The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to ta...The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to target protein,which often requires time-consuming and labor-intensive processes such as isolation and enrichment.To address this issue,in this study we developed a method that combines ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry(UHPLCESI-MS)with molecular dynamics(MD)simulation to identify and observe,rapidly and efficiently,the bioactive components in NPs that bind to specific protein target.In this method,a specific protein target was introduced online using a three-way valve to form a protein-ligand complex.The complex was then detected in real time using high-resolution MS to identify potential ligands.Based on our method,only 10 molecules from green tea(a representative natural product),including the commonly reported epigallocatechin gallate(EGCG)and epicatechin gallate(ECG),as well as the previously unreported eepicatechin(4β→8)-epigallocatechin 3-O-gallate(EC-EGCG)and eepiafzelechin 3-O-gallate-(4β→8)-epigallocatechin 3-O-gallate(EFG-EGCG),were screened out,which could form complexes with Aβ_(1-42)(a representative protein target),and could be potential ligands of Aβ_(1-42).Among of them,EC-EGCG demonstrated the highest binding free energy with Aβ_(1-42)(−68.54±3.82 kcal/mol).On the other side,even though the caffeine had the highest signal among green tea extracts,it was not observed to form a complex with Aβ_(1-42).Compared to other methods such as affinity selection mass spectrometry(ASMS)and native MS,our method is easy to operate and interpret the data.Undoubtedly,it provides a new methodology for potential drug discovery in NPs,and will accelerate the research on screening ligands for specific proteins from complex NPs.展开更多
In the R&D phase of Gravity-1(YL-1), a multi-domain modeling and simulation technology based on Modelica language was introduced, which was a recent attempt in the practice of modeling and simulation method for la...In the R&D phase of Gravity-1(YL-1), a multi-domain modeling and simulation technology based on Modelica language was introduced, which was a recent attempt in the practice of modeling and simulation method for launch vehicles in China. It realizes a complex coupling model within a unified model for different domains, so that technologists can work on one model. It ensured the success of YL-1 first launch mission, supports rapid iteration, full validation, and tight design collaboration.展开更多
Background:Missing data are frequently occurred in clinical studies.Due to the development of precision medicine,there is an increased interest in N-of-1 trial.Bayesian models are one of main statistical methods for a...Background:Missing data are frequently occurred in clinical studies.Due to the development of precision medicine,there is an increased interest in N-of-1 trial.Bayesian models are one of main statistical methods for analyzing the data of N-of-1 trials.This simulation study aimed to compare two statistical methods for handling missing values of quantitative data in Bayesian N-of-1 trials.Methods:The simulated data of N-of-1 trials with different coefficients of autocorrelation,effect sizes and missing ratios are obtained by SAS 9.1 system.The missing values are filled with mean filling and regression filling respectively in the condition of different coefficients of autocorrelation,effect sizes and missing ratios by SPSS 25.0 software.Bayesian models are built to estimate the posterior means by Winbugs 14 software.Results:When the missing ratio is relatively small,e.g.5%,missing values have relatively little effect on the results.Therapeutic effects may be underestimated when the coefficient of autocorrelation increases and no filling is used.However,it may be overestimated when mean or regression filling is used,and the results after mean filling are closer to the actual effect than regression filling.In the case of moderate missing ratio,the estimated effect after mean filling is closer to the actual effect compared to regression filling.When a large missing ratio(20%)occurs,data missing can lead to significantly underestimate the effect.In this case,the estimated effect after regression filling is closer to the actual effect compared to mean filling.Conclusion:Data missing can affect the estimated therapeutic effects using Bayesian models in N-of-1 trials.The present study suggests that mean filling can be used under situation of missing ratio≤10%.Otherwise,regression filling may be preferable.展开更多
