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Abstract Background Cucumis melon is a medicinal plant with multiple pharmacological properties such as anti-inflammatory, antioxidant, and diuretic effects. An increasing body of scientific evidence established the anti-diabetic/anti-obesity effects of Cucumis melo in humans, mice, and hamster models. However, there are no tangible reports on its ability to prevent cardiovascular complications following diet-induced obesity. The anti-atherogenic and cardioprotective effects of the Methanolic extract of Cucumis melo. L. Inodorus seeds on a high-fat diet (HFD)-induced obese rats was assessed in this study. Methods Forty male Wistar rats were randomly divided into five groups, (n = 8/group); i.e., Normal (N), HFD, HFD + 50 mg/kg b.w. of MCMs (Methanolic extract of Cucumis melon seeds), HFD + 100 mg/Kg b.w. of MCMs and HFD + 200 mg/kg b.w. of MCMs. The experimental animals were anaesthetized and sacrificed after 10 weeks, and blood samples and heart tissue were collected for further analysis. Using the Graph Pad Prism version 5.0, the results expressed as Mean ± SD was tested using the one-way ANOVA to show intergroup differences, followed by Bonferonni ‘s post hoc test. The level of significance was determined at P ≤ 0.05. Results MCMs significantly (P

Dual-phase magnesium-lithium alloys sheets were rolled at four different rolling methods: asynchronous rolling, multi-directional asynchronous rolling, high temperature asynchronous rolling and high temperature multi-directional asynchronous rolling. The microstructure, mechanical properties and texture characteristics were comprehensively analyzed through optical microscope, MTS E43 universal testing machine and X-ray diffraction, respectively. The effects of temperature and rolling direction on microstructure and mechanical properties of magnesium-lithium alloy were discussed. The results show that α-Mg phase is largely elongated along the rolling direction and becomes thinner along the normal direction. The lowest thickness of the α-Mg phase is 2.6 μm rolled by high temperature multi-directional asynchronous rolling. Multi-directional asynchronous rolling samples have the best mechanical properties as its yield strength, ultimate tensile strength, elongation are 149 MPa and 167 MPa, 14.5%, respectively.The double peaks texture is tilt along the normal direction with an angle of 45° by multi-directional rolling, while the RD tilt angle of double peaks texture decreases due to the high temperature rolling. The intensity of R-cube texture is the strongest after rolling. β-Li rolling texture is transformed into {001}〈100〉 texture by high temperature multi-directional asynchronous rolling, which is beneficial to the multi-slip of {011}〈111〉 slip system.

Cryptocurrency is a digital asset designed by cryptography, such as Secure Hash Algorithm 2 (SHA-2) and Message Digest 5 (MD5). Cryptocurrency uses Blockchain technology to ensure security, transparency, ease of locating, and unchangeability. This makes cryptocurrency very popular in many sectors, especially in the financial industry. Although, the uncertainty and the dynamic change of cryptocurrency price make the risk for investment in this digital asset high. This is the reason why studies about cryptocurrency price prediction became popular globally. This study intended to predict cryptocurrency prices using hybrid GRU LSTM than setting up the epoch to get the most accurate prediction model. The researcher would make a web-based application that can be used by the public, especially those involved in cryptocurrency investment. The result was a web-based application that could predict the price of cryptocurrency for the next few days, which had been validated using data from the previous 7 days, 14 days, 30 days, 60 days, and 90 days.

This paper introduces the principle of RF MEMS switch and performs modeling analysis. By analyzing the low control voltage and microwave power of the switch, phenomena such as long response time and susceptibility to mechanical failure appear. Therefore, this paper analyzes the current research on RF MEMS switches, improves the internal structure of the switch by adding support columns, fixes the double ends of the beam, and increases the spring coefficient K to slow down the falling speed of the internal cantilever of the switch. The impact force between the cantilever and the dielectric layer is reduced, which greatly reduces the loss of the switch and the problems of mechanical fatigue failure, thus improving the service life of the switch. The simulation shows that the stability of the model is relatively high when the length of the cantilever is 300 um. After adding a 0.7 um support column at a distance of 25 um from the dielectric layer, the turn-on voltage is increased from 42.5 V to 61 V, and the switching capacitance remains unchanged. Finally, by calculating the percentage error between the simulation value and the model theory of 1.6%, the validity and accuracy of the model are checked.

This study is a systematic review of 20 years of research on the usage of virtual reality (VR) in K-12 and higher education settings, which aims to consolidate, evaluate, and communicate evidence that can inform both the theory and practice of VR-based instruction. A total of 149 articles were selected from three major academic databases using search strings and manual screening protocols. The literature analysis emphasized four interrelated aspects of VR-based instruction: instructional context, instructional design, technological affordances, and research findings. The results revealed evolving trends in the VR literature in terms of publication patterns, pedagogical assumptions, equipment usage, and research methodologies, as well as the contextual factors behind VR adoption in education. Additionally, a meta-analysis was conducted to examine the efficacy of VR-based instruction, with results indicating an overall medium effect and several moderating factors. Finally, practical implications and a future research agenda for VR-based instruction are discussed.

Abstract Road damage detection is an important task to ensure road safety and realize the timely repair of road damage. The previous manual detection methods are low in efficiency and high in cost. To solve this problem, an improved YOLOv5 road damage detection algorithm, MN-YOLOv5, was proposed. We optimized the YOLOv5s model and chose a new backbone feature extraction network MobileNetV3 to replace the basic network of YOLOv5, which greatly reduced the number of parameters and GFLOPs of the model, and reduced the size of the model. At the same time, the coordinate attention lightweight attention module is introduced to help the network locate the target more accurately and improve the target detection accuracy. The KMeans clustering algorithm is used to filter the prior frame to make it more suitable for the dataset and to improve the detection accuracy. To improve the generalization ability of the model, a label smoothing algorithm is introduced. In addition, the structure reparameterization method is used to accelerate model reasoning. The experimental results show that the improved YOLOv5 model proposed in this paper can effectively identify pavement cracks. Compared with the original model, the mAP increased by 2.5%, the F1 score increased by 2.6%, and the model volume was smaller than that of YOLOv5. 1.62 times, the parameter was reduced by 1.66 times, and the GFLOPs were reduced by 1.69 times. This method can provide a reference for the automatic detection method of pavement cracks.

