High-purity graphite is extensively utilized in the semiconductor industry.Enhancing its corrosion resistance is crucial for reducing the manufacturing costs of the third-generation semiconductors.In this study,a cont...High-purity graphite is extensively utilized in the semiconductor industry.Enhancing its corrosion resistance is crucial for reducing the manufacturing costs of the third-generation semiconductors.In this study,a continuous and dense TaC coating was fabricated on the surface of graphite using CVD method.The corrosion resistance and mechanism of the coating were investigated in a high-temperature steam environment.This environment involved temperatures exceeding 2200 K and the erosion of the coating by Si-containing mixed steam flows.The results indicated that the corrosion in the affected areas was primarily due to chemical reactions,characterized by the formation of pores and micro-cracks,whereas failure areas were dominated by mechanical delamination,which led to macroscopic defects.Moreover,the mixed high-temperature steam corrosion of the TaC coating showed preferential selectivity,resulting in a stepped corrosion morphology at the crystalline level.The surface roughness of the samples significantly increased after corrosion,from 0.36 to 5.28μm,although the surface composition remained largely unchanged.The TaC coating provides a certain level of protection to the graphite substrate,enhancing the service life of graphite components and demonstrating promising application potential.展开更多
AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induc...AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.展开更多
Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.展开更多
The penetration rate of new wind and photovoltaic energy in the power system has increased significantly,and the dramatic fluctuation of the net load of the grid has led to a severe lack of flexibility in the regional...The penetration rate of new wind and photovoltaic energy in the power system has increased significantly,and the dramatic fluctuation of the net load of the grid has led to a severe lack of flexibility in the regional grid.This paper proposes a hierarchical optimal dispatch strategy for a high proportion of new energy power systems that considers the balanced response of grid flexibility.Firstly,various flexibility resource regulation capabilities on the source-load side are analyzed,and then flexibility demand and flexibility response are matched,and flexibility demand response assessment is proposed;then,a hierarchical optimal dispatch model of the grid taking flexibility adjustment capability into account is established,and the upper model optimizes the net load curve with the objectives of minimizing the fluctuation of the net load,maximizing the benefits of energy storage and controllable loads,and optimizing the flexibility adjustment capability.The upper layer model optimizes the net load curve by minimizing net load fluctuation,maximizing energy storage and controllable load revenue,and optimizing flexibility adjustment capability.In contrast,the lower layer model optimizes the power allocation of thermal power units and regulates the lost load of wind and solar power generation by minimizing the total system operating cost.The results show that the proposed strategy improves the flexibility of the grid by 15.2%,gives full play to the regulation capability of each flexibility resource,and reduces the fluctuation of the net load by 15.6%to achieve optimal coordination between different types of flexibility resources.展开更多
Background:Circular RNAs(circRNAs)play a pivotal role in the development and advancement of various cancer types.However,the involvement of circ-PAN3 in hepatocellular carcinoma(HCC)is not well understood.To shed ligh...Background:Circular RNAs(circRNAs)play a pivotal role in the development and advancement of various cancer types.However,the involvement of circ-PAN3 in hepatocellular carcinoma(HCC)is not well understood.To shed light on this,we conducted a comprehensive study through biochemistry,cell biology,molecular biology,and bioinformatics techniques to investigate the role of circ-PAN3 and its associated pathway in the progression of HCC.Methods:Cell Counting Kit-8(CCK-8)assay and colony formation assay were utilized to evaluate cell proliferation;Quantitative real-time PCR(RT-qPCR)and Western blot were adopted for assessing mRNA and protein expression;Annexin V/propidium iodide(PI)staining was applied to detect cellular apoptosis;CircInteractome and Targetscan databases were searched to predict potential targets of circRNA and miRNA;Luciferase reporter assay and RNA pulldown assay were performed to examine the interaction of RNA molecules.Conclusions:Our findings revealed a significant increase in circ-PAN3 expression in HCC clinical specimens,which correlated with a poor survival rate in HCC patients.Knockdown of circ-PAN3 resulted in impaired cell proliferation,reduced cell survival,and inhibited tumorigenesis of HCC in vivo.Further analysis demonstrated that circ-PAN3 could serve as a sponge for miR-153,leading to a decrease in its expression level.This in turn upregulated cyclin D1 and ultimately promoted the proliferation of HCC cells.Additionally,overexpression of cyclin D1 mitigated the inhibitory effect on HCC proliferation induced by circ-PAN3 knockdown.Our study highlights the presence of a novel circ-PAN3/miR-153/cyclin D1 regulatory axis that plays a crucial role in the progression of HCC.展开更多
