Exploring the molecular mechanism of action of curcumin for the treatment of diabetic retinopathy,using network pharmacology,molecular docking,and molecular dynamics simulation

Background:Based on network pharmacology and molecular docking,the present study investigated the mechanism of curcumin(CUR)in diabetic retinopathy treatment.Methods:Based on the DisGeNET,Swiss TargetPrediction,GeneCards,Online Mendelian Inheritance in Man,Gene Expression Omnibus,and Comparative Toxicogenomics Database,the intersection core targets of CUR and diabetic retinopathy were identified.The intersection target was imported into the STRING database to obtain the protein-protein interaction map.According to the Database for Annotation,Visualization and Integrated Discovery database,the intersected targets were enriched in Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes pathways.Then Cytoscape 3.9.1 is used to make the drug-target-disease-pathway network.The mechanism of CUR and diabetic retinopathy was further verified by molecular docking and molecular dynamics simulation.Results:There were 203 intersecting targets of CUR and diabetic retinopathy identified.1320 GO entries were enriched for GO functions,which were primarily involved in the composition of cells such as identical protein binding,protein binding,enzyme binding,etc.It was found that 175 pathways were enriched using Kyoto Encyclopedia of Genes and Genomes pathway enrichment methods,which were mainly included in the lipid and atherosclerosis,AGE-RAGE signaling pathway in diabetic complications,pathways in cancer,etc.In the molecular docking analysis,CUR was found to have a good ability to bind to the core targets of albumin,IL-1B,and IL-6.The binding of albumin to CUR was further verified by molecular dynamics simulation.Conclusion:As a result of this study,CUR may exert a role in the treatment of diabetic retinopathy through multi-target and multi-pathway regulation,which indicates a possible direction of future research.

The Effect of Key Nodes on theMalware Dynamics in the Industrial Control Network

As industrialization and informatization becomemore deeply intertwined,industrial control networks have entered an era of intelligence.The connection between industrial control networks and the external internet is becoming increasingly close,which leads to frequent security accidents.This paper proposes a model for the industrial control network.It includes a malware containment strategy that integrates intrusion detection,quarantine,and monitoring.Basedonthismodel,the role of keynodes in the spreadofmalware is studied,a comparisonexperiment is conducted to validate the impact of the containment strategy.In addition,the dynamic behavior of the model is analyzed,the basic reproduction number is computed,and the disease-free and endemic equilibrium of the model is also obtained by the basic reproduction number.Moreover,through simulation experiments,the effectiveness of the containment strategy is validated,the influence of the relevant parameters is analyzed,and the containment strategy is optimized.In otherwords,selective immunity to key nodes can effectively suppress the spread ofmalware andmaintain the stability of industrial control systems.The earlier the immunization of key nodes,the better.Once the time exceeds the threshold,immunizing key nodes is almost ineffective.The analysis provides a better way to contain the malware in the industrial control network.

Hydrocarbon gas huff-n-puff optimization of multiple horizontal wells with complex fracture networks in the M unconventional reservoir

The oil production of the multi-fractured horizontal wells(MFHWs) declines quickly in unconventional oil reservoirs due to the fast depletion of natural energy. Gas injection has been acknowledged as an effective method to improve oil recovery factor from unconventional oil reservoirs. Hydrocarbon gas huff-n-puff becomes preferable when the CO_(2) source is limited. However, the impact of complex fracture networks and well interference on the EOR performance of multiple MFHWs is still unclear. The optimal gas huff-n-puff parameters are significant for enhancing oil recovery. This work aims to optimize the hydrocarbon gas injection and production parameters for multiple MFHWs with complex fracture networks in unconventional oil reservoirs. Firstly, the numerical model based on unstructured grids is developed to characterize the complex fracture networks and capture the dynamic fracture features.Secondly, the PVT phase behavior simulation was carried out to provide the fluid model for numerical simulation. Thirdly, the optimal parameters for hydrocarbon gas huff-n-puff were obtained. Finally, the dominant factors of hydrocarbon gas huff-n-puff under complex fracture networks are obtained by fuzzy mathematical method. Results reveal that the current pressure of hydrocarbon gas injection can achieve miscible displacement. The optimal injection and production parameters are obtained by single-factor analysis to analyze the effect of individual parameter. Gas injection time is the dominant factor of hydrocarbon gas huff-n-puff in unconventional oil reservoirs with complex fracture networks. This work can offer engineers guidance for hydrocarbon gas huff-n-puff of multiple MFHWs considering the complex fracture networks.

