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During high-current vacuum arcing, asymmetric arcing with off-center plasma columns may occur due to stochastic discharge initiation and mechanical motion, receiving less research attention than symmetric arcing. The objective of this paper is to numerically analyze the influence law of asymmetric arc ignition on arc parameters. For 60 mm diameter contacts, three arc conditions of symmetric arcing, 33% arc offset, and 67% arc offset were modeled. The results show that the arc offset causes asymmetry in the arc’s distribution. For 33% offset, the pressure and number density on the side away from the root of the arc is about 50% of root values, while these parameters fall below 20% for the 67% offset. Simultaneously, arc offset elevates peak parameter values: under 33% offset, maxima for ion pressure, ion density, ion temperature, electron temperature, and current density rise 12%, 11%, 6%, 6%, and 14% versus symmetric arcing; during 67% offset, these escalate significantly to 67%, 61%, 12%, 18%, and 47%. This study contributes to providing reference for the analysis of vacuum interruption processes under asymmetric arcing conditions.

Anemoside B4 (AB4), a major bioactive saponin isolated from the roots of , exhibits anti-inflammatory and antioxidant properties. While recent study has demonstrated its ability to inhibit ferroptosis in arthritis, its role in sepsis-induced acute lung injury (SALI) remains undefined. This study aims to clarify the mechanism underlying AB4's action in SALI. To explore the therapeutic mechanism of AB4 in SALI, an integrated approach was employed, combining network pharmacology, molecular dynamics simulation, surface plasmon resonance (SPR) assays, experiments using cecal ligation and puncture (CLP)-induced mouse models, and studies with lipopolysaccharide (LPS)-stimulated RAW264.7 cells. The therapeutic effects of AB4 on SALI were evaluated through histopathological examination, biochemical analysis, immunofluorescence staining, and Western blotting, which collectively elucidated its and mechanisms of action. AB4 ameliorated CLP-induced lung injury in mice, as evidenced by reduced pathological damage, lower injury scores, and a decreased lung wet-to-dry weight ratio. , AB4 significantly reduced levels of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), decreased oxidative stress markers MDA and DHE, and increased GSH levels. , AB4 inhibited ferroptosis in macrophages, with a pharmacological effect comparable to the known ferroptosis inhibitor Ferrostatin-1 (Fer-1). Network pharmacology analysis identified the AGE/RAGE signaling pathway as a primary target of AB4. AB4 dose-dependently downregulated RAGE expression and restored levels of GPX4 and SLC7A11. SPR and molecular docking experiments confirmed a high affinity between AB4 and RAGE, with a dissociation constant (KD) of 3.86 μM. Consistently, co-administration of the RAGE inhibitor FPS-ZM1 effectively suppressed ferroptosis and enhanced Nrf2 activity in CLP-induced mice. AB4 directly targets RAGE to inhibit the AGE/RAGE-Nrf2 axis, thereby suppressing both ferroptosis and inflammation in SALI. This previously unreported mechanism establishes AB4 as a novel multifaceted therapeutic candidate for SALI.

Sepsis-induced acute lung injury (SALI) is characterized by dysregulated inflammation with limited therapeutic options. Although Anemoside B4 (AB4) exhibits anti-inflammatory properties, its clinical application is hindered by poor bioavailability. To address this limitation, we developed magnetically guided gelatin microrobots (MG-AB4) for targeted AB4 delivery. The MG-AB4 system consists of a Fe3O4-loaded gelatin shell for enabling precise magnetic navigation (velocity: 110 μm/s), an AB4 core for rapid drug release which is advantageous for acute inflammatory responses, and surface modifications to enhance cellular uptake. Compared with free AB4, MG-AB4 significantly suppressed key inflammatory cytokines (Interleukin-6 (IL-6), Interleukin-1 beta (IL-1β), Tumor necrosis factor-alpha (TNF-α); p < 0.01), inhibited NF-κB activation (p < 0.01), and improved cell viability in an inflammatory model (p < 0.05). This study demonstrates that magnetically guided AB4 delivery using rapidly releasing microrobots is a promising strategy for SALI treatment, wherein the synergy of targeted delivery and potent anti-inflammatory action may effectively mitigate disease progression.