This study investigates the mechanism by which baicalin inhibits cancer cell growth through estrogen receptor 1 (ESR1) using molecular dynamics simulations. The results show that baicalin primarily binds to the ligand...This study investigates the mechanism by which baicalin inhibits cancer cell growth through estrogen receptor 1 (ESR1) using molecular dynamics simulations. The results show that baicalin primarily binds to the ligand-binding domain (LBD) of ESR1, interacting through hydrogen bonds and hydrophobic interactions. After binding, the overall and local conformations of ESR1 change, affecting its interactions with other proteins and thus modulating the signaling pathways of cancer cells. Binding free energy analysis indicates that the binding of baicalin to ESR1 is spontaneous and relatively stable. Additionally, baicalin can inhibit the binding of ESR1 to estrogen, blocking the estrogen signaling pathway and thereby suppressing the growth and proliferation of cancer cells. This study provides theoretical and experimental foundations for the potential use of baicalin as an anticancer drug, offering new insights and methods for the development of novel anticancer drugs. However, the study has some limitations, such as limited simulation time and simplified systems. Future research can extend the simulation time and consider more physiological factors to more accurately simulate the interactions between baicalin and ESR1.展开更多
In meandering rivers, the flow pattern is highly complex, with specific characteristics at bends that are not observed along straight paths. A numerical model can be effectively used to predict such flow fields. Since...In meandering rivers, the flow pattern is highly complex, with specific characteristics at bends that are not observed along straight paths. A numerical model can be effectively used to predict such flow fields. Since river bends are not uniform-some are divergent and others convergent-in this study, after the SSIIM 3-D model was calibrated using the result of measurements along a uniform 180° bend with a width of 0.6 m, a similar but convergent 180v bend, 0.6 m to 0.45 m wide, was simulated using the SSI1M 3-D numerical model. Flow characteristics of the convergent 180° bend, including lengthwise and vertical velocity profiles, primary and secondary flows, lengthwise and widtbwise slopes of the water surface, and the helical flow strength, were compared with those of the uniform 180° bend. The verification results of the model show that the numerical model can effectively simulate the flow field in the uniform bend. In addition, this research indicates that, in a convergent channel, the maximum velocity path at a plane near the water surface crosses the channel＇s centerline at about a 30° to 40° cross-section, while in the uniform bend, this occurs at about the 50° cross-section. The varying range of the water surface elevation is wider in the convergent channel than in the uniform one, and the strength of the helical flow is generally greater in the uniform channel than in the convergent one. Also, unlike the uniform bend, the convergent bend exhibits no rotational cell against the main direction of secondary flow rotation at the 135° cross-section.展开更多
At Kuwana illegal dumping site in Japan, where hazardous waste was illegally dumped, groundwater was severely contaminated by Volatile Organic Compounds (VOCs). Groundwater was already remedied by conducting Pump-and-...At Kuwana illegal dumping site in Japan, where hazardous waste was illegally dumped, groundwater was severely contaminated by Volatile Organic Compounds (VOCs). Groundwater was already remedied by conducting Pump-and-Treat (P&T) after containment of all the waste by vertical slurry walls from 2002 to 2007. However, 1,4-dioxane was detected in both waste and groundwater outside of slurry walls after it was newly added into Japan environmental standards in late 2009, which suggested that the walls did not contain 1,4-dioxane completely. Our previous study developed a model to predict the 1,4-dioxane distribution in groundwater after the previous remediation at the site. In this study, numerical simulation was applied for remediation planning at the site based on the concept of Verified Follow Up (VF-UP) that had been proposed as a new approach to complete remediation effectively with consideration of future risks. The amount of waste to be removed and pumping plans were discussed by