The spatial distribution of interrill and rill erosion is essential for unravelling soil erosion principles and the application of soil and water conservation practices. To quantify interrill and rill erosion and their spatial development, four 30-min rainfalls at 90 mm h−1 intensity were consecutively simulated on runoff plots packed with a loess at six slopes of 10°, 15°, 20°, 25°, 30° and 35°. The soil surface was measured using the structure from motion (SfM) photogrammetry upon each simulation run, and the runoff and sediment samples were collected and measured at every 10 min. Rills did not develop until the third simulation run. During the initial two runs, the lower third section was more severely eroded than the upper and middle thirds along the slope direction, yet the interrill erosion was statistically uniform from left to right. Rills tended to emerge by both sidewalls and in the lower portion in the third run. The corresponding rill erosion increased with slope from 10° to 20° and then decreased for the slopes steeper, which was consistent with the slope trend of the sediment yield directly measured. The rills expanded substantially primarily via head retreat and to a lesser extent via sideward erosion after receiving another 30-min rainfall. Rill erosion contributed 69.3% of the total erosion loss, and shifted the critical slope corresponding to the maximum loss from 20° to 25°. These findings demonstrate the significance of rill erosion not only in total soil loss but also in its relation to slope, as well as the effectiveness of SfM photogrammetry in quantifying interrill and rill erosion.

BackgroundThe activation patterns and functional network characteristics between stroke survivors and healthy individuals based on resting-or task-state neuroimaging and neurophysiological techniques have been extensively explored. However, the discrepancy between stroke patients at different recovery stages remains unclear.ObjectiveTo investigate the changes in brain connectivity and network topology between subacute and chronic patients, and hope to provide a basis for rehabilitation strategies at different stages after stroke.MethodsFifteen stroke survivors were assigned to the subacute group (SG, N = 9) and chronic group (CG, N = 6). They were asked to perform hand grasping under active, passive, and MI conditions when recording EEG. The Fugl-Meyer Assessment Upper Extremity subscale (FMA_UE), modified Ashworth Scale (MAS), Manual Muscle Test (MMT), grip and pinch strength, modified Barthel Index (MBI), and Berg Balance Scale (BBS) were measured.ResultsFunctional connectivity analyses showed significant interactions on frontal, parietal and occipital lobes connections in each frequency band, particularly in the delta band. The coupling strength of premotor cortex, M1, S1 and several connections linked to frontal, parietal, and occipital lobes in subacute subjects were lower than in chronic subjects in low alpha, high alpha, low beta, and high beta bands. Nodal clustering coefficient (CC) analyses revealed that the CC in chronic subjects was higher than in subacute subjects in the ipsilesional S1 and occipital area, contralesional dorsolateral prefrontal cortex and parietal area. Characteristic path length (CPL) analyses showed that CPL in subacute subjects was lower than in chronic subjects in low beta, high beta, and gamma bands. There were no significant differences between subacute and chronic subjects for small-world property.ConclusionSubacute stroke survivors were characterized by higher transfer efficiency of the entire brain network and weak local nodal effects. Transfer efficiency was reduced, the local nodal role was strengthened, and more neural resources needed to be mobilized to perform motor tasks for chronic survivors. Overall, these results may help to understand the remodeling pattern of the brain network for different post-stroke stages on task conditions and the mechanism of spontaneous recovery.

PurposeIridocorneal endothelial (ICE) syndrome is a progressive anterior segment disorder that can be tricky to treat. Keratoplasty is commonly used to treat corneal edema in ICE syndrome. However, glaucoma is an important risk factor affecting graft survival. To address this question, we designed a retrospective cohort study to evaluate the effect of Spokewise Iridotomy (SI) on Descemet Stripping Automated Endothelial Keratoplasty (DSAEK) Grafts in Iridocorneal Endothelial (ICE) Syndrome.MethodsThis was a retrospective cohort study. A total of 29 patients were included; 31 eyes with ICE syndrome underwent DSAEK at Peking University Third Hospital between June 2015 and June 2022, including 11 eyes with combined SI during DSAEK. The aim was to explore the effect of SI on vision, glaucoma control, complications, peripheral anterior synechiae recurrence, endothelial cell count, and graft survival.ResultsThe median follow-up time was 30.83 months (mo.) in the SI+Endothelial Keratoplasty (EK) group and 6.17 mo in the EK group. The 2-year cumulative survival rate of grafts in the SI+EK group was 100%, compared with the 6-month and 1-year cumulative survival rates of 80.2 and 63.2%, respectively, in the EK group (p = 0.043). The SI+EK group had a lower incidence of immediate postoperative complications (p = 0.005), fewer postoperative anti-glaucoma medications (AGMs) (p = 0.029), smaller peripheral anterior synechiae recurrence (p = 0.001), and significant visual acuity improvement (p < 0.05). More AGMs were used in failed grafts (p = 0.002).ConclusionSI can help control intraocular pressure, improve visual acuity, and increase graft survival after DSAEK in ICE syndrome patients.