The hydrolysis behavior of CaMg_(2)In_(0.1),CaMg_(2)In_(0.3),CaMg_(2)In_(0.5),and CaMg_(2)In_(0.7)ternary alloys in an MgCl_(2) solution following casting and hydrogenation were investigated.The hydrolysis mechanism o...The hydrolysis behavior of CaMg_(2)In_(0.1),CaMg_(2)In_(0.3),CaMg_(2)In_(0.5),and CaMg_(2)In_(0.7)ternary alloys in an MgCl_(2) solution following casting and hydrogenation were investigated.The hydrolysis mechanism of these alloys is elucidated through an analysis of microstructure,phase composition,and kinetics before and after hydrolysis.The nucleation-growth Avrami model is employed to accurately model the hydrolysis kinetics,revealing improved hydrolysis yields and reaction rates following hydrogenation.Notably,CaMg_(2)In_(0.1)has demonstrated exceptional hydrolysis characteristics,exhibiting a yield of 1140 mL/g,an initial hydrolysis rate of 113 mL/g·s,and an activation energy of 24.3±1.7 kJ·mol^(-1).The yield of H-CaMg_(2)In_(0.1)further escalates to 1800 mL/g with a rate of 221 mL/g·s,attributed to the formation of Ca_(4)Mg_(3)H_(14)and In phases subsequent to the hydrogenation of In_(2)Ca and Mg_(3)In phases in the alloy.These newly formed phases act as catalysts and actively participate in the hydrolysis process,providing active sites for hydrogen production,thus enhancing hydrolysis yields and kinetics.It is observed that with increasing In content,the order of hydrolysis performance of the alloy is as follows:CaMg_(2)In_(0.1)>CaMg_(2)In_(0.3)>CaMg_(2)In_(0.5)>CaMg_(2)In_(0.7),consistent with the trend after hydrogenation.These findings indicate that the addition of In significantly enhances the hydrolysis performance of CaMg_(2)alloys,offering a promising strategy for preparing magnesium-based alloys with high yields and favorable kinetic properties.展开更多
Hybridization remains an important method for breeding new poplar varieties.It results in significant variation in leaf phenotype among parents and offspring,and among offspring themselves.This study aimed to investig...Hybridization remains an important method for breeding new poplar varieties.It results in significant variation in leaf phenotype among parents and offspring,and among offspring themselves.This study aimed to investigate whether leaf shape variations were similar in offspring produced from reciprocal crosses.Specifically,two hybrid combinations were produced:the direct cross with Populus ussuriensis as the maternal parent and P.simonii×P.nigra as the paternal parent(HY53),and the reciprocal cross with P.simonii×P.nigra as the maternal parent and P.ussuriensis as the paternal parent(HY268).Using 3-month-old rooted cuttings from 40 clones(36 F1 hybrids and their parents)growing in a greenhouse,we measured and analyzed 14 leaf morphological traits to assess genetic variation and heterosis.The results showed HY53 clones generally exhibited greater average height than HY268 clones.Leaf phenotypes differed between the two hybrid combinations,with significant differences observed among parents and offspring for almost all traits,as revealed by analysis of variance(ANOVA).The phenotypic coefficient of variation was higher in HY268 clones.Additionally,leaf traits demonstrated high repeatability.Notably,some hybrid offspring exhibited positive or negative mid-parent heterosis,as well as over-parent heterosis for certain leaf phenotypes.The systematic cluster analysis further indicated distinct separation among HY268 clones.This research provides valuable materials for poplar breeding and offers insights into hybrid vigor in wood plants.The findings highlight the importance of reciprocal crossing in influencing leaf phenotype variation and heterosis,offering practical insights for future breeding strategies.展开更多
AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mor...AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kB, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined. RESULTS: SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymphnodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kB protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group. CONCLUSION: Dexamethasone can protect mesen-teric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.展开更多
The replacement of the disulfide bridge of CPI-1, a peptide inhibitor of light chain of Botulinum toxin serotype A, with the thioether-containing and biscarba-containing diaminodiacid bridge leads to a significant dec...The replacement of the disulfide bridge of CPI-1, a peptide inhibitor of light chain of Botulinum toxin serotype A, with the thioether-containing and biscarba-containing diaminodiacid bridge leads to a significant decrease in the degradation by trypsin and increase in the detoxification activity in vivo, the addition of hydrophobic or positive amino acid at C-terminus of modified peptides further improves the inhibitory activity.展开更多
The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer （CRC）...The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer （CRC） tissue specimens and investigated their correlation with patient clinicopathologic characteristics. We determined CXCR4 and Nrf2 expression in 76 CRC tissue specimens and paired normal tissue specimens by immunohistochemistry and real-time PCR. We found that the protein and mRNA transcript levels of CXCR4 were significantly higher in CRC tissue specimens than in paired normal tissues, while the expressions of Nrf2 protein and mRNA were increased in CRC tissues compared to distant non-cancerous tissues. High expression level of CXCR4 was positively correlated with poorly differentiated （P=0.031）, more advanced tumor-node-metastasis （TNM） stage （P=0.019）, lymph node metastasis （P=0.007） and distant metastasis （P=0.018）. However, the expression of Nrf2 protein was positively correlated with larger tumor size （P=0.049）, more advanced TNM stage （P=0.013）, lymph node metastasis （P=0.016） and distant metastasis （P=0.023）. Moreover, there was a strong relationship between CXCR4 and Nrf2 expression in CRC tissues, indicating that high Nrf2 expression may contribute to CXCR4 overexpression. In addition, combined expression of CXCR4 and Nrf2 strongly correlated with lymph node metastasis and distant metastasis （P=0.003）. Furthermore, we found that combined high expression of CXCR4 and Nrf2 had stronger correlation with lymph node metastasis and distant metastasis than any single molecule did. This study indicated that the abnormal expression of CXCR4 and Nrf2 contributed to the progression of CRC.展开更多
