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Abstract Threshold voltage ( $$V_{th}$$ V th ) assignment is convenient for leakage optimization due to the exponential relation between leakage power and $$V_{th}$$ V th by swapping logic cells without routing effort. However, it poses great challenge in large scale circuit design as an NP-hard problem. Machine learning-based approaches have been proposed to solve this problem, aiming to achieve well tradeoff between leakage power reduction and runtime speed up without new induced timing violation. In this paper, a leakage power optimization framework based on reinforcement learning (RL) with graph neural network (GNN) is first-ever proposed to formulate $$V_{th}$$ V th assignment as a RL process by learning timing and physical characteristics of each circuit instance with GNN. Multiple instances are selected in a non-overlapped manner for each RL action iteration to speed up convergence and decouple timing interdependence along circuit path, where the corresponding reward is carefully defined to tradeoff between leakage reduction and potential timing violation. The proposed framework was validated by the Opencores and IWLS 2005 benchmark circuits with TSMC 28 nm technology. Experimental results demonstrate that our work outperforms prior non-analytical and GNN-based methods with better leakage power optimization by additional 5% to 17% reduction, which is highly consistent with the commercial tool. When transferring the trained RL-based framework to unseen circuits, it achieves the roughly identical leakage optimization results as seen circuit and speed up the runtime by 5.7 $$\times$$ × to 8.5 $$\times$$ × compared with commercial tool.

Abstract The mine wind speed sensor is an important intelligent sensing equipment in the mine intelligent ventilation system that can provide accurate and key wind speed parameters for the intelligent ventilation system. The turbulent pulsation characteristics of the airflow in the underground tunnel are a major factor for the inaccurate measurement of mine wind speed. Therefore, according to the random non-stationary characteristics of a turbulent pulsation signal, a denoising method based on adaptive complete ensemble empirical mode decomposition (CEEMDAN) combined with the wavelet threshold is proposed for suppressing the turbulent pulsation noise in the wind speed signal. First, the CEEMDAN algorithm is used for decomposing the wind speed signal into a series of IMF components. Second, the continuous mean square error criterion is used for determining the high-frequency IMF components with more noise. The wavelet threshold denoising method is used for denoising the high-frequency IMF components with more noise. Finally, the denoised IMF components and remaining low-frequency IMF components are reconstructed for obtaining the denoised signal. The results of the denoising analysis of measured turbulent pulsation signals, comparative analysis of denoising of simulated turbulent pulsation signals by different joint denoising methods, and denoising analysis of actual mine wind speed sensor data indicate that the joint denoising method proposed in this study has a higher signal-to-noise ratio and lower root mean square error of the wind speed signal after denoising. Compared with the EMD-wavelet threshold and EEMD-wavelet threshold denoising methods, the denoising method proposed in this study is better and has higher denoising accuracy, which provides a new method for processing actual mine wind speed sensor data.

Introduction: Obesity and asthma are closely linked, but the current state of research on this topic and future research directions have yet to be comprehensively explored. This study aims to provide an up-to-date overview of the research landscape in the field of obesity and asthma. Methods: A bibliometric analysis was conducted using the Web of Science Core Collection database to identify papers published on obesity and asthma between 2013 and 2023. VOSviewer software was utilized for statistical analysis and visualization of collaborative networks, research trends, literature sources, citation analysis, co-citation analysis, and keyword analysis. Results: A total of 3406 records from 1010 journals authored by 17347 researchers affiliated with 4573 institutes across 117 countries and regions were retrieved. The number of publications and citations increased annually. The United States and China contributed the majority of records. Major nodes in the collaboration network map included Harvard Medical School, Johns Hopkins University, University of Newcastle, Karolinska Institution, University of Toronto, and Seoul National University. Prolific authors included Anne E. Dixon, Erick Forno, Lisa G. Wood, Deepa Rastogi, and Fernando Holguin. Research trends and hotspots focused on metabolism studies, Mendelian randomization, gut microbiome, inflammation response, gene, biomarker research, and comorbidities were identified as potential future research frontiers. Conclusion: This study provides a comprehensive overview of the current research status and trends in the field of obesity and asthma. Our findings highlight the importance of understanding collaboration patterns, research hotspots, and emerging frontiers to guide future research in this area.

Abstract P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor’s ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3’s physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3 +/+, but not in P2rx3 −/−, mice, indicating that the 1α3β, a “tunable” region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors.

High stress and multi faults lead to rising burst frequency in deep coal mine. Though backfilling mining serves as the most straightforward method for stress-decreasing and burst-preventing, it fails to eliminate coal burst completely. In order to decrease the influence of coal burst on safety mining of deep-buried seam with bursting liability, stress surge and drop mechanisms emerging in backfilling panel are studied with field measurement, theoretical analysis and laboratory test, and destressing effect of roof pre-blasting and large borehole drilling methods is analyzed. High stress, multi faults, width-changing pillar and mining disturbance leads to the emergence of stress concentration, stress surge and stress drop phenomenon in backfilling panel, but the concentration coefficient is smaller than 2.0. At the normal region, influence range reaches 30 m. It increases to 50 m when fault influence is considered and the value grows to 70 m if both fault and pillar influences are added to the panel. Fault activation and rock failure results in sudden release of strain energy, the mechanisms underlying the transition between strain energy and kinetic energy as well as dynamic stress wave are revealed. Note transition ratio reaches 17%. The superposition between dynamic stress wave and static stress field leads to sudden change in mining induced stress. Surrounding rock presents consolidation hardening behavior if it fails before load superposition, resulting in stress surge. Brittle caving behavior emerges if surrounding rock transits from intact into broken state, leading to stress drop. If surrounding rock still keeps intact after stress superposition, it presents elastic rebound behavior and experiences dynamic load. Large-scale rupture of hard roof is not observed due to supporting effect provided by backfilling materials and thus, microseismic energy associated with single event is smaller than 105 J. But microseicmic events presents asymmetrical distribution due to fault influences. They present high frequency and low energy mode at maingate side while low frequency and high energy mode is observed at tailgate side. As a result, burst monitoring pre-warning happens two times in the latter roadway and one time is observed in the former one. Hard roof pre-blasting and large borehole drilling methods are used to decrease mining-induced stress. Large-scale blasting fractures are formed in roof strata, which control stress concentration degree and stress increase speed effectively. Thus, coal burst danger is significantly decreased in deep mining.

The temperature and moisture of the pavement structure can be greatly influenced by the wind speed above pavement surface. The wind speed above pavement surface not only is dominated by the wind speed of atmosphere, but also it is highly related to the landform and buildings around road. However, currently there are no studies about the wind field above pavement surface in consideration of the effect of the landform and buildings. A simulation method, which is combined with geographic information system (GIS), wind data from meteorological observatory and computational fluid dynamics (CFD) software, is employed to study the effect of the landform and the wind speed of atmosphere on the wind field above pavement surface. Three cases are studied, including an urban road, a coastal road and a mountainous road. Furthermore, the wind field distribution above road surface in different wind directions was studied in our work. Results indicate that the wind field above pavement surface can be greatly affected by the landforms, buildings and wind direction. This simulation method can provide reliable results for the wind field above pavement surface. The maximum relative errors between simulated and measured wind speed can be less than 20% in the analysis of the three cases. It is recommended that the CFD simulation method is a good tool to accurately know the wind field above pavement surface.