Network pharmacology and molecular dynamics study of the effect of the Astragalus-Coptis drug pair on diabetic kidney disease

BACKGROUND Diabetic kidney disease(DKD)is the primary cause of end-stage renal disease.The Astragalus-Coptis drug pair is frequently employed in the management of DKD.However,the precise molecular mechanism underlying its therapeutic effect remains elusive.AIM To investigate the synergistic effects of multiple active ingredients in the Astragalus-Coptis drug pair on DKD through multiple targets and pathways.METHODS The ingredients of the Astragalus-Coptis drug pair were collected and screened using the TCMSP database and the SwissADME platform.The targets were predicted using the SwissTargetPrediction database,while the DKD differential gene expression analysis was obtained from the Gene Expression Omnibus database.DKD targets were acquired from the GeneCards,Online Mendelian Inheritance in Man database,and DisGeNET databases,with common targets identified through the Venny platform.The protein-protein interaction network and the“disease-active ingredient-target”network of the common targets were constructed utilizing the STRING database and Cytoscape software,followed by the analysis of the interaction relationships and further screening of key targets and core active ingredients.Gene Ontology(GO)function and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichments were performed using the DAVID database.The tissue and organ distributions of key targets were evaluated.PyMOL and AutoDock software validate the molecular docking between the core ingredients and key targets.Finally,molecular dynamics(MD)simulations were conducted to simulate the optimal complex formed by interactions between core ingredients and key target proteins.RESULTS A total of 27 active ingredients and 512 potential targets of the Astragalus-Coptis drug pair were identified.There were 273 common targets between DKD and the Astragalus-Coptis drug pair.Through protein-protein interaction network topology analysis,we identified 9 core active ingredients and 10 key targets.GO and KEGG pathway enrichment analyses revealed that Astragalus-Coptis drug pair treatment for DKD involves various biological processes,including protein phosphorylation,negative regulation of apoptosis,inflammatory response,and endoplasmic reticulum unfolded protein response.These pathways are mainly associated with the advanced glycation end products(AGE)-receptor for AGE products signaling pathway in diabetic complications,as well as the Lipid and atherosclerosis.Molecular docking and MD simulations demonstrated high affinity and stability between the core active ingredients and key targets.Notably,the quercetin-AKT serine/threonine kinase 1(AKT1)and quercetin-tumor necrosis factor(TNF)protein complexes exhibited exceptional stability.CONCLUSION This study demonstrated that DKD treatment with the Astragalus-Coptis drug pair involves multiple ingredients,targets,and signaling pathways.We propose a novel approach for investigating the molecular mechanism underlying the therapeutic effects of the Astragalus-Coptis drug pair on DKD.Furthermore,we suggest that quercetin is the most potent active ingredient and specifically targets AKT1 and TNF,providing a theoretical foundation for further exploration of pharmacologically active ingredients and elucidating their molecular mechanisms in DKD treatment.

Elucidating the molecular targets of Curcuma longa for breast cancer treatment using network pharmacology,molecular docking and molecular dynamics simulation

Background:To elucidate the molecular mechanisms of Curcuma longa(C.longa)in breast cancer treatment.Methods:Phytocompounds of C.longa were obtained from Dr.Duke’s Phytochemical and Ethnobotanical Database.Potential active targets were retrieved from Bindingdb,SEA and Swiss Target Prediction databases.Breast cancer targets were retrieved from the Therapeutic Target Database.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were done using DAVID and KOBAS3.0 databases respectively.The Cytoscape software was used to construct the phytocompound-target-pathway network.The PyRx and Desmond software were utilized for molecular docking and molecular dynamics simulation respectively.Results:Out of one hundred and fifty-six phytocompounds,fifty-four modulated proteins involved in breast cancer.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated C.longa exerts its therapeutic effect through regulating several key pathways.Molecular docking analysis revealed that most phytocompounds of C.longa had a good affinity with the key targets.Molecular dynamics simulation showed that ethinylestradiol formed stable ligand-protein complexes.Conclusion:The results of this study will enhance our understanding of the potential molecular mechanisms by which C.longa inhibits breast cancer and lay a foundation for future experimental studies.