AIM:To evaluate the efficacy and safety of Usights UC100 illuminated microcatheter in microcatheter-assisted trabeculotomy(MAT).METHODS:Totally 10 eyes of 10 patients with primary open angle glaucoma(POAG)who underwen...AIM:To evaluate the efficacy and safety of Usights UC100 illuminated microcatheter in microcatheter-assisted trabeculotomy(MAT).METHODS:Totally 10 eyes of 10 patients with primary open angle glaucoma(POAG)who underwent MAT facilitated by Usights UC100(5 eyes)or iTrack(5 eyes)were reviewed.The success of this surgery was defined as intraocular pressure(IOP)<22 mm Hg with>30%reduction,without oral glaucoma medications,or additional glaucoma surgery.RESULTS:The mean pre-operative IOP was 25.38±10.22 mm Hg in the Usights UC100 group and 19.98±3.87 mm Hg in the iTrack group.MAT was achieved in all eyes in both groups.The success rates for the Usights UC100 group and iTrack groups were in all and 4 eyes,respectively.Both microcatheters produced a statistically significant reduction in IOP,and eyes using Usights UC100 achieved a lower IOP than the iTrack group at 3mo followup(12.58±1.52 and 14.84±1.89 mm Hg,respectively),but no statistical significance was there.No severe side effects were observed in either group.CONCLUSION:MAT using Usights UC100 or iTrack both achieve significant pressure reduction in cases of POAG,and Usights UC100 is as safe as iTrack.展开更多
In the domain of quantitative trading,the imperative is to translate historical financial data into predictive signals,commonly referred to as alpha factors,which serves to anticipate future market trends.Notably,form...In the domain of quantitative trading,the imperative is to translate historical financial data into predictive signals,commonly referred to as alpha factors,which serves to anticipate future market trends.Notably,formulaic alphas that are expressible via explicit mathematical formulas are highly sought after by certain investors for better interpretability.The evolving landscape of technology has witnessed the increasing deployment of large language models(LLMs)across various domains,which raises the question of whether LLMs can be effective in the context of formulaic alpha-mining tasks.This paper presents several paradigms aimed at integrating LLMs into the optimization loop of alpha mining,including scenarios where an LLM serves as the sole alpha generator,as well as instances where LLMs enhance existing frameworks.Empirical evaluations on real-world stock data demonstrate significant performance improvements,with our hybrid method achieving an average information coefficient(IC)of 0.0515,a 75%improvement over the baseline—a state-of-the-art reinforcement learning-based framework;backtesting further reveals a cumulative excess return more than double the baseline framework.These results underscore the potential of LLM-enhanced approaches in advancing formulaic alpha discovery and driving innovation in quantitative trading.展开更多
The existing discrete element model of wheat plants lacks the glume,which hinders the simulation of the entire threshing process.To address this issue,this paper takes wheat at the harvest stage as the research object...The existing discrete element model of wheat plants lacks the glume,which hinders the simulation of the entire threshing process.To address this issue,this paper takes wheat at the harvest stage as the research object and constructs a complete discrete element model of wheat plants with glumes based on the Hertz-Mindlin with bonding model in the EDEM simulation software.The parameter calibration of wheat glumes discrete element model is studied through collision bounce experiments,slope experiments,and accumulation experiments.The results show that the coefficient of restitution,coefficient of static friction,and coefficient of rolling friction between glume and steel are 0.488,0.625,and 0.048,respectively,and the coefficient of restitution,coefficient of static friction,and coefficient of rolling friction between glume and glume are 0.232,0.966,and 0.059,respectively.The relative errors between the simulation results and the measured values are less than 5%,and the calibration parameters are effective.Based on the structural parameters of the self-developed experiment-bed of tangential axial-flow grain threshing device,a three-dimensional model of the wheat threshing device is established to simulate the whole threshing process of the complete wheat plant,and the bench-scale experiments are carried out with the non-threshing rate as the performance index.The results indicate that the model can completely simulate the separation process of glume and grain and the movement law of different grains,and the relative error of non-threshing rate between the simulation experiments and bench-scale experiments is 4.36%.This further demonstrates that the proposed model can provide a reference for the wheat threshing process research and device performance optimization design.展开更多
Stray current can cause corrosion of underground structural rebar,adding rubber particles to the invert-filling concrete is an effective prevent method to reduce stray current corrosion.In our research,the corrosion c...Stray current can cause corrosion of underground structural rebar,adding rubber particles to the invert-filling concrete is an effective prevent method to reduce stray current corrosion.In our research,the corrosion calculation model of multi-ring shield tunnel containing rubber concrete invert-filling was established,the coupling analysis of electric field and chemical field in composite structures was realized through mesoscale simulations,and the accuracy of calculation model was verified by full-scale test.Through calculation,the corrosion characteristic of segment rebar and bolt of multi-ring shield tunnel were investigated under different rubber content.The result shows that adding rubber particles to the invert-filling can not only reduce the corrosion current density of segment rebar and tunnel bolt effectively,but also affect the distribution form of rebar corrosion current density in both circumferential and longitudinal directions.When the rubber content increases from 5%to 20%,the maximum corrosion density of segment rebar and tunnel bolt will decrease from 31%to 58%and 30%to 32%,respectively.Under different stray current leakage modes,when the rubber content and input voltage are the same,the segment and bolt corrosion current density under single rail-two points leakage mode is greater than that in the two rails-single point leakage mode.展开更多