Abstract The rapid degradation of magnesium (Mg) alloy implants erodes mechanical performance and interfacial bioactivity, thereby limiting their clinical utility. Surface modification is among the solutions to improve corrosion resistance and bioefficacy of Mg alloys. Novel composite coatings that incorporate nanostructures create new opportunities for their expanded use. Particle size dominance and impermeability may increase corrosion resistance and thereby prolong implant service time. Nanoparticles with specific biological effects may be released into the peri‐implant microenvironment during the degradation of coatings to promote healing. Composite nanocoatings provide nanoscale surfaces to promote cell adhesion and proliferation. Nanoparticles may activate cellular signaling pathways, while those with porous or core–shell structures may carry antibacterial or immunomodulatory drugs. Composite nanocoatings may promote vascular reendothelialization and osteogenesis, attenuate inflammation, and inhibit bacterial growth, thus increasing their applicability in complex clinical microenvironments such as those of atherosclerosis and open fractures. This review combines the physicochemical properties and biological efficiency of Mg‐based alloy biomedical implants to summarize the advantages of composite nanocoatings, analyzes their mechanisms of action, and proposes design and construction strategies, with the purpose of providing a reference for promoting the clinical application of Mg alloy implants and to further the design of nanocoatings.

Background and purposeWith the acceleration of the aging process of society, stroke has become a major health problem in the middle-aged and elderly population. A number of new stroke risk factors have been recently found. It is necessary to develop a predictive risk stratification tool using multidimensional risk factors to identify people at high risk for stroke.MethodsThe study included 5,844 people (age ≥ 45 years) who participated in the China Health and Retirement Longitudinal Study in 2011 and its follow-up up to 2018. The population samples were divided into training set and validation set according to 1:1. A LASSO Cox screening was performed to identify the predictors of new-onset stroke. A nomogram was developed, and the population was stratified according to the score calculated through the X-tile program. Internal and external verifications of the nomogram were performed by ROC and calibration curves, and the Kaplan-Meier method was applied to identify the performance of the risk stratification system.ResultsThe LASSO Cox regression screened out 13 candidate predictors from 50 risk factors. Finally, nine predictors, including low physical performance and the triglyceride-glucose index, were included in the nomogram. The nomogram's overall performance was good in both internal and external validations (AUCs at 3-, 5-, and 7-year periods were 0.71, 0.71, and 0.71 in the training set and 0.67, 0.65, and 0.66 in the validation set, respectively). The nomogram was proven to excellently discriminate between the low-, moderate-, and high-risk groups, with a prevalence of 7-year new-onset stroke of 3.36, 8.32, and 20.13%, respectively (P < 0.001).ConclusionThis research developed a clinical predictive risk stratification tool that can effectively identify the different risks of new-onset stroke in 7 years in the middle-aged and elderly Chinese population.

The clinical success of immune-checkpoint inhibitors (ICI) in both resected and metastatic melanoma has confirmed the validity of therapeutic strategies that boost the immune system to counteract cancer. However, half of patients with metastatic disease treated with even the most aggressive regimen do not derive durable clinical benefit. Thus, there is a critical need for predictive biomarkers that can identify individuals who are unlikely to benefit with high accuracy so that these patients may be spared the toxicity of treatment without the likely benefit of response. Ideally, such an assay would have a fast turnaround time and minimal invasiveness. Here, we utilize a novel platform that combines mass spectrometry with an artificial intelligence-based data processing engine to interrogate the blood glycoproteome in melanoma patients before receiving ICI therapy. We identify 143 biomarkers that demonstrate a difference in expression between the patients who died within six months of starting ICI treatment and those who remained progression-free for three years. We then develop a glycoproteomic classifier that predicts benefit of immunotherapy (HR=2.7; p=0.026) and achieves a significant separation of patients in an independent cohort (HR=5.6; p=0.027). To understand how circulating glycoproteins may affect efficacy of treatment, we analyze the differences in glycosylation structure and discover a fucosylation signature in patients with shorter overall survival (OS). We then develop a fucosylation-based model that effectively stratifies patients (HR=3.5; p=0.0066). Together, our data demonstrate the utility of plasma glycoproteomics for biomarker discovery and prediction of ICI benefit in patients with metastatic melanoma and suggest that protein fucosylation may be a determinant of anti-tumor immunity.

The response of plants to waterlogging stress is a complex process, with ethylene playing a crucial role as a signaling molecule. However, it remains unclear how ethylene is initially triggered in response to waterlogging stress when plants are continuously waterlogged for less than 12 hours. Here, we have shown that ethylene-induced autophagy leads to the degradation of damaged mitochondria (the main organelles producing reactive oxygen species (ROS)) to reduce ROS production during oxidative stress in Arabidopsis thaliana, which improves the survival rate of root cells in the early stages of waterlogging stress. Waterlogging stress activated ethylene-related genes, including ACO2, ACS2, ERF72, ERF73, and EIN3, and ethylene content of plants increased significantly within 24 h of continuous waterlogging. As stress duration increased, increased amounts of ROS accumulated in Arabidopsis thaliana roots, and the activity of antioxidant enzymes initially increased and then decreased. Concurrently, the level of ethylene-induced autophagy, which participates in antioxidant defense, is higher in wild-type plants than in the octuple acs mutant cs16651 (acs2-1/acs4-1/acs5-2/acs6-1/acs7-1/acs9-1/amiRacs8acs11). Exogenous application of 1-aminocyclopropanecarboxylic acid (ACC), resulted in a more pronounced manifestation of autophagy in the stele of Arabidopsis roots. Compared with the waterlogging treatment group or the ACC treatment group, the waterlogging + ACC treatment can induce autophagy to occur earlier and expand the autophagic range to the epidermis of Arabidopsis thaliana roots. Overall, our results provide insight into the important role of ethylene-induced autophagy in enhancing the antioxidative capacity of Arabidopsis thaliana during the early stages of waterlogging stress. Furthermore, we suggest ethylene as a potential candidate for mitigating the deleterious effects caused by waterlogging in Arabidopsis thaliana.