The influence of inter-band rock on rib spalling in longwall panel with large mining height

In order to improve rib stability,failure criteria and instability mode of a thick coal seam with inter-band rock layer are analysed in this study.A three-dimensional mechanical model is established for the rib by considering the rock layer.A safety factor is defined foy the rib,and it is observed that the safety factor exhibits a positive correlation with the thickness and strength of the inter-band rock.A calculation method for determining critical parameters of the rock layer is presented to ensure the rib stability.It is revealed that incomplete propagation of the fracture at the hard rock constitutes a fundamental prerequisite for ensuring the rib stability.The influence of the position of the inter-band rock in the coal seam on failure mechanism of the rib was thoroughly investigated by developing a series of physical models for the rib at the face area.The best position for the inter-band rock in the coal seam is at a height of 1.5 m away from the roof line,which tends to provide a good stability state for the rib.For different inter-band rock positions,two ways of controlling rib by increasing supports stiffness and flexible grouting reinforcement are proposed.

From the perspective of experimental practice: High-throughput computational screening in photocatalysis

Photocatalysis,a critical strategy for harvesting sunlight to address energy demand and environmental concerns,is underpinned by the discovery of high-performance photocatalysts,thereby how to design photocatalysts is now generating widespread interest in boosting the conversion effi-ciency of solar energy.In the past decade,computational technologies and theoretical simulations have led to a major leap in the development of high-throughput computational screening strategies for novel high-efficiency photocatalysts.In this viewpoint,we started with introducing the challenges of photocatalysis from the view of experimental practice,especially the inefficiency of the traditional“trial and error”method.Sub-sequently,a cross-sectional comparison between experimental and high-throughput computational screening for photocatalysis is presented and discussed in detail.On the basis of the current experimental progress in photocatalysis,we also exemplified the various challenges associated with high-throughput computational screening strategies.Finally,we offered a preferred high-throughput computational screening procedure for pho-tocatalysts from an experimental practice perspective(model construction and screening,standardized experiments,assessment and revision),with the aim of a better correlation of high-throughput simulations and experimental practices,motivating to search for better descriptors.

Numerical Study on the Effect of Gap Diffraction on the Hydrodynamic Performance of A Floating Breakwater

Two-dimensional(2D)flume experiments are useful in investigating the performances of floating breakwaters(FBs),including hydrodynamic performances,motion responses,and mooring forces.Designing a reasonable gap between the flume wall and the FBs is a critical step in 2D flume tests.However,research on the effect of the gap on the accuracy of 2D FB experimental results is scarce.To address this issue,a numerical wave tank is developed using CFD to estimate the wave-FB interaction of a moored dual-cylindrical FB,and the results are compared to experimental data from a previously published work.There is good agreement between them,indicating that the numerical model is sufficiently accurate.The numerical model is then applied to explore the effect of gap diffraction on the performance of FBs in2D experiments.It was discovered that the nondimensional gap length L_(Gap)/W_(Pool)should be smaller than 7.5%to ensure that the relative error of the transmission coefficient is smaller than 3%.The influence of the gap is also related to the entering wave properties,such as the wave height and period.

Analysis of the Erosion-Corrosion Mechanism of the Air Cooler in a Hydrocracking Unit:A Numerical and Experimental Study

Corrosion leakages often occur in the air cooler of a hydrocracking unit,with the failure sites mainly located in the entrance area of the tubes.An analysis of the macroscopic morphology and corrosion products confirmed that the damage was caused by erosion-corrosion(E-C).Numerical and experimental methods were applied to investigate the E-C mechanism in the air cooler.Computational fluid dynamics(CFD)was used to calculate the hydrodynamic parameters of the air cooler.The results showed that there was a biased flow in the air cooler,which led to a significant increase in velocity,turbulent kinetic energy and wall shear within 0.2 m of the tube entrance.A visualization experiment was then performed to determine the principles of migration and transformation of multiphase flow in the air cooler tubes.Various flow patterns(pure droplet flow,mist flow,and annular flow)and their evolutionary processes were clearly depicted experimentally.The initiation mechanism and processes leading to the development of E-C in the air cooler were also determined.This study provided a comprehensive explanation for the E-C failures that occur in air coolers during operation.

