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A central challenge in fusion energy is reconciling the high-confinement mode required for reactor performance with the intense intermittent relaxation events it produces, known as edge-localized modes. These instabilities arise in the steep pressure pedestal at the plasma edge when magnetohydrodynamic thresholds are crossed, inflicting damaging heat loads on reactor components. Here, we show that multiscale interactions between microscopic turbulence and macroscopic magnetohydrodynamic modes provide encouraging prospects for self-organized edge-localized modes regulation. Using direct quantitative measurements of multiscale modes, eddy dynamics, and turbulent flux, we show that small-scale electron drift wave turbulence actively scatters the large-scale peeling-ballooning modes. This scattering decorrelates the pressure and velocity fields of the instability, so arresting its growth. Our modeling and theoretical analysis confirm this suppression mechanism is effective even when conventional linear stability thresholds are exceeded. This work establishes a nonlinear principle for edge-localized modes stability, revealing how ambient micro-turbulence can be leveraged to maintain a macro-stable, high-performance pedestal for future fusion reactors. Edge localised modes (ELMs) in highly confined plasmas are notoriously difficult to regulate. Here, the authors analyse multiscale modes and interactions by combining experimental measurements from DIII-D and modeling, showing promising results in ELM control.

Modular charging is an advanced technique designed to meet the requirements of auto-loading artillery, whereby granular propellants are stored within modular cartridges that are loaded into the gun chamber. This study employed an extended coupled computational fluid dynamics-discrete element method (CFD-DEM) approach to investigate the gas-particle flow within modular charges. After model validation, we analyzed the distribution characteristics, velocity, coordination number, and orientation of cylindrical pellets in a simulator chamber. Four different loading positions for modular cartridges were examined to assess their impact on particle distribution. Numerical simulations revealed a combination of gentle, horizontal, and steep slopes in the particle distribution. The maximum particle velocity experienced a rapid increase during the initial phase, followed by a zigzag decline after reaching its peak. High-coordination number particles tended to accumulate primarily in the middle layer of steep accumulation. Additionally, the particles exhibited an inverted V-shape orientation range from 0° to 180°, suggesting their tendency to assume upright positions. This established model significantly enhanced our understanding of particle distribution following module cartridge rupture and provided valuable guidance for optimizing the design of large-caliber artillery charges.

Vanilloid receptor-1 (VR1) was originally found in the nervous system. Recent evidence indicates that VR1 is also expressed in various cell types. We hypothesized that VR1 exists in the human submandibular gland (SMG) and is involved in regulating salivary secretion. VR1 mRNA and protein were expressed in human SMGs and a human salivary intercalated duct cell line. VR1 was mainly located in serous acinar and ductal cells, but not in mucous acinar cells. Capsaicin, an agonist of VR1, increased intracellular free calcium, enhanced phosphorylation of extracellular signal-regulated kinase, and induced the trafficking of aquaporin 5 (AQP5) from the cytoplasm to the plasma membrane. These effects were abolished by pre-treatment with the VR1 antagonist capsazepine. Furthermore, capsaicin cream applied to the skin covering the submandibular area increased salivary secretion. These findings indicated that a functional VR1 is expressed in the human SMG and is involved in regulating salivary secretion by mediating AQP5 trafficking.

The propellant particles distribution in the ignition process of the modular charge has a significant effect on the interior ballistic stability. Thereinto, the particles final distribution is determined by the particles motion process. Based on the CFD-DEM method, a 3D transient gas-solid flow model is constructed to investigate the motion process and the dispersion of propellant particles. Moreover, the cold state test of the ignition process of modular charge is accomplished based on a visual ignition test platform. The simulated data are consistent with the test one. Furthermore, the effect of the initial loading position on the propellant particles distribution of two-module charge is predicted by the numerical simulation. All of two-module cases show that the distributions of particles are made up of a gentle-downhill, a horizontal, and a steep-uphill accumulation. As the initial loading position of modules moves to the right, the slope angle of the uphill is decreased first and then increased, with the minimum slope angle of 20.5°. When the initial loading position of modules is 40mm, the spatial distribution gradient of particles gets the minimum in the uphill accumulation area, and the particles axial-distribution is the most uniform.