ObjectiveTo explore the effects of inspiratory muscle training (IMT) on hypertension and provide guidance for its clinical application as an auxiliary approach.MethodsArticles published prior to July 2022 were searched in Cochrane Library, Web of Science, PubMed, Embase, CNKI, and Wanfang databases. Included were randomized controlled studies that used IMT to treat individuals with hypertension. The mean difference (MD) was computed using the Revman 5.4 software. In individuals with hypertension, the effects of IMT on systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and pulse pressure (PP) were compared and studied.ResultsThere were found to be eight randomized controlled trials totaling 215 patients. According to a meta-analysis, the IMT reduced the SBP (MD: −12.55 mmHg, 95% CI: −15.78, −9.33), DBP (MD: −4.77 mmHg, 95% CI: −6.00, −3.54), HR (MD: −5.92 bpm, 95% CI: −8.72, −3.12), and PP (MD: −8.92 mmHg, 95% CI: −12.08, −5.76) in patients with hypertension. In subgroup analyses, low-intensity IMT showed a better reduction in SBP (MD: −14.47 mmHg, 95% CI: −17.60, −11.34), DBP (MD: −7.70 mmHg, 95% CI: −10.21, −5.18).ConclusionIMT may become an auxiliary means to improve the four hemodynamic indexes (SBP, DBP, HR and PP) in patients with hypertension. In subgroup analyses, low-intensity IMT was more effective in regulating blood pressure than medium-high-intensity IMT.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42022300908.

Objective To evaluate the association between bilirubin levels and stroke risk.Design Systematic review and meta-analysis, reported in accordance with Meta-analysis Of Observational Studies in Epidemiology guidelines.Data sources The PubMed, Embase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure Databases were searched from inception up to 27 February 2022.Eligibility criteria Cohort studies assessing the dose–response relationship between bilirubin levels and risk of stroke were eligible for inclusion. There were no language restrictions.Data extraction and synthesis All data from eligible studies were collected and assessed by two independent investigators. We generated pooled relative risks (RRs) with 95% CIs. We used a restricted cubic spline model for the dose–response analyses. Subsequent subgroup analyses were conducted according to stroke outcomes, follow-up duration, geographical area and size of the cohort.Results Nine articles including results from 11 cohort studies with 7835 cases of stroke and 263 596 participants met the inclusion criteria. The summarised RR of stroke comparing the highest and lowest bilirubin level was 0.85 (95% CI 0.72 to 0.99). The dose–response analysis indicated that a 15 µmol/L increment of bilirubin level was associated with an 18% lower risk of stroke (RR=0.82, 95% CI 0.67 to 0.99). For ischaemic stroke, the RR was 0.76 (95% CI 0.58 to 0.99). Significant publication bias was not detected.Conclusions Elevated bilirubin levels were associated with a decreased risk of stroke among adults.PROSPERO registration number CRD42017071497.

Nucleolin protein expression is higher on the ovarian cancer cell surface. AS1411, a DNA aptamer, can bind with nucleolin protein specifically. In this study, we developed HA and ST DNA tiles to assemble six AS1411 aptamers to deliver doxorubicin. In addition, to superior serum stability and drug loading, HA-6AS and ST-6AS outperformed TDN-AS in cellular uptake. HA-6AS and ST-6AS exhibited satisfactory targeted cytotoxicity and achieved resounding lysosomal escape. Moreover, when injected into nude mice subcutaneous xenograft models, HA-6AS reached the peak in tumor more quickly than ST-6AS, and better expressed the active targeting ability of AS1411. Our study suggests that designing appropriate DNA tiles to assemble different aptamers to deliver different chemotherapeutic drugs is a promising treatment for ovarian cancer.

Background: The use of NSAIDs have caused stomach injury by inhibiting endogenous mucosal prostaglandin production. Cucumis melo is reported to possess antiulcer potential. This study investigates the mechanism underlying the antiulcer potentials of Cucumis melo (CUM). Methods: Thirty-five male Wistar rat were randomly assigned to each of seven groups; A(control given water and rat pellets), B(gastric ulcer induced with ibuprofen 400 mg/kg), C (Misoprotol 200 μg/kg), D to G (pretreated with different variation of CUM extract; 25 %, 50 %, 75 % and 100 % at a dose of 1 ml/kg for 3 weeks prior to gastric ulcer induction). Ulcer score, ulcer index and percentage inhibition, total gastric acidity was measured. Antioxidant activities, Malondialdehyde, H+/K+ ATPase, PGE2, TNF-α was done by spectrophotometry. Molecular docking investigation of Cucumis melo compounds against Prostaglandin E2 was carried out. Level of significance was tested at P ≤ 0.05 using Tukey post hoc. Result: Total gastric acidity, ulcer score, ulcer index, MDA, TNF-α significantly decreased after CUM treatment when compared to group B. The percentage inhibition, antioxidant activities, PGE2 concentration was significantly increased in all treatment groups compared to group B. Interactions of selected compounds of CUM with Prostaglandin E2 at various docking pockets showed folic acid has highest binding affinity followed by delta7-avenasterol and codisterol to PGE2 receptor. this study shows that one of the mechanisms by which CUM exhibits its antiulcer potential by enhancing Prostaglandin synthesis and antioxidant capacity. Therefore, Cucumis melo can therefore be explored as novel antiulcer agents.