Effect of particle composition and consolidation degree on the wave-induced liquefaction of soil beds

The wave-induced liquefaction of seabed is responsible for causing damage to marine structures.Particle composition and consolidation degree are the key factors affecting the pore water pressure response and liquefaction behavior of the seabed under wave action.The present study conducted wave flume experiments on silt and silty fine sand beds with varying particle compositions.Furthermore,a comprehensive analysis of the differences and underlying reasons for liquefaction behavior in two different types of soil was conducted from both macroscopic and microscopic perspectives.The experimental results indicate that the silt bed necessitates a lower wave load intensity to attain the liquefaction state in comparison to the silty fine sand bed.Additionally,the duration and development depth of liquefaction are greater in the silt bed.The dissimilarity in liquefaction behavior between the two types of soil can be attributed to the variation in their permeability and plastic deformation capacity.The permeability coefficient and compression modulus of silt are lower than those of silty fine sand.Consequently,silt is more prone to the accumulation of pore pressure and subsequent liquefaction under external loading.Prior research has demonstrated that silt beds with varying consolidation degrees exhibit distinct initial failure modes.Specifically,a dense bed undergoes shear failure,whereas a loose bed experiences initial liquefaction failure.This study utilized discrete element simulation to examine the microscopic mechanisms that underlie this phenomenon.

Advances and outlook of integrated reservoir-wellbore-pipe network simulation technology

The integrated simulation and optimization technology of reservoir-wellbore-pipe network is developed to reflect the mutual influence and restriction among reservoir engineering,oil production engineering and surface engineering,and to obtain the scheme with minimum conflict and optimal benefit in each step.This technology is based on the concept of global optimization to maximize production and profit,reduce costs and increase benefit.This paper elaborates the current situation of integrated simulation technology of reservoir-wellbore-pipe network both at home and abroad,discusses its correlation with the primary business of Sinopec and its development from three aspects of modeling,cloud platform and intellectualization.Suggestions on its future development are put forward from underlying data,software platform,popularization and application,and cross-border integration to provide means and guidance for the construction of intelligent oil and gas fields.The results show that the integrated simulation of reservoir-wellbore-pipe network can better reflect the optimization requirements of each step,avoid the ineffective operation of field equipment,and effectively improve the efficiency of research and management.Coupling solution,global optimization method and pressure fitting,which can make the simulation results reflect the real situation,are the key technologies for the network.The theoretical technology and main function research of integrated simulation technology have been mature,but the large-scale application and local function improvement of oil and gas fields are yet to be promoted.In the future,the integrated simulation of reservoir-wellbore-pipe network will develop from digitalization to modeling and intellectualization,from local simulation to cloud computing,and from manual intervention to intelligent decision-making.We suggest speeding up the construction of the unified database and model base of the whole underlying platform,strengthening the construction of software integration and integration platform with independent intellectual property rights,speeding up the popularization and application of intelligent oil and gas field demonstration projects,and strengthening the integration of oil and gas industry with artificial intelligence(AI),big data and block chain for its development.

A sub-grid scale model for Burgers turbulence based on the artificial neural network method

The present study proposes a sub-grid scale model for the one-dimensional Burgers turbulence based on the neuralnetwork and deep learning method.The filtered data of the direct numerical simulation is used to establish thetraining data set,the validation data set,and the test data set.The artificial neural network(ANN)methodand Back Propagation method are employed to train parameters in the ANN.The developed ANN is applied toconstruct the sub-grid scale model for the large eddy simulation of the Burgers turbulence in the one-dimensionalspace.The proposed model well predicts the time correlation and the space correlation of the Burgers turbulence.