numerical simulation to achieve the remedial objective in which 1,4-dioxane in groundwater outside of walls is remedied within 10 years and 1,4-dioxane spreading throughout the walls is prevented in the case where a portion of waste is remained. Firstly, the amount of waste to be removed considering pumping plans for P&T was determined by scenario analysis. As a result, at least two-third of waste should be removed by combining with P&T. However, if the waste is remained, future risks of 1,4-dioxane spreading through the slurry walls may occur. Our simulation suggested that groundwater within the remaining waste must be pumped up at least 20 m3/d for containment of 1,4-dioxane within the remaining waste. In conclusion, our numerical simulation determined the amount of waste to be removed and the pumping plans for P&T to achieve the remedial objective effectively considering future risks based on the concept of VF-UP.展开更多
Molecular dynamics simulation was carried out to study the behavior of liquid 1,2-dichloroethane molecules under external electric fields including direct current field, alternating current field and positive-half-per...Molecular dynamics simulation was carried out to study the behavior of liquid 1,2-dichloroethane molecules under external electric fields including direct current field, alternating current field and positive-half-period cosin field. The maximum applied field strength was 10^8 V/m , the maximum frequency of the alternating current field and that of the positive-half-period cosine field was 10^12 Hz . The simulation revealed that the field type and field strength act on the population of the molecular configuration. In the strong direct current field, all trans forms converted completely into gauche forms. Order parameter and the correlation of the system torsion angle were also investigated. The results suggested that these two dynamical parameters depended also on the field type and the field strength. The maximum of order parameter was found to be at 0.6in the strong direct current field.展开更多
目的探讨(1-3)-β-D葡聚糖联合降钙素原(procalcitonin,PCT)、CD4^(+)T淋巴细胞多指标在艾滋病患者马尔尼菲篮状菌感染早期诊断临床研究。方法回顾性选取我院2020年1月—2022年6月住院的120例艾滋病患者为研究对象。依据实验室结果,将...目的探讨(1-3)-β-D葡聚糖联合降钙素原(procalcitonin,PCT)、CD4^(+)T淋巴细胞多指标在艾滋病患者马尔尼菲篮状菌感染早期诊断临床研究。方法回顾性选取我院2020年1月—2022年6月住院的120例艾滋病患者为研究对象。依据实验室结果,将其分为马尔尼菲篮状菌感染确诊组(血或组织液培育养出马尔尼菲篮状菌),简称A组(62例),及马尔尼菲篮状菌感染临床诊断组[根据临床症状、体征、血常规及(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞多指标诊断],简称B组(58例)。检测患者(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞的表达水平,采用受试者工作特征(receiver-operating characteristic,ROC)曲线下面积(area under the curve,AUC)评估上述指标联合检测对艾滋病患者感染马尔尼菲篮状菌的诊断效能。结果A组的(1-3)-β-D葡聚糖和PCT水平均高于B组,CD4^(+)T淋巴细胞个数低于B组(P<0.05);(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞联合检测的AUC为0.933,(1-3)-β-D葡聚糖单独检测的AUC是0.812,PCT单独检测的AUC为0.883,CD4^(+)T淋巴细胞单独检测的AUC是0.810,(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的AUC皆优于三项单独检测,表明(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的诊断价值皆优于单一指标诊断,且联合检测的特异度、约登指数分别为92.43%和0.580,均高于三项单独检测。结论(1-3)-β-D葡聚糖联合PCT和CD4^(+)T淋巴细胞多指标对艾滋病马尔尼菲篮状菌感染具有非常高的临床诊断价值,能够帮助医生分析出高危风险患者,及时制定治疗方案,同时也承担预后效果的判断依据,对治疗艾滋病马尔尼菲篮状菌感染具有非常重要的研究价值。展开更多
Molecular dynamic simulation was employed to predict the melting points Tm of TNAD/HMX, TNAD/RDX, TNAD/DINA, and TNAD/DNP systems （tans-1,4,5,8- tetranitro-1,4,5,8-tetraazadacalin （TNAD）, dinitropiperazine （DNP）,...Molecular dynamic simulation was employed to predict the melting points Tm of TNAD/HMX, TNAD/RDX, TNAD/DINA, and TNAD/DNP systems （tans-1,4,5,8- tetranitro-1,4,5,8-tetraazadacalin （TNAD）, dinitropiperazine （DNP）, cyclotetramethylenetetranitroamine （HMX）, cyclotrimethylenetrinitramine （RDX）, and N-nitrodihydroxyethylaminedinitrate （DINA））. Tm was determined from the inflexion point on the curve of mean specific volume vs. temperature. The result shows that the Tm values of TNAD/HMX, TNAD/RDX, and TNAD/DINA systems are 500, 536, and 488 K, respectively. The TNAD/DNP system has no obvious Tm value, which shows the system is insoluble. Using Tm, the solubility of the four systems was analyzed. The radial distribution functions of the four systems were analyzed and the main intermolecular forces between TNAD and other energetic components are short-range interactions. The better the solubility is, the stronger the intermoleenlar interaction is. In addition, the force field energy at different temperature was also analyzed to predict Tm of the four systems.展开更多
基金supported by the National Key R&D Program of China(No.2018YFA0800900).
