cryobiopsy (TBLC) is increasingly used to diagnose interstitial lung disease (ILD). The 1.1-mm cryoprobe has recently been available in clinical practice. The diagnostic yield and safety of TBLC using a 1.1-mm cryoprobe need to be confirmed.A prospective, randomized controlled trial was conducted in patients with suspected ILD and randomly assigned to 1.1-mm and 1.9-mm cryoprobe groups. The primary outcome was the diagnostic yield of multidisciplinary discussion. Secondary outcomes were sample quality and incidence of complications. The tension and stress effects during TBLC onto the target lobe caused by 1.1-mm and 1.9-mm cryoprobes were also evaluated using finite element analysis.A total of 224 patients were enrolled. No significant differences were observed in the diagnostic yield (80.4% vs. 79.5%, p = 0.845) and sample quality scores (5.73 ± 0.64 vs. 5.66 ± 0.77; p = 0.324) between the 1.9-mm cryoprobe group and 1.1-mm cryoprobe group. The average surface areas of samples in 1.1-mm cryoprobe group were smaller, while no difference in sample weights was observed. A decreased incidence of moderate bleeding was found in the 1.1-mm cryoprobe group (17.0% vs. 6.2%, p = 0.027), while there was no difference in the incidence of the pneumothorax, there was a trend to higher rate of pneumothorax in 1.1-mm group. In finite element analysis, the 1.1-mm cryoprobe required the largest tension and produced the largest stress.Compared with a 1.9-mm cryoprobe, there was no difference in specimen quality or diagnostic rate but smaller sample size with a 1.1-mm cryoprobe. There was a decreased risk of moderate bleeding, but a trend towards increased risk for pneumothorax with 1.1-mm cryoprobe.Trail Registration: Clinicaltrials.gov identifier NCT04047667; registered August 4, 2019. [ABSTRACT FROM AUTHOR]

Background: Ephrin receptors (Eph) and their ligands, called ephrins, function in various disease processes. However, the expression level and prognostic value of Eph/ephrins in lung adenocarcinoma (LUAD) are still unclear. Methods: The Oncomine and GEPIA databases were used to explore the differential expression of Eph/ephrins in LUAD. Kaplan–Meier plotter was selected to explore the prognostic value of Eph/ephrins. The cBioPortal database was used to analyze the genetic variation of the EFNA3 gene. Immunohistochemistry was used to analyze the expression level and clinical value of ephrin-A3 protein in clinical LUAD tissue. Weighted coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) identified the potential regulatory mechanism of EFNA3. CCK-8 assays and colony-forming experiments were used to investigate whether EFNA3 can regulate cell proliferation ability in LUAD. Analysis of lactate, ATP, and glucose uptake levels was used to explore the effect of EFNA3 on glycolysis ability. In addition, we investigated the relationship between EFNA3 and tumor infiltrating immune cells (TIICs). Finally, the potential immunotherapy response prediction value of EFNA3 was also explored. Results: In this study, we found that EFNA3 expression was significantly correlated with both overall survival (OS) and progression-free survival (PFS) in LUAD patients based on a comprehensive analysis of the Eph/Ephrin family. Next, the expression of the EFNA3 protein was increased in LUAD tissues and was designated an independent prognostic risk factor. Mechanistically, EFNA3 may be involved in nuclear division, synaptic function, and ion channel activity-related pathways. In vitro experiments confirmed the role of EFNA3 in promoting LUAD cells and showed that it could regulate glycolytic capacity. Moreover, EFNA3 was negatively associated with immunity, stromal infiltration, and several TIICs. Finally, EFNA3 was found to be positively related to multiple immunotherapy biomarkers. Conclusions: In conclusion, increased EFNA3 in LUAD patients predicted worse clinical prognosis, promoted LUAD cell proliferation and glycolysis ability, and was related to immunotherapy response. [ABSTRACT FROM AUTHOR]

In this study, an eye-tracking experiment was conducted on an actual website to explore information acquisition, emotion experience and behaviour intention on two information displays (attribute-oriented versus product-oriented) in two contexts of online shopping task (browsing versus searching). Results show that the chosen computer product received more eye fixations than other non-chosen products for both displays. Participants who had more cross-product-attribute eye movements accomplished tasks quicker. For the browsing task, participants had more cross-product-attribute eye movements and accomplished the task faster on the attribute -oriented display than the product-oriented display, whereas no significant difference was observed in the searching task. For emotion experience, participants had more positive emotions in completing the browsing task than the searching task on the attribute-oriented display, whereas no significant difference was observed on the product-oriented display. Approach tendency to a website is positively correlated with positive emotion, and negatively correlated with avoidance tendency. Based on the results, the design of an attribute-oriented information display is recommended if consumers perform mostly experiential behaviour on a website, such as browsing. [ABSTRACT FROM AUTHOR]

Little is known about the association between sarcopenia and multimorbidity among middle-aged and older adults. This study investigated whether sarcopenia is associated with multimorbidity in middle-aged and older Chinese individuals. A total of 12,760 participants from China Health and Retirement Longitudinal Study (CHARLS) 2015, with data on 14 specified chronic diseases and sarcopenia status were included in the cross-sectional analysis. A total of 7345 participants without multimorbidity from the CHARLS 2015 were included and followed up in 2018 in the longitudinal analysis. Logistic regression models were used in a cross-sectional investigation to assess the association between sarcopenia status and multimorbidity. In a longitudinal analysis, the relationships between sarcopenia status and multimorbidity were investigated using Cox proportional hazards models. Multimorbidity was prevalent in the no sarcopenia, possible sarcopenia, and sarcopenia groups at 38.8 % (3765/9713), 56.6 % (1199/2118), and 48.5 % (451/929), respectively. Multivariable regression revealed that both possible sarcopenia (β = 0.088, P <0.001) and sarcopenia (β = 0.028, P = 0.009), contributed to the number of chronic diseases. Logistic regression revealed that possible sarcopenia (OR: 1.56, 95 % CI: 1.39–1.76) was associated with multimorbidity. In the longitudinal analysis, participants in the possible sarcopenia group (HR: 1.19, 95 % CI:1.03–1.38) were more prone to experience new onset multimorbidity than did participants in the no sarcopenia group. Possible sarcopenia is associated with the development of multimorbidity in middle-aged and older Chinese populations. Health screening of populations with possible sarcopenia can facilitate early detection of multimorbidity. • Possible sarcopenia and sarcopenia contributed to the number of chronic diseases. • Possible sarcopenia is associated with multimorbidity in middle-aged and older Chinese populations. • Health screening of populations with possible sarcopenia can facilitate early detection of multimorbidity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Occludin/ELL domain containing 1 (OCEL1) is a novel discovered protein with its molecular functions remaining unknown and its role in lung cancer has not been directly explored. OBJECTIVES: This study focused on the role of OCEL1 in the progression and prognosis of non-small cell lung cancer (NSCLC). METHODS: A public database and tissue samples (80 NSCLC tissue samples and paired normal lung samples) were used to compare differences in OCEL1 expression and investigate its relationship with clinical characteristics and prognosis. RESULTS: Compared to adjacent normal lung tissue samples, OCEL1 expression was significantly down-regulated in tumor tissues. In addition, there was a negative correlation between OCEL1 and Ki67 expression levels. Low OCEL1 expression was significantly associated with lymph node metastasis, higher TNM stage, and poor prognosis. Importantly, multivariate analysis identified OCEL1 expression as an independent predictor for unfavorable NSCLC prognosis. CONCLUSIONS: These results indicated that OCEL1 protein may serve as a novel prognostic biomarker in NSCLC. [ABSTRACT FROM AUTHOR]