Variability is a prominent observational feature of blazars. The high-energy radiation mechanism of jets has always been important but is still unclear. In this work, we performed a detailed analysis using Fermi-LAT data across 15 yr and obtained GeV light-curve information for 78 TeV blazars detected by Fermi. We provided annual GeV fluxes and corresponding spectral indices for the 78 TeV blazars and thorough monthly GeV fluxes for a subsample of 41 bright blazars. Our results suggest a strong correlation between the γ -ray photon index and $\mathrm{log}{L}_{\gamma }$ for the flat spectrum radio quasars (FSRQs) and high-energy peaked BL Lacs. Fourteen sources in our sample show significant GeV outbursts/flares above the relatively stable, low-flux light curve, with six of them showing a clear sharp peak profile in their 5 day binned light curves. We quantified the variability utilizing the fractional variability parameter F _var , and found that the flux of the FSRQs showed significantly stronger variability than that of the BL Lacs. The 41 bright blazars in this work are best fit by a log-normal flux distribution. We checked the spectral behavior and found 11 out of the 14 sources show a bluer-when-brighter trend, suggesting this spectral behavior for these TeV blazars at the GeV band arises from the mechanism in which the synchrotron-self Compton process dominates the GeV emission. Our research offers a systematic analysis of the GeV variability properties of TeV blazars and serves as a helpful resource for further associated blazar studies.

Extracellular vesicles, as bioactive molecules, have been extensively studied. There are abundant studies in the literature on their biogenesis, secretion, structure, and content, and their roles in pathophysiological processes. Extracellular vesicles have been reviewed as biomarkers for use in diagnostic tools. Saliva contains many extracellular vesicles, and compared with other body fluids, it is easier to obtain in a non-invasive way, making its acquisition more easily accepted by patients. In recent years, there have been numerous new studies investigating the role of salivary extracellular vesicles as biomarkers. These studies have significant implications for future clinical diagnosis. Therefore, in this paper, we summarize and review the potential applications of salivary extracellular vesicles as biomarkers, and we also describe their other functions (e.g., hemostasis, innate immune defense) in both oral and non-oral diseases.

The peritoneum is the most common metastatic site of advanced gastric cancer and is associated with extremely poor prognosis. Endothelial-specific molecule 1 (ESM1) was found to be significantly associated with gastric cancer peritoneal metastasis (GCPM); however, the biological functions and molecular mechanisms of ESM1 in regulating GCPM remain unclear. Herein, we demonstrated that ESM1 expression was significantly upregulated in gastric cancer tissues and positively correlated with platelet endothelial cell adhesion molecule-1 (CD31) levels. Moreover, clinical validation, in in vitro and in vivo experiments, confirmed that ESM1 promoted gastric cancer angiogenesis, eventually promoting gastric cancer peritoneal metastasis. Mechanistically, ESM1 promoted tumor angiogenesis by binding to c-Met on the vascular endothelial cell membrane. In addition, our results confirmed that ESM1 upregulated VEGFA, HIF1α, and MMP9 expression and induced angiogenesis by activating the MAPK/ERK pathway. In conclusion, our findings identified the role of ESM1 in gastric cancer angiogenesis and GCPM, thus providing insights into the diagnosis and treatment of advanced gastric cancer.

G protein-coupled receptors (GPCRs) represent promising therapeutic targets due to their involvement in numerous physiological processes mediated by downstream G protein- and β-arrestin-mediated signal transduction cascades. Although the precise control of GPCR signaling pathways is therapeutically valuable, the molecular details for governing biased GPCR signaling remain elusive. The Angiotensin II type 1 receptor (AT1R), a prototypical class A GPCR with profound implications for cardiovascular functions, has become a focal point for biased ligand-based clinical interventions. Herein, we used single-molecule live-cell imaging techniques to evaluate the changes in stoichiometry and dynamics of AT1R with distinct biased ligand stimulations in real time. It was revealed that AT1R existed predominantly in monomers and dimers and underwent oligomerization upon ligand stimulation. Notably, β-arrestin-biased ligands induced the formation of higher-order aggregates, resulting in a slower diffusion profile for AT1R compared to G protein-biased ligands. Furthermore, we demonstrated that the augmented aggregation of AT1R, triggered by activation from each biased ligand, was completely abrogated in β-arrestin knockout cells. These findings furnish novel insights into the intricate relationship between GPCR aggregation states and biased signaling, underscoring the pivotal role of molecular behaviors in guiding the development of selective therapeutic agents.

As a promising material for petroleum industrial applications, titanium (Ti) and its alloys receive wide attention due to their outstanding physicochemical properties. However, the harsh industrial environment requires an antifouling surface with a desired corrosion resistance for Ti and its alloys. In order to achieve the desired antifouling properties, micro-arc oxidation (MAO) was used to prepare a Cu-doped TiO2 coating. The microstructure of the Cu-doped TiO2 coating was investigated by TF-XRD, SEM, and other characterization techniques, and its antifouling and anticorrosion properties were also tested. The results show the effects of the incorporation of Cu (~1.73 wt.%) into TiO2 to form a Cu-doped TiO2, namely, a Ti–Cu coating. The porosity (~4.8%) and average pore size (~0.42 μm) of the Ti–Cu coating are smaller than the porosity (~5.6%) and average pore size (~0.66 μm) of Ti–blank coating. In addition, there is a significant reduction in the amount of SRB adhesion on the Ti–Cu coating compared to the Ti–blank coating under the same conditions, while there is little difference in corrosion resistance between the two coatings. There, the addition of copper helps to improve the fouling resistance of TiO2 coatings without compromising their corrosion resistance. Our work provides a practical method to improve the antifouling function of metallic Ti substrates, which could promote the application of Ti in the petroleum industry.

