Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism rem...Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.展开更多
In order to better understand the specific substituent effects on the electrochemical oxidation process of β-O-4 bond, a series of methoxyphenyl type β-O-4 dimer model compounds with different localized methoxyl gro...In order to better understand the specific substituent effects on the electrochemical oxidation process of β-O-4 bond, a series of methoxyphenyl type β-O-4 dimer model compounds with different localized methoxyl groups, including 2-(2-methoxyphenoxy)-1-phenylethanone, 2-(2-methoxyphenoxy)-1-phenylethanol, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanol, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanol have been selected and their electrochemical properties have been studied experimentally by cyclic voltammetry, and FT-IR spectroelectrochemistry. Combining with electrolysis products distribution analysis and density functional theory calculations, oxidation mechanisms of all six model dimers have been explored. In particular, a total effect from substituents of both para-methoxy(on the aryl ring closing to Cα) and Cα-OH on the oxidation mechanisms has been clearly observed, showing a significant selectivity on the Cα-Cβbond cleavage induced by electrochemical oxidations.展开更多
A comparative study is conducted to compare the theory and application effect of two accident causation models, the human factors analysis and classification system（HFACS） and the accident causation ＂2-4＂ model（2...A comparative study is conducted to compare the theory and application effect of two accident causation models, the human factors analysis and classification system（HFACS） and the accident causation ＂2-4＂ model（24 Model）, as well as to provide a reference for safety researchers and accident investigators to select an appropriate accident analysis method. The two models are compared in terms of their theoretical foundations, cause classifications, accident analysis processes, application ranges, and accident prevention strategies. A coal and gas outburst accident is then analyzed using both models, and the application results are compared. This study shows that both the 24 Model and HFACS have strong theoretical foundations, and they can each be applied in various domains. In addition, the cause classification in HFACS is more practical, and its accident analysis process is more convenient. On the other hand, the 24 Model includes external factors, which makes the cause analysis more systematic and comprehensive. Moreover, the 24 Model puts forward more corresponding measures to prevent accidents.展开更多
ATP-binding cassette（ABC） transporter multidrug resistance protein 4（MRP4, ABCC4） is involved in multidrug resistance（MDR）, which is an increasing challenge to the treatment of cancers and infections. MRP4 is ov...ATP-binding cassette（ABC） transporter multidrug resistance protein 4（MRP4, ABCC4） is involved in multidrug resistance（MDR）, which is an increasing challenge to the treatment of cancers and infections. MRP4 is overexpressed in several types of cancers, and MRP4 inhibition shows striking effects against cancer progression and drug resistance. However, the structural knowledge of this protein remains unclear due to lack of an MRP4 X-ray structure, and homology modeling approach is an effective way to obtain three-dimensional structure of MRP4. We constructed three molecular models of human MRP4 mainly based on the inward facing Caenorhabditis elegans P-glycoprotein（P-gp）, the Thermotoga maritima heterodimeric ABC transporter TM287-TM288（TM287/288） and the outward facing Staphylococcus aureus Sav1866 crystal structures, which represented substrate uptake, transport and release state, respectively. The structures were further energy minimized and optimized by molecular dynamic simulations（MDS）. All the models were validated by various tools and servers, and the results showed that the quality of the models was reasonable and acceptable. These MRP4 models could be used as working tools for experimental studies on the structure and functions of MRP4 and designing more specific membrane transport modulating agents（MTMA）.展开更多
Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known ...Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)complexes.The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management.In this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid cycle.Leveraging this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4.Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.展开更多