The recognition of learners' speech intention in the online collaborative learning scene is of great significance for exploring the rules of knowledge construction such as knowledge development and emotional communication in the collaborative process. The essence of speech intention recognition is text classification. At present, text classification is mostly based on deep learning model. However, online collaborative discussion has the characteristics of strong contextual semantic relationship and key characteristic words. When only the deep learning method is used for text classification, there may be insufficient acquisition of contextual semantic relations and neglect of key feature words, resulting in a decline in the accuracy of classification results. Therefore, this paper proposes a multi-feature fusion model, which uses BERT to represent the text as a word vector, BiLSTM to extract the context features of the text, CNN to extract the local features of the text, and average pooling model to extract the average representation features of the text. The results show that the overall classification accuracy of the multi-feature fusion model is 84.30%. [ABSTRACT FROM AUTHOR]

Oxidative stress and chronic inflammation play key roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and anti-inflammatory effects This study aimed to explore the protective role and underlying mechanism of AXT in the pathogenesis of COPD. In this study, we found AXT alleviated pulmonary emphysema in a CS-exposed mouse model and regulated the expression of MMP-9/TIMP-1. And, AXT attenuates CSE-induced small airway fibrosis. Meanwhile, AXT inhibited Nrf2-modulated oxidative stress and the p65 NF-κB-regulated inflammatory pathway in both the mouse model and CSE-treated HBE cells. Mechanistically, AXT could directly bind to SIRT1 (the binding energy of the complex was −8.8 kcal/mol) and regulate the deacetylation activity of SIRT1. Finally, by activating SIRT1 deacetylation, AXT deacetylated Nrf2 and contributed to its action of reducing oxidative stress by generating antioxidant enzymes, and inhibiting p65 NF-κB transcriptional activity to suppress the inflammatory response. Our results show that treatment with AXT significantly reverses the oxidative stress and inflammation induced by cigarette smoke both in vivo and in vitro in a sirtuin 1-dependent manner. [Display omitted] • Astaxanthin alleviated cigarette smoke extract-induced pulmonary emphysema and small airway fibrosis. • Astaxanthin inhibited Nrf2-modulated oxidative stress and the NF-κB-regulated inflammatory pathway. • Astaxanthin directly binds and activates SIRT1. • AXT upregulates the deacetylation levels of Nrf2 and NF-κB p65 exert antioxidant and anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

In this work, effects of running-in process on achieving super-low friction between silicon nitride ball and sapphire disc under lubrication of mixtures of sulfuric acid and glycerin, was investigated. The results revealed that sulfuric acid plays the key role in the running-in process. Owing to this acid, a smooth worn region was generated on the silicon nitride ball through chemical-mechanical abrasion, which provided favorable conditions for super-low friction under elastohydrodynamic lubrication. Meantime, a silica layer formed on part of the worn region through tribochemical reaction during running-in process, contributing to the realization of super-low friction under boundary and mixed lubrication. Moreover, the adsorption of hydrogen ions on friction surfaces generated a repulsive double-layer force that also contributed to super-low friction. [ABSTRACT FROM AUTHOR]

The limited N2 solubility in the present aqueous electrolyte critically restricts the selectivity and activity of environment-friendly electrochemical NH3 production at high current density. Here we developed a high-performance electrolyzer for the electrochemical N2 reduction reaction (eNRR) using amorphous RuAu clusters anchored on CeO1.88 nanorods with rich oxygen vacancies (OVs) as the catalyst and a proton exchange membrane (PEM) as the solid-state electrolyte, in which N2 is directly delivered to the electrode across a gas diffusion layer. The PEM electrolyzer achieved a remarkable NH3 yield rate of 185.53 μg mg−1 h−1 at −0.3 V vs. RHE under an applied N2 pressure of 4 bar, which is 5 times higher than that in aqueous electrolyte. [ABSTRACT FROM AUTHOR]

Background: Recent studies have emphasized the importance of the biological processes of different forms of cell death in tumor heterogeneity and anti-tumor immunity. Nonetheless, the relationship between cuproptosis and lung adenocarcinoma (LUAD) remains largely unexplored. Methods: Data for 793 LUAD samples and 59 normal lung tissues obtained from TCGA-LUAD cohort GEO datasets were used in this study. A total of 165 LUAD tissue samples and paired normal lung tissue samples obtained from our hospital were used to verify the prognostic value of dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide branched chain transacylase E2 (DBT) for LUAD. The cuproptosis-related molecular patterns of LUAD were identified using consensus molecular clustering. Recursive feature elimination with random forest and a tenfold cross-validation method was applied to construct the cuproptosis score (CPS) for LUAD. Results: Bioinformatic and immunohistochemistry (IHC) analyses revealed that 13 core genes of cuproptosis were all significantly elevated in LUAD tissues, among which DBT and DLAT were associated with poor prognosis (DLAT, HR = 6.103; DBT, HR = 4.985). Based on the expression pattern of the 13 genes, two distinct cuproptosis-related patterns have been observed in LUAD: cluster 2 which has a relatively higher level of cuproptosis was characterized by immunological ignorance; conversely, cluster 1 which has a relatively lower level of cuproptosis is characterized by TILs infiltration and anti-tumor response. Finally, a scoring scheme termed the CPS was established to quantify the cuproptosis-related pattern and predict the prognosis and the response to immune checkpoint blockers of each individual patient with LUAD. Conclusion: Cuproptosis was found to influence tumor microenvironment (TME) characteristics and heterogeneity in LUAD. Patients with a lower CPS had a relatively better prognosis, more abundant immune infiltration in the TME, and an enhanced response to immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