In order to study the heating process of the modular charge loaded into the chamber after the continuous firing of the large caliber gun in the high-temperature environment, a 2D transient cook-off model of the modular charge retained in the chamber was established with cook-off method. When the ambient temperature is 323K and the critical temperature of the inner wall of the gun chamber is 443K, the wall temperature distribution of the gun is solved after 2 rounds/min of continuous firing. Taking this as the initial temperature condition, the cook-off process of the modular charge in the chamber is numerically simulated, and then the cook-off-odd characteristics of the modular charge in the high-temperature environment are analyzed. The results show that after 33 rounds of continuous firing at 2 rounds/min at 323K ambient temperature, the temperature of the inner wall of the gun chamber reaches 442.7K, and the modular charge would have a cook-off response after 107.5s after loading into the chamber, and the response temperature is 483.5K. The initial response position of the modular charge is located at the inner wall of the upper right corner of the module cartridge. The consistency between numerical calculation and experimental results shows that the model could analyze the cook-off problem of modular charge in bore well.

The impact of an accidental drop of modular charge may inevitably cause the charge to fail. In order to deeply understand the safety of modular charge under drop impact conditions and promote the safety evaluation and structural design of modular charge, a dynamic finite element model of modular charge was established based on nonlinear finite element theory. The module charge drop test was simulated by using ANSYS/LS-DYNA software. A numerical simulation was performed to evaluate the influence of drop postures on the stress, strain and acceleration response of the modular charge. The stress, strain and acceleration data of the modular charge when it dropped from a height of 1.5m onto Q235 steel plate, with three drop postures: bottom-downward vertical drop, horizontal drop and a 45° inclined drop. Results show that the ranking of dropping postures in terms of risk of modular charge rupture from highest to lowest is: 45° inclined drop, horizontal drop, and vertical drop. Under the condition of 45° drop, the maximum stress and strain in the modular charge are observed, with the minimum acceleration and the longest time to reach peak values. Under all three drop postures, the safety risk areas are located at the bottom of the combustible cartridge. The bottom of the combustible cartridge is the first to rupture when the modular charge is dropped at a 45° angle. Therefore, in the subsequent research on the improvement of modular charge, the impact resistance of combustible cartridges should be focused on.

Autotransplantation of the submandibular gland is effective for severe keratoconjunctivitis sicca. However, most transplants show decreased secretion shortly after the operation, which leads to obstruction of Wharton’s duct. The hypothesis that decreased catecholamine release due to denervation contributes to hypofunction in the early phase was tested in transplanted glands in rabbits. We found that salivary flow, expression of β1 - and β2-adrenoceptor, and the maximum binding capacity were markedly decreased in the transplanted glands. Isoproterenol significantly reversed the decreased secretion, enhanced the expressions of β1 - and β2-adrenoceptor, and ameliorated the atrophy of acinar cells. The contents of cAMP and phospho-ERK 1/2 were increased after isoproterenol treatment. These results indicate that lack of β-adrenoceptor stimulation is involved in early dysfunction of the transplanted gland. Isoproterenol treatment moderates structural injury and improves secretory function in the transplanted submandibular gland through up-regulating β1 - and β2-adrenoceptor expression and post-receptor signal transduction.