High temperature and humidity affect the tribological performance of nitrile butadiene rubber (NBR) seals, which affects the precise positioning of cylinder systems. Therefore, it is crucial to study the effect of hydrothermal aging on the tribological performance of the NBR seals. In this study, the changes in the tribological performance of the NBR seals under hydrothermal aging conditions were investigated. The results show that the volatilization of additives and the increase in crosslink density of the NBR seals occurs in the hydrothermal aging environment, leading to the deterioration of their surface quality, elastic deformability, and tribological performance. The formation of surface micropores due to additive volatilization is the main factor in the degradation of tribological performance.

This study provides a comprehensive review of the application of virtual reality (VR) in social and emotional learning (SEL) for children and adolescents over the past decade (January 2013–May 2023), with a specific interest in the relations between their technological and instructional design features. A search in Web of Science resulted in 32 relevant articles that were then manually screened. Coding analysis was conducted from four perspectives: participant characteristics, research design, technological features, and instructional design. The analysis provides insights into the VR literature regarding publication trends, target populations, technological features, instructional scenarios, and tasks. To test the effectiveness of VR interventions for promoting SEL, a meta-analysis was also conducted, which revealed an overall medium effect size and significant moderating effects of SEL disorder type and instructional task. Finally, based on the research results, the practical implications of and future research directions for applying VR in SEL were discussed.

With green and low-carbon developments in oil fields, an increasing amount of repaired oil tubing is being used as oil and gas transmission pipelines in China. However, due to differences in manufacturing standards between oil tubing and transmission pipelines, there are inevitably some issues during their use. This paper investigates a case of cracking failure in repaired oil tubing used as a gathering and transportation pipeline. The failure occurred after eight months of operation and was characterized by a circumferential crack at the male thread end of the tubing joint. To determine the root cause of the failure, a series of experiments were conducted on the oil tubing. The experiments included visual inspection, chemical composition analysis, mechanical properties testing, hardness testing, metallographic examination, and microstructure analysis. The results revealed that the thread of the cracked tubing was not tightened to the specified position; the connection between the tubing and the coupling was welded in a circumferential direction; and cracks occurred in the heat-affected zone of the weld. Chemical composition, tensile performance, and the Charpy impact of the tubing meet the requirements of API 5CT for P110 material, and no abnormalities were found in the metallographic structure. The microstructure at the weld toe of the fracture is martensite, and the hardness is 476 HV10. Based on the thermal simulation verification test, when the material of the tubing cools from 1200 °C, which is located in the coarse HAZ temperature zone, the base metal transforms into martensite with a little granular bainite, exhibiting its highest hardness value at 371 HV10, which is higher than the allowable hardness for carbon steel and indicates the material has poor weldability. The reasons for the cracking and failure of the tubing are that the P110 repaired tubing has a high carbon equivalent and poor weldability. During the welding process, martensitic structure was formed at the weld toe, and cold cracks appeared in the heat-affected zone, resulting in failure. To avoid the reoccurrence of such failure, recommendations are proposed.

BackgroundProteins in human milk are essential and known to support the growth, development, protection, and health of the newborn. These proteins are highly modified by glycans that are currently being recognized as vital to protein structure, stability, function, and health of the intestinal mucosa. Although milk proteins have been studied, the quantitative changes in milk proteins and their respective site-specific glycosylation are unknown.ObjectiveThis study expanded the analytical tools for milk proteins and their site-specific glycosylation and applied these tools to a large cohort to determine changes in individual protein concentrations and their site-specific N-glycosylation across lactation.DesignA tandem mass spectrometry method was applied to 231 breast-milk samples from 33 mothers in Davis, California, obtained during 7 different periods of lactation. Dynamic changes in the absolute abundances of milk proteins, as well as variation in site-specific N-glycosylation of individual proteins, were quantified.Resultsα-Lactalbumin, β-casein, k-casein, and α-antitrypsin were significantly increased from colostrum to transitional milk (4.37 ± 1.33 g/L to 6.41 ± 0.72 g/L, 2.25 ± 0.86 g/L to 2.59 ± 0.78 g/L, 1.33 ± 0.44 g/L to 1.60 ± 0.39 g/L, and 0.09 ± 0.10 g/L to 0.11 ± 0.04 g/L, respectively; P

Cell membrane protein glycosylation is dependent on the metabolic state of the cell as well as exogenous nutrients available. Although the metabolism and interconversion of monosaccharides have been well-studied, their incorporation into cell surface glycans and their corresponding glycoproteins remains relatively unknown. In this study, we developed a method to investigate quantitatively the incorporation pathways of dietary saccharides into specific glycans and glycoproteins on the cell membrane by treating intestinal Caco-2 and hepatic KKU-M213 cells with 13C-labeled monosaccharides and characterizing the resulting cell surface glycans and glycopeptides by LC-MS/MS. Time-course studies using uniformly labeled glucose revealed that the rate of incorporation was both glycan-specific and protein-dependent. Comparative studies using different dietary saccharides and multiple cell lines revealed the variance of monosaccharide utilization and interconversion in different tissues and organisms. The robust isotope-labeling and glycan profiling methods can provide a useful tool for differentiating glycosylation pathways and enhance the understanding of how dietary sugar intake affects health.

The cell membrane contains a highly interactive glycan surface on a scaffold of proteins and lipids. Sialic acids are negatively charged monosaccharides, and the proteins that bind to sialic acids play an important role in maintaining the integrity and collective functions of this interactive space. Sialic acid binding proteins are not readily identified and have nearly all been discovered empirically. In this research, we developed a proximity labeling method to characterize proteins with oxidation by localized radicals produced in situ. The sites of oxidation were identified and quantified using a standard proteomic workflow. In this method, a clickable probe was synthesized and attached to modified sialic acids on the cell membrane, which functioned as a catalyst for the localized formation of radicals from hydrogen peroxide. The proteins in the sialic acid environment were labeled through amino acid oxidation, and were categorized into three groups including sialylated proteins, non-sialylated proteins with transmembrane domains, and proteins that are associated with the membrane with neither sialylated nor transmembrane domains. The analysis of the last group of proteins showed that they were associated with binding functions including carbohydrate binding, anion binding, and cation binding, thereby revealing the nature of the sialic acid-protein interaction. This new tool identified potential sialic acid-binding proteins in the extracellular space and proteins that were organized around sialylated glycans in cells.