The rise of online social platforms has enhanced connectivity and access to information.Still,it has also enabled the proliferation of malicious social bots that threaten platform security and disrupt social order.In ...The rise of online social platforms has enhanced connectivity and access to information.Still,it has also enabled the proliferation of malicious social bots that threaten platform security and disrupt social order.In this paper,we introduce a unified framework for defining and classifying malicious social bots along three dimensions:behavior,interaction,and operation.We then present a comprehensive review of social bot detection methods,tracing their evolution from traditional machine learning techniques to deep learning architectures and graph neural networks,with particular emphasis on recent advances in group-level detection.We also explore the emerging paradigm of Large Language Model(LLM)based bot detection.This paper reviews the current state of research,identifies key challenges,and outlines future directions.It provides a cohesive foundation for building more robust detection frameworks to counter the evolving threats posed by malicious social bots.展开更多
It was a challenge to monitor concrete structure crack under complex environmental action.To obtain conductive hydrogel material with higher stretchability,signal response sensitivity and stability to monitor concrete...It was a challenge to monitor concrete structure crack under complex environmental action.To obtain conductive hydrogel material with higher stretchability,signal response sensitivity and stability to monitor concrete structure cracking,the conductive hydrogel reinforced by different content of cellulose nanocrystals,which is called polyacrylic acid-cellulose nanocrystals(PAA-CNC),were developed in this paper.The performance improvement of PAA-CNC was studied by scanning electron microscope,resistance,uniaxial tensile and cyclic tensile test.Finally,the concrete crack monitoring accuracy of PAA-CNC was verified by three-point bend loading test.The result showed that combining cellulose nanocrystals with hydroxyl in conductive hydrogels can form uniformly dispersed micelles and three-dimensional network structure,which can increase the ionic conductive path and connection strength between molecules.When cellulose nanocrystals content of hydrogel was 0.12%,the effective strain sensing range and sensitivity within the range reached the maximum.When the content of cellulose nanocrystals was 0.12,the effective strain sensing range and sensitivity of PAA-CNC will reach maximum value.Compared with other contents of cellulose nanocrystals,PAA-CNC_(0.12)can produce a stable signal response when tested and quickly recover to the initial resistance after cyclic stretching.The crack width obtained by PAA-CNC_(0.12)does not exceed 5%of that obtained by digital image correlation equipment.展开更多
ω-Conotoxins inhibit N-type voltage-gated calcium(Ca_(v)2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index.Here,we synthesized and characterized a novelω-conotoxin,Bu8...ω-Conotoxins inhibit N-type voltage-gated calcium(Ca_(v)2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index.Here,we synthesized and characterized a novelω-conotoxin,Bu8 from Conus bullatus,which consists of 25 amino acid residues and three disulfide bridges.Bu8 selectively and potently inhibits depolarization-activated Ba^(2+)currents mediated by rat Ca_(v)2.2 expressed in HEK293 T cells(IC_(50)=89 nmol/L).Bu8 is two-fold more potent thanω-conotoxin MVIIA,aω-conotoxin currently used for the treatment of severe chronic pain.It also displays potent analgesic activity in animal pain models of hot plate and acetic acid writhing but has fewer side effects on mouse motor function and lower toxicity in goldfish.Its lower side effects may be attributed to its faster binding rate and higher recovery ratios.The NMR structure demonstrates that Bu8 contains a small irregular tripleβ-strand.The structure-activity relationships of Bu8 Ala mutants and Bu8/MVIIA hybrid mutants demonstrate that the binding mode of Ca_(v)2.2 with the amino acid residues in loop 1 and loop 2 of Bu8 is different from that of MVIIA.This study characterizes a novel,more potentω-conotoxin and provides new insights for designing Ca_(v)2.2 antagonists.展开更多
文摘High-purity graphite is extensively utilized in the semiconductor industry.Enhancing its corrosion resistance is crucial for reducing the manufacturing costs of the third-generation semiconductors.In this study,a continuous and dense TaC coating was fabricated on the surface of graphite using CVD method.The corrosion resistance and mechanism of the coating were investigated in a high-temperature steam environment.This environment involved temperatures exceeding 2200 K and the erosion of the coating by Si-containing mixed steam flows.The results indicated that the corrosion in the affected areas was primarily due to chemical reactions,characterized by the formation of pores and micro-cracks,whereas failure areas were dominated by mechanical delamination,which led to macroscopic defects.Moreover,the mixed high-temperature steam corrosion of the TaC coating showed preferential selectivity,resulting in a stepped corrosion morphology at the crystalline level.The surface roughness of the samples significantly increased after corrosion,from 0.36 to 5.28μm,although the surface composition remained largely unchanged.The TaC coating provides a certain level of protection to the graphite substrate,enhancing the service life of graphite components and demonstrating promising application potential.
基金Supported by the National Natural Science Fundation of China(No.82101107No.81471575).
