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Abstract In tumor therapeutics, the transition from conventional cytotoxic drugs to targeted molecular therapies, such as those targeting receptor tyrosine kinases, has been pivotal. Despite this progress, the clinical outcomes have remained modest, with glioblastoma patients' median survival stagnating at less than 15 months. This underscores the urgent need for more specialized treatment strategies. Our review delves into the progression toward immunomodulation in glioma treatment. We dissect critical discoveries in immunotherapy, such as spotlighting the instrumental role of tumor-associated macrophages, which account for approximately half of the immune cells in the glioma microenvironment, and myeloid-derived suppressor cells. The complex interplay between tumor cells and the immune microenvironment has been explored, revealing novel therapeutic targets. The uniqueness of our review is its exhaustive approach, synthesizing current research to elucidate the intricate roles of various molecules and receptors within the glioma microenvironment. This comprehensive synthesis not only maps the current landscape but also provides a blueprint for refining immunotherapy for glioma, signifying a paradigm shift toward leveraging immune mechanisms for improved patient prognosis.

ObjectivesWater-saving and drought-resistance rice (WDR) plays a vital role in the sustainable development of agriculture. Nevertheless, the impacts and processes of water and nitrogen on grain yield in WDR remain unclear.MethodsIn this study, Hanyou 73 (WDR) and Hyou 518 (rice) were used as materials. Three kinds of nitrogen fertilizer application rate (NFAR) were set in the pot experiment, including no NFAR (nitrogen as urea applied at 0 g/pot), medium NFAR (nitrogen as urea applied at 15.6 g/pot), and high NFAR (nitrogen as urea applied at 31.2 g/pot). Two irrigation regimes, continuous flooding cultivation and water stress, were set under each NFAR. The relationships between root and shoot morphophysiology and grain yield in WDR were explored.ResultsThe results demonstrated the following: 1) under the same irrigation regime, the grain yield of two varieties increased with the increase of NFAR. Under the same NFAR, the reduction of irrigation amount significantly reduced the grain yield in Hyou 518 (7.1%–15.1%) but had no substantial influence on the grain yield in Hanyou 73. 2) Under the same irrigation regime, increasing the NFAR could improve the root morphophysiology (root dry weight, root oxidation activity, root bleeding rate, root total absorbing surface area, root active absorbing surface area, and zeatin + zeatin riboside contents in roots) and aboveground physiological indexes (leaf photosynthetic rate, non-structural carbohydrate accumulation in stems, and nitrate reductase activity in leaves) in two varieties. Under the same NFAR, increasing the irrigation amount could significantly increase the above indexes in Hyou 518 (except root dry weight) but has little effect on Hanyou 73. 3) Analysis of correlations revealed that the grain yield of Hyou 518 and Hanyou 73 was basically positively correlated with aboveground physiology and root morphophysiology, respectively.ConclusionThe grain yield could be maintained by water stress under medium NFAR in WDR. The improvement of root morphophysiology is a major factor for high yield under the irrigation regime and NFAR treatments in WDR.

With the emergence of Level 4 automated vehicles, it is necessary to investigate the impact of these vehicles on mode choice. Previous studies have looked at the potential benefits and drawbacks of automated vehicles, but there has been little research done on how these vehicles will impact individuals’ travel behaviors. This paper proposes a needs-based approach to study the impact of Level 4 automated vehicles on mode choice. The approach takes into consideration the travel needs of different individuals and their willingness to adopt new technologies. Through a stated preference survey in China, the data on travel preferences and the perceived safety levels of automated vehicles can be collected. Then, a model is built to simulate the adoption of Level 4 automated vehicles and estimate the mode split for different scenarios. The results indicated that private AV modes are preferred, and business and nonwork trips may be the targeted market for all AV modes. Overall, value of automation increases with income for private modes, with large variance. Furthermore, Pro-AV attitude has a positive effect on value of automation, especially for self-owned AV and AV subscription. Accordingly, the needs-based approach demonstrates a promising method to study the impact of new technologies on travel behaviors and provides insights for policy makers to promote more sustainable transportation systems.

