Influence of Angiotensin II on α1-Adrenergic Receptors Function in Rat Aorta and Expression in Vascular Smooth Muscle Cells

Angiotensin II (Ang II) is the main mediator of the Renin-Angiotensin-System acting on AT1 and other AT receptors. It is regarded as a pleiotropic agent that induces many actions, including functioning as a growth factor, and as a contractile hormone, among others. The aim of this work was to examine the impact of Ang II on the expression and function of α1-adrenergic receptors (α1-ARs) in cultured rat aorta, and aorta-derived smooth muscle cells. Isolated Wistar rat aorta was incubated for 24 h in DMEM at 37˚C, then subjected to isometric tension and to the action of added norepinephrine, in concentration-response curves. Ang II was added (1 × 10−5 M), and in some experiments, 5-Methylurapidil (α1A-AR antagonist), AH11110A (α1B-AR antagonist), or BMY-7378 (α1D-AR antagonist), were used to identify the α1-AR involved in the response. Desensitization of the contractile response to norepinephrine was observed due to incubation time, and by the Ang II action. α1D-AR was protected from desensitization by BMY-7378;while RS-100329 and prazosin partially mitigated desensitization. In another set of experiments, isolated aorta-derived smooth muscle cells were exposed to Ang II and α1-ARs proteins were evaluated. α1D-AR increased at 30 and 60 min post Ang II exposure, the α1A-AR diminished from 1 to 4 h, while α1B-AR remained unchanged over 24 h of Ang II exposure. Ang II induced an increase of α1D-AR at short times, and BMY-7378 protected α1D-AR from desensitization.

MicroRNA-146a Promotes Embryonic Stem Cell Differentiation towards Vascular Smooth Muscle Cells through Regulation of Kruppel-like Factor 4

Objective Vascular smooth muscle cell(VSMC)differentiation from stem cells is one source of the increasing number of VSMCs that are involved in vascular remodeling-related diseases such as hypertension,atherosclerosis,and restenosis.MicroRNA-146a(miR-146a)has been proven to be involved in cell proliferation,migration,and tumor metabolism.However,little is known about the functional role of miR-146a in VSMC differentiation from embryonic stem cells(ESCs).This study aimed to determine the role of miR-146a in VSMC differentiation from ESCs.Methods Mouse ESCs were differentiated into VSMCs,and the cell extracts were analyzed by Western blotting and RT-qPCR.In addition,luciferase reporter assays using ESCs transfected with miR-146a/mimic and plasmids were performed.Finally,C57BL/6J female mice were injected with mimic or miR-146a-overexpressing ESCs,and immunohistochemistry,Western blotting,and RT-qPCR assays were carried out on tissue samples from these mice.Results miR-146a was significantly upregulated during VSMC differentiation,accompanied with the VSMC-specific marker genes smooth muscle-alpha-actin(SMαA),smooth muscle 22(SM22),smooth muscle myosin heavy chain(SMMHC),and h1-calponin.Furthermore,overexpression of miR-146a enhanced the differentiation process in vitro and in vivo.Concurrently,the expression of Kruppel-like factor 4(KLF4),predicted as one of the top targets of miR-146a,was sharply decreased in miR-146a-overexpressing ESCs.Importantly,inhibiting KLF4 expression enhanced the VSMC-specific gene expression induced by miR-146a overexpression in differentiating ESCs.In addition,miR-146a upregulated the mRNA expression levels and transcriptional activity of VSMC differentiation-related transcription factors,including serum response factor(SRF)and myocyte enhancer factor 2c(MEF-2c).Conclusion Our data support that miR-146a promotes ESC-VSMC differentiation through regulating KLF4 and modulating the transcription factor activity of VSMCs.

THE ANALYTIC SMOOTHING EFFECT OF LINEAR LANDAU EQUATION WITH SOFT POTENTIALS

In this work,we study the linearized Landau equation with soft potentials and show that the smooth solution to the Cauchy problem with initial datum in L^(2)(ℝ^(3))enjoys an analytic regularization effect,and that the evolution of the analytic radius is the same as the heat equations.