G-protein-signaling modulator 2 (GPSM2) belongs to a protein family that regulates activation of G proteins and plays an important role in mitotic spindle orientation. However, the role of GPSM2 in lung adenocarcinoma (LUAD) is still unclear. In this study, it was found that GPSM2 correlates with clinicopathological features and patient's prognosis in LUAD. Knocking down GPSM2 promoted LUAD cell proliferation in vitro and in vivo. Mechanistically, it was demonstrated that GPSM2 knockdown accelerates cell proliferation via the EGFR pathway. These results confirmed that GPSM2 played an important role in LUAD. Moreover, GPSM2, as an independent prognostic factor, may serve as a potential drug target and prognostic biomarker in LUAD. [ABSTRACT FROM AUTHOR]

The newly invented triboelectric nanogenerator (TENG) is deemed to be a more efficient strategy than an electromagnetic generator (EMG) in harvesting low‐frequency (<2 Hz) water wave energy. Various TENGs with different structures and functions for blue energy have been developed, which can be roughly divided into two types: liquid–solid contact electrification TENGs and fully enclosed solid–solid contact electrification TENGs. Robustness and packaging are critical factors in the development of TENGs toward practical applications. Furthermore, for fully enclosed TENGs, the requirements and costs of packaging are very high, and they can difficult to disassemble after enclosed, if there is something wrong with the devices. Herein, a nonencapsulative pendulum‐like paper based hybrid nanogenerator for energy harvesting is designed, which mainly consists of three parts, one solar panel, two paper based zigzag multilayered TENGs, and three EMG units. This unique structure reveals the superior robustness and a maximum peak power of zigzag multilayered TENGs up to 22.5 mW is realized. Moreover, the device can be used to collect the mechanical energy of human motion in hand shaking. This work presents a new platform of hybrid generators toward energy harvesting as a portable practical power source, which has potential applications in navigation and lighting. [ABSTRACT FROM AUTHOR]

Background: Astaxanthin (AXT) is a keto-carotenoid with a variety of biological functions, including antioxidant and antifibrotic effects. Small airway remodeling is the main pathology of chronic obstructive pulmonary disease (COPD) and is caused by epithelial-to-mesenchymal transition (EMT) and fibroblast differentiation and proliferation. Effective therapies are still lacking. This study aimed to investigate the role of AXT in small airway remodeling in COPD and its underlying mechanisms. Methods: First, the model of COPD mice was established by cigarette smoke (CS) exposure combined with intraperitoneal injection of cigarette smoke extract (CSE). The effects of AXT on the morphology of CS combined with CSE -induced emphysema, EMT, and small airway remodeling by using Hematoxylin-eosin (H&E) staining, immunohistochemical staining, and western blot. In addition, in vitro experiments, the effects of AXT on CSE induced-EMT and fibroblast function were further explored. Next, to explore the specific mechanisms underlying the protective effects of AXT in COPD, potential targets of AXT in COPD were analyzed using network pharmacology. Finally, the possible mechanism was verified through molecular docking and in vitro experiments. Results: AXT alleviated pulmonary emphysema, EMT, and small airway remodeling in a CS combined with CSE -induced mouse model. In addition, AXT inhibited the EMT process in airway cells and the differentiation and proliferation of fibroblasts. Mechanistically, AXT inhibited myofibroblast activation by directly binding to and suppressing the phosphorylation of AKT1. Therefore, our results show that AXT protects against small airway remodeling by inhibiting AKT1. Conclusions: The present study identified and illustrated a new food function of AXT, indicating that AXT could be used in the therapy of COPD-induced small airway remodeling. [ABSTRACT FROM AUTHOR]

Ultra-high strength steel has a wide application of gear transmission systems in the aerospace field, owing to its high hardness, good impact toughness, fracture toughness, etc. Grinding is the important method to guarantee the final quality of ultra-high strength gears. However, the service life of grinding wheels is seriously shortened due on the numerous reinforced particles inside the hardened layer on gear surface, deteriorating the ground quality eventually. In order to resolve this issue, ultrasonic vibration-assisted grinding (UVAG) technology is applied, and then comparative trials are conducted between UVAG and conventional grinding (CG) during ultra-high strength steel machining. Here, the grinding performance, such as the variation of grinding force and temperature under two grinding modes, and the variation of tool wear morphology with the increase of grinding step are analyzed. Subsequently, the grinding surface quality of UVAG process is discussed in view of ground surface roughness and surface morphology. Results show that the CG possesses a rapid increase in grinding forces and temperature, and eventually, surface quality deteriorates gradually, whereas they have been improved in UVAG. In the range of experimental parameters, the force Fn and temperature of grinding maximum decreased by 35.5 and 39.2%, respectively, compared with CG. Moreover, due to the self-sharpening of abrasive grains, the UVAG process produces a finer ground surface quality. The research provides technical support for high quality and efficient machining of ultra-high strength aviation transmission gear. [ABSTRACT FROM AUTHOR]

Peritoneal dissemination threatens the survival of patients with gastric cancer (GC). Bufalin is an extract of traditional Chinese medicine, which has been proved to have anticancer effect. The target of bufalin in suppressing gastric cancer peritoneal dissemination (GCPD) and the underlying mechanism are still unclear. In this research, GC cell line MGC‐803 and high‐potential peritoneal dissemination cell line MKN‐45P were treated with bufalin or L‐NAME. Malignant biological behavior and protein level of GC cell lines were detected with MTT, wound healing, transwell, adhesion, and western blotting. Bioinformatics analysis and patient tissues were used to verify the role of endothelial nitric oxide synthase (NOS3) in GC. Mice model was used to assess the effect of bufalin and role of NOS3 in vivo. We found that bufalin inhibited the proliferation, invasion, and migration in GC cell lines. NOS3, which was an independent prognostic factor of GC patients, was predicted to be a potential target of bufalin. Further experiments proved that bufalin reduced the phosphorylation of NOS3, thereby inhibiting the mitogen‐activated protein kinase (MAPK) signaling pathway, and ultimately suppressed GCPD by inhibiting EMT process. In conclusion, NOS3 was a potential therapeutic target and prognostic biomarker of GC. Bufalin could suppress GCPD through NOS3‐MAPK signaling pathway, which provided more evidence support for intraperitoneal perfusion of bufalin to treat GCPD. [ABSTRACT FROM AUTHOR]