Purpose: In this study, we aim to investigate the potential of nintedanib as a therapeutic approach to proliferative vitreoretinopathy (PVR), which is the leading cause of failure in retinal detachment repair. PVR is characterized by the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells, and understanding the effects of nintedanib on EMT in the normal human vitreous (HV)-induced RPE cells is crucial. Methods: Our research focuses on assessing the impact of nintedanib on HV-induced EMT in human retinal pigment epithelial (ARPE-19) cells in vitro. We employed various techniques, including quantitative real-time PCR (qPCR), western blot analysis, and immunofluorescence staining, to evaluate the mRNA and protein expression of EMT biomarkers in HV-induced ARPE-19 cells. Additionally, we measured the proliferation of RPE cells using cell counting, CCK-8, and Ki-67 assays. Migration was assessed through wound healing and transwell migration assays, while contraction was determined using a collagen gel contraction assay. Morphological changes were examined using phase-contrast microscopy. Results: Our results demonstrate that nintedanib selectively attenuates the upregulation of mesenchymal markers in HV-induced ARPE-19 cells, at both the mRNA and protein levels. Furthermore, nintedanib effectively suppresses the HV-induced proliferation, migration, and contraction of ARPE-19 cells, while maintaining the cells' basal activity. These findings strongly suggest that nintedanib exhibits protective effects against EMT in ARPE-19 cells and could be a promising therapeutic option for PVR. Conclusions: By elucidating the anti-EMT effects of nintedanib in HV-induced RPE cells, our study highlights the potential of this oral triple tyrosine kinase inhibitor in the treatment of PVR. These findings contribute to the growing body of research aimed at developing novel strategies to prevent and manage PVR, ultimately improving the success rates of retinal detachment repair.

Abstract Background Increased acid sphingomyelinase (ASMase) activity is associated with insulin resistance and cardiac dysfunction. However, the effects of ASMase on diabetic cardiomyopathy (DCM) and the molecular mechanism(s) underlying remain to be elucidated. We here investigated whether ASMase caused DCM through NADPH oxidase 4-mediated apoptosis. Methods and results We used pharmacological and genetic approaches coupled with study of murine and cell line samples to reveal the mechanisms initiated by ASMase in diabetic hearts. The protein expression and activity of ASMase were upregulated, meanwhile ceramide accumulation was increased in the myocardium of HFD mice. Inhibition of ASMase with imipramine (20 mg Kg−1 d−1) or siRNA reduced cardiomyocyte apoptosis, fibrosis, and mitigated cardiac hypertrophy and cardiac dysfunction in HFD mice. The similar effects were observed in cardiomyocytes treated with high glucose (HG, 30 mmol L−1) + palmitic acid (PA, 100 μmol L−1) or C16 ceramide (CER, 20 μmol L−1). Interestingly, the cardioprotective effect of ASMase inhibition was not accompanied by reduced ceramide accumulation, indicating a ceramide-independent manner. The mechanism may involve activated NADPH oxidase 4 (NOX4), increased ROS generation and triggered apoptosis. Suppression of NOX4 with apocynin prevented HG + PA and CER incubation induced Nppb and Myh7 pro-hypertrophic gene expression, ROS production and apoptosis in H9c2 cells. Furthermore, cardiomyocyte-specific ASMase knockout (ASMaseMyh6KO) restored HFD-induced cardiac dysfunction, remodeling, and apoptosis, whereas NOX4 protein expression was downregulated. Conclusions These results demonstrated that HFD-mediated activation of cardiomyocyte ASMase could increase NOX4 expression, which may stimulate oxidative stress, apoptosis, and then cause metabolic cardiomyopathy.

Abstract The high instantaneous luminosity of the CERN Large Hadron Collider leads to multiple proton–proton interactions in the same or nearby bunch crossings (pileup). Advanced pileup mitigation algorithms are designed to remove this noise from pileup particles and improve the performance of crucial physics observables. This study implements a semi-supervised graph neural network for particle-level pileup noise removal, by identifying individual particles produced from pileup. The graph neural network is firstly trained on charged particles with known labels, which can be obtained from detector measurements on data or simulation, and then inferred on neutral particles for which such labels are missing. This semi-supervised approach does not depend on the neutral particle pileup label information from simulation, and thus allows us to perform training directly on experimental data. The performance of this approach is found to be consistently better than widely-used domain algorithms and comparable to the fully-supervised training using simulation truth information. The study serves as the first attempt at applying semi-supervised learning techniques to pileup mitigation, and opens up a new direction of fully data-driven machine learning pileup mitigation studies.

Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a key fibrosis pathogenesis in proliferative vitreoretinopathy (PVR). However, few medicines can prevent proliferative membranes and cell proliferation in the clinic. Nintedanib, a tyrosine kinase inhibitor, has been shown to prevent fibrosis and be anti-inflammatory in multiple organ fibrosis. In our study, 0.1, 1, 10 μM nintedanib was added to 20 ng/mL transforming growth factor beta 2 (TGF-β2)-induced EMT in ARPE-19 cells. Western blot and immunofluorescence assay showed that 1 μM nintedanib suppressed TGF-β2-induced E-cadherin expression decreased and Fibronectin, N-cadherin, Vimentin, and α-SMA expression increased. Quantitative real-time PCR results showed that 1 μM nintedanib decreased TGF-β2-induced increase in SNAI1, Vimentin, and Fibronectin expression and increased TGF-β2-induced decrease in E-cadherin expression. In addition, the CCK-8 assay, wound healing assay, and collagen gel contraction assay also showed that 1 μM nintedanib ameliorated TGF-β2-induced cell proliferation, migration, and contraction, respectively. These results suggested that nintedanib inhibits TGF-β2-induced EMT in ARPE-19 cells, which may be a potential pharmacological treatment for PVR.

In agricultural and fishery production, the occurrence of cyanobacterial blooms and the contamination of freshwater systems with microplastics have become increasingly important research focuses. However, the individual and combined toxic mechanisms of these two pollutants are not yet fully understood. Therefore, in this study, we analyzed the effects of these two stressors, microcystins (MC) and nanoplastics (NP), on the transcriptome and metabolome of the hepatopancreas of river clams. RNA and metabolites extracted from river clams treated with MC, NP, and a combination of MC and NP were used to construct standardized cDNA libraries, which were then subjected to integrated analysis. Significant enrichment of 49 pathways, 34 pathways, and 44 pathways was observed in the MC group compared to the control group, NP group compared to the control group, and NP-MC group compared to the control group, respectively. In these three experimental groups, we found that the lysosome pathway, which affects immune function and cell apoptosis, was enriched with numerous differentially expressed genes and metabolites. Changes in ATP6N and ADP may impair lysosomal acidification and disrupt normal lysosomal degradation processes, indicating interference with the hepatopancreatic metabolism of pollutants. Interestingly, we observed significant alterations in the cathepsin family, and the downregulation of cathepsin genes, along with the downregulation of ATP6N, implies a potential disruption in lysosomal proteolysis. In the NP-MC group, the downregulation of purine expression levels suggests an impact on the immune system of river clams by NP-MC. In conclusion, while there is some overlap in the damage caused to the hepatopancreas of river clams by MCs, MPs, and the combination of NP-MC, further research is necessary to fully understand their effects.

Glioma is a malignant tumor of the central nervous system with complex pathogenesis, difficult operation, and a high postoperative recurrence rate. At present, there is still a lack of effective treatment. Long non-coding RNA DDX11 antisense RNA 1 (DDX11-AS1) has been shown to promote tumor development, such as hepatocellular carcinoma, esophageal cancer, etc. However, its molecular mechanism in glioma is poorly understood. In this study, we found that the expression of DDX11-AS1 was elevated in glioma tissues, and patients with high expression of DDX11-AS1 had poor prognosis. DDX11-AS1 was a potential prognostic marker. Functionally, DDX11-AS1 promoted glioma cell proliferation and migration. Mechanistically, DDX11-AS1 interacted with RNA-binding protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) to promote Wnt/β-catenin and AKT pathways and the epithelial-mesenchymal transition process. In summary, our study manifests that the DDX11-AS1/HNRNPC axis may play a vital part in the occurrence and development of glioma, which provides new ideas and therapeutic targets for the diagnosis, treatment, and prognosis of glioma.