Application of Smoothed Particle Hydrodynamics(SPH)for the Simulation of Flow-Like Landslides on 3D Terrains

Flow-type landslide is one type of landslide that generally exhibits characteristics of high flow velocities,long jump distances,and poor predictability.Simulation of its propagation process can provide solutions for risk assessment and mitigation design.The smoothed particle hydrodynamics(SPH)method has been successfully applied to the simulation of two-dimensional(2D)and three-dimensional(3D)flow-like landslides.However,the influence of boundary resistance on the whole process of landslide failure is rarely discussed.In this study,a boundary condition considering friction is proposed and integrated into the SPH method,and its accuracy is verified.Moreover,the Navier-Stokes equation combined with the non-Newtonian fluid rheologymodel was utilized to solve the dynamic behavior of the flow-like landslide.To verify its performance,the Shuicheng landslide event,which occurred in Guizhou,China,was taken as a case study.In the 2D simulation,a sensitivity analysis was conducted,and the results showed that the shearing strength parameters have more influence on the computation accuracy than the coefficient of viscosity.Afterwards,the dynamic characteristics of the landslide,such as the velocity and the impact area,were analyzed in the 3D simulation.The simulation results are in good agreement with the field investigations.The simulation results demonstrate that the SPH method performs well in reproducing the landslide process,and facilitates the analysis of landslide characteristics as well as the affected areas,which provides a scientific basis for conducting the risk assessment and disaster mitigation design.

A Discussion on the Establishment That a Fibre Metric on the Positive Definite Real Inner-Product of a Properly Embedded Smooth Submanifold Be Always Extended to a Riemannian Metric on the Positive Definite Real Inner-Product

Let M be a smooth manifold and S ⊆ M a properly embedded smooth submanifold. Suppose that we have a fibre metric on TM|s i.e. a positive definite real inner-product on TpM for all p ∈ S, which depends smoothly on p ∈ S. The purpose of this article is to figure out that the fibre metric on TM|s can always be extended to a Riemannian metric on TM from a special perspective.

High-order targeted essentially non-oscillatory scheme for two-fluid plasma model

The weakly ionized plasma flows in aerospace are commonly simulated by the single-fluid model,which cannot describe certain nonequilibrium phenomena by finite collisions of particles,decreasing the fidelity of the solution.Based on an alternative formulation of the targeted essentially non-oscillatory(TENO)scheme,a novel high-order numerical scheme is proposed to simulate the two-fluid plasmas problems.The numerical flux is constructed by the TENO interpolation of the solution and its derivatives,instead of being reconstructed from the physical flux.The present scheme is used to solve the two sets of Euler equations coupled with Maxwell's equations.The numerical methods are verified by several classical plasma problems.The results show that compared with the original TENO scheme,the present scheme can suppress the non-physical oscillations and reduce the numerical dissipation.

Value of enhanced computed tomography in differentiating small mesenchymal tumours of the gastrointestinal from smooth muscle tumours

BACKGROUND Computed tomography(CT)technology has been gradually used in the differen-tiation of small mesenchymal tumors of the stomach and intestines from smooth muscle tumours.AIM To explore the value of enhanced CT in the differentiation of small mesenchymal tumors of the stomach and intestines from smooth muscle tumours.METHODS Clinical data of patients with gastric mesenchymal or gastric smooth muscle tu-mours who were treated in our hospital from May 2018 to April 2023 were retrospectively analysed.Patients were divided into the gastric mesenchymal tumor group and the gastric smooth muscle tumor group respectively(n=50 cases per group).Clinical data of 50 healthy volunteers who received physical examinations in our hospital during the same period were selected and included in the control group.Serum levels of carcinoembryonic antigen(CEA),alpha-fetoprotein(AFP),carbohydrate antigen 19-9(CA19-9),CA-125 and cytokeratin 19 fragment antigen 21-1 were compared among the three groups.The value of CEA and CA19-9 in the identification of gastric mesenchymal tumours was analysed using the receiver operating characteristic(ROC)curve.The Kappa statistic was used to analyse the consistency of the combined CEA and CA19-9 test in identi-fying gastric mesenchymal tumours.RESULTS CEA levels varied among the three groups in the following order:The gastric mesenchymal tumour group>the control group>the gastric smooth muscle tumour group.CA19-9 levels varied among the three groups in the following order:The gastric mesenchymal group>the gastric smooth muscle group>the control group,the difference was statistically significant(P<0.05).ROC analysis showed that the area under the curve of CEA and CA19-9 was 0.879 and 0.782,respectively.CONCLUSION Enhanced CT has shown value in differentiating small mesenchymal tumors of the stomach and intestines from smooth muscle tumors.