Abstract Background The efficacy of levodopa, the most crucial metric for Parkinson’s disease diagnosis and treatment, is traditionally gauged through the levodopa challenge test, which lacks a predictive model. This study aims to probe the predictive power of T1-weighted MRI, the most accessible modality for levodopa response. Methods This retrospective study used two datasets: from the Parkinson’s Progression Markers Initiative (219 records) and the external clinical dataset from Ruijin Hospital (217 records). A novel feature extraction method using MedicalNet, a pre-trained deep learning network, along with three previous approaches was applied. Three machine learning models were trained and tested on the PPMI dataset and included clinical features, imaging features, and their union set, using the area under the curve (AUC) as the metric. The most significant brain regions were visualized. The external clinical dataset was further evaluated using trained models. A paired one-tailed t-test was performed between the two sets; statistical significance was set at p

Abstract Background KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. Methods Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. Results Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. Conclusions We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

Abstract Background Saiga antelope horn (SAH) is a traditional Chinese medicine for treating febrile seizure (FS) with precise efficacy, but its mechanism of action and functional substances are still unclear. Given the need for further research on SAH, our group conducted studies to elucidate its mechanisms and active substances. Methods An FS rat pup model was constructed through intraperitoneal injection of LPS and hyperthermia induction. Behavioural indicators of seizures, hippocampal histopathological alterations, serum levels of inflammatory cytokines and hippocampal levels of neurotransmitters were observed and measured to investigate the effects of SAH on FS model rats. Hippocampal metabolomics and network pharmacology analyses were conducted to reveal the differential metabolites, key peptides and pathways involved in the suppression of FS by SAH. Results SAH suppressed FS, decreased the inflammatory response and regulated the Glu-GABA balance. Metabolomic analysis revealed 13 biomarkers of FS, of which SAH improved the levels of 8 differential metabolites. Combined with network pharmacology, a “biomarker-core target-key peptide” network was constructed. The peptides of SAH, such as YGQL and LTGGF, could exert therapeutic effects via the arachidonic acid pathway. Molecular docking and ELISA results indicated that functional peptides of SAH could bind to PTGS2 target, inhibiting the generation of AA and its metabolites in hippocampal samples. Conclusion In summary, the functional peptides contained in SAH are the main material basis for the treatment of FS, potentially acting through neurotransmitter regulation and the arachidonic acid pathway. Graphical abstract

Abstract Ferroptosis, an iron-dependent regulated cell death mechanism, holds significant promise as a therapeutic strategy in oncology. In the current study, we explored the regulatory effects of epigallocatechin gallate (EGCG), a prominent polyphenol in green tea, on ferroptosis and its potential therapeutic implications for non-small cell lung cancer (NSCLC). Treatment of NSCLC cell lines with varying concentrations of EGCG resulted in a notable suppression of cell proliferation, as evidenced by a reduction in Ki67 immunofluorescence staining. Western blot analyses demonstrated that EGCG treatment led to a decrease in the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) while increasing the levels of acyl-CoA synthetase long-chain family member 4 (ACSL4). These molecular changes were accompanied by an increase in intracellular iron, malondialdehyde (MDA), and reactive oxygen species (ROS), alongside ultrastructural alterations characteristic of ferroptosis. Through small RNA sequencing and RT-qPCR, transfer RNA-derived small RNA 13502 (tsRNA-13502) was identified as a significant target of EGCG action, with its expression being upregulated in NSCLC tissues compared to adjacent non-tumorous tissues. EGCG was found to modulate the ferroptosis pathway by downregulating tsRNA-13502 and altering the expression of key ferroptosis regulators (GPX4/SLC7A11 and ACSL4), thereby promoting the accumulation of iron, MDA, and ROS, and ultimately inducing ferroptosis in NSCLC cells. This study elucidates EGCG’s multifaceted mechanisms of action, underscoring the modulation of ferroptosis as a viable therapeutic approach for enhancing NSCLC treatment outcomes.

Abstract In the context of the growing importance of heterocyclic compounds across various disciplines, numerous strategies for their construction have emerged. Exploiting the distinctive properties of cyclopropenes, this study introduces an innovative approach for the synthesis of benzo‐fused five‐membered oxa‐ and aza‐heterocycles through a formal [4+1] cyclization and subsequent acid‐catalyzed intramolecular O‐ to N‐ rearrangement. These transformations exhibit mild reaction conditions and a wide substrate scope. The applications in the late‐stage modification of complex molecules and in the synthesis of a potential PD‐L1 gene down‐regulator, make this method highly appealing in related fields. Combined experimental mechanistic studies and DFT calculations demonstrate Rh(III)‐mediated sequential C─H coupling/π‐allylation/dynamically favorable O‐attack route.

Background: Fruquintinib is a third-line and subsequent targeted therapy for patients with metastatic colorectal cancer (mCRC). Identifying survival predictors after fruquintinib is crucial for optimizing the clinical use of this medication. Objectives: We aimed to identify factors influencing the prognosis of patients with mCRC treated with fruquintinib and to leverage these insights to develop a nomogram model for estimating survival rates in this patient population. Design: Multicenter retrospective observational study. Methods: We collected patient data from January 2019 to October 2023, with one healthcare institution’s data serving as the training cohort and the other three hospitals’ data serving as the multicenter validation cohort. The nomogram for overall survival was calculated from Cox regression models, and variable selection was screened using the univariate Cox regression analysis with additional variables based on clinical experience. Model performance was measured by the concordance index (C-index), calibration curves, decision curve analyses (DCA), and utility (patient stratification into low-risk vs high-risk groups). Results: Data were ultimately collected on 240 patients, with 144 patients included in the training cohort and 96 included in the multicenter validation cohort. Predictors included in the nomogram were CA199, body mass index, T stage, the primary site of the tumor, and other metastatic and pathological differentiation. The C-index of the nomogram in the training set and multicenter validation was 0.714 and 0.729, respectively. The models were fully calibrated and their predictions aligned closely with the observed data. DCA curves indicated the promising clinical benefits of the predictive model. Finally, the reliability of the model was also verified through the risk classification using the nomogram. Conclusions: We constructed a nomogram for mCRC treated with fruquintinib based on six variables that may be used to assist in personalizing the use of the drug.