Many bacterial pathogens hijack macrophages to egress from the port of entry to the lymphatic drainage and/or bloodstream, causing dissemination of life-threatening infections. However, the underlying mechanisms are not well understood. Here, we report that Salmonella infection generates directional electric fields (EFs) in the follicle-associated epithelium of mouse cecum. In vitro application of an EF, mimicking the infection-generated electric field (IGEF), induces directional migration of primary mouse macrophages to the anode, which is reversed to the cathode upon Salmonella infection. This infection-dependent directional switch is independent of the Salmonella pathogenicity island 1 (SPI-1) type III secretion system. The switch is accompanied by a reduction of sialic acids on glycosylated surface components during phagocytosis of bacteria, which is absent in macrophages challenged by microspheres. Moreover, enzymatic cleavage of terminally exposed sialic acids reduces macrophage surface negativity and severely impairs directional migration of macrophages in response to an EF. Based on these findings, we propose that macrophages are attracted to the site of infection by a combination of chemotaxis and galvanotaxis; after phagocytosis of bacteria, surface electrical properties of the macrophage change, and galvanotaxis directs the cells away from the site of infection.

Abstract Flexible multichannel electrode arrays (fMEAs) with multiple filaments can be flexibly implanted in various patterns. It is necessary to develop a method for implanting the fMEA in different locations and at various depths based on the recording demands. This study proposed a strategy for reducing the microelectrode volume with integrated packaging. An implantation system was developed specifically for semiautomatic distributed implantation. The feasibility and convenience of the fMEA and implantation platform were verified in rodents. The acute and chronic recording results provied the effectiveness of the packaging and implantation methods. These methods could provide a novel strategy for developing fMEAs with more filaments and recording sites to measure functional interactions across multiple brain regions.

Abstract Background Aberrant DNA repair pathways contribute to malignant transformation or disease progression and the acquisition of drug resistance in multiple myeloma (MM); therefore, these pathways could be therapeutically exploited. Ribonucleotide reductase (RNR) is the rate-limiting enzyme for the biosynthesis of deoxyribonucleotides (dNTPs), which are essential for DNA replication and DNA damage repair. In this study, we explored the efficacy of the novel RNR inhibitor, 4-hydroxysalicylanilide (HDS), in myeloma cells and xenograft model. In addition, we assessed the clinical activity and safety of HDS in patients with MM. Methods We applied bioinformatic, genetic, and pharmacological approaches to demonstrate that HDS was an RNR inhibitor that directly bound to RNR subunit M2 (RRM2). The activity of HDS alone or in synergy with standard treatments was evaluated in vitro and in vivo. We also initiated a phase I clinical trial of single-agent HDS in MM patients (ClinicalTrials.gov: NCT03670173) to assess safety and efficacy. Results HDS inhibited the activity of RNR by directly targeting RRM2. HDS decreased the RNR-mediated dNTP synthesis and concomitantly inhibited DNA damage repair, resulting in the accumulation of endogenous unrepaired DNA double-strand breaks (DSBs), thus inhibiting MM cell proliferation and inducing apoptosis. Moreover, HDS overcame the protective effects of IL-6, IGF-1 and bone marrow stromal cells (BMSCs) on MM cells. HDS prolonged survival in a MM xenograft model and induced synergistic anti-myeloma activity in combination with melphalan and bortezomib. HDS also showed a favorable safety profile and demonstrated clinical activity against MM. Conclusions Our study provides a rationale for the clinical evaluation of HDS as an anti-myeloma agent, either alone or in combination with standard treatments for MM. Trial registration: ClinicalTrials.gov, NCT03670173, Registered 12 September 2018.

To reduce the complexity of large-scene high-resolution maps while using the dead-end information distributed in the unmanned vehicle driving environment, we propose a novel non-uniform quadtree map-building method including dead-end semantic information extraction. By utilizing quadtree data structures, submaps and a positive-order tree depth organization approach, our proposed map can adapt to the large-scale high-resolution requirement and expand more easily to larger environments. To verify the practicality of our proposed map, we have successfully implemented map matching and path planning in real environments. Additionally, we effectively extract the dead-end semantic information that widely distributes in the environment, which can help unmanned vehicles avoid collisions and improve the search efficiency of the planning procedure. We evaluate our method with KITTI datasets, CARLA Simulator, and our self-collected real-world datasets. The experimental results show that our proposed method significantly reduces the complexity of large-scale high-resolution maps, effectively extracts dead-end semantic information, and has good practicality in real environments. The implementation of our method is released here: https://github.com/biter0088/Non-uniform-quadtree-map.