The availability of asparagine is the limitation of cell growth and metastasis. Asparagine synthetase (ASNS) was an essential enzyme for endogenous asparagine products. In our study, ASNS-induced asparagine products were essential to maintain tumor growth and colony formations in vitro. But mutated ASNS which defected endogenous asparagine products still upregulated cell invasiveness, which indicated that ASNS promoted invasiveness by alternative pathways. Mechanically, ASNS modulated Wnt signal transduction by promoting GSK3β phosphorylation on ser9 and stabilizing the β-catenin complex, as result, ASNS could promote more β-catenin translocation into nucleus independent of endogenous asparagine. At the same time, ASNS modulated mitochondrial response to Wnt stimuli with increased mitochondrial potential and membrane fusion. In summary, ASNS promoted metastasis depending on Wnt pathway and mitochondrial functions even without endogenous asparagine products. In the Wnt pathway, phosphorylation of GSK3β(S9) is very important to stabilize β-catenin complex, ASNS can upregulate phosphorylation of AKT on Ser473, then promote GSK3β phosphorylation on Ser9 to stabilize β-catenin complex. When Wnt pathway is activated, ASNS elevates p-DRP1(637) and decreases p-DRP1(616) to suppress mitochondrial fission.

Objectives To evaluate signal enhancement ratio (SER) for tissue characterization and prognosis stratification in pancreatic adenocarcinoma (PDAC), with quantitative histopathological analysis (QHA) as the reference standard. Methods This retrospective study included 277 PDAC patients who underwent multi-phase contrast-enhanced (CE) MRI and whole-slide imaging (WSI) from three centers (2015–2021). SER is defined as (SI lt  − SI pre )/(SI ea  − SI pre ), where SI pre , SI ea, and SI lt represent the signal intensity of the tumor in pre-contrast, early-, and late post-contrast images, respectively. Deep-learning algorithms were implemented to quantify the stroma, epithelium, and lumen of PDAC on WSIs. Correlation, regression, and Bland-Altman analyses were utilized to investigate the associations between SER and QHA. The prognostic significance of SER on overall survival (OS) was evaluated using Cox regression analysis and Kaplan–Meier curves. Results The internal dataset comprised 159 patients, which was further divided into training, validation, and internal test datasets ( n  = 60, 41, and 58, respectively). Sixty-five and 53 patients were included in two external test datasets. Excluding lumen, SER demonstrated significant correlations with stroma ( r  = 0.29–0.74, all p  < 0.001) and epithelium ( r  = −0.23 to −0.71, all p  < 0.001) across a wide post-injection time window (range, 25–300 s). Bland-Altman analysis revealed a small bias between SER and QHA for quantifying stroma/epithelium in individual training, validation (all within ± 2%), and three test datasets (all within ± 4%). Moreover, SER-predicted low stromal proportion was independently associated with worse OS (HR = 1.84 (1.17–2.91), p  = 0.009) in training and validation datasets, which remained significant across three combined test datasets (HR = 1.73 (1.25–2.41), p  = 0.001). Conclusion SER of multi-phase CE-MRI allows for tissue characterization and prognosis stratification in PDAC. Clinical relevance statement The signal enhancement ratio of multi-phase CE-MRI can serve as a novel imaging biomarker for characterizing tissue composition and holds the potential for improving patient stratification and therapy in PDAC. Key Points Imaging biomarkers are needed to better characterize tumor tissue in pancreatic adenocarcinoma. Signal enhancement ratio ( SER ) -predicted stromal/epithelial proportion showed good agreement with histopathology measurements across three distinct centers. Signal enhancement ratio ( SER ) -predicted stromal proportion was demonstrated to be an independent prognostic factor for OS in PDAC. Graphical Abstract

Glucagon-like peptide-1 (GLP-1) analogs are important therapeutics for type 2 diabetes and obesity. Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog. We conducted a Phase 2, randomized, double-blind, placebo-controlled study enrolling 145 adults with T2DM. Participants were randomized to 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once-weekly injections for 20 weeks. The primary objective was to evaluate the efficacy of ecnoglutide, as measured by HbA1c change from baseline at Week 20. Secondary endpoints included body weight, glucose and lipid parameters, as well as safety. We show that, at end of treatment, the 0.4, 0.8, and 1.2 mg groups had statistically significant HbA1c reductions from baseline of −1.81%, −1.90%, and −2.39%, respectively, compared to −0.55% for placebo (P < 0.0001). At end of treatment, 71.9% of the 1.2 mg group had HbA1c ≤ 6.5% versus 9.1% on placebo, and 33.3% had body weight reductions ≥5% versus 3.0% for placebo. Ecnoglutide was generally safe and well tolerated. China Drug Trials Registry CTR20211014. A Phase 2, randomized, placebo-controlled study evaluated novel GLP-1 analog ecnoglutide in adults with type 2 diabetes. Here we show that ecnoglutide significantly reduced HbA1c from baseline up to -2.39% compared to -0.55% for placebo (P<0.0001), with a safety profile similar to approved GLP-1 analogs.