Sanguinarine (SAG) is the most abundant constituent of Macleaya cordata (Willd.) R. Br. (Popaceae). SAG has shown antimammary and colorectal metastatic effects in mice in vivo, suggesting its potential for cancer chemotherapy. To determine the antimetastatic effect and underlying molecular mechanisms of SAG on melanoma. CCK8 assay was used to determine the inhibition of SAG on the proliferation of A375 and A2058 cells. Network pharmacology analysis was applied to construct a compound-target network and select potential therapeutic targets of SAG against melanoma. Molecular docking simulation was conducted for further analysis of the selected targets. In vitro migration/invasion/western blot assay with 1, 1.5, 2 μM SAG and in vivo effect of 2, 4, 8 mg/kg SAG in xenotransplantation model in nude mice. The key targets of SAG treatment for melanoma were mainly enriched in PI3K-AKT pathway, and the binding energy of SAG to PI3K, AKT, and mTOR were −6.33, −6.31, and −6.07 kcal/mol, respectively. SAG treatment inhibited the proliferation, migration, and invasion ability of A375 and A2058 cells (p < 0.05) with IC50 values of 2.378 μM and 2.719 μM, respectively. It also decreased the phosphorylation levels of FAK, PI3K, AKT, mTOR and protein expression levels of MMP2 and ICAM-2. In the nude mouse xenograft model, 2, 4, 8 mg/kg SAG was shown to be effective in inhibiting tumour growth. Our research offered a theoretical foundation for the clinical antitumor properties of SAG, further suggesting its potential application in the clinic. [ABSTRACT FROM AUTHOR]

Super high-strength steel has an important demand in manufacturing key components inside gear transmission systems of heavy-duty helicopter owing to its superior comprehensive mechanical property. However, the high-performance machining of super high-strength steel is confronted with great challenges owing to the high cutting force, serious tool wear, and impoverished machining quality. Comparative trials in grinding ultra-high strength steel under conventional grinding (CG) and ultrasonic vibration-assisted grinding (UVAG) processes were conducted with white alumina (WA) and microcrystalline alumina (MA) wheels. Grinding performances, including grinding forces, force ratio, ground surface quality, and abrasive wheel morphologies, were discussed in detail. Experimental results show that the separation property between wheels and workpiece in UVAG process contributes to alter the material removal process, reducing the chip clogging and adhesion. In addition, the micro-fracture of abrasive grains can effectively improve the self-sharpening ability of abrasive wheels. UVAG possesses a shorter grinding scratch owing to the ultrasonic vibration than that of CG, which is beneficial to improve machining quality under the same wheel. Meanwhile, in comparison of WA wheels, MA wheels have the narrower grinding marks and better surface quality, which is due to the sharp edges produced by its higher strength, toughness, and excellent self-sharpening. [ABSTRACT FROM AUTHOR]

Ultrasonic vibration-assisted grinding (UVAG) is a highly effective technique for improving the grindability of difficult-to-cut materials, making it widely applicable in various industrial fields. However, the conventional optimization of grinding parameters necessitates extensive experimental analyses and is susceptible to converging towards a local optimum. A multiobjective particle swarm optimization (MOPSO) model is developed in this study to predict grinding forces and surface roughness based on comparative experiments between UVAG and conventional grinding. Optimized process parameters are utilized to perform experiments on ultrasonic vibration-assisted profile grinding, resulting in a reduction of 20.51% and 18.91% in tangential and normal grinding forces, respectively, as well as a decrease of 9.47% in ground surface roughness. In addition, UVAG can maintain the sharpness of grinding wheels. The MOPSO algorithm yields a Pareto solution set comprising 15 noninferior solutions, indicating that superior surface roughness is achieved by increasing wheel speed and cutting depth while decreasing feed speed. The ultrasonic vibration-assisted profile grinding process enables the formation of workpieces with exceptional shape accuracy and high surface quality, while also optimizing machining parameters. [ABSTRACT FROM AUTHOR]

The most promising energy storage devices are lithium-sulfur batteries (LSBs), which offer a high theoretical energy density that is five times greater than that of lithium-ion batteries. However, there are still significant barriers to the commercialization of LSBs, and mesoporous carbon-based materials (MCBMs) have attracted much attention in solving LSBs' problems, due to their large specific surface area (SSA), high electrical conductivity, and other unique advantages. The synthesis of MCBMs and their applications in the anodes, cathodes, separators, and "two-in-one" hosts of LSBs are reviewed in this study. Most interestingly, we establish a systematic correlation between the structural characteristics of MCBMs and their electrochemical properties, offering recommendations for improving performance by altering the characteristics. Finally, the challenges and opportunities of LSBs under current policies are also clarified. This review provides ideas for the design of cathodes, anodes, and separators for LSBs, which could have a positive impact on the performance enhancement and commercialization of LSBs. The commercialization of high energy density secondary batteries is of great importance for the achievement of carbon neutrality and to meet the world's expanding energy demand. [ABSTRACT FROM AUTHOR]

Ultrasonic vibration-assisted grinding has been employed in machining difficult-to-cut materials (e.g. titanium alloys, superalloys, composites, hardened steels, etc.) aiming at improving wear-resistance abilities of abrasive wheels. In this paper, comparative experiments between the conventional grinding (CG) and ultrasonic vibration-assisted grinding (UVAG) were performed on AISI 9310 steel to study grain wear mechanisms. Results shows that UVAG achieves a significant reduction in grinding forces, force ratio and machined quality as material removal volumes raise. Moreover, the wear flat of grains and a sharp change in grinding forces occur. Then, the surface quality gradually deteriorates from the more severe chip clogging of wheels and increasing grinding forces during the CG process. Meanwhile, the steady wear stage of UVAG is longer by 23.07%, and the ground surface roughness in UVAG remain lower and more stably fluctuating than those in CG. Furthermore, UVAG possesses a small fluctuating height of worn grains according to the analysis of the protrusion height distribution at various wear stages, owing to the consistent micro-fractures of the grains under uniform alternating loads. In contrast, pull-out defects can be observed under high grinding forces on the tool–workpiece intersection during the CG process, affecting the ground surface quality. [ABSTRACT FROM AUTHOR]

High dropout rates have always been a problem for massive open online courses (MOOCs) to address. Dropout prediction has been used as an important method to address this situation. Learners' online learning behaviour is a good indicator of MOOC learning status. However, traditional prediction models treat each learning behaviour as an independent variable and ignore the correlation between learning behaviours. To address this issue, we propose a fusion deep dropout prediction model. The convolutional neural network (CNN) is used to obtain local feature representations based on learners' behaviour data, and the self-attention mechanism is used to learn correlations between different feature representations. At the same time, a bidirectional long short-term memory network (Bi-LSTM) is used to obtain a time-series feature vector representation and input the vector representation into the sigmoid function for prediction. We use the fusion deep model to predict behaviour data of 55,045 learners on the KDD Cup 2015 dataset. The experimental results show that the accuracy of the fusion deep model is 3% higher than that of the traditional method, which effectively improves the accuracy of dropout prediction. [ABSTRACT FROM AUTHOR]