Summary: Lavender essential oil (LEO) has been shown to relieve pain in humans, but the underlying neural mechanisms remain unknown. Here, we found that inhalation exposure to 0.1% LEO confers antinociceptive effects in mice with complete Freund adjuvant (CFA)-induced inflammatory pain through activation of projections from the anterior piriform cortex (aPir) to the insular cortex (IC). Specifically, in vivo fiber photometry recordings and viral tracing data show that glutamatergic projections from the aPir (aPirGlu) innervate GABAergic neurons in the IC (ICGABA) to inhibit local glutamatergic neurons (ICGlu) that are hyperactivated in inflammatory pain. Optogenetic or chemogenetic activation of this aPirGlu→ICGABA→Glu pathway can recapitulate the antinociceptive effects of LEO inhalation in CFA mice. Conversely, artificial inhibition of IC-projecting aPirGlu neurons abolishes LEO-induced antinociception. Our study thus depicts an LEO-responsive olfactory system circuit mechanism for alleviating inflammatory pain via aPir→IC neural connections, providing evidence to support development of aroma-based treatments for alleviating pain.

A multi-physical field numerical model considering the thermo-chemical and mechanical effects was used to simulate the curing process of a nitrate ester plasticized polyether (NEPE) solid propellant. The curing process of solid rocket propellants was detected through physical experiments such as differential scanning calorimetry (DSC) and heat transfer. The variation laws and distribution patterns of the temperature field and curing degree field during the propellant curing process were numerically and experimentally analyzed, and the residual and contact stresses caused by the effects of temperature, chemical reaction, and pressure were studied. The results showed that the internal temperature field of the NEPE propellant during the curing process was closely related to the curing time. At about 3 d of curing time, the propellant curing rate was the fastest, and the temperature reached a maximum value of 58 °C. During curing, the NEPE solid propellant produces an unevenly distributed temperature field and curing degree field distribution, which aggravates the residual stress. The molding pressure can reduce the residual stress; however, when the pressure exceeds approximately 3 MPa, it causes extrusion stress on the interface layer between propellant-to-case and propellant-to-core mold. Based on the numerical calculation results, an optimal pressure calculation formula for multiple parameters that can quickly estimate the optimal pressure is derived.

Based on the Shenzhen-Zhongshan Link, the transient analytical solution of the steel shell immersed tunnel under the protection of fireproof board was deduced and verified through fire test. Then, the variation of the maximum temperature of the bottom steel shell with the thickness and thermal conductivity of the fireproof board was analyzed and suggestions on the selection of fireproof boards were given. Finally, a fitting formula for the maximum temperature of bottom steel shell was proposed. The results show that: (1) When the thermal contact resistance of the steel-concrete interface and the thermal resistance of cavity are 0.01 m2 °C/W and 0.02 m2 °C/W respectively under the case of 25 mm thick fireproof board, the variation of the analytical solution is consistent with test results, and the peak value is similar. (2) Based on the three-dimensional diagram of d -λ-T, with 300 °C as the fire resistance limit of structure, the range of the fireproof board parameters is obtained: when λ reaches 0.14 and 0.4 respectively, d shall not be less than 10 mm and 28.38 mm (3) The scatter points obtained from analysis were fitted using quadratic polynomials and linear functions respectively. Considering the accuracy and simplicity, the linear fitting formula is given as T = 275.66–7.41*d+644.6*λ.

Lung cancer, one of the most prevalent cancers worldwide, stands as the primary cause of cancer-related deaths. As is well-known, the utmost crucial risk factor contributing to lung cancer is smoking. In recent years, remarkable progress has been made in treating lung cancer, particularly non-small cell lung cancer (NSCLC). Nevertheless, the absence of effective and accurate biomarkers for diagnosing and treating lung cancer remains a pressing issue. Interleukin 22 (IL-22) is a member of the IL-10 cytokine family. It exerts biological functions (including induction of proliferation and anti-apoptotic signaling pathways, enhancement of tissue regeneration and immunity defense) by binding to heterodimeric receptors containing type 1 receptor chain (R1) and type 2 receptor chain (R2). IL-22 has been identified as a pro-cancer factor since dysregulation of the IL-22-IL-22R system has been implicated in the development of different cancers, including lung, breast, gastric, pancreatic, and colon cancers. In this review, we discuss the differential expression, regulatory role, and potential clinical significance of IL-22 in lung cancer, while shedding light on innovative approaches for the future.

Abstract The development of dietary fibers as safe and effective food additives or nutrients for preventing and alleviating inflammatory bowel disease (IBD) is increasingly important. β‐glucans, renowned prebiotics, have shown promise in alleviating IBD symptoms by modulating gut flora diversity and repairing the intestinal barrier. Auricularia auricula‐judae, an edible fungus, contains a β‐glucan with a triple‐helical structure polysaccharide from black fungus Auricularia auricula‐judae (BFP), which exhibits unique sol–gel properties. This study revealed that BFP forms weak gels or sols at increasing concentrations, enhancing swallow ability and extending intestinal transit time, beneficial for patients with dysphagia requiring targeted intestinal administration. The impact of BFP on dextran sulfate sodium (DSS)‐induced ulcerative colitis was examined, showing that BFP sols maintain intestinal barrier integrity by up‐regulating MUC2, ZO‐1, Occludin, and Claudin expressions and reducing inflammatory factors. Furthermore, BFP sols augmented probiotics abundance, decreased harmful bacteria, and restored Bacteroidetes/Firmicutes balance. These findings suggest BFP sols’ potential as functional food or alternative IBD treatment.

An environment-friendly solvent debinding process for polyoxymethylene (POM) for metal injection molding (MIM) is presented as an alternative to the traditional catalytic debinding method. This study investigated the influence of various acid solvents and debinding temperature. The optimal debinding parameters were 5 M nitric acid solution at 60 °C. Based on the calculation of effective diffusivity and activation energy, the solvent-debinding mechanism for POM is proposed. The removal of POM was controlled by three processes: dissolution, diffusion, and chemical reaction. The resulting final titanium parts have a high density of over 95% and an ultimate tensile strength of 406 MPa.

Abstract Virus-induced gene silencing (VIGS) is a powerful technology for molecular characterization of gene functions in plants and has the potential to prevent and control plant diseases. Unfortunately, VIGS in many woody perennials such as citrus are severely hindered because they have a long juvenile period and are recalcitrant to infection compared to herbaceous plants. Here, we report the development of a simple and effective VIGS system based on citrus leaf blotch virus (CLBV), a virus endemic in most citrus-producing countries but showing no symptoms in most citrus varieties. By Agrobacterium-mediated vacuum-infiltration (AVI), pCLBV201-su245 and pCLBV201-pds391 triggered efficient gene silencing (85%) and silencing phenotypes began to appear at 30 days post infiltration/inoculation (dpi), a similar period for achieving that on herbaceous plants. Moreover, the silencing phenotypes could still be observed four years post inoculation. Further, pCLBV201-lob369 was constructed to silence the gene lateral organ boundaries1 (lob1), encoding a key factor for susceptibility to citrus canker that caused by Xanthomonas citri ssp. citri (Xcc). The resistance evaluation results showed that the lesion area, disease index, and bacterial content in the pCLBV201-lob369 treatment group were decreased by 64%, 14%, and 67%, respectively. This work provides a simple and effective VIGS system for citrus which has the potential to be used for diseases control.