文摘The bioactive constituents found in natural products(NPs)are crucial in protein-ligand interactions and drug discovery.However,it is difficult to identify ligand molecules from complex NPs that specifically bind to target protein,which often requires time-consuming and labor-intensive processes such as isolation and enrichment.To address this issue,in this study we developed a method that combines ultra-high performance liquid chromatography-electrospray ionization-mass spectrometry(UHPLCESI-MS)with molecular dynamics(MD)simulation to identify and observe,rapidly and efficiently,the bioactive components in NPs that bind to specific protein target.In this method,a specific protein target was introduced online using a three-way valve to form a protein-ligand complex.The complex was then detected in real time using high-resolution MS to identify potential ligands.Based on our method,only 10 molecules from green tea(a representative natural product),including the commonly reported epigallocatechin gallate(EGCG)and epicatechin gallate(ECG),as well as the previously unreported eepicatechin(4β→8)-epigallocatechin 3-O-gallate(EC-EGCG)and eepiafzelechin 3-O-gallate-(4β→8)-epigallocatechin 3-O-gallate(EFG-EGCG),were screened out,which could form complexes with Aβ_(1-42)(a representative protein target),and could be potential ligands of Aβ_(1-42).Among of them,EC-EGCG demonstrated the highest binding free energy with Aβ_(1-42)(−68.54±3.82 kcal/mol).On the other side,even though the caffeine had the highest signal among green tea extracts,it was not observed to form a complex with Aβ_(1-42).Compared to other methods such as affinity selection mass spectrometry(ASMS)and native MS,our method is easy to operate and interpret the data.Undoubtedly,it provides a new methodology for potential drug discovery in NPs,and will accelerate the research on screening ligands for specific proteins from complex NPs.
文摘In the R&D phase of Gravity-1(YL-1), a multi-domain modeling and simulation technology based on Modelica language was introduced, which was a recent attempt in the practice of modeling and simulation method for launch vehicles in China. It realizes a complex coupling model within a unified model for different domains, so that technologists can work on one model. It ensured the success of YL-1 first launch mission, supports rapid iteration, full validation, and tight design collaboration.
基金supported by the National Natural Science Foundation of China (No.81973705).
文摘Background:Missing data are frequently occurred in clinical studies.Due to the development of precision medicine,there is an increased interest in N-of-1 trial.Bayesian models are one of main statistical methods for analyzing the data of N-of-1 trials.This simulation study aimed to compare two statistical methods for handling missing values of quantitative data in Bayesian N-of-1 trials.Methods:The simulated data of N-of-1 trials with different coefficients of autocorrelation,effect sizes and missing ratios are obtained by SAS 9.1 system.The missing values are filled with mean filling and regression filling respectively in the condition of different coefficients of autocorrelation,effect sizes and missing ratios by SPSS 25.0 software.Bayesian models are built to estimate the posterior means by Winbugs 14 software.Results:When the missing ratio is relatively small,e.g.5%,missing values have relatively little effect on the results.Therapeutic effects may be underestimated when the coefficient of autocorrelation increases and no filling is used.However,it may be overestimated when mean or regression filling is used,and the results after mean filling are closer to the actual effect than regression filling.In the case of moderate missing ratio,the estimated effect after mean filling is closer to the actual effect compared to regression filling.When a large missing ratio(20%)occurs,data missing can lead to significantly underestimate the effect.In this case,the estimated effect after regression filling is closer to the actual effect compared to mean filling.Conclusion:Data missing can affect the estimated therapeutic effects using Bayesian models in N-of-1 trials.The present study suggests that mean filling can be used under situation of missing ratio≤10%.Otherwise,regression filling may be preferable.