Semaphorin 7A promotes human vascular smooth muscle cell proliferation and migration through theβ-catenin signaling pathway

Background:Vascular smooth muscle cells(VSMCs)undergo a conversion from a contractile phenotype to a proliferative synthetic phenotype,contributing to the pathogenesis of cardiovascular diseases.Semaphorin 7A(SEMA7A)is a glycosylphosphatidylinositol-anchored membrane protein that plays an important role in vascular homeostasis by regulating endothelial cell behaviors.However,the expression and role of SEMA7A in VSMCs remain unclear.Methods:In this study,we screened for VSMC-regulating genes in publicly available datasets and analyzed the expression of SEMA7A in human coronary artery smooth muscle cells(hCASMCs)treated with platelet-derived growth factor-BB(PDGF-BB).The effects of SEMA7A overexpression and knockdown on hCASMC proliferation and migration were examined.The signaling pathways involved in the action of SEMA7A in hCASMCs were determined.Results:Bioinformatic analysis showed that SEMA7A was significantly dysregulated in VSMCs treated with oxidized low-density lipoprotein or overexpressing progerin,a pro-atherogenic gene.The PDGF-BB stimulation led to a concentration-and time-dependent induction of SEMA7A.Depletion of SEMA7A attenuated PDGF-BB-induced hCASMC proliferation and migration.Conversely,overexpression of SEMA7A enhanced hCASMC proliferation and migration.Mechanistically,SEMA7A stimulated the activation of theβ-catenin pathway and upregulated c-Myc,CCND1,and MMP7.Knockdown ofβ-catenin impaired SEMA7A-induced hCASMC proliferation and migration.Conclusions:SEMA7A triggers phenotype switching in VSMCs through theβ-catenin signaling pathway and may serve as a potential therapeutic target for cardiovascular diseases.

Lateral interaction by Laplacian‐based graph smoothing for deep neural networks

Lateral interaction in the biological brain is a key mechanism that underlies higher cognitive functions.Linear self‐organising map(SOM)introduces lateral interaction in a general form in which signals of any modality can be used.Some approaches directly incorporate SOM learning rules into neural networks,but incur complex operations and poor extendibility.The efficient way to implement lateral interaction in deep neural networks is not well established.The use of Laplacian Matrix‐based Smoothing(LS)regularisation is proposed for implementing lateral interaction in a concise form.The authors’derivation and experiments show that lateral interaction implemented by SOM model is a special case of LS‐regulated k‐means,and they both show the topology‐preserving capability.The authors also verify that LS‐regularisation can be used in conjunction with the end‐to‐end training paradigm in deep auto‐encoders.Additionally,the benefits of LS‐regularisation in relaxing the requirement of parameter initialisation in various models and improving the classification performance of prototype classifiers are evaluated.Furthermore,the topologically ordered structure introduced by LS‐regularisation in feature extractor can improve the generalisation performance on classification tasks.Overall,LS‐regularisation is an effective and efficient way to implement lateral interaction and can be easily extended to different models.

A SUPERLINEARLY CONVERGENT SPLITTING FEASIBLE SEQUENTIAL QUADRATIC OPTIMIZATION METHOD FOR TWO-BLOCK LARGE-SCALE SMOOTH OPTIMIZATION

This paper discusses the two-block large-scale nonconvex optimization problem with general linear constraints.Based on the ideas of splitting and sequential quadratic optimization(SQO),a new feasible descent method for the discussed problem is proposed.First,we consider the problem of quadratic optimal(QO)approximation associated with the current feasible iteration point,and we split the QO into two small-scale QOs which can be solved in parallel.Second,a feasible descent direction for the problem is obtained and a new SQO-type method is proposed,namely,splitting feasible SQO(SF-SQO)method.Moreover,under suitable conditions,we analyse the global convergence,strong convergence and rate of superlinear convergence of the SF-SQO method.Finally,preliminary numerical experiments regarding the economic dispatch of a power system are carried out,and these show that the SF-SQO method is promising.