Background and objective Brivudine has been used in herpes zoster (HZ) treatment for years, but the safety and efficacy of brivudine are inconclusive. Here we perform a meta-analysis to assess the efficacy, safety, incidence of postherpetic neuralgia of brivudine.Methods Data of randomized controlled Trials (RCTS) were obtained from the databases of both English (PubMed, Embase, and Cochrane Library) and Chinese (China National Knowledge Infrastructure, China Science Journal Database, and WanFang Database) literatures from inception to 12 September 2022. Meta-analyses of efficacy and safety of Brivudine for the treatment of herpes zoster for RCTS were conducted.Results The analyses included seven RCTS (2095 patients in experimental group and 2076 patients in control group) in the treatment of HZ with brivudine. It suggested that the brivudine group was superior to the control group in terms of efficacy (p = .0002) and incidence of postherpetic neuralgia (p = .04). But the incidence of adverse reactions has no significant difference between the brivudine and the control groups (p = .22). In addition, subgroup analysis of adverse events also showed that brivudine was about the same safety as other modalities in the treatment of HZ (p > .05).Conclusions Brivudine is effective for HZ. However, the evidence on the safety of brivudine is insufficient.

AbstractThe oxidation of unsaturated lipids, facilitated by the enzyme Arachidonic acid 15-lipoxygenase (ALOX15), is an essential element in the development of ferroptosis. This study combined a dual-score exclusion strategy with high-throughput virtual screening, naive Bayesian and recursive partitioning machine learning models, the already established ALOX15 inhibitor i472, and a docking-based fragment substitution optimisation approach to identify potential ALOX15 inhibitors, ultimately leading to the discovery of three FDA-approved drugs that demonstrate optimal inhibitory potential against ALOX15. Through fragment substitution-based optimisation, seven new inhibitor structures have been developed. To evaluate their practicality, ADMET predictions and molecular dynamics simulations were performed. In conclusion, the compounds found in this study provide a novel approach to combat conditions related to ferroptosis-related injury by inhibiting ALOX15.

The intrinsic magnetization compensation behaviors of rare-earth iron garnets (REIGs) make the material promising for applications in ultrafast spin storage devices. REIG/heavy metal heterostructures such as TbIG/Pt often display two sign crossovers of anomalous Hall effect resistance with varying temperatures. One of these crossovers is attributed to the magnetization compensation of REIG, and the other to the competition between the magnetic proximity effect and the spin Hall effect. Here, we design trilayer REIG heterostructures based on two rare-earth species (Tb and Eu). We modulate the layer stacking of the TbIG/EuIG/TbIG sandwich with a fixed total thickness and explore the contributions of REIG bulk and REIG/Pt interfaces on these two crossover points. As TbIG gradually moves away from Pt, the compensation temperature shows some fluctuations. However, when TbIG is entirely out of contact with Pt, the second crossover point undergoes a change that shows REIG/Pt interface dependency. The results highlight the dominance of REIG bulk on the compensation behavior and the interface sensitivity of the second crossover point. This study provides a reference for designing controllable spintronics devices, such as magnon valve applications.

Fully ceramic microencapsulated (FCM) fuel is a five-layer intercalation system material consisting of a UO2 core, a sparse pyrolytic carbon layer (Buffer), an inner dense pyrolytic carbon layer (IPyC), an outer dense pyrolytic carbon layer (OPyC), and a silicon carbide matrix (SiC). At first, this paper researched the thermodynamic models of the materials, including heat conduction coefficient, Young’s modulus, thermal expansion coefficient, etc. Then DIGIMAT, the finite element software, was used to establish the equivalent volume element (RVE) for the equivalent analysis of the thermodynamic properties of the FCM fuel pellet. Finally, the thermodynamic equivalent performance model of FCM fuel was obtained by multi-factor fitting analysis. The results show that among these thermodynamic properties of FCM fuel pellets, the Young’s modulus, thermal expansion coefficient and plastic performance are mainly affected by temperature, fast neutron fluence, and UO2 volume fraction; the specific heat capacity is mainly affected by UO2 volume fraction and temperature; the heat conduction coefficient is mainly affected by temperature and UO2 volume fraction. The thermal conductivity is mainly affected by temperature, burnup and UO2 volume fraction. In this study, the equivalent models obtained through the fitting analysis of RVE model parameters can well describe the thermodynamic behavior of FCM fuel particles.

In recent years, the application of textile reinforced mortar (TRM) as an overlay has become an important method for repairing and strengthening old masonry structures. However, the quantitative analysis and design of TRM-strengthened reinforced concrete (RC) beams are still limited. To address this gap, a nonlinear finite element (FE) model is proposed in this study to simulate the flexural behavior of TRM-strengthened RC beams. The developed model is validated using experimental results and subsequently utilized for the design of TRM-strengthened RC beams. Various TRM design parameters, including the number of textile layers, textile longitudinal length, and textile mesh size, are parametrically investigated. The modelling results reveal that increasing the number of textile layers and longitudinal length while decreasing the textile mesh size can enhance the bending strength of TRM-strengthened RC beams. Furthermore, an analytical model is proposed to predict the flexural strength of TRM-strengthened RC beams, facilitating rapid strength estimation of TRM-strengthened RC beams. The predicted results demonstrate good agreement with the numerical simulation results. The established FE models can predict the bending performance of TRM-strengthened RC beams under different reinforcement conditions, and the simulation outcomes can provide valuable guidance for their design.

Steel embedded parts welded on the surface of steel-concrete-steel tunnel elements serve as thermal bridges in tunnel fires. Their influence on temperature field and macroscopic thermal damage of steel-concrete-steel structure were investigated through fire tests, and their heat transfer forms were analyzed. Then, a thermal bridge disposal scheme was proposed and examined. The results show that steel embedded parts significantly cause an increase and an uneven distribution of steel shell temperature in tunnel fires. As time exposed to fire increases, the extent and range of these influences grow. Thermal bridges raise the average temperature by 45.2 % inside the steel-concrete-steel structure, worsen the unevenness of temperature distribution in horizontal and vertical directions. Thermal bridges worsen surface macroscopic damage, lengthening cracks by more than 32.5 % and widening them by more than 22.6 times. Within a distance of 30 cm from the embedded part, heat provided by embedded parts accounts for over 79.9 % of the steel shell's total heat, and heat conveyed along the steel shell through thermal conduction accounts for over 53.7 %. GX-3 high-temperature adhesive is an effective method for thermal bridge treatment. These detailed findings offer new insights into the design of fire insulation schemes for the steel-concrete-steel structure.