Acteoside, an active ingredient found in various medicinal herbs, is effective in the treatment of diabetic kidney disease (DKD); however, the intrinsic pharmacological mechanism of action of acteoside in the treatment of DKD remains unclear. This study utilizes a combined approach of network pharmacology and experimental validation to investigate the potential molecular mechanism systematically. First, acteoside potential targets and DKD-associated targets were aggregated from public databases. Subsequently, utilizing protein-protein interaction (PPI) networks, alongside GO and KEGG pathway enrichment analyses, we established target-pathway networks to identify core potential therapeutic targets and pathways. Further, molecular docking facilitated the confirmation of interactions between acteoside and central targets. Finally, the conjectured molecular mechanisms of acteoside against DKD were verified through experimentation on unilateral nephrectomy combined with streptozotocin (STZ) rat model. The underlying downstream mechanisms were further investigated. Network pharmacology identified 129 potential intersected targets of acteoside for DKD treatment, including targets such as AKT1, TNF, Casp3, MMP9, SRC, IGF1, EGFR, HRAS, CASP8, and MAPK8. Enrichment analyses indicated the PI3K-Akt, MAPK, Metabolic, and Relaxin signaling pathways could be involved in this therapeutic context. Molecular docking revealed high-affinity binding of acteoside to PIK3R1, AKT1, and NF-κB1. In vivo studies validated the therapeutic efficacy of acteoside, demonstrating reduced blood glucose levels, improved serum Scr and BUN levels, decreased 24-hour urinary total protein (P<0.05), alongside mitigated podocyte injury (P<0.05) and ameliorated renal pathological lesions. Furthermore, this finding indicates that acteoside inhibits the expression of pyroptosis markers NLRP3, Caspase-1, IL-1β, and IL-18 through the modulation of the PI3K/AKT/NF-κB pathway. Acteoside demonstrates renoprotective effects in DKD by regulating the PI3K/AKT/NF-κB signaling pathway and alleviating pyroptosis. This study explores the pharmacological mechanism underlying acteoside's efficacy in DKD treatment, providing a foundation for further basic and clinical research.

Inhibition of protein neddylation, particularly cullin neddylation, has emerged as a promising anticancer strategy, as evidenced by the antitumor activity in preclinical studies of the Nedd8-activating enzyme (NAE) inhibitor MLN4924. This small molecule can block the protein neddylation pathway and is now in clinical trials. We and others have previously shown that the antitumor activity of MLN4924 is mediated by its ability to induce apoptosis, autophagy and senescence in a cell context-dependent manner. However, whether MLN4924 has any effect on tumor angiogenesis remains unexplored. Here we report that MLN4924 inhibits angiogenesis in various in vitro and in vivo models, leading to the suppression of tumor growth and metastasis in highly malignant pancreatic cancer, indicating that blockage of angiogenesis is yet another mechanism contributing to its antitumor activity. At the molecular level, MLN4924 inhibits Cullin–RING E3 ligases (CRLs) by cullin deneddylation, causing accumulation of RhoA at an early stage to impair angiogenic activity of vascular endothelial cells and subsequently DNA damage response, cell cycle arrest and apoptosis due to accumulation of other tumor-suppressive substrates of CRLs. Furthermore, we showed that inactivation of CRLs, via small interfering RNA (siRNA) silencing of its essential subunit ROC1/RBX1, recapitulates the antiangiogenic effect of MLN4924. Taken together, our study demonstrates a previously unrecognized role of neddylation in the regulation of tumor angiogenesis using both pharmaceutical and genetic approaches, and provides proof of concept evidence for future development of neddylation inhibitors (such as MLN4924) as a novel class of antiangiogenic agents.

The tobacco N and Arabidopsis RPS2 genes, among several recently cloned disease-resistance genes, share a highly conserved structure, a nucleotide-binding site (NBS). Using degenerate oligonucleotide primers for the NBS region of N and RPS2, we have amplified and cloned the NBS sequences from soybean. Each of these PCR-derived NBS clones detected low- or moderate-copy soybean DNA sequences and belongs to 1 of 11 different classes. Sequence analysis showed that all PCR clones encode three motifs (P-loop, kinase-2, and kinase-3a) of NBS nearly identical to those in N and RPS2. The intervening region between P-loop and kinase-3a of the 11 classes has high (26% average) amino acid sequence similarity to the N gene although not as high (19% average) to RPS2. These 11 classes represent a superfamily of NBS-containing soybean genes that are homologous to N and RPS2. Each class or subfamily was assessed for its positional association with known soybean disease-resistance genes through near-isogenic line assays, followed by linkage analysis in F2 populations using restriction fragment length polymorphisms. Five of the 11 subfamilies have thus far been mapped to the vicinity of known soybean genes for resistance to potyviruses (Rsv1 and Rpv), Phytophthora root rot (Rps1, Rps2, and Rps3), and powdery mildew (rmd). The conserved N- or RPS2-homologous NBS sequences and their positional associations with mapped soybean-resistance genes suggest that a number of the soybean disease-resistance genes may belong to this superfamily. The candidate subfamilies of NBS-containing genes identified by genetic mapping should greatly facilitate the molecular cloning of disease-resistance genes