A Smooth Bidirectional Evolutionary Structural Optimization of Vibrational Structures for Natural Frequency and Dynamic Compliance

A smooth bidirectional evolutionary structural optimization(SBESO),as a bidirectional version of SESO is proposed to solve the topological optimization of vibrating continuum structures for natural frequencies and dynamic compliance under the transient load.A weighted function is introduced to regulate the mass and stiffness matrix of an element,which has the inefficient element gradually removed from the design domain as if it were undergoing damage.Aiming at maximizing the natural frequency of a structure,the frequency optimization formulation is proposed using the SBESO technique.The effects of various weight functions including constant,linear and sine functions on structural optimization are compared.With the equivalent static load(ESL)method,the dynamic stiffness optimization of a structure is formulated by the SBESO technique.Numerical examples show that compared with the classic BESO method,the SBESO method can efficiently suppress the excessive element deletion by adjusting the element deletion rate and weight function.It is also found that the proposed SBESO technique can obtain an efficient configuration and smooth boundary and demonstrate the advantages over the classic BESO technique.

Research progress on the effect of oocyte smooth endoplasmic reticulum clusters on early embryo development and pregnancy outcome

With the clinical development and application of intracytoplasmic sperm injection(ICSI)technology in human assisted reproduction,the influence of oocyte quality on embryo development has been paid more and more attention.So far,there have been many reports on oocyte morphology affecting embryo development.It has been found in some works that the appearance of smooth endoplasmic reticulum clusters(SERC)in oocytes may affect the fertilization and embryo development of oocytes.However,with the increasing reports of SERC-containing oocytes obtained by in vitro fertilization and healthy offspring in recent years,there is still some controversy on whether to continue to use SERC-containing oocytes for the following assisted reproductive therapy in clinical practice.Based on this,this review aims to review the research progress of SERC in oocytes in recent years.

Inhibitory Effect of PPARδAgonist GW501516 on Proliferation of Hypoxia-induced Pulmonary Arterial Smooth Muscle Cells by Regulating the mTOR Pathway

Objective This study aimed to investigate the effects of the peroxisome proliferator-activated receptorδ(PPARδ)agonist GW501516 on the proliferation of pulmonary artery smooth muscle cells(PASMCs)induced by hypoxia,in order to search for new drugs for the treatment and prevention of pulmonary vascular remodeling.Methods PASMCs were incubated with different concentrations of GW501516(10,30,100 nmol/L)under the hypoxic condition.The proliferation was determined by a CCK-8 assay.The cell cycle progression was analyzed by flow cytometry.The expression of PPARδ,S phase kinase-associated protein 2(Skp2),and cell cycle-dependent kinase inhibitor p27 was detected by Western blotting.Then PASMCs were treated with 100 nmol/L GW501516,100 nmol/L mammalian target of rapamycin(mTOR)inhibitor rapamycin and/or 2µmol/L mTOR activator MHY1485 to explore the molecular mechanisms by which GW501516 reduces the proliferation of PASMCs.Results The presented data demonstrated that hypoxia reduced the expression of PPARδin an oxygen concentration-and time-dependent manner,and GW501516 decreased the proliferation of PASMCs induced by hypoxia by blocking the progression through the G0/G1 to S phase of the cell cycle.In accordance with these findings,GW501516 downregulated Skp2 and upregulated p27 in hypoxia-exposed PASMCs.Further experiments showed that rapamycin had similar effects as GW501516 in inhibiting cell proliferation,arresting the cell cycle,regulating the expression of Skp2 and p27,and inactivating mTOR in hypoxia-exposed PASMCs.Moreover,MHY1485 reversed all the beneficial effects of GW501516 on hypoxia-stimulated PASMCs.Conclusion GW501516 inhibited the proliferation of PASMCs induced by hypoxia through blocking the mTOR/Skp2/p27 signaling pathway.