Wood, a widely used eco-friendly material in ancient architecture, has endured for thousands of years. However, environmental changes over time cause varying degrees of internal damage, degrading mechanical properties and compromising overall building safety. Investigating wood's mechanical properties and damage mechanisms in ancient structures is crucial. This study simulates real conditions of ancient wooden structures by subjecting three common fresh woods (beech, maple, sylvestris pine) to extreme environments: high-temperature treatments (100, 150, 200, and 250 °C for 15, 30, 45 min), water immersion, and exposure to acidic/alkaline environments. Using the MTS instrument, longitudinal compression and bending tests are conducted, analyzing compressive strength and flexural performance. DIC tracks both test processes, and SEM provides a microscopic analysis of damage mechanisms. Results show that beech and maple outperform sylvestris pine under high temperatures and acidic/alkaline conditions. In extreme environments, wood's mechanical strength correlates with moisture content and hemicellulose decomposition. High temperatures enhance wood's mechanical properties through dehydration reactions, but prolonged exposure leads to continuous hemicellulose, cellulose, and lignin decomposition, ultimately reducing wood's mechanical performance.

Abstract Cancer cell growth, metastasis, and drug resistance pose significant challenges in the management of lung adenocarcinoma (LUAD). However, there is a deficiency in optimal predictive models capable of accurately forecasting patient prognoses and guiding the selection of targeted treatments. Programmed cell death (PCD) pathways play a pivotal role in the development and progression of various cancers, offering potential as prognostic indicators and drug sensitivity markers for LUAD patients. The development and validation of predictive models were conducted by integrating 13 PCD patterns with comprehensive analysis of bulk RNA, single-cell RNA transcriptomics, and pertinent clinicopathological details derived from TCGA-LUAD and six GEO datasets. Utilizing the machine learning algorithms, we identified ten critical differentially expressed genes associated with PCD in LUAD, namely CHEK2, KRT18, RRM2, GAPDH, MMP1, CHRNA5, TMPRSS4, ITGB4, CD79A, and CTLA4. Subsequently, we conducted a programmed cell death index (PCDI) based on these genes across the aforementioned cohorts and integrated this index with relevant clinical features to develop several prognostic nomograms. Furthermore, we observed a significant correlation between the PCDI and immune features in LUAD, including immune cell infiltration and the expression of immune checkpoint molecules. Additionally, we found that patients with a high PCDI score may exhibit resistance to immunotherapy and standard adjuvant chemotherapy regimens; however, they may benefit from other FDA-supported drugs such as docetaxel and dasatinib. In conclusion, the PCDI holds potential as a prognostic signature and can facilitate personalized treatment for LUAD patients.

Abstract Background R140Q mutation in isocitrate dehydrogenase 2 (IDH2) promotes leukemogenesis. Targeting IDH2/R140Q yields encouraging therapeutic effects in the clinical setting. However, therapeutic resistance occurs in 12% of IDH2/R140Q inhibitor treated patients. The IDH2/R140Q mutant converted TF-1 cells to proliferate in a cytokine-independent manner. This study investigated the signaling pathways involved in TF-1(R140Q) cell proliferation conversion as alternative therapeutic strategies to improve outcomes in patients with acute myeloid leukemia (AML) harboring IDH2/R140Q. Methods The effects of IDH2/R140Q mutation on TF-1 cell survival induced by GM-CSF withdrawal were evaluated using flow cytometry assay. The expression levels of apoptosis-related proteins, total or phosphorylated STAT3/5, ERK, and AKT in wild-type TF-1(WT) or TF-1(R140Q) cells under different conditions were evaluated using western blot analysis. Cell viability was tested using MTT assay. The mRNA expression levels of GM-CSF, IL-3, IL-6, G-CSF, leukemia inhibitory factor (LIF), oncostatin M (OSM), and IL-11 in TF-1(WT) and TF-1(R140Q) cells were quantified via RT-PCR. The secretion levels of GM-CSF, OSM, and LIF were determined using ELISA. Results Our results showed that STAT3 and STAT5 exhibited aberrant constitutive phosphorylation in TF-1(R140Q) cells compared with TF-1(WT) cells. Inhibition of STAT3/5 phosphorylation suppressed the cytokine-independent proliferation of TF-1(R140Q) cells. Moreover, the autocrine GM-CSF, LIF and OSM levels increased, which is consistent with constitutive STAT5/3 activation in TF-1(R140Q) cells, as compared with TF-1(WT) cells. Conclusions The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q) cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a novel strategy for the treatment of AML in patients harboring the IDH2/R140Q mutation. Video Abstract

Abstract Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.

Abstract Anxiety-associated symptoms following acute stress usually become extinct gradually within a period of time. However, the mechanisms underlying how individuals cope with stress to achieve the extinction of anxiety are not clear. Here we show that acute restraint stress causes an increase in the activity of GABAergic neurons in the CeA (GABACeA) in male mice, resulting in anxiety-like behaviors within 12 hours; meanwhile, elevated GABACeA neuronal CX3CL1 secretion via MST4 (mammalian sterile-20-like kinase 4)-NF-κB-CX3CL1 signaling consequently activates microglia in the CeA. Activated microglia in turn inhibit GABACeA neuronal activity via the engulfment of their dendritic spines, ultimately leading to the extinction of anxiety-like behaviors induced by restraint stress. These findings reveal a dynamic molecular and cellular mechanism in which microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress.

Ralstonia solanacearum causes a lethal bacterial wilt disease in many crops, leading to huge losses in crop production every year. Understanding of plant–R. solanacearum interactions will aid to develop efficient strategies to control the disease. As a soilborne pathogen, R. solanacearum naturally infects plants via roots. A huge limitation in studying plant–R. solanacearum interactions is the large variation of R. solanacearum infection assay due to the variable soil conditions and uneven inoculum exposure. Here, we developed a robust and reliable Petri-dish inoculation method which allows consistent and stable infection in young plant seedlings. This method is easy to use, takes about only 10 days from seed germination to the completion of inoculation assay, and requires less inoculum of bacteria as well as growth chamber space. We proved the efficacy of the seedling Petri-dish inoculation method by analyzing plant defense primed by molecular patterns, resistance of defense-related plant mutants, and virulence of R. solanacearum mutants. Furthermore, we demonstrated that the seedling Petri-dish inoculation method can be applied to other host plants such as tobacco and has great potential for high-throughput screening of resistant plant germplasms to bacterial wilt in the future.

The Casparian strip membrane domain proteins (CASPs) are pivotal for the formation of the Casparian strip (CS) in endodermal cells and play a crucial role in a plant’s response to environmental stresses. However, existing research on the CASP gene family in rice and Arabidopsis lacks a comprehensive bioinformatics analysis and necessitates further exploration. In this study, we identified 41 OsCASP and 39 AtCASP genes, which were grouped into six distinct subgroups. Collinearity analysis underscored the pivotal roles of WGD and TD events in driving the evolution of CASPs, with WGDs being the dominant force. On the one hand, the analysis of cis-elements indicated that most OsCASP and AtCASP genes contain MYB binding motifs. On the other hand, RNA-seq revealed that the majority of OsCASP and AtCASP genes are highly expressed in roots, particularly in endodermal cells, where OsCASP_like11/9 and AtCASP_like1/31 demonstrated the most pronounced expression. These results suggest that OsCASP_like11/9 and AtCASP_like1/31 might be candidate genes involved in the formation of the endodermis CS. RT-qPCR results demonstrated that OsCASP_like2/3/13/17/21/30 may be candidate genes for the ion defect process. Collectively, this study offers a theoretical foundation for unraveling the biological functions of CASP genes in rice and Arabidopsis.