文摘This study investigates the mechanism by which baicalin inhibits cancer cell growth through estrogen receptor 1 (ESR1) using molecular dynamics simulations. The results show that baicalin primarily binds to the ligand-binding domain (LBD) of ESR1, interacting through hydrogen bonds and hydrophobic interactions. After binding, the overall and local conformations of ESR1 change, affecting its interactions with other proteins and thus modulating the signaling pathways of cancer cells. Binding free energy analysis indicates that the binding of baicalin to ESR1 is spontaneous and relatively stable. Additionally, baicalin can inhibit the binding of ESR1 to estrogen, blocking the estrogen signaling pathway and thereby suppressing the growth and proliferation of cancer cells. This study provides theoretical and experimental foundations for the potential use of baicalin as an anticancer drug, offering new insights and methods for the development of novel anticancer drugs. However, the study has some limitations, such as limited simulation time and simplified systems. Future research can extend the simulation time and consider more physiological factors to more accurately simulate the interactions between baicalin and ESR1.
文摘In meandering rivers, the flow pattern is highly complex, with specific characteristics at bends that are not observed along straight paths. A numerical model can be effectively used to predict such flow fields. Since river bends are not uniform-some are divergent and others convergent-in this study, after the SSIIM 3-D model was calibrated using the result of measurements along a uniform 180° bend with a width of 0.6 m, a similar but convergent 180v bend, 0.6 m to 0.45 m wide, was simulated using the SSI1M 3-D numerical model. Flow characteristics of the convergent 180° bend, including lengthwise and vertical velocity profiles, primary and secondary flows, lengthwise and widtbwise slopes of the water surface, and the helical flow strength, were compared with those of the uniform 180° bend. The verification results of the model show that the numerical model can effectively simulate the flow field in the uniform bend. In addition, this research indicates that, in a convergent channel, the maximum velocity path at a plane near the water surface crosses the channel＇s centerline at about a 30° to 40° cross-section, while in the uniform bend, this occurs at about the 50° cross-section. The varying range of the water surface elevation is wider in the convergent channel than in the uniform one, and the strength of the helical flow is generally greater in the uniform channel than in the convergent one. Also, unlike the uniform bend, the convergent bend exhibits no rotational cell against the main direction of secondary flow rotation at the 135° cross-section.
文摘At Kuwana illegal dumping site in Japan, where hazardous waste was illegally dumped, groundwater was severely contaminated by Volatile Organic Compounds (VOCs). Groundwater was already remedied by conducting Pump-and-Treat (P&T) after containment of all the waste by vertical slurry walls from 2002 to 2007. However, 1,4-dioxane was detected in both waste and groundwater outside of slurry walls after it was newly added into Japan environmental standards in late 2009, which suggested that the walls did not contain 1,4-dioxane completely. Our previous study developed a model to predict the 1,4-dioxane distribution in groundwater after the previous remediation at the site. In this study, numerical simulation was applied for remediation planning at the site based on the concept of Verified Follow Up (VF-UP) that had been proposed as a new approach to complete remediation effectively with consideration of future risks. The amount of waste to be removed and pumping plans were discussed by numerical simulation to achieve the remedial objective in which 1,4-dioxane in groundwater outside of walls is remedied within 10 years and 1,4-dioxane spreading throughout the walls is prevented in the case where a portion of waste is remained. Firstly, the amount of waste to be removed considering pumping plans for P&T was determined by scenario analysis. As a result, at least two-third of waste should be removed by combining with P&T. However, if the waste is remained, future risks of 1,4-dioxane spreading through the slurry walls may occur. Our simulation suggested that groundwater within the remaining waste must be pumped up at least 20 m3/d for containment of 1,4-dioxane within the remaining waste. In conclusion, our numerical simulation determined the amount of waste to be removed and the pumping plans for P&T to achieve the remedial objective effectively considering future risks based on the concept of VF-UP.