NR4A1 enhances glycolysis in hypoxia-exposed pulmonary artery smooth muscle cells by upregulating HIF-1αexpression

Background:Pulmonary arterial hypertension(PAH)is a chronic and progressive disease that is strongly associated with dysregulation of glucose metabolism.Alterations in nuclear receptor subfamily 4 group A member 1(NR4A1)activity alter the outcome of PAH.This study aimed to investigate the effects of NR4A1 on glycolysis in PAH and its underlying mechanisms.Methods:This study included twenty healthy volunteers and twenty-three PAH patients,and plasma samples were collected from the participants.To mimic the conditions of PAH in vitro,a hypoxia-induced model of pulmonary artery smooth muscle cell(PASMC)model was established.The proliferation of PASMCs was assessed using CCK8 assays.Results:Levels of NR4A1,hypoxia-inducible factor-1α(HIF-1α),and various glycolysis-related enzymes were measured.In addition,extracellular glucose and lactate production were assessed.The interaction between NR4A1 and HIF-1αwas evaluated by co-immunoprecipitation assays.Levels of NR4A1 and HIF-1αwas increased in PAH patients,and exposure to hypoxia resulted in increased levels of NR4A1 and HIF-1αin PASMCs.NR4A1 interacted with HIF-1α.NR4A1 overexpression enhanced hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,decreased glucose levels,increased lactate levels and promoted hypoxic PASMC viability.Conversely,silencing NR4A1 decreased hypoxia-induced expression of HIF-1α,GLUT1,PKM2,HK2,and CD36,promoted glucose production,reduced lactate levels and inhibited hypoxic PASMC viability.Furthermore,overexpression of HIF-1αreversed the regulation of glycolysis caused by NR4A1 knockdown.Conclusion:NR4A1 enhances glycolysis in hypoxia-induced PASMCs by upregulating HIF-1α.Our findings indicate that the management of NR4A1 activity may be a promising strategy for PAH therapy.

Gas kinetic flux solver based finite volume weighted essentially non-oscillatory scheme for inviscid compressible flows

A high-order gas kinetic flux solver(GKFS)is presented for simulating inviscid compressible flows.The weighted essentially non-oscillatory(WENO)scheme on a uniform mesh in the finite volume formulation is combined with the circular function-based GKFS(C-GKFS)to capture more details of the flow fields with fewer grids.Different from most of the current GKFSs,which are constructed based on the Maxwellian distribution function or its equivalent form,the C-GKFS simplifies the Maxwellian distribution function into the circular function,which ensures that the Euler or Navier-Stokes equations can be recovered correctly.This improves the efficiency of the GKFS and reduces its complexity to facilitate the practical application of engineering.Several benchmark cases are simulated,and good agreement can be obtained in comparison with the references,which demonstrates that the high-order C-GKFS can achieve the desired accuracy.

K-Hyperparameter Tuning in High-Dimensional Space Clustering:Solving Smooth Elbow Challenges Using an Ensemble Based Technique of a Self-Adapting Autoencoder and Internal Validation Indexes

k-means is a popular clustering algorithm because of its simplicity and scalability to handle large datasets.However,one of its setbacks is the challenge of identifying the correct k-hyperparameter value.Tuning this value correctly is critical for building effective k-means models.The use of the traditional elbow method to help identify this value has a long-standing literature.However,when using this method with certain datasets,smooth curves may appear,making it challenging to identify the k-value due to its unclear nature.On the other hand,various internal validation indexes,which are proposed as a solution to this issue,may be inconsistent.Although various techniques for solving smooth elbow challenges exist,k-hyperparameter tuning in high-dimensional spaces still remains intractable and an open research issue.In this paper,we have first reviewed the existing techniques for solving smooth elbow challenges.The identified research gaps are then utilized in the development of the new technique.The new technique,referred to as the ensemble-based technique of a self-adapting autoencoder and internal validation indexes,is then validated in high-dimensional space clustering.The optimal k-value,tuned by this technique using a voting scheme,is a trade-off between the number of clusters visualized in the autoencoder’s latent space,k-value from the ensemble internal validation index score and one that generates a value of 0 or close to 0 on the derivative f″′(k)(1+f′(k)^(2))−3 f″(k)^(2)f″((k)2f′(k),at the elbow.Experimental results based on the Cochran’s Q test,ANOVA,and McNemar’s score indicate a relatively good performance of the newly developed technique in k-hyperparameter tuning.

Smoothed Empirical Likelihood Inference for Nonlinear Quantile Regression Models with Missing Response

In this paper, three smoothed empirical log-likelihood ratio functions for the parameters of nonlinear models with missing response are suggested. Under some regular conditions, the corresponding Wilks phenomena are obtained and the confidence regions for the parameter can be constructed easily.