Utilizing liquid rubber to toughen epoxy resin is one of the most mature and promising methods. However, the dielectric relaxation characteristics of the epoxy/liquid rubber composites have not been studied systematically, while the relaxation behaviours are a critical factor for both micro and macro properties. In this paper, hydroxyl-terminated liquid nitrile rubber (HTBN) is employed to reinforce a kind of room-temperature-cured epoxy resin. The dielectric spectrum is measured and analysed. Results show that two relaxation processes are introduced in the binary composites. The α relaxation of HTBN shows a similar temperature dependence with the β relaxation of epoxy resin. The interfacial polarization leads to an increase of complex permittivity, which reaches its maximum at 70 °C. In addition, affected by interfacial polarization, the thermionic polarization is inhibited, and the samples with filler ratios of 15% and 25% show lower DC-conductivity below 150 °C. In addition, the α relaxation and thermionic polarization of epoxy resin obey the Vogel‒Fulcher‒Tammann law, while the interfacial polarization and DC-conductivity satisfy with the Arrhenius law. Furthermore, the fitting results of the Vogel temperature of α relaxation, glass transition temperature, apparent activation energy of interfacial polarization and DC-conductivity all decline with HTBN content. These results can provide a reference and theoretical guidance for the assessment of dielectric properties and the improvement of the formulation of liquid-rubber-toughened epoxy resin.

Palmatine is an isoquinoline alkaloid isolated from many medicinal plants with diverse pharmacological activities, with potential for the treatment of chronic metabolic disorders and infectious diseases. In the present study, a highly rapid, simple, and sensitive ultra‐performance liquid chromatography coupled with an ultra‐violet (UPLC‐UV) method was developed and validated for the pharmacokinetics and tissue distribution of palmatine following single intramuscular injection to Partridge Shank chickens. The process was sensitive, with a lower limit of quantification and good linearity over the range of 0.005‐10 µg/mL for UPLC‐UV in all biological matrices. Following a single intramuscular dose of 5 mg/kg b.w, palmatine was absorbed quickly and reached peak concentration (0.24 µg/mL) at 0.19 h and was still present in plasma at 12 h with a concentration of 0.011 µg/mL. The CL/F and Vd/F were 10.43 L·h−1·kg −1 and 56.69 L/kg, respectively. The Cmax values of palmatine in tissues decreased as follows: kidneys > liver > spleen > heart > lung > muscles, and were almost completely cleared from lungs 26 h after administration and were not detectable or significantly reduced in other tissues after 48 h. The results can provide a basis for exploring the therapeutic potential of palmatine and looking for new ways of wide clinical applications in poultry farming. Palmatine is an isoquinoline alkaloid isolated from many medicinal plants with diverse pharmacological activities, with potential for the treatment of chronic metabolic disorders and infectious diseases. In the present study, a highly rapid, simple and sensitive ultra‐performance liquid chromatography coupled with an ultra‐violet (UPLC‐UV) method was developed and validated for the pharmacokinetics and tissue distribution of palmatine following single intramuscular injection to Partridge Shank chickens. The process was sensitive, with a lower limit of quantification and good linearity over the range of 0.005‐10 µg/mL for UPLC‐UV in all biological matrices. Following a single intramuscular dose of 5 mg/kg b.w, palmatine was absorbed quickly and reached peak concentration (0.24 µg/mL) at 0.19 h and was still present in plasma at 12 h with a concentration of 0.011 µg/mL. The CL/F and Vd/F were 10.43 L·h−1·kg −1 and 56.69 L/kg, respectively. The Cmax values of palmatine in tissues decreased as follows: kidneys > liver > spleen > heart > lung > muscles, and were almost completely cleared from lungs 26 h after administration and were not detectable or significantly reduced in other tissues after 48 h. The results can provide a basis for exploring the therapeutic potential of palmatine and looking for new ways of wide clinical applications in poultry farming.

Five new nucleoside antibiotics, named streptcytosines A–E (1–5), and six known compounds, de-amosaminyl-cytosamine (6), plicacetin (7), bamicetin (8), amicetin (9), collismycin B (10), and SF2738 C (11), were isolated from a culture broth of Streptomyces sp. TPU1236A collected in Okinawa, Japan. The structures of new compounds were elucidated on the basis of their spectroscopic data (HRFABMS, IR, UV, and 2D NMR experiments including 1H-1H COSY, HMQC, HMBC, and NOESY spectra). Streptcytosine A (1) belonged to the amicetin group antibiotics, and streptcytosines B–E (2–5) were derivatives of de-amosaminyl-cytosamine (6), 2,3,6-trideoxyglucopyranosyl cytosine. Compound 1 inhibited the growth of Mycobacterium smegmatis (MIC = 32 µg/mL), while compounds 2–5 were not active at 50 µg/disc. Bamicetin (8) and amicetin (9) showed the MICs of 16 and 8 µg/mL, respectively.