文摘AIM:To identify key genes and inflammatory signaling pathways involved in the anti-inflammatory effects of Hedysarum polybotrys polysaccharide(HPS)in a rat model of endotoxin-induced uveitis(EIU).METHODS:EIU was induced in Wistar rats through subcutaneous injection of lipopolysaccharide(LPS,200μg)and the rats were then randomly assigned to EIU group(n=5)and the HPS intervention group(n=5).HPS(400 mg/kg,intraperitoneally)or its carrier was administered 24h and 1h prior to EIU induction.Eyes were examined and enucleated 24h post-induction,and total RNA was extracted from the iris-ciliary body.Gene expression microarrays were used to identify differentially expressed genes(DEGs),followed by bioinformatics analyses,including gene ontology(GO)and pathway analysis.Key findings were not experimentally validated at the mRNA or protein level.RESULTS:A total of 322 DEGs were identified,comprising 254 mRNA and 68 lncRNA genes.GO analysis revealed significant functional categories,including response to LPS.Pathway analysis identified key signaling pathways involved in uveitis,such as cytokine-cytokine receptor interactions.Notably,16 mRNA and 7 lncRNA DEGs emerged as central nodes in the gene correlation network.CONCLUSION:HPS exerts its anti-inflammatory effects through coordinated signaling pathways,offering insights into potential therapeutic targets for managing uveitis.
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
文摘The penetration rate of new wind and photovoltaic energy in the power system has increased significantly,and the dramatic fluctuation of the net load of the grid has led to a severe lack of flexibility in the regional grid.This paper proposes a hierarchical optimal dispatch strategy for a high proportion of new energy power systems that considers the balanced response of grid flexibility.Firstly,various flexibility resource regulation capabilities on the source-load side are analyzed,and then flexibility demand and flexibility response are matched,and flexibility demand response assessment is proposed;then,a hierarchical optimal dispatch model of the grid taking flexibility adjustment capability into account is established,and the upper model optimizes the net load curve with the objectives of minimizing the fluctuation of the net load,maximizing the benefits of energy storage and controllable loads,and optimizing the flexibility adjustment capability.The upper layer model optimizes the net load curve by minimizing net load fluctuation,maximizing energy storage and controllable load revenue,and optimizing flexibility adjustment capability.In contrast,the lower layer model optimizes the power allocation of thermal power units and regulates the lost load of wind and solar power generation by minimizing the total system operating cost.The results show that the proposed strategy improves the flexibility of the grid by 15.2%,gives full play to the regulation capability of each flexibility resource,and reduces the fluctuation of the net load by 15.6%to achieve optimal coordination between different types of flexibility resources.
基金the National Natural Science Foundation of China(Grants No.81272659 to Renyin Qin,81602475 to Xingjun Guo,81502633 Xu Li)。
文摘Background:Circular RNAs(circRNAs)play a pivotal role in the development and advancement of various cancer types.However,the involvement of circ-PAN3 in hepatocellular carcinoma(HCC)is not well understood.To shed light on this,we conducted a comprehensive study through biochemistry,cell biology,molecular biology,and bioinformatics techniques to investigate the role of circ-PAN3 and its associated pathway in the progression of HCC.Methods:Cell Counting Kit-8(CCK-8)assay and colony formation assay were utilized to evaluate cell proliferation;Quantitative real-time PCR(RT-qPCR)and Western blot were adopted for assessing mRNA and protein expression;Annexin V/propidium iodide(PI)staining was applied to detect cellular apoptosis;CircInteractome and Targetscan databases were searched to predict potential targets of circRNA and miRNA;Luciferase reporter assay and RNA pulldown assay were performed to examine the interaction of RNA molecules.Conclusions:Our findings revealed a significant increase in circ-PAN3 expression in HCC clinical specimens,which correlated with a poor survival rate in HCC patients.Knockdown of circ-PAN3 resulted in impaired cell proliferation,reduced cell survival,and inhibited tumorigenesis of HCC in vivo.Further analysis demonstrated that circ-PAN3 could serve as a sponge for miR-153,leading to a decrease in its expression level.This in turn upregulated cyclin D1 and ultimately promoted the proliferation of HCC cells.Additionally,overexpression of cyclin D1 mitigated the inhibitory effect on HCC proliferation induced by circ-PAN3 knockdown.Our study highlights the presence of a novel circ-PAN3/miR-153/cyclin D1 regulatory axis that plays a crucial role in the progression of HCC.
基金supported by the Fundamental Research Program of Shanxi Province(Nos.202203021211193 and 202203021211190)the Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi(Nos.2022L291 and 2022L274)+1 种基金the National Natural Science Foundations of China(Nos.51761032,51871125 and 52071227)the Key Scientific Research Project in Shanxi Province(No.202102050201003).
文摘The hydrolysis behavior of CaMg_(2)In_(0.1),CaMg_(2)In_(0.3),CaMg_(2)In_(0.5),and CaMg_(2)In_(0.7)ternary alloys in an MgCl_(2) solution following casting and hydrogenation were investigated.The hydrolysis mechanism of these alloys is elucidated through an analysis of microstructure,phase composition,and kinetics before and after hydrolysis.The nucleation-growth Avrami model is employed to accurately model the hydrolysis kinetics,revealing improved hydrolysis yields and reaction rates following hydrogenation.Notably,CaMg_(2)In_(0.1)has demonstrated exceptional hydrolysis characteristics,exhibiting a yield of 1140 mL/g,an initial hydrolysis rate of 113 mL/g·s,and an activation energy of 24.3±1.7 kJ·mol^(-1).The yield of H-CaMg_(2)In_(0.1)further escalates to 1800 mL/g with a rate of 221 mL/g·s,attributed to the formation of Ca_(4)Mg_(3)H_(14)and In phases subsequent to the hydrogenation of In_(2)Ca and Mg_(3)In phases in the alloy.These newly formed phases act as catalysts and actively participate in the hydrolysis process,providing active sites for hydrogen production,thus enhancing hydrolysis yields and kinetics.It is observed that with increasing In content,the order of hydrolysis performance of the alloy is as follows:CaMg_(2)In_(0.1)>CaMg_(2)In_(0.3)>CaMg_(2)In_(0.5)>CaMg_(2)In_(0.7),consistent with the trend after hydrogenation.These findings indicate that the addition of In significantly enhances the hydrolysis performance of CaMg_(2)alloys,offering a promising strategy for preparing magnesium-based alloys with high yields and favorable kinetic properties.