Temperature variation structures the composition and diversity of gut microbiomes in ectothermic animals, key regulators of host physiology, with potential benefit to host or lead to converse results (i.e., negative). So, the significance of either effect may largely depend on the length of time exposed to extreme temperatures and how rapidly the gut microbiota can be altered by change in temperature. However, the temporal effects of temperature on gut microbiota have rarely been clarified. To understand this issue, we exposed two juvenile fishes (Cyprinus carpio and Micropterus salmoides), which both ranked among the 100 worst invasive alien species in the world, to increased environmental temperature and sampled of the gut microbiota at multiple time points after exposure so as to determine when differences in these communities become detectable. Further, how temperature affects the composition and function of microbiota was examined by comparing predicted metagenomic profiles of gut microbiota between treatment groups at the final time point of the experiment. The gut microbiota of C. carpio was more plastic than those of M. salmoides. Specifically, communities of C. carpio were greatly altered by increased temperature within 1 week, while communities of M. salmoides exhibit no significant changes. Further, we identified 10 predicted bacterial functional pathways in C. carpio that were temperature-dependent, while none functional pathways in M. salmoides was found to be temperature-dependent. Thus, the gut microbiota of C. carpio was more sensitive to temperature changes and their functional pathways were significantly changed after temperature treatment. These results showed the gut microbiota of the two invasive fishes differ in response to temperature change, which may indicate that they differ in colonization modes. Broadly, we have confirmed that the increased short-term fluctuations in temperatures are always expected to alter the gut microbiota of ectothermic vertebrates when facing global climate change.

IntroductionThe gut microbiota plays an important role in the development of nonalcoholic steatohepatitis (NASH). This study investigated the preventive effect of Dendrobium officinale (DO), including whether its effect was related to the gut microbiota, intestinal permeability and liver inflammation.MethodsA NASH model was established in rats using a high-fat diet (HFD) and gavage with different doses of DO or Atorvastatin Calcium (AT) for 10 weeks. Body weight and body mass index along with liver appearance, weight, index, pathology, and biochemistry were measured to assess the preventive effects of DO on NASH rats. Changes in the gut microbiota were analyzed by 16S rRNA sequencing, and intestinal permeability and liver inflammation were determined to explore the mechanism by which DO treatment prevented NASH.ResultsPathological and biochemical indexes showed that DO was able to protect rats against HFD-induced hepatic steatosis and inflammation. Results of 16S rRNA sequencing showed that Proteobacteria, Romboutsia, Turicibacter, Lachnoclostridium, Blautia, Ruminococcus_torques_group, Sutterella, Escherichia-Shigella, Prevotella, Alistipes, and Lactobacillus_acidophilus differed significantly at the phylum, genus, and species levels. DO treatment modulated the diversity, richness, and evenness of gut microbiota, downregulated the abundance of the Gram-negative bacteria Proteobacteria, Sutterella, and Escherichia-Shigella, and reduced gut-derived lipopolysaccharide (LPS) levels. DO also restored expression of the tight junction proteins, zona occludens-1 (ZO-1), claudin-1, and occludin in the intestine and ameliorated the increased intestinal permeability caused by HFD, gut microbiota such as Turicibacter, Ruminococcus, Escherichia-Shigella, and Sutterella, and LPS. Lower intestinal permeability reduced LPS delivery to the liver, thus inhibiting TLR4 expression and nuclear factor-kappaB (NF-κB) nuclear translocation, improving liver inflammation.DiscussionThese results suggest that DO may alleviate NASH by regulating the gut microbiota, intestinal permeability, and liver inflammation.

MIL-101(Fe)-based catalysts have been widely used for degradation of organic pollutants based on peroxymonosulfate (PMS) activation. Hence, a facile calcination and hydrothermal method was used in this study to prepare a MIL-101(Fe)/g-C3N4 composite catalyst with high activity and high stability for PMS activation to degrade tetracycline hydrochloride (TC) under visible-light irradiation. We clearly elucidated the mechanism involved in the MIL-101(Fe)/g-C3N4 photo Fenton-catalyzed PMS activation process by separating the PMS activation and pollutant oxidation processes. The synergetic effects of MIL-101(Fe) and g-C3N4 involved MIL-101(Fe) acting as an electron shuttle mediating electron transfer from the organic substrate to PMS, accompanied by redox cycling of the surface Fe(II)/Fe(III). Multiple experimental results indicated that PMS was bound to the surface of MIL-101(Fe)/g-C3N4 during visible irradiation and generation of sulfate radicals (SO4•-), hydroxyl radicals (•OH) and superoxide anion free radicals (•O2-) for the radical pathway and singlet oxygen (1O2) and holes (h+) for the nonradical pathway. The major degradation pathways for TC can be described as demethylation, deamination, deamidation and carbonylation. This work provides valuable information and advances the fundamental understanding needed for design and syntheses of metal-free conjugated polymers modified by metal-organic frameworks for heterogeneous photo-Fenton reactions.

Ginsenoside compound K (CK) has garnered considerable attention due to its versatile pharmacological properties, including anti-inflammatory, anti-allergic, anti-aging, anti-diabetic, and hepatoprotective effects, along with neuroprotection. The conventional approach to synthesizing ginsenoside CK involves enzymatic conversion. However, the purification of enzymes necessitates effort and expense, and enzymes are prone to inactivation. Additionally, whole-cell catalysis suffers from inefficiency due to limited cell permeability. To address these challenges, we harnessed the YiaT protein as an anchoring motif, establishing a surface display system for β-glycosidase Bgp3. This innovative system served as a whole-cell catalyst for the efficient synthesis of ginsenoside CK. We further optimized the YiaT-Bgp3 system, enhancing display levels and significantly increasing ginsenoside CK production. Optimal conditions were achieved at an IPTG concentration of 0.5 mM, an induction temperature of 16 °C, a ginsenoside substrate concentration of 15 mg/mL, and a catalytic temperature of 30 °C. Ultimately, the YiaT-Bgp3 system synthesized 5.18 ± 0.08 mg/mL ginsenoside CK within 24 h, with a conversion of 81.83 ± 1.34%. Furthermore, the YiaT-Bgp3 system exhibited good reusability, adding to its practicality and value. This study has successfully developed an efficient whole-cell Bgp3 biocatalyst, offering a convenient, highly productive, and economically viable solution for the industrial production of ginsenoside CK.