Numerical Investigation of Thermal Behavior of CNC Machine Tool and Its Effects on Dimensional Accuracy of Machined Parts

The dimensional accuracy of machined parts is strongly influenced by the thermal behavior of machine tools (MT). Minimizing this influence represents a key objective for any modern manufacturing industry. Thermally induced positioning error compensation remains the most effective and practical method in this context. However, the efficiency of the compensation process depends on the quality of the model used to predict the thermal errors. The model should consistently reflect the relationships between temperature distribution in the MT structure and thermally induced positioning errors. A judicious choice of the number and location of temperature sensitive points to represent heat distribution is a key factor for robust thermal error modeling. Therefore, in this paper, the temperature sensitive points are selected following a structured thermomechanical analysis carried out to evaluate the effects of various temperature gradients on MT structure deformation intensity. The MT thermal behavior is first modeled using finite element method and validated by various experimentally measured temperature fields using temperature sensors and thermal imaging. MT Thermal behavior validation shows a maximum error of less than 10% when comparing the numerical estimations with the experimental results even under changing operation conditions. The numerical model is used through several series of simulations carried out using varied working condition to explore possible relationships between temperature distribution and thermal deformation characteristics to select the most appropriate temperature sensitive points that will be considered for building an empirical prediction model for thermal errors as function of MT thermal state. Validation tests achieved using an artificial neural network based simplified model confirmed the efficiency of the proposed temperature sensitive points allowing the prediction of the thermally induced errors with an accuracy greater than 90%.

Scheduling on tractor and trailer transportation considering the influence of disrupted events based on the contract net and simulated annealing algorithm

To provide a much more resilient transport scheme for tractor and trailer transportation systems,this paper explores the generation method of tractor and trailer transport schemes considering the influence of disrupted events.Three states of tractors including towing loaded trailers,towing empty trailers,and idle driving are taken into account.Based on the disruption management theory,a scheduling model is constructed to minimize the total deviation cost including transportation time,transportation path,and number of used vehicles under the three states of tractors.A heuristics based on the contract net and simulated annealing algorithm is designed to solve the proposed model.Through comparative analysis of examples with different numbers of newly added transportation tasks and different types of road networks,the performance of the contract net algorithm in terms of deviations in idle driving paths,empty trailer paths,loaded trailer paths,time,number of used vehicles,and total deviation cost are analyzed.The results demonstrate the effectiveness of the model and algorithm,highlighting the superiority of the disruption management model and the contract net annealing algorithm.The study provides a reference for handling unexpected events in the tractor and trailer transportation industry.

On the Choice of Parameter Values for Simulation Based Experiments on Mobile Ad Hoc Networks

Over the course of the last 10 years, research on Mobile Ad Hoc Networks has witnessed high levels of focus. Because of this field being a relatively new topic, most researchers have focused on using simulation as the first choice for performance measurement and evaluation. In order to contribute to the credibility and reliability of research results on Ad Hoc networks, this paper addresses the issue of choosing parameter values that are used as input for simulators used in such experiments by surveying a sample of recently published papers on Ad Hoc Networks. Results show that in the majority of revised papers, the simulation environment is not carefully planned as reflected by the diversity and quality of parameters used.

Simulation of the Production Performances of Horizontal Wells with a Fractured Shale Gas Reservoir

The production performances of a well with a shale gas reservoir displaying a complex fracture network are simulated.In particular,a micro-seismic cloud diagram is used to describe the fracture network,and accordingly,a production model is introduced based on a multi-scale flow mechanism.A finite volume method is then exploited for the integration of the model equations.The effects of apparent permeability,conductivity,Langmuir volume,and bottom hole pressure on gas well production are studied accordingly.The simulation results show that ignoring the micro-scale flow mechanism of the shale gas leads to underestimating the well gas production.It is shown that after ten years of production,the cumulative gas production difference between the two scenarios with and without considering the micro-scale flow mechanisms is 19.5%.The greater the fracture conductivity,the higher the initial gas production of the gas well and the cumulative gas production.The larger the Langmuir volume,the higher the gas production rate and the cumulative gas production.With the reduction of the bottom hole pressure,the cumulative gas production increases,but the growth rate gradually decreases.