基金supported by“National Key R&D Program of China(2021YFD2200203)”“the Fundamental Research Funds for the Central Universities(No.2572022AW02 and No.2572023CT19)”。
文摘Hybridization remains an important method for breeding new poplar varieties.It results in significant variation in leaf phenotype among parents and offspring,and among offspring themselves.This study aimed to investigate whether leaf shape variations were similar in offspring produced from reciprocal crosses.Specifically,two hybrid combinations were produced:the direct cross with Populus ussuriensis as the maternal parent and P.simonii×P.nigra as the paternal parent(HY53),and the reciprocal cross with P.simonii×P.nigra as the maternal parent and P.ussuriensis as the paternal parent(HY268).Using 3-month-old rooted cuttings from 40 clones(36 F1 hybrids and their parents)growing in a greenhouse,we measured and analyzed 14 leaf morphological traits to assess genetic variation and heterosis.The results showed HY53 clones generally exhibited greater average height than HY268 clones.Leaf phenotypes differed between the two hybrid combinations,with significant differences observed among parents and offspring for almost all traits,as revealed by analysis of variance(ANOVA).The phenotypic coefficient of variation was higher in HY268 clones.Additionally,leaf traits demonstrated high repeatability.Notably,some hybrid offspring exhibited positive or negative mid-parent heterosis,as well as over-parent heterosis for certain leaf phenotypes.The systematic cluster analysis further indicated distinct separation among HY268 clones.This research provides valuable materials for poplar breeding and offers insights into hybrid vigor in wood plants.The findings highlight the importance of reciprocal crossing in influencing leaf phenotype variation and heterosis,offering practical insights for future breeding strategies.
基金Technological Foundation Project of Traditional Chinese Medicine Science of Zhejiang Province, No. 2003C130 and No. 2004C142Foundation Project for Medical Science and Technology of Zhejiang Province, No. 2003B134+5 种基金Grave Foundation Project for Technological and Development of Hangzhou, No. 2003123B19Intensive Foundation Project for Technology of Hangzhou No. 2004Z006Foundation Project for Medical Science and Technology of Hangzhou No. 2003A004Foundation Project for Technology of Hangzhou, No. 2005224
文摘AIM: To study the influence and mechanisms of dexamethasone on mesenteric lymph node of rats with severe acute pancreatitis (SAP). METHODS: The SAP rats were assigned to model, treated or sham-operated groups. The mortality, pathological changes of mesenteric lymph nodes, expression levels of NF-kB, P-selectin, Bax, Bcl-2 and caspase-3 protein and changes in apoptotic indexes in lymph nodes were observed at 3, 6 and 12 h after operation. The blood levels of endotoxin, superoxide dismutase (SOD), malondialdehyde (MDA), and endothelin-1 (ET-1) in blood were determined. RESULTS: SOD content, expression of Bax protein and apoptotic index were significantly higher in the treated group than in the model group at different time points (P < 0.05 or P < 0.01). Other blood-detecting indexes and histopathological scores of mesenteric lymphnodes were lower in the treated than in the model group (P < 0.05, P < 0.01 or P < 0.01). NF-kB protein expression was negative in all groups. Comparing P-selectin and caspase-3 expression levels among all three groups, there was no marked difference between the model and treated group. CONCLUSION: Dexamethasone can protect mesen-teric lymph nodes. The mechanism may be by reducing the content of inflammatory mediators in the blood and inducing lymphocyte apoptosis.
基金supported by the National Key Research and Development Project of China (2017YFC1200905)。
文摘The replacement of the disulfide bridge of CPI-1, a peptide inhibitor of light chain of Botulinum toxin serotype A, with the thioether-containing and biscarba-containing diaminodiacid bridge leads to a significant decrease in the degradation by trypsin and increase in the detoxification activity in vivo, the addition of hydrophobic or positive amino acid at C-terminus of modified peptides further improves the inhibitory activity.