BackgroundOsteoporosis (OP) and cardiovascular disease (CVD) are major global public health issues, especially exacerbated by the challenges of an aging population. As these problems intensify, the associated burden on global health is expected to increase significantly. Despite extensive epidemiological investigations into the potential association between OP and CVD, establishing a clear causal relationship remains elusive.MethodsInstrumental variables were selected from summary statistics of the IEU GWAS database. Five different components of BMD (heel BMD, LS BMD, FA BMD, FN BMD, and TB BMD) were used as OP phenotypes. CHD, MI, and stroke were selected to represent CVD. Multiple analysis methods were used to evaluate the causal relationship between CVD and OP comprehensively. In addition, sensitivity analyses(Cochran’s Q test, MR-Egger intercept test, and “leave one out” analysis) were performed to verify the reliability of the results.ResultsThe MR showed a significant causal relationship between CHD on heel BMD and TB BMD; in the reverse analysis, there was no evidence that OP has a significant causal effect on CVD. The reliability of the results was confirmed through sensitivity analysis.ConclusionThe study results revealed that CHD was causally associated with Heel BMD and TB BMD, while in the reverse MR analysis, the causal relationship between OP and CVD was not supported. This result posits CHD as a potential etiological factor for OP and prompts that routine bone density assessment at traditional sites (forearm, femoral neck, lumbar spine) using DAX may inadequately discern underlying osteoporosis issues in CHD patients. The recommendation is to synergistically incorporate heel ultrasound or DAX for total body bone density examinations, ensuring clinical diagnostics are both precise and reliable. Moreover, these findings provide valuable insights for public health, contributing to the development of pertinent prevention and treatment strategies.

Abstract Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM‐NPs) are formed by hybridizing ginseng‐derived extracellular vesicles‐like particles (G‐EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G‐EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor‐specific cytotoxic T lymphocytes (CTLs). HM‐NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long‐term immune protection can be obtained after vaccinating with HM‐NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G‐EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

Effective treatment of infected diabetic wound (IDW) requires delivering therapeutic agents to both wound surface and deep layers, as well as improving the wound microenvironment through antibacterial actions, clearing excessive reactive oxygen species (ROS), and promoting vascular regeneration. Here, we present a novel inorganic nanosheet called MnO2/PDA@Cu, consisting of manganese dioxide (MnO2) with copper (Cu) ions loaded on its surface through in-situ polymerization, using polydopamine (PDA) as an intermediate. We then encapsulated the MnO2/PDA@Cu nanosheet into a methacrylated hyaluronic acid (HA) soluble microneedle patch, creating a photodynamic-controllable multifunctional MnO2/PDA@Cu-HA microneedle. We used this microneedle to treat IDWs in a rat full-thickness skin defect model. Results demonstrated that the MnO2/PDA@Cu-HA microneedle effectively delivered therapeutic agents to both wound surface and deep layers, where PDA's photodynamic therapy swiftly combated bacteria under 808 nm near-infrared irradiation. Simultaneously, MnO2 acted as a nanoenzyme, mitigating ROS levels and providing oxygen for wound healing. In addition, the photothermal effect of PDA further facilitated the release of Cu, promoting vascularization. The MnO2/PDA@Cu-HA microneedle significantly accelerated wound closure, re-epithelialization, and collagen deposition, enhancing IDW healing. In conclusion, our synthesized MnO2/PDA@Cu-HA microneedle represents a photodynamic-controllable multifunctional platform for IDW treatment, offering a promising approach for effective wound management.

Emerging research into metabolic dysfunction-associated steatotic liver disease (MASLD) up until January 2024 has highlighted the critical role of cuproptosis, a unique cell death mechanism triggered by copper overload, in the disease's development. This connection offers new insights into MASLD's complex pathogenesis, pointing to copper accumulation as a key factor that disrupts lipid metabolism and insulin sensitivity. The identification of cuproptosis as a significant contributor to MASLD underscores the potential for targeting copper-mediated pathways for novel therapeutic approaches. This promising avenue suggests that managing copper levels could mitigate MASLD progression, offering a fresh perspective on treatment strategies. Further investigations into how cuproptosis influences MASLD are essential for unraveling the detailed mechanisms at play and for identifying effective interventions. The focus on copper's role in liver health opens up the possibility of developing targeted therapies that address the underlying causes of MASLD, moving beyond symptomatic treatment to tackle the root of the problem. The exploration of cuproptosis in the context of MASLD exemplifies the importance of understanding metal homeostasis in metabolic diseases and represents a significant step forward in the quest for more effective treatments. This research direction lights path for innovative MASLD management and reversal.

Mineralized collagen scaffold is one of the best choices for bone defects treatment, but weak mechanical strength is the main factor restricting its development. Recent studies demonstrated that despite being a fundamental form of mechanical stimulation in human activities, the impact of cyclic compressive stress on collagen mineralization remains unclear, with even less known about the dynamic mechanical mechanism. This study employed cyclic compressive stress to investigate its effect on collagen mineralization. The findings revealed that cyclic compressive strain promotes collagen mineralization by facilitating increased mineral penetration into the collagen and altering mineral morphology on the collagen surface. As the mineral volume fraction of mineralized collagen rises, its elastic modulus also increases. Additionally, the finite element simulation results proved that cyclic compressive stress can impact mineral distribution by affecting their transport and deposition, consequently influencing the stress distribution and regulating mechanical properties of mineralized collagen. Alterations in mechanical properties provide feedback on internal stress distribution, subsequently impacting mineral mineralization. This study achieves a closed-loop study on the mechanical regulated collagen mineralization, offers insight into the mechanism of collagen mineralization, paving the way for further exploration of biomineralization mechanisms and potentially inspiring novel approaches for the fabrication of mineralized collagen scaffolds.

Abstract Background Lines of evidence indicated that, immune checkpoints (ICs) inhibitors enhanced T cell immune response to exert anti-tumor effects. However, T cell exhaustion has been so far a major obstacle to antitumor immunotherapy in colorectal cancer patients. Our previous studies showed that ginseng-derived nanoparticles (GDNPs) inhibited the growth of various tumors by reprograming tumor-associated macrophages (TAMs) and downregulated the ICs expression on T cells in tumor microenvironment (TME), but the underlying effector mechanisms remained unclear. Methods The correlation between arginase-1 (ARG1) and T cells was computed based on the colorectal cancer patients in TCGA database. In vitro, we observed that GDNPs reprogrammed TAMs inhibited ARG1 release and ultimately ameliorated T cell exhaustion according to several techniques including WB, PCR, ELISA and flow cytometry. We also used an in vivo MC38 tumor-bearing model and administered GDNPs to assess their anti-tumor effects through multiple indices. The mechanism that GDNPs improved T cell exhaustion was further clarified using the bioinformatics tools and flow cytometry. Results GDNPs reprogramed TAMs via reducing ARG1 production. Moreover, normalized arginine metabolism ameliorated T cell exhaustion through mTOR-T-bet axis, resulting in reduced ICs expression and enhanced CD8+ T cells expansion. Conclusions By regulating the mTOR-T-bet axis, GDNPs reprogramed macrophages to regulate ARG1 release, which further ameliorated T cell exhaustion in TME. These findings provided new insights into comprehending the mechanisms underlying the mitigation of T cell exhaustion, which may facilitate the development of innovative therapeutic strategies in the field of cancer treatment.