To analyse speech intention based on discussion texts in online collaborative discussions, automatic classification of discussion texts is conducted to assist teachers improve their abilities to diagnose and analyse the discussion process. The current study proposes a deep learning network model that incorporates multi-head attention mechanism with bidirectional long short-term memory (MA-BiLSTM). The proposed algorithm acquires contextual semantic connections from a global perspective and the role of key feature words within sentences from a local perspective to further strengthen the semantic features of the texts. The proposed model was employed to classify 12,000 interactive texts generated during online collaborative discussion activities. Results show that MA-BiLSTM achieved an overall classification accuracy of 83.25%, which is at least 2.83% higher than those of other baseline models. However, the classification of consultative and administrative interactive texts is minimally effective. MA-BiLSTM achieved better than the existing classification methods for interactive text classification. [ABSTRACT FROM AUTHOR]

The combination of ultrasonic vibration-assisted grinding (UVAG), the ultrasonic vibrating method, and the conventional grinding (CG) process is proposed to improve the grindability of hardened steel in the CG process. Comparative investigations on grinding force, temperature, and specific grinding energy for both grinding processes were conducted. In addition, the morphologies of the wheel wear and ground surfaces were also studied. Findings show that compared with the CG processes, the normal and tangential grinding forces in UVAG are reduced greatly by 16.44% and 17.44%, respectively. The UVAG process decreases the specific grinding energy by 8.30% owing to the increase of the maximum undeformed chip thickness and the grinding temperature by 19.01% due to the improvement of the coolant heat transfer capacity in the grinding arc zone. Meanwhile, the promising grain sharpness of wheels can be guaranteed from the enhanced cooling function on the grinding arc zone and the grain's micro-fracture caused by ultrasonic impacting actions. [ABSTRACT FROM AUTHOR]

Aims: To investigate the differences in disrupted rhythms between healthy people and patients with functional gastrointestinal disorders (FGIDs) and their associations with mood disorders during the coronavirus disease 2019 (COVID-19) pandemic. Methods: The rhythm scales were composed of subscales 1 and 2 for the assessment of life-work and entertainment rhythms, respectively; Zung's Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were used to assess mood disorders. Results: A total of 671 patients with FGIDs and 4373 healthy people successfully participated. The scores of subscales 1 and 2 for patients with FGIDs were significantly higher than those for healthy people (p <.005). The SAS and SDS scores, their prevalence rates were significantly higher than those for the healthy group (all p <.001). Health status, current occupation, life-work rhythm, SDS, and SAS were independent related factors of FGIDs. The score of life-work-entertainment rhythm was significantly positively correlated with SDS and SAS (both p <.001). Conclusion: Disrupted rhythms in patients with FGIDs under the COVID-19 pandemic were more frequently and significantly positively associated with mood disorders. [ABSTRACT FROM AUTHOR]

Background. Inflammation plays an important role in the development of tumors. Several serum based-markers and ratios have been investigated for their prognostic value in pancreatic cancer. However, the prognostic value of the neutrophil-to-monocyte ratio (NMR) and platelet-to-white blood cell ratio (PWR) for patients with pancreatic cancer has scarcely been investigated. Methods. From October 2013 to November 2018, a retrospective cohort study was performed on 269 pancreatic cancer patients without treatment. Receiver operating characteristic curves were generated, and areas under the curve were compared for the evaluation of the discriminatory ability of inflammation-based prognostic scoring systems. Kaplan-Meier curves and the Cox proportional hazard model were employed to analyze the relationships among NMR, PWR, and overall survival (OS). Results. The optimal cutoff values of NMR and PWR were 48 and 6, respectively. In univariate analysis, the survival time of NMR > 48 and PWR ≤ 6 was shorter than that of NMR ≤ 48 and PWR > 6 in patients with pancreatic cancer (P < 0.001). In Cox univariate and multivariate analyses, NMR (hazard ratio (HR), 9.095; 95% confidence interval (CI), 3.64–22.72; P < 0.001) and PWR (HR, 8.230; 95% CI, 3.32–20.43; P < 0.001) were significantly correlated with OS. Conclusions. The current study demonstrated that NMR and PWR may serve as novel and promising inflammatory prognostic scores for patients with pancreatic cancer. Elevated NMR (>48) and depressed PWR (<6) were independently associated with poor prognosis in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background & aim: The coronavirus disease 2019 (COVID-19) pandemic has affected the life and work of people worldwide. The present study aimed to evaluate the rhythm disruptions of life, work, and entertainment, and their associations with the psychological impacts during the initial phase of the COVID-19 pandemic. Method: A cross-sectional study was conducted from the 10th to 17th March 2020 in China. A structured e-questionnaire containing general information, the Chinese version of Brief Social Rhythm Scale, and Zung's self-rating scales of depression and anxiety (SDS and SAS) was posted and collected online through a public media (i.e. EQxiu online questionnaire platform). Scores in sleeping, getting up, and socializing (SGS) rhythm and eating, physical practice, and entertainment (EPE) rhythm were compared among and between participants with different sociodemographic backgrounds including gender, age, education, current occupation, annual income, health status, and chronic disease status. Correlations of SDS and SAS with SGS-scale and EPE-scale were also analyzed. Results: Overall, 5854 participants were included. There were significant differences in the scores of SGS-scale and EPE-scale among people with different sociodemographic backgrounds. The scores were significantly higher in the groups with female gender, low education level, lower or higher than average income, poor health status, ages of 26–30 years or older than 61 years, nurses and subjects with divorce or widow status. There were also significant differences in SAS and SDS scores among people with different sociodemographic backgrounds (all P< 0.05). The overall prevalence of depression and anxiety was 24.3% and 12.6%, respectively, with nurses having the highest rates of depression (32.94%) and anxiety (18.98%) among the different occupational groups. SGS-scale was moderately correlated with SDS and SAS, and disruption of SGS rhythm was an independent risk factor for depression and anxiety. Conclusion: Social rhythm disruption was independently associated with depression and anxiety. Interventions should be applied to people vulnerable to the rhythm disruption during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL. [ABSTRACT FROM AUTHOR]