基金supported by the National Natural Science Foundation of China(No.81172361,81001090 and 81201824)Specialized Research Fund for the Doctoral Program of Higher Education of China,the First Affiliated Hospital of Medical School of Xi'an Jiaotong University,the Fundamental Research of Xi'an Jiaotong University(No.20110201120061)Fundamental Research Funds for the Central Universities(No.xjj2010013)
文摘The CXCR4 and Nrf2 signaling pathways are abnormally activated in response to cellular stress in various types of human cancers. In this study, we examined the expression of CXCR4 and Nrf2 in colorectal cancer （CRC） tissue specimens and investigated their correlation with patient clinicopathologic characteristics. We determined CXCR4 and Nrf2 expression in 76 CRC tissue specimens and paired normal tissue specimens by immunohistochemistry and real-time PCR. We found that the protein and mRNA transcript levels of CXCR4 were significantly higher in CRC tissue specimens than in paired normal tissues, while the expressions of Nrf2 protein and mRNA were increased in CRC tissues compared to distant non-cancerous tissues. High expression level of CXCR4 was positively correlated with poorly differentiated （P=0.031）, more advanced tumor-node-metastasis （TNM） stage （P=0.019）, lymph node metastasis （P=0.007） and distant metastasis （P=0.018）. However, the expression of Nrf2 protein was positively correlated with larger tumor size （P=0.049）, more advanced TNM stage （P=0.013）, lymph node metastasis （P=0.016） and distant metastasis （P=0.023）. Moreover, there was a strong relationship between CXCR4 and Nrf2 expression in CRC tissues, indicating that high Nrf2 expression may contribute to CXCR4 overexpression. In addition, combined expression of CXCR4 and Nrf2 strongly correlated with lymph node metastasis and distant metastasis （P=0.003）. Furthermore, we found that combined high expression of CXCR4 and Nrf2 had stronger correlation with lymph node metastasis and distant metastasis than any single molecule did. This study indicated that the abnormal expression of CXCR4 and Nrf2 contributed to the progression of CRC.
基金Supported by the Clinical Medicine Plus X-Young Scholars Project,Peking University(No.PKU2020LCXQ023)National Natural Science Foundation of China(No.82101107).
文摘AIM:To evaluate the efficacy and safety of Usights UC100 illuminated microcatheter in microcatheter-assisted trabeculotomy(MAT).METHODS:Totally 10 eyes of 10 patients with primary open angle glaucoma(POAG)who underwent MAT facilitated by Usights UC100(5 eyes)or iTrack(5 eyes)were reviewed.The success of this surgery was defined as intraocular pressure(IOP)<22 mm Hg with>30%reduction,without oral glaucoma medications,or additional glaucoma surgery.RESULTS:The mean pre-operative IOP was 25.38±10.22 mm Hg in the Usights UC100 group and 19.98±3.87 mm Hg in the iTrack group.MAT was achieved in all eyes in both groups.The success rates for the Usights UC100 group and iTrack groups were in all and 4 eyes,respectively.Both microcatheters produced a statistically significant reduction in IOP,and eyes using Usights UC100 achieved a lower IOP than the iTrack group at 3mo followup(12.58±1.52 and 14.84±1.89 mm Hg,respectively),but no statistical significance was there.No severe side effects were observed in either group.CONCLUSION:MAT using Usights UC100 or iTrack both achieve significant pressure reduction in cases of POAG,and Usights UC100 is as safe as iTrack.
基金supported by the National Key R&D Program of China(No.2022YFC3303302)the National Natural Science Foundation of China(Grant Nos.62476263 and U2436209)+1 种基金the Project of Youth Innovation Promotion Association CAS,Beijing Nova Program 20230484430the Innovation Funding of ICT,CAS(No.E461060).
文摘In the domain of quantitative trading,the imperative is to translate historical financial data into predictive signals,commonly referred to as alpha factors,which serves to anticipate future market trends.Notably,formulaic alphas that are expressible via explicit mathematical formulas are highly sought after by certain investors for better interpretability.The evolving landscape of technology has witnessed the increasing deployment of large language models(LLMs)across various domains,which raises the question of whether LLMs can be effective in the context of formulaic alpha-mining tasks.This paper presents several paradigms aimed at integrating LLMs into the optimization loop of alpha mining,including scenarios where an LLM serves as the sole alpha generator,as well as instances where LLMs enhance existing frameworks.Empirical evaluations on real-world stock data demonstrate significant performance improvements,with our hybrid method achieving an average information coefficient(IC)of 0.0515,a 75%improvement over the baseline—a state-of-the-art reinforcement learning-based framework;backtesting further reveals a cumulative excess return more than double the baseline framework.These results underscore the potential of LLM-enhanced approaches in advancing formulaic alpha discovery and driving innovation in quantitative trading.
基金supported by the Major Scientific and Technological Project of Henan Province(Grant No.231100110200)the Open Subject of State Key Laboratory of Intelligent Agricultural Power Equipment(Grant No.SKLIAPE2023015)the Open Subject of Key Laboratory of Agricultural Equipment Technology for Hilly and Mountainous Areas(Grant No.2023KLOP03).
文摘The existing discrete element model of wheat plants lacks the glume,which hinders the simulation of the entire threshing process.To address this issue,this paper takes wheat at the harvest stage as the research object and constructs a complete discrete element model of wheat plants with glumes based on the Hertz-Mindlin with bonding model in the EDEM simulation software.The parameter calibration of wheat glumes discrete element model is studied through collision bounce experiments,slope experiments,and accumulation experiments.The results show that the coefficient of restitution,coefficient of static friction,and coefficient of rolling friction between glume and steel are 0.488,0.625,and 0.048,respectively,and the coefficient of restitution,coefficient of static friction,and coefficient of rolling friction between glume and glume are 0.232,0.966,and 0.059,respectively.The relative errors between the simulation results and the measured values are less than 5%,and the calibration parameters are effective.Based on the structural parameters of the self-developed experiment-bed of tangential axial-flow grain threshing device,a three-dimensional model of the wheat threshing device is established to simulate the whole threshing process of the complete wheat plant,and the bench-scale experiments are carried out with the non-threshing rate as the performance index.The results indicate that the model can completely simulate the separation process of glume and grain and the movement law of different grains,and the relative error of non-threshing rate between the simulation experiments and bench-scale experiments is 4.36%.This further demonstrates that the proposed model can provide a reference for the wheat threshing process research and device performance optimization design.