Based on network pharmacology and molecular docking technology to explore the mechanism of Panax notoginseng in the treatment of membranous nephropathy

Objective:Based on network pharmacology and molecular docking technology to explore the mechanism of Professor Cao Enze's application of Panax notoginseng in the treatment of membranous nephropathy.Methods:TCMSP database was used to obtain the effective components and corresponding target information of Panax notoginseng,and Gene Cards database was used to obtain the disease target genes of membranous nephropathy.The intersection targets of the two were taken and the Venn diagram was drawn.The STRING database was used to obtain the protein interaction relationship,and the PPI network diagram was constructed by Cytoscape 3.9.1 software to screen out the core targets of Panax notoginseng in the treatment of membranous nephropathy.GO function and KEGG pathway enrichment analysis were performed using the David database to obtain the potential pathway of Panax notoginseng in the treatment of membranous nephropathy.Finally,Autodock software was used to verify the molecular docking of the main active components of the drug with the core targets.Results:A total of 7 effective components such as quercetin,ginsenoside rh2,Mandenol and Stigmasterol were retrieved,and 127 potential targets of Panax notoginseng in the treatment of membranous nephropathy were screened out.By PPI network topology analysis,23 core targets such as JUN,TP53,RELA,AKT1 and MAPK1 were screened out.GO functional enrichment analysis contained 703 biological processes,55 cell components and 121 molecular functions,and KEGG signal pathway enrichment analysis enriched 171 signal pathways.The results of molecular docking showed that there was a strong binding ability between the main core targets and the main components of Panax notoginseng.Conclusion:Through network pharmacology,it is concluded that Panax notoginseng treats membranous nephropathy through multiple targets and multiple pathways,which provides a theoretical basis for subsequent basic research.

Simulation Experiments on the Reaction of CH_4-CaSO_4 and Its Carbon Kinetic Isotope Fractionation

Thermochemical sulfate reduction (TSR) in geological deposits can account for the accumulation of H2S in deep sour gas reservoirs. In this paper, thermal simulation experiments on the reaction of CH4-CaSO4 were carried out using an autoclave at high temperatures and high pressures. The products were characterized with analytical methods including carbon isotope analysis. It is found that the reaction can proceed to produce H2S, H2O and CaCO3 as the main products. Based on the experimental results, the carbon kinetic isotope fractionation was investigated, and the value of Ki (kinetic isotope effect) was calculated. The results obtained in this paper can provide useful information to explain the occurrence of H2S in deep carbonate gas reservoirs.

Simulation of the Pressure-Sensitive Seepage Fracture Network in Oil Reservoirs with Multi-Group Fractures

Stress sensitivity is a very important index to understand the seepage characteristics of a reservoir.In this study,dedicated experiments and theoretical arguments based on the visualization of porous media are used to assess the effects of the fracture angle,spacing,and relevant elastic parameters on the principal value of the permeability tensor.The fracture apertures at different angles show different change rates,which influence the relative permeability for different sets of fractures.Furthermore,under the same pressure condition,the fractures with different angles show different degrees of deformation so that the principal value direction of permeability rotates.This phenomenon leads to a variation in the water seepage direction in typical water-injection applications,thereby hindering the expected exploitation effect of the original well network.Overall,the research findings in this paper can be used as guidance to improve the effectiveness of water injection exploitation in the oil field industry.

A LAYERED NUMERICAL MODEL FOR SIMULATING THE GENERATION AND PROPAGATION OF INTERNAL TIDES OVER CONTINENTAL SLOPE Ⅲ. NUMERICAL EXPERIMENTS AND SIMULATION

The layered model in Part I was used to simulate the internal tide in a stratified, two layer, and rectangular sea area with step like topography. The internal tide current velocities of the upper and lower layers and the interfacial elevations were computed and the effect of the upper layer water depth and density difference were studied. Numerical experiments verified that the model can correctly simulate internal tides. The model was also applied to the northwestern part of the South China Sea to simulate the internal tides there with real topography. The distributions of internal tide amplitude in interfaces were delineated.