This study aimed to develop a novel and practical fluorescent method for GSH detection in complex biological samples. To this end, a series of coumarin-based fluorescent probes was designed and synthesized using various aliphatic halogens as the sensing group. By using a new evaluation method of GSH/Cys/Hcy coexisting conditions, the probe with chloropropionate (CBF3) showed a high selectivity, excellent sensitivity, good stability for GSH detection. The reaction mechanism is proposed as nucleophilic substitution/cyclization and intramolecular charge transfer (ICT), which was confirmed by LC-MS and NMR analysis, as well as density functional theory calculations. In addition, CBF3 was demonstrated to be competent not only for the quantitative detection of GSH in real serum samples, but also for sensing GSH changes in different oxidative stress models in living cells and nematodes. This study showed a practical strategy for constructing GSH-specific fluorescent probes, and provided a sensitive tool for real-time sensing of GSH in real biological samples. The findings would greatly facilitate further investigations on GSH-associated clinical diagnosis and biomedical studies. Image 1 • A novel SN 2 -triggered and ICT-based fluorescent probe was developed for sensing GSH. • The reaction mechanism was confirmed by experimental and theoretical investigations. • The probe selectively responded to GSH in the GSH/Cys/Hcy coexisting conditions. • The probe exhibited a low detection limit of 9.2 nM. • The probe could monitor GSH in real serum sample, and in living cells and nematodes. [ABSTRACT FROM AUTHOR]

In this study, an imidazole-coumarin based fluorescent probe was developed for the selective and sensitive detection of Ag+ in aqueous solution. Using a combination of Job plot, NMR titrations, and DFT calculations, the binding properties between Ag+ and the probe were deeply investigated, and the results revealed a 1:1 binding stoichiometry between the probe and Ag+ with a binding constant of 1.02 × 106 M−1. The detection limit was found to be 150 nM, which satisfies the requirement for the quantitative detection of Ag+ in real water samples. Moreover, the new probe, Ic, was successfully applied to sense Ag+ in HeLa and HepG2 cells as well as in C. elegans, indicating that it could be a useful tool for the environmental monitoring of Ag+ pollution. These results demonstrated that Ic could serve as a high-efficiency and low-cost fluorescent probe for tracking Ag+ in an aquatic environment and biological organisms. [ABSTRACT FROM AUTHOR]

The electrochemical nitrogen reduction reaction (NRR) is a promising but extremely challenging approach for ammonia synthesis under ambient conditions. Herein, we report the excellent NRR performance of gold nanoparticles (AuNPs) with multiple high-index facets, prepared by a modified seed-mediated method. At −0.3 V vs. RHE and in 0.1 M Li2SO4 aqueous solution, the AuNPs afford the highest faradaic efficiency (FE) of 73.32% reported so far, with a remarkable ammonia generation rate of 9.22 μg h−1 cm−2. Density functional theory (DFT) calculations reveal that the high-index faceted surfaces of the AuNPs have greater preference for the adsorption of NRR intermediates (*NNH) and significantly hinder the adsorption of competing hydrogen evolution intermediates (*H). [ABSTRACT FROM AUTHOR]

[Display omitted] • The SAR profiles of 1,4-naphthoquinones for activating XO were first investigated. • Introduction of electron-donor/acceptor units in the A/B ring improved the effect. • The effect was well predicted using the HOMO-LUMO gap and the binding free energy. • The risk of 1,4-naphthoquinones was evaluated with kinetic data and in vivo exposure. Oral intake of 1,4-naphthoquinones could be a potential risk factor for hyperuricemia and gout via activation of xanthine oxidase (XO). Herein, 1,4-naphthoquinones derived from food and food-borne pollutants were selected to investigate the structure and activity relationship (SAR) and the relative mechanism for activating XO in liver S9 fractions from humans (HLS9) and rats (RLS9). The SAR analysis showed that introduction of electron-donating substituents on the benzene ring or electron-withdrawing substituents on the quinone ring improved the XO-activating effect of 1,4-naphthoquinones. Different activation potential and kinetics behaviors were observed for activating XO by 1,4-naphthoquinones in HLS9/RLS9. Molecular docking simulation and density functional theory calculations showed a good correlation between -LogEC 50 and docking free energy or HOMO-LUMO energy gap. The risk of exposure to the 1,4-naphthoquinones was evaluated and discussed. Our findings are helpful to guide diet management in clinic and avoid adverse events attributable to exposure to food-derived 1,4-naphthoquinones. [ABSTRACT FROM AUTHOR]

Atomically dispersed Zn–N–C nanomaterials are promising platinum‐free catalysts for the oxygen reduction reaction (ORR). However, the fabrication of Zn–N–C catalysts with a high Zn loading remains a formidable challenge owing to the high volatility of the Zn precursor during high‐temperature annealing. Herein, we report that an atomically dispersed Zn–N–C catalyst with an ultrahigh Zn loading of 9.33 wt % could be successfully prepared by simply adopting a very low annealing rate of 1° min−1. The Zn–N–C catalyst exhibited comparable ORR activity to that of Fe–N–C catalysts, and significantly better ORR stability than Fe–N–C catalysts in both acidic and alkaline media. Further experiments and DFT calculations demonstrated that the Zn–N–C catalyst was less susceptible to protonation than the corresponding Fe–N–C catalyst in an acidic medium. DFT calculations revealed that the Zn–N4 structure is more electrochemically stable than the Fe–N4 structure during the ORR process. [ABSTRACT FROM AUTHOR]

Atomically dispersed Zn–N–C nanomaterials are promising platinum‐free catalysts for the oxygen reduction reaction (ORR). However, the fabrication of Zn–N–C catalysts with a high Zn loading remains a formidable challenge owing to the high volatility of the Zn precursor during high‐temperature annealing. Herein, we report that an atomically dispersed Zn–N–C catalyst with an ultrahigh Zn loading of 9.33 wt % could be successfully prepared by simply adopting a very low annealing rate of 1° min−1. The Zn–N–C catalyst exhibited comparable ORR activity to that of Fe–N–C catalysts, and significantly better ORR stability than Fe–N–C catalysts in both acidic and alkaline media. Further experiments and DFT calculations demonstrated that the Zn–N–C catalyst was less susceptible to protonation than the corresponding Fe–N–C catalyst in an acidic medium. DFT calculations revealed that the Zn–N4 structure is more electrochemically stable than the Fe–N4 structure during the ORR process. [ABSTRACT FROM AUTHOR]

Here, we develop inert V2O3 oxide to enhance the HER activity of industrial Ni catalysts with the assistance of abundant metal/oxide interfaces. The as-synthesized Ni/V2O3 catalyst exhibits over 5 times the activity of a pure Ni sample due to the particle size control and metal/oxide interaction, and excellent durability as a result of oxide anchoring. [ABSTRACT FROM AUTHOR]