文摘Molecular dynamics simulation was carried out to study the behavior of liquid 1,2-dichloroethane molecules under external electric fields including direct current field, alternating current field and positive-half-period cosin field. The maximum applied field strength was 10^8 V/m , the maximum frequency of the alternating current field and that of the positive-half-period cosine field was 10^12 Hz . The simulation revealed that the field type and field strength act on the population of the molecular configuration. In the strong direct current field, all trans forms converted completely into gauche forms. Order parameter and the correlation of the system torsion angle were also investigated. The results suggested that these two dynamical parameters depended also on the field type and the field strength. The maximum of order parameter was found to be at 0.6in the strong direct current field.
文摘目的探讨(1-3)-β-D葡聚糖联合降钙素原(procalcitonin,PCT)、CD4^(+)T淋巴细胞多指标在艾滋病患者马尔尼菲篮状菌感染早期诊断临床研究。方法回顾性选取我院2020年1月—2022年6月住院的120例艾滋病患者为研究对象。依据实验室结果,将其分为马尔尼菲篮状菌感染确诊组(血或组织液培育养出马尔尼菲篮状菌),简称A组(62例),及马尔尼菲篮状菌感染临床诊断组[根据临床症状、体征、血常规及(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞多指标诊断],简称B组(58例)。检测患者(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞的表达水平,采用受试者工作特征(receiver-operating characteristic,ROC)曲线下面积(area under the curve,AUC)评估上述指标联合检测对艾滋病患者感染马尔尼菲篮状菌的诊断效能。结果A组的(1-3)-β-D葡聚糖和PCT水平均高于B组,CD4^(+)T淋巴细胞个数低于B组(P<0.05);(1-3)-β-D葡聚糖、PCT、CD4^(+)T淋巴细胞联合检测的AUC为0.933,(1-3)-β-D葡聚糖单独检测的AUC是0.812,PCT单独检测的AUC为0.883,CD4^(+)T淋巴细胞单独检测的AUC是0.810,(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的AUC皆优于三项单独检测,表明(1-3)-β-D葡聚糖、PCT和CD4^(+)T淋巴细胞联合检测的诊断价值皆优于单一指标诊断,且联合检测的特异度、约登指数分别为92.43%和0.580,均高于三项单独检测。结论(1-3)-β-D葡聚糖联合PCT和CD4^(+)T淋巴细胞多指标对艾滋病马尔尼菲篮状菌感染具有非常高的临床诊断价值,能够帮助医生分析出高危风险患者,及时制定治疗方案,同时也承担预后效果的判断依据,对治疗艾滋病马尔尼菲篮状菌感染具有非常重要的研究价值。
基金V. ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China （No.U1304111）, the Laboratory of Science and Technology on Combustion and Explosion （No.9140C3501021101）, China Postdoctoral Science Foundation （No.2013M531361）, and Jiangsu Planned Projects for Postdoctoral Research Funds （No.1201015B）.
文摘Molecular dynamic simulation was employed to predict the melting points Tm of TNAD/HMX, TNAD/RDX, TNAD/DINA, and TNAD/DNP systems （tans-1,4,5,8- tetranitro-1,4,5,8-tetraazadacalin （TNAD）, dinitropiperazine （DNP）, cyclotetramethylenetetranitroamine （HMX）, cyclotrimethylenetrinitramine （RDX）, and N-nitrodihydroxyethylaminedinitrate （DINA））. Tm was determined from the inflexion point on the curve of mean specific volume vs. temperature. The result shows that the Tm values of TNAD/HMX, TNAD/RDX, and TNAD/DINA systems are 500, 536, and 488 K, respectively. The TNAD/DNP system has no obvious Tm value, which shows the system is insoluble. Using Tm, the solubility of the four systems was analyzed. The radial distribution functions of the four systems were analyzed and the main intermolecular forces between TNAD and other energetic components are short-range interactions. The better the solubility is, the stronger the intermoleenlar interaction is. In addition, the force field energy at different temperature was also analyzed to predict Tm of the four systems.