Background: Mesalazine is the first-line inflammatory bowel disease (IBD) treatment. However, it can cause fatal cardiotoxicity. We aimed to analyze the clinical characteristics of mesalazine-induced cardiotoxicity and provide evidence for clinical diagnosis, treatment, and prevention.Methods: We collected Chinese and English literature on mesalazine-induced cardiotoxicity from 1970 to 2021 for retrospective analysis.Results: A total of 52 patients (40 males and 12 females) were included, with a median age of 24.5 years (range 9–62) and a median onset time of 14 days (range 2–2880). Cardiotoxicity manifested as myocarditis, pericarditis, and cardiac pericarditis. The main clinical manifestations are chest pain (82.7%), fever (46.2%), and respiratory symptoms such as dyspnea and cough (40.4%). The levels of troponin T, creatine kinase, C-reactive protein, leukocyte count, erythrocyte sedimentation rate, and other biochemical markers were significantly increased. Cardiac imaging often suggests myocardial infarction, pericardial effusion, myocardial necrosis, and other symptoms of cardiac injury. It is essential to discontinue mesalamine immediately in patients with cardiotoxicity. Although corticosteroids are a standard treatment option, the benefits remain to be determined. Re-challenge of mesalamine should be carefully considered as cardiotoxic symptoms may reoccur.Conclusion: Mesalazine may cause cardiotoxicity in patients with inflammatory bowel disease, which should be comprehensively diagnosed based on clinical manifestations, biochemical indicators, and cardiac function imaging examinations. Mesalazine should be immediately discontinued, and corticosteroids may be an effective treatment for cardiotoxicity.

It is very important to rapidly test the key indicators of water in the field to fully evaluate the quality of the regional water environment. However, a high-resolution measuring device that can generate small currents for low-concentration analytes in water samples is often bulky, complex to operate, and difficult for data sharing. This work introduces a portable multi-channel electrochemical device with a small volume, good interaction, and data-sharing capabilities called PMCED. The PMCED provides an easy-to-operate graphical interactive interface to conveniently set the parameters for cyclic voltammetry or a differential pulse method performed by the four electrode channels. At the same time, the device, with a current sensitivity of 100 nA V−1, was applied to the detection of water samples with high background current and achieved a high-resolution measurement at low current levels. The PMCED uses the Narrow Band Internet of Things (NB-IoT) to meet the needs for uploading data to the cloud in remote areas. The electrochemical signal preprocessing and chemometrics models run in the cloud, and the final results are visualized on a web page, providing a remote access channel for on-site testing results.

The voltammetric electrochemical sensing method combined with biosensors and multi-sensor systems can quickly, accurately, and reliably analyze the concentration of the main analyte and the overall characteristics of complex samples. Simultaneously, the high-dimensional voltammogram contains the rich electrochemical features of the detected substances. Chemometric methods are important tools for mining valuable information from voltammetric data. Chemometrics can aid voltammetric biosensor calibration and multi-element detection in complex matrix conditions. This review introduces the voltammetric analysis techniques commonly used in the research of voltammetric biosensor and electronic tongues. Then, the research on optimizing voltammetric biosensor results using classical chemometrics is summarized. At the same time, the incorporation of machine learning and deep learning has brought new opportunities to further improve the detection performance of biosensors in complex samples. Finally, smartphones connected with miniaturized voltammetric biosensors and chemometric methods provide a high-quality portable analysis platform that shows great potential in point-of-care testing.

Semantic segmentation of mitochondria from electron microscopy (EM) images is an essential step to obtain reliable morphological statistics about mitochondria. However, automatically delineating plenty of mitochondria of varied shapes from complex backgrounds with sufficient accuracy is challenging. To address these challenges, we develop a hierarchical encoder-decoder network (HED-Net), which has a three-level nested U-shape architecture to capture rich contextual information. Given the irregular shape of mitochondria, we introduce a novel soft label-decomposition strategy to exploit shape knowledge in manual labels. Rather than simply using the ground truth label maps as the unique supervision in the model training, we introduce additional subcategory-aware supervision by softly decomposing each manual label map into two complementary label maps according to mitochondria's ovality. The three label maps are integrated with our HED-Net to supervise the model training. While the original label map guides the network to segment all the mitochondria of varied shapes, the auxiliary label maps guide the network to segment subcategories of mitochondria of circular shape and elliptic shape, respectively, which are much more manageable tasks. Extensive experiments on two public benchmarks show that our HED-Net performs favorably against state-of-the-art methods.