Acute pancreatitis is a human disease with multiple causes that leads to autodigestion of the pancreas. There is sufficient evidence to support the key role of sustained increase in cytosolic calcium concentrations in the early pathogenesis of the disease. To clarify the mechanism of maintaining calcium homeostasis in the cell and pathological processes caused by calcium overload would help to research directly targeted therapeutic agents. We will specifically review the following: intracellular calcium homeostasis and regulation, the occurrence of calcium overload in acinar cells, the role of calcium overload in the pathogenesis of AP, the treatment strategy proposed for calcium overload. [ABSTRACT FROM AUTHOR]

Graphical abstract BRIEFS. "Monometallic NiO-Ni 3 S 2 /NF heteronanosheets" were rationally designed as highly-active bifunctional electrocatalysts for overall water splitting. The electron transfer between tightly combined metallic Ni 3 S 2 and NiO domains creates a highly active interface zone, emerging as electrocatalysts that are superior to their single-component counterparts and most of the state-of-the-art catalysts for HER or OER so far. Highlights • Monometallic NiO-Ni 3 S 2 heteronanosheets array is in situ constructed on Ni foam. • The NiO-Ni 3 S 2 /NF can act as bifunctional electrocatalysts for water splitting. • The NiO-Ni 3 S 2 /NF show a cell voltage of 1.57 V at 10 mA cm−2 for water splitting. • The role of NiO-Ni 3 S 2 interfaces for the excellent activity has been established. Abstract Developing cost-effective and stable bifunctional catalysts for overall water splitting is of enormous importance for the realization of sustainable clean-energy technologies. Herein, a monometallic NiO-Ni 3 S 2 heteronanosheets supported on Ni foam are rationally constructed as bifunctional electrocatalysts for overall water splitting. On account of the unique electronic property of the abundant interface and its 3D interconnected integration structure, NiO-Ni 3 S 2 heteronanosheets exhibit high electrocatalytic activity toward both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Utilizing NiO-Ni 3 S 2 /NF as both the anode and the cathode for overall water splitting, a current density of 10 mA cm−2 is achieved at a cell voltage of as low as 1.57 V with excellent stability, exceeding that of the integrated performance of Pt/C and RuO 2. DFT calculations further reveal that key role of the established interfaces between Ni 3 S 2 and NiO in modulating the chemisorption of hydrogen and oxygen-containing intermediates, and consequently improving the overall electrochemical water-splitting activity. [ABSTRACT FROM AUTHOR]

The differences in catalytic mechanism and domain between the soluble (S-COMT) and membrane-bound catechol- O -methyltransferase (MB-COMT) are poorly documented due to the unavailable crystal structure of MB-COMT. Considering the enzymatic nature of S-COMT and MB-COMT, the challenge could be solvable by probing the interactions between the enzymes with the ligands with minor differences in structures. Herein, isomeric shikonin and alkannin bearing a R/S -OH group in side chain at the C2 position were used for domain profiling of COMTs. Human and rat liver-derived COMTs showed the differences in inhibitory response (human's IC 50 and K i values for S-COMT < rat's, 5.80–19.56 vs. 19.56–37.47 μM; human's IC 50 and K i values for MB-COMT > rat's) and mechanism (uncompetition vs. noncompetition) towards the two isomers. The inhibition of the two isomers against human and rat S-COMTs was stronger than those for MB-COMTs (S-COMT's IC 50 and K i values < MB-COMT's, 5.80–37.47 vs. 40.01–111.8 μM). Additionally, the inhibition response of alkannin was higher than those of shikonin in no matter human and rat COMTs. Molecular docking stimulation was used for analysis. The inhibitory effects observed in in vitro and in silico tests were confirmed in vivo. These findings would facilitate further COMT-associated basic and applied research. [Display omitted] • The catalytic mechanism and domain of S-COMT and MB-COMT were probed using isomeric shikonin and alkannin. • S-COMT is more subject to inhibition by shikonin and alkannin compared with MB-COMT. • Alkannin has a higher inhibitory potency towards COMTs than that of shikonin. • The tendency mentioned above was investigated using inhibition kinetics and molecular docking, and further validated in vivo. • Species difference in inhibiting human and rat COMTs by shikonin and alkannin was studied and discussed mechanistically. [ABSTRACT FROM AUTHOR]

Esophageal cancer is a malignant digestive tract cancer with high mortality. Although studies have found that esophageal cancer is involved in a complex and important gene regulation network, the pathogenesis remains unclear. The recently described long non-coding RNAs (lncRNAs) are one effective part of the gene regulation network. However, in past decades, lncRNAs were thought to be "transcript noise" or "pseudogenes" and were thus ignored. Early studies indicated that lncRNAs play pivotal roles during evolution. However, in recent years, increasing research has revealed that many lncRNAs are associated with tumorigenesis. In particular, lncRNAs may act as important elements for epigenetic regulation, transcription, post-transcriptional regulation and post-translational modification of proteins. Additionally, they may be novel biomarkers for tumors and therapeutic targets in cancer. Here, we summarize the functions of lncRNAs in esophageal cancer, with an emphasis on lncRNA-mediated regulatory mechanisms that affect the biological characteristics of esophageal cancer. [ABSTRACT FROM AUTHOR]

Recent studies have emphasized the close relationship between macrophages and tumor immunity, and the prognosis of lung adenocarcinoma (LUAD) patients is intimately linked to this. Nonetheless, the prognostic signature and classification of different immune patterns in LUAD patients based on the macrophages is largely unexplored. Two sc-RNAseq datasets of LUAD patients were collected and reprocessed. The differentially expressed genes (DEGs) related to macrophages between LUAD tissues and normal lung tissues were then identified. Based upon the above genes, three distinct immune patterns in the TCGA-LUAD cohort were identified. The ssGSEA and CIBERSORT were applied for immune profiling and characterization of different subtypes. A four-gene prognostic signature for LUAD patients was established based on the DEGs between the subtypes using stepwise multi-Cox regression. TCGA-LUAD cohort was used as training set. Five GEO-LUAD datasets and an independent cohort containing 112 LUAD samples were used for validation. TIDE (tumor immune dysfunction and exclusion) and drug sensitivity analyses were also performed. Macrophage-related differentially expressed genes were found out using the publicly available scRNA-seq data of LUAD. Three different immune patterns which were proved to have distinct immune infiltration characteristics in the TCGA-LUAD cohort were recognized based on the above macrophage-related genes. Thereafter, 174 DEGs among the above three different immune patterns were figured out; on the basis of this, a four-gene prognostic signature was constructed. This signature distinguished the prognosis of LUAD patients well in various GSE datasets as well as our independent cohort. Further analyses revealed that patients which had a higher risk score also accompanied with a lower immune infiltration level and a worse response to several immunotherapy biomarkers. This study highlighted that macrophage were significantly associated with TME diversity and complexity. The four-gene prognostic signature could be used for predicting outcomes and immune landscapes for patients with LUAD. [Display omitted] • Depicting the LUAD landscape and acquiring macrophage-related differentially expressed genes from scRNAseq data of LUAD. • Identifying and depicting 3 distinct LUAD subtypes with distinct immune landscapes which were termed as "immune-infiltrated phenotype", "immune-excluded phenotype" and "immune-desert phenotype". • Establishment of a four-gene prognostic model for LUAD patients and validation of the signature using publicly attainable LUAD cohorts and an independent cohort containing 112 LUAD samples. [ABSTRACT FROM AUTHOR]