Abstract There has been an increase in cardiovascular morbidity and mortality over the past few decades, making cardiovascular disease (CVD) the leading cause of death worldwide. However, the pathogenesis of CVD is multi-factorial, complex, and not fully understood. The gut microbiome has long been recognized to play a critical role in maintaining the physiological and metabolic health of the host. Recent scientific advances have provided evidence that alterations in the gut microbiome and its metabolites have a profound influence on the development and progression of CVD. Among the trillions of microorganisms in the gut, bifidobacteria, which, interestingly, were found through the literature to play a key role not only in regulating gut microbiota function and metabolism, but also in reducing classical risk factors for CVD (e.g., obesity, hyperlipidemia, diabetes) by suppressing oxidative stress, improving immunomodulation, and correcting lipid, glucose, and cholesterol metabolism. This review explores the direct and indirect effects of bifidobacteria on the development of CVD and highlights its potential therapeutic value in hypertension, atherosclerosis, myocardial infarction, and heart failure. By describing the key role of Bifidobacterium in the link between gut microbiology and CVD, we aim to provide a theoretical basis for improving the subsequent clinical applications of Bifidobacterium and for the development of Bifidobacterium nutritional products.

Abstract Background Epstein–Barr virus (EBV)‐associated gastric lymphoepithelioma‐like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking. Aims Here, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options. Materials & Methods A retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV‐positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out. Discussion 13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV‐associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV‐positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52‐year‐old male with advanced EBV‐positive GLELC who showed a favorable response to the combined therapy with . A repeat evaluation showed sustained partial response (PR), and the progression‐free survival (PFS) was more than 34 months until now. Conclusion Compared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively “hot” TME that may provide the rationality to treat with immunotherapy in EBV‐related GLELC.

Abstract Background A later chronotype has been found to be associated with unhealthy habits and diseases, such as an unhealthy diet and metabolic syndrome in adults. Little is known about the association between chronotype, eating habits, physical activity and obesity. Thus, this study aimed to explore the relationships between chronotype, eating behaviors, physical activity, and overweight in Chinese school-aged children. Methods Data from this study was based on 952 schoolchildren (10–12 y) from six primary schools that participated in China. Anthropometric measurements of height and body weight were performed. Information about sleeping habits, dietary behaviors, and other lifestyle behaviors was gathered using a self-administered questionnaire. Multiple linear regression analysis or multivariable logistic regression model was performed to assess the associations between chronotype, eating behaviors, physical activity, and overweight. Results Nearly 70% (69.9%) of the participants had a self-reported morning chronotype. Multiple linear regression analysis revealed chronotype score was positively associated with physical activities (all P values < 0.001) and sleep duration (all P values < 0.001) and negatively associated with BMI, meal time, eating jet lag and social jet lag (all P values < 0.001). Multivariable logistic regression analysis showed that compared to morning types, non-morning types individuals were more likely to be overweight (OR = 1.593, P value < 0.05), and had more frequent consumption of fast food (OR = 1.616, P value < 0.05), but less frequent consumption of milk (OR = 0.716, P value < 0.05), less time taking part in moderate (OR = 1.356, P value < 0.05) or muscle strengthening (OR = 1.393, 1.877, P value < 0.05) physical activity. Conclusions This study indicates that early chronotype children are more active, have healthier dietary habits, get more sleep, have shorter social jet lag, and are less likely to be overweight than non-early chronotype children. Our findings suggest that later chronotype may be a potential indicator in the early detection of overweight, unhealthy eating, and physical inactivity behaviors. Plain english summary Chronotype has been found to have an important impact on individual’s health. In the present study, we conducted a cross-sectional study to investigate the association between chronotype, eating behaviors, physical activity, and overweight in school-aged children. The findings showed that children with early chronotype is associated with more active, healthier dietary behaviors, longer sleep duration, short social jet lag, and a lower risk of overweight.

Background: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a preparation widely used in chemotherapy for cancers. However, only some patients benefit from this treatment. Therefore, identifying which patients will respond to nab-paclitaxel therapy is crucial. Methods: A cohort of 32 patients with lung squamous cell carcinoma (LUSC) treated with nab-paclitaxel were enrolled in this study. Plasma samples were collected before chemotherapy and used to perform metabolomic and lipidomic analyses. Tumor response to two cycles of chemotherapy was evaluated. Metabolites differentially present among populations were screened and analyzed. Results: According to the RECIST criteria, one-third of patients had a significant response to nab-paclitaxel, whereas one-fifth showed no discernible benefit. According to the criteria of variable importance in projection >1 and fold change >2, we identified 61, 81 and 54 differential metabolites between the progressive disease (PD) vs partial response (PR), PD vs stable disease (SD), and SD vs PR groups, respectively. Moreover, we used three variation in logistic regression models and ROC diagnostic curves to identify optimal metabolites for stratifying patients with differing chemotherapeutic responses. The PD vs SD, SD vs PR, and PD vs PR groups were well separated on the basis of cis-9,10-epoxystearic acid/octapentaenoic acid (AUC 0.9330), salicyluric acid/DG (18:1/20:5/0:0) (AUC 1.0000) and D-glyceric acid/9,12-octadecadienoic acid (AUC 1.0000), respectively. Conclusion: The baseline metabolic profiles significantly differed between responder and non-responder patients with LUSC treated with nab-paclitaxel. These differential metabolites have the potential to predict the outcomes of patients with LUSC before chemotherapy.

Abstract Background Long-chain polyunsaturated fatty acids (LC-PUFAs), such as docosahexaenoic acid (DHA), are essential for human health and have been widely used in the food and pharmaceutical industries. However, the limited availability of natural sources, such as oily fish, has led to the pursuit of microbial production as a promising alternative. Yarrowia lipolytica can produce various PUFAs via genetic modification. A recent study upgraded Y. lipolytica for DHA production by expressing a four-gene cluster encoding a myxobacterial PKS-like PUFA synthase, reducing the demand for redox power. However, the genetic architecture of gene expression in Y. lipolytica is complex and involves various control elements, offering space for additional improvement of DHA production. This study was designed to optimize the expression of the PUFA cluster using a modular cloning approach. Results Expression of the monocistronic cluster with each gene under the control of the constitutive TEF promoter led to low-level DHA production. By using the minLEU2 promoter instead and incorporating additional upstream activating UAS1B4 sequences, 5' promoter introns, and intergenic spacers, DHA production was increased by 16-fold. The producers remained stable over 185 h of cultivation. Beneficially, the different genetic control elements acted synergistically: UAS1B elements generally increased expression, while the intron caused gene-specific effects. Mutants with UAS1B16 sequences within 2–8 kb distance, however, were found to be genetically unstable, which limited production performance over time, suggesting the avoidance of long repetitive sequence blocks in synthetic multigene clusters and careful monitoring of genetic stability in producing strains. Conclusions Overall, the results demonstrate the effectiveness of synthetic heterologous gene clusters to drive DHA production in Y. lipolytica. The combinatorial exploration of different genetic control elements allowed the optimization of DHA production. These findings have important implications for developing Y. lipolytica strains for the industrial-scale production of valuable polyunsaturated fatty acids.