Transcranial electrical stimulation is an important neuromodulation tool, which has been widely applied in the cognitive sciences and in the treatment of neurological and psychiatric diseases. In this work, a novel non-invasive method of transcranial electrical stimulation with high-resolution transcranial magneto-acoustic stimulation (TMAS) method has been tested experimentally in living mice for the first time. It can achieve spatial resolution of 2 mm in the cortex and even in the deep brain regions. The induced electrical field of TMAS was simulated and measured using a test sample. Then, an animal experimental system was built, and the healthy as well as Parkinson’s disease (PD) mice were simulated by TMAS in vivo. To investigate the effect of transcranial ultrasound stimulation (TUS) at the same time as TMAS, a TUS group was added in the experiments and its results compared with those of the TMAS group. The results not only demonstrate the high-resolution ability and safety of TMAS, but also show that both TMAS and TUS improved the synaptic plasticity of the PD mice and might improve the spatial learning and memory ability of the healthy mice and the PD mice, although the improvement performance of the TMAS group was superior to that of the TUS-group. Based on the in vivo TMAS studies, we propose that TMAS functions as a dual-mode stimulation combining the electric field of the magneto-acoustic effect and the mechanical force of TUS. Our results also provide an explanation of the mechanism of TMAS. This research suggests that future use of US stimulation in magnetic resonance imaging (MRI)-guided studies should involve careful consideration of the induced magneto-acoustic electrical field caused by the static magnetic field of MRI.

Due to the low efficiency and high pollution of conventional internal combustion engine vehicles, the fuel cell hybrid electric vehicles are expected to play a key role in the future of clean energy transportation attributed to the long driving range, short hydrogen refueling time and environmental advantages. The development of energy management strategies has an important impact on the economy and durability, but most strategies ignore the aging of fuel cells and the corresponding impact on hydrogen consumption. In this paper, a rule-based fuzzy control strategy is proposed based on the constructed data-driven online estimation model of fuel cell health. Then, a genetic algorithm is used to optimize this fuzzy controller, where the objective function is designed to consider both the economy and durability by combining the hydrogen consumption cost and the degradation cost characterized by the fuel cell health status. Considering that the rule-based strategy is more sensitive to operating conditions, this paper uses an artificial neural network for predictive control. The results are compared with those obtained from the genetic algorithm optimized fuzzy controller and are found to be very similar, where the prediction accuracy is assessed using MAPE, RMSE and 10-fold cross-validation. Experiments show that the developed strategy has a good generalization capability for variable driving cycles.

Splicing is the most common operation in image forgery, where the tampered background regions are imported from different images. Illumination maps are inherent attribute of images and provide significant clues when searching for splicing locations. This paper proposes an end-to-end dual-stream network for splicing location, where the illumination stream, which includes Grey-Edge (GE) and Inverse-Intensity Chromaticity (IIC), extract the inconsistent features, and the image stream extracts the global unnatural tampered features. The dual-stream feature in our network is fused through Multiple Feature Pyramid Network (MFPN), which contains richer context information. Finally, a Cluster Region Proposal Network (C-RPN) with spatial attention and an adaptive cluster anchor are proposed to generate potential tampered regions with greater retention of location information. Extensive experiments, which were evaluated on the NIST16 and CASIA standard datasets, show that our proposed algorithm is superior to some state-of-the-art algorithms, because it achieves accurate tampered locations at the pixel level, and has great robustness in post-processing operations, such as noise, blur and JPEG recompression.

BACKGROUND:There is no single standard chemotherapy regimen for elderly patients with advanced gastric cancer (AGC). A phase III trial has confirmed that both capecitabine monotherapy and capecitabine plus oxaliplatin are well tolerated for elderly patients with AGC, but their economic influence in China is unknown. OBJECTIVE:The purpose of this cost-effectiveness analysis was to estimate the effects of capecitabine monotherapy and capecitabine plus oxaliplatin in elderly patients with AGC on health and economic outcomes in China. METHODS:We created a Markov model based on data from a Korean clinical phase III trial to analyze the cost-effectiveness of the treatment of elderly patients in the capecitabine monotherapy (X) group and capecitabine plus oxaliplatin (XELOX) group. The costs were obtained from published reports and the local health system. The utilities were assumed on the basis of the published literature. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. One-way and probabilistic sensitivity analyses (Monte Carlo simulations) were performed. RESULTS:In the cost-effectiveness analysis, X had a lower total cost ($45,731.68) and cost-effectiveness ratio ($65,918.93/QALY). The one-way sensitivity analysis suggested that the most influential parameter was the risk of requiring second-line chemotherapy in XELOX group. The probabilistic sensitivity analysis predicted that the X regimen was cost-effective 100% of the time, given a willingness-to-pay threshold of $26,598. CONCLUSIONS:Our findings show that the XELOX regimen is less cost-effective compared to the X regimen for elderly patients with AGC in China from a Chinese healthcare perspective.