Biothiols, including homocysteine (Hcy), cysteine (Cys) and reduced glutathione (GSH), play various roles in physiological and pathological processes. Because these biothiols possess similar in structures, it is difficult to discriminate Hcy, Cys and GSH from one another. In this work, a novel fluorescent probe, 4-BrCP , based on coumarin as a fluorophore to discriminate GSH from Hcy and Cys was rationally designed and synthesized in three steps with good total yield. The benzothiazol ring played the role of a fluorescent emission wavelength adjuster, while the ester part served as a fluorescent quencher and reactive sites with Hcy, Cys and GSH. The results of responsive experiment indicated that the probe could discriminate GSH from Hcy and Cys distinctly and exhibited a relatively high fluorescence quantum yield (0.84) and low detection limit (9.8 nM). In addition, the probe 4-BrCP also showed good stability and low toxicity. The reaction mechanism of 4-BrCP with GSH was speculated on according to the LC-MS data. Most importantly, because of the length of the skeletons of Hcy, Cys and GSH, different dynamic fluorescent phenomena were observed. Furthermore, imaging experiments suggested that the probe could be used to monitor GSH in living cells and organisms. [Display omitted] • A novel fluorescent probe based on coumarin was rationally designed and synthesized. • The probe could selectively discriminate GSH from Hcy, Cys, or Hcy/Cys/GSH coexisting condition. • The probe showed a good quantum yield (0.84) and low detection limit (9.8 nM). • The probe could trace endogenous GSH in living cells and organisms. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were first-line treatments for NSCLC patients with EGFR-mutations. However, about 30 % of responders relapsed within six months because of acquired resistance. In this study, we used Connectivity Map (CMap) to discover a drug capable of reversing acquired EGFR-TKIs resistance. To investigate Lymecycline's ability to reverse acquired EGFR-TKIs resistance, two Icotinib resistant cell lines were constructed. Lymecycline's ability to suppress the proliferation of Icotinib resistant cells in vitro and in vivo was then evaluated. Molecular targets were predicted using network pharmacology and used to identify the molecular mechanism. Growth factor receptor-bound protein 2 (GRB2) is an EGFR-binding adaptor protein essential for EGFR phosphorylation and regulation of AKT/ERK/STAT3 signaling pathways. Lymecycline targeted GRB2 and inhibited the resistance of the cell cycle to EGFR-TKI, arresting disease progression and inducing apoptosis in cancer cells. Combined Lymecycline and Icotinib treatment produced a synergistic effect and induced apoptosis in HCC827R5 and PC9R10 cells. Cell proliferation in resistant cancer cells was significantly inhibited by the combined Lymecycline and Icotinib treatment in mouse models. Lymecycline inhibited the resistance of the cell cycle to EGFR-TKI and induced apoptosis in NSCLC by inhibiting EGFR phosphorylation and GRB2-mediated AKT/ERK/STAT3 signaling pathways. This provided strong support that Lymecycline when combined with EGFR targeting drugs, enhanced the efficacy of treatments for drug-resistant NSCLC. [ABSTRACT FROM AUTHOR]

A novel two-photon pH probe, 3-benzimidazole-7-hydroxycoumarin (BHC), was designed and synthesized based on the structures of hydroxycoumarin and benzimidazole. BHC showed good linearity in the pH ranges of 3.30–5.40 (pKa = 4.20) and 6.50–8.30 (pKa = 7.20) at a maximum emission wavelength of 480 nm. BHC in acidic and alkaline media could be distinguished by an obvious spectral shift of the maximum absorption wavelength from 390 nm to 420 nm. In addition, BHC was well localized to mitochondria and successfully applied to one-photon and two-photon imaging of pH changes in the mitochondria of HeLa cells. The findings presented herein suggest that BHC can serve as an excellent fluorescent probe for selectively sensing mitochondrial pH changes with remarkable photostability and low cytotoxicity. Unlabelled Image • A new fluorescent probe for one- and two-photon sensing of pH was developed. • The probe responded sensitively and selectively to pH changes within 3.0–6.0 (pKa = 4.20) and 6.0–9.0 (pKa = 7.20). • The probe was successfully applied for monitoring and imaging of mitochondrial pH in living cells. [ABSTRACT FROM AUTHOR]

Compared with coumarin, 7-hydroxycoumarin could serve as a better hit for developing CYP2A6 inhibitors. In this study, a series of 7-hydroxycoumarin and its structural analogues were collected to study their structure-activity relationship (SAR) and isoform selectivity for inhibiting CYP2A6. All tested coumarins except a C4 phenyl derivative (11) showed higher inhibitory activities for CYP2A6 over the other CYP isoforms, including CYP1A2, CYP2D6, CYP2E1, CYP3A4, CYP2C8, and CYP2C9. Of these coumarins, 6,7-dihydroxycoumarin (1) and 7,8-dihydroxycoumarin (9) were found to be potent inhibitors of CYP2A6 with IC 50 / K i value of 0.39/0.25 and 4.61/3.02 μM, respectively, compared to methoxalen as positive control (IC 50 / K i = 0.43/0.26 μM). In contrast, other coumarins showed low or decreased CYP2A6-inhibiting activities. SAR analysis showed that hydroxy groups might be important for CYP2A6 inhibition, and the rank order of sites for hydroxy substitution was C6 > C7 > C8. In addition, either hydrophobic or hydrophilic substituents introduced into C4, C6 and C8 led to a reduction in CYP2A6-inhibiting activity, and the degree of influence was dependent on the size and electrical charge of substituents. Furthermore, inhibition kinetic analysis and docking simulations demonstrated that the 8- O -glucosylated coumarin derivative (17) exhibited noncompetitive inhibition against CYP2A6, while competitive inhibition patterns were noted for the other tested coumarins. The mechanisms underlying the inhibitors binding to CYP2A6 were further investigated by molecular docking study. The findings presented herein are very helpful for developing highly selective and more potent CYP2A6 inhibitors. Unlabelled Image [ABSTRACT FROM AUTHOR]