基于Smooth-Joint模型的层状页岩力学特性研究

普光气田陆相页岩气资源潜力巨大,侏罗系千佛崖组一段页岩气大面积分布,埋深适中,页岩气资源量为4239.5亿m^(3)。为实现页岩气的高效开发,在室内页岩单轴压缩力学试验的基础上,利用颗粒离散元法建立页岩的单轴压缩模型和Smooth-Joint节理模型,探讨宏观各向同性页岩单轴压缩破坏、变形及强度特征,以及不同Smooth-Joint节理倾角对岩石力学特性的影响。数值试验与室内试验分析结果表明,节理面的存在降低了岩石的抗压强度;岩体的抗压强度随着节理倾角的改变而改变,随着节理倾角的增大,岩体的强度先降低随后增大;当节理面与潜在破坏面的方向相近时,即节理面倾角θ=45°+φ_(s)/2时,岩体受压破坏沿节理面发生,岩体强度下降得最多;层状页岩单轴压缩全应力-应变曲线可以分为5个阶段,阶段Ⅰ岩样内部裂纹闭合体积减小、阶段Ⅱ弹性变形过程(总体积应变增量等于弹性体积应变增量)、阶段Ⅲ裂纹稳定扩展(弹性变形)、阶段Ⅳ裂缝非稳定扩展(塑性变形阶段)、阶段Ⅴ试件裂缝继续扩展延伸直至达到峰后强度σ_(p)停止。该研究结果为普光陆相千佛崖组页岩气的开发提供了一定参考,以普光气田页X井为例,该井成功压裂,压后产气量较高,储层改造应用效果较好。

A bioinformatics-based study of the mechanism of JQ-1 on BET protein and atherosclerosis induced by vascular smooth muscle cell proliferation

Background:Based on previous theoretical studies,JQ-1 as a common inhibitor of bromodomain and extraterminal(BET)proteins was used to treat a variety of diseases.Therefore,we aimed to explore the mechanism of action of JQ-1 on BET proteins based on bioinformatics and build the novel hypothesis of JQ-1 in treating atherosclerosis(AS)caused by proliferation of vascular smooth muscle cells(VSMCs).Methods:We selected the chip GSE138323 which was searched with the key words“Vascular smooth muscle cell proliferation”in Gene Expression Omnibus(GEO)database,and differential gene analysis was performed between the GRO and JQ-1 groups.Then the top twenty significantly up-regulated genes and the top twenty significantly down-regulated genes were selected for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis.Thirdly,structured the PPI network of forty differential genes,and the core genes were screened by using the MCC algorithm which in“Cytohubba”plugin in the Cytoscapev3.9.1 software.After that,single gene Gene Set Enrichment Analysis(GSEA)enrichment analysis was performed on the selected core genes in R language.Finally molecular docking validation was performed.Results:Five core genes was selected:H3C2,H3C4,H3C7,H3C10 and AREG.The GO enrichment analysis results showed that there were twenty-five entries in biological process,eight entries in cellular components(CC),and twenty-five entries in molecular function.The KEGG enrichment analysis results showed that there were seven pathways,mainly including systemic lupus erythematosus and external neutrophil trap formation.The GSEA results showed that the five genes were mainly through the regulation of cytochrome P450 metabolism,PPAR signaling pathway and other pathways.The molecular docking results showed that JQ-1 had binding activity with these five genes.Conclusions:JQ-1 may regulate the expression of the genes that H3C2,H3C4,H3C7,H3C10 and AREG,to mainly regulate the genes in cytochrome P450 metabolism,PPAR singling pathway and other pathways,to make some influence in the proliferation of VSMCs,and improved atherosclerotic symptoms due to vascular smooth muscle proliferation,thus treating cardiovascular disease.

基于学生核心素养培养的评价体系建构及实践初探

从学生核心素养培养视角出发,尝试构建基于学生核心素养培养的评价体系,并将其应用于能源与环境创新创业实训课程的教学。研究指出,新构建的评价体系的评价主体、评价方法、评价指标和评价结果四个方面都有对学生核心素养的培养起到促进作用,最大程度发挥了教师和学生两大生态主体的积极性,有效加强针对学生核心素养的培养。