基金sponsored by the National Natural Science Foundation of China(Grant No.52378443)The opinions and conclusions presented in this article are those of the authors and do not necessarily reflect the views of the sponsoring organizations.
文摘Stray current can cause corrosion of underground structural rebar,adding rubber particles to the invert-filling concrete is an effective prevent method to reduce stray current corrosion.In our research,the corrosion calculation model of multi-ring shield tunnel containing rubber concrete invert-filling was established,the coupling analysis of electric field and chemical field in composite structures was realized through mesoscale simulations,and the accuracy of calculation model was verified by full-scale test.Through calculation,the corrosion characteristic of segment rebar and bolt of multi-ring shield tunnel were investigated under different rubber content.The result shows that adding rubber particles to the invert-filling can not only reduce the corrosion current density of segment rebar and tunnel bolt effectively,but also affect the distribution form of rebar corrosion current density in both circumferential and longitudinal directions.When the rubber content increases from 5%to 20%,the maximum corrosion density of segment rebar and tunnel bolt will decrease from 31%to 58%and 30%to 32%,respectively.Under different stray current leakage modes,when the rubber content and input voltage are the same,the segment and bolt corrosion current density under single rail-two points leakage mode is greater than that in the two rails-single point leakage mode.
基金supported by the National Natural Science Foundation of China(No.62302213)Key Laboratory of Social Computing and Cognitive Intelligence(Dalian University of Technology),Ministry of Education,China.
文摘The rise of online social platforms has enhanced connectivity and access to information.Still,it has also enabled the proliferation of malicious social bots that threaten platform security and disrupt social order.In this paper,we introduce a unified framework for defining and classifying malicious social bots along three dimensions:behavior,interaction,and operation.We then present a comprehensive review of social bot detection methods,tracing their evolution from traditional machine learning techniques to deep learning architectures and graph neural networks,with particular emphasis on recent advances in group-level detection.We also explore the emerging paradigm of Large Language Model(LLM)based bot detection.This paper reviews the current state of research,identifies key challenges,and outlines future directions.It provides a cohesive foundation for building more robust detection frameworks to counter the evolving threats posed by malicious social bots.
基金supported by the National Natural Science Foundation of China(Grant No.52378443).
文摘It was a challenge to monitor concrete structure crack under complex environmental action.To obtain conductive hydrogel material with higher stretchability,signal response sensitivity and stability to monitor concrete structure cracking,the conductive hydrogel reinforced by different content of cellulose nanocrystals,which is called polyacrylic acid-cellulose nanocrystals(PAA-CNC),were developed in this paper.The performance improvement of PAA-CNC was studied by scanning electron microscope,resistance,uniaxial tensile and cyclic tensile test.Finally,the concrete crack monitoring accuracy of PAA-CNC was verified by three-point bend loading test.The result showed that combining cellulose nanocrystals with hydroxyl in conductive hydrogels can form uniformly dispersed micelles and three-dimensional network structure,which can increase the ionic conductive path and connection strength between molecules.When cellulose nanocrystals content of hydrogel was 0.12%,the effective strain sensing range and sensitivity within the range reached the maximum.When the content of cellulose nanocrystals was 0.12,the effective strain sensing range and sensitivity of PAA-CNC will reach maximum value.Compared with other contents of cellulose nanocrystals,PAA-CNC_(0.12)can produce a stable signal response when tested and quickly recover to the initial resistance after cyclic stretching.The crack width obtained by PAA-CNC_(0.12)does not exceed 5%of that obtained by digital image correlation equipment.
基金supported by the National Natural Science Foundation of China(grant number 81473192)the National Basic Research Program of China(grant number 2010CB529802)
文摘ω-Conotoxins inhibit N-type voltage-gated calcium(Ca_(v)2.2)channels and exhibit efficacy in attenuating neuropathic pain but have a low therapeutic index.Here,we synthesized and characterized a novelω-conotoxin,Bu8 from Conus bullatus,which consists of 25 amino acid residues and three disulfide bridges.Bu8 selectively and potently inhibits depolarization-activated Ba^(2+)currents mediated by rat Ca_(v)2.2 expressed in HEK293 T cells(IC_(50)=89 nmol/L).Bu8 is two-fold more potent thanω-conotoxin MVIIA,aω-conotoxin currently used for the treatment of severe chronic pain.It also displays potent analgesic activity in animal pain models of hot plate and acetic acid writhing but has fewer side effects on mouse motor function and lower toxicity in goldfish.Its lower side effects may be attributed to its faster binding rate and higher recovery ratios.The NMR structure demonstrates that Bu8 contains a small irregular tripleβ-strand.The structure-activity relationships of Bu8 Ala mutants and Bu8/MVIIA hybrid mutants demonstrate that the binding mode of Ca_(v)2.2 with the amino acid residues in loop 1 and loop 2 of Bu8 is different from that of MVIIA.This study characterizes a novel,more potentω-conotoxin and provides new insights for designing Ca_(v)2.2 antagonists.