Abstract P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Abstract Background Oxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora. Methods In this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora’s role in HGWD for chronic OIPN by pain scoring and related pathological analysis. Results HGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis. Conclusions HGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.

Sorghum northern anthracnose is a leaf disease affecting sorghum, which results in plant death and substantial yield loss. This study aimed to effectively understand the disease, clarify its biological characteristics, and evaluate the resistance of germplasm resources. A field sample was collected to isolate and purify the pathogen. The pathogen, identified as Kabatiella zeae Narita et Hiratsuka using both morphological and molecular techniques, was further confirmed as the causative agent of northern anthracnose of sorghum following Robert Koch’s principles. The results revealed the optimal culture temperature to be 25 °C, preferred dark culture conditions, and the best growth on potato glucose agar medium with sucrose and L-leucine as the optimal carbon and nitrogen sources, respectively. A total of 138 sorghum germplasm resources were inoculated and evaluated using the isolated pathogen, with 20 lines (14.49%) exhibiting high resistance, 18 lines (13.04%) showing disease resistance, 27 lines (19.57%) demonstrating medium resistance, 37 lines (26.81%) being susceptible, and 36 lines (26.09%) classified as highly susceptible. The indoor fungicide screening was conducted through pathogen medium application, and enilconazole, pyraclostrobin, methylthiophanate, and flusilazole were screened for the best fungicide inhibition with a 100% inhibition rate compared with the control. This study provides reference for field pharmaceutical control in sorghum production.

The inferior mechanical performance and freeze–thaw (FT) resistance of recycled concrete are mostly due to the significant water absorption and porosity of recycled coarse particles. In this study, different dosages of zeolite powder were used in recycled concrete. A series of macroscopic tests were used to evaluate the workability and FT durability of zeolite powder-modified recycled concrete (ZPRC). X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to reveal the micro-mechanisms of FT resistance in ZPRC. The results show that the increase in zeolite powder content leads to a decrease in the slump and water absorption of ZPRC. Additionally, ZPRC with 10% zeolite powder has superior mechanical characteristics and tolerance to FT conditions. The higher strength and FT resistance of the ZPRC can be attributed to the particle-filling effect, water storage function, and pozzolanic reaction of zeolite powder, which results in a denser microstructure. The particle-filling effect of zeolite powder promotes the reduction of surface pores in recycled coarse aggregates (RCAs). The water storage function of zeolite powder can provide water for the secondary hydration of cement particles while reducing the free water content in ZPRC. The pozzolanic reaction of zeolite powder can also promote the generation of hydrated calcium silicate and anorthite, thereby making the microstructure of ZPRC more compact. These results provide theoretical guidance for the engineering application of recycled concrete in cold regions.

Abstract This study aimed to evaluate the potential of exosomes from cancer cells to predict chemoresistance in pancreatic cancer (PC) and explore the molecular mechanisms through RNA-sequencing and mass spectrometry. We sought to understand the connection between the exosomal Medium-chain acyl-CoA dehydrogenase (ACADM) level and the reaction to gemcitabine in vivo and in patients with PC. We employed loss-of-function, gain-of-function, metabolome mass spectrometry, and xenograft models to investigate the effect of exosomal ACADM in chemoresistance in PC. Our results showed that the molecules involved in lipid metabolism in exosomes vary between PC cells with different gemcitabine sensitivity. Exosomal ACADM (Exo-ACADM) was strongly correlated with gemcitabine sensitivity in vivo, which can be used as a predictor for postoperative gemcitabine chemosensitivity in pancreatic patients. Moreover, ACADM was found to regulate the gemcitabine response by affecting ferroptosis through Glutathione peroxidase 4 (GPX4) and mevalonate pathways. It was also observed that ACADM increased the consumption of unsaturated fatty acids and decreased intracellular lipid peroxides and reactive oxygen species (ROS) levels. In conclusion, this research suggests that Exo-ACADM may be a viable biomarker for predicting the responsiveness of patients to chemotherapy.

Abstract Large Scale Natural Draft Cooling Tower has become a hot topic in China because it is an important part of the nuclear power plant, and its environmental impacts include shading, solar energy loss, water deposition and salt deposition. In China, there is no built large-scale natural draft cooling tower of nuclear power plant. Therefore, model prediction becomes an effective way to solve this problem. This paper introduces the basic principles and structure of SACTI (Seasonal and Annual Cooling Tower Impact) model. SACTI is a cooling tower assessment model developed by Argonne National Laboratory, USA. A comparative case study between China's Pengze Nuclear Power Plant and the US Amos Power Plant is also presented. Calculations were carried out for the Pengze and Amos power plants, and the results showed that the maximum value of salt deposition at the Pengze plant was about 166.5 kg/(km2-month) at a distance of 800 m from the cooling tower. The maximum value of salt deposition at the Amos plant was about 92.85 kg/(km2-month) at a distance of 600 m from the cooling tower. Conclusions show that the research work can provide a useful solution in future work, the simulation results of the SACTI model have a potential mean in the absence of monitoring data. This research provides a way to generate simulation data through SACTI program in the design process of nuclear power plant cooling tower, and designers can use these data to determine how the cooling tower will affect the natural environment and manage within an appropriate range to reduce the impact on the environment.

Summary: Neural mechanisms underlying amputation-related secondary pain are unclear. Using in vivo two-photon imaging, three-dimensional reconstruction, and fiber photometry recording, we show that a microglial activation cascade from the primary somatosensory cortex of forelimb (S1FL) to the primary somatosensory cortex of hindlimb (S1HL) mediates the disinhibition and subsequent hyperexcitation of glutamatergic neurons in the S1HL (S1HLGlu), which then drives secondary mechanical hypersensitivity development in ipsilateral hindpaws of mice with forepaw amputation. Forepaw amputation induces rapid S1FL microglial activation that further activates S1HL microglia via the CCL2-CCR2 signaling pathway. Increased engulfment of GABAergic presynapses by activated microglia stimulates S1HLGlu neuronal activity, ultimately leading to secondary mechanical hypersensitivity of hindpaws. It is widely believed direct neuronal projection drives interactions between distinct brain regions to prime specific behaviors. Our study reveals microglial interactions spanning different subregions of the somatosensory cortex to drive a maladaptive neuronal response underlying secondary mechanical hypersensitivity at non-injured sites.