Warm rotary draw bending provides a feasible method to form the large-diameter thin-walled（LDTW）TC4 bent tubes, which are widely used in the pneumatic system of aircrafts. An accurate prediction of flow behavior of ...Warm rotary draw bending provides a feasible method to form the large-diameter thin-walled（LDTW）TC4 bent tubes, which are widely used in the pneumatic system of aircrafts. An accurate prediction of flow behavior of TC4 tubes considering the couple effects of temperature,strain rate and strain is critical for understanding the deformation behavior of metals and optimizing the processing parameters in warm rotary draw bending of TC4 tubes. In this study, isothermal compression tests of TC4 tube alloy were performed from 573 to 873 K with an interval of 100 K and strain rates of 0.001, 0.010 and0.100 s^（-1）. The prediction of flow behavior was done using two constitutive models, namely modified Arrhenius model and artificial neural network（ANN） model. The predictions of these constitutive models were compared using statistical measures like correlation coefficient（R）, average absolute relative error（AARE） and its variation with the deformation parameters（temperature, strain rate and strain）. Analysis of statistical measures reveals that the two models show high predicted accuracy in terms of R and AARE. Comparatively speaking, the ANN model presents higher predicted accuracy than the modified Arrhenius model. In addition, the predicted accuracy of ANN model presents high stability at the whole deformation parameter ranges, whereas the predictability of the modified Arrhenius model has some fluctuation at different deformation conditions. It presents higher predicted accuracy at temperatures of 573-773 K, strain rates of 0.010-0.100 s^（-1）and strain of 0.04-0.32, while low accuracy at temperature of 873 K, strain rates of 0.001 s^（-1）and strain of 0.36-0.48.Thus, the application of modified Arrhenius model is limited by its relatively low predicted accuracy at some deformation conditions, while the ANN model presents very high predicted accuracy at all deformation conditions,which can be used to study the compression behavior of TC4 tube at the temperature range of 573-873 K and the strain rate of 0.001-0.100 s^（-1）. It can provide guideline for the design of processing parameters in warm rotary draw bending of LDTW TC4 tubes.展开更多
Forming limit diagram (FLD) is an important performance index to describe the maximum limit of principal strains that can be sustained by sheet metals till to the onset of localized necking. It offers a convenient and...Forming limit diagram (FLD) is an important performance index to describe the maximum limit of principal strains that can be sustained by sheet metals till to the onset of localized necking. It offers a convenient and useful tool to predict the forming limit in the sheet metal forming processes. In the present study, FLD has been determined experimentally for Ti?6Al?4V alloy at 400 °C by conducting a Nakazima test with specimens of different widths. Additionally, for theoretical FLD prediction, various anisotropic yield criteria (Barlat 1989, Barlat 1996, Hill 1993) and different hardening models viz., Hollomon power law (HPL), Johnson?Cook (JC), modified Zerilli–Armstrong (m-ZA), modified Arrhenius (m-Arr) models have been developed. Theoretical FLDs have been determined using Marciniak and Kuczynski (M?K) theory incorporating the developed yield criteria and constitutive models. It has been observed that the effect of yield model is more pronounced than the effect of constitutive model for theoretical FLDs prediction. However, the value of thickness imperfection factor (f0) is solely dependent on hardening model. Hill (1993) yield criterion is best suited for FLD prediction in the right hand side region. Moreover, Barlat (1989) yield criterion is best suited for FLD prediction in left hand side region. Therefore, the proposed hybrid FLD in combination with Barlat (1989) and Hill (1993) yield models with m-Arr hardening model is in the best agreement with experimental FLD.展开更多
In recent years, West Africa has been confronted with hydro-climatic disasters causing crises in both urban and rural areas. The tragedy in the occurrence of such events lies in the recurrent aspect of high water and ...In recent years, West Africa has been confronted with hydro-climatic disasters causing crises in both urban and rural areas. The tragedy in the occurrence of such events lies in the recurrent aspect of high water and associated floods. The devastating floods observed in Africa’s major rivers have revealed the need to understand the causes of these phenomena and to predict their behavior in order to improve the safety of exposed people and property. The aim of this study is to reproduce flood flows using the GR4J (Rural Engineering Four Daily Parameters) model to analyze flood risk in the Oti watershed in Togo. Daily data on flows (m3/s), potential evapotranspiration (mm/day) and average precipitation (mm) over the basin from 1961-2022 collected at the National Meteorological Agency of Togo (ANAMET) and the Department of Water Resources in Lome, were used with the R software package airGR. The Data from the West African Cordex program from 1961-2100 were used to analyze projected flows. The results obtained show the GR4J model’s effectiveness in reproducing flood flows, indicating that observed flows are well simulated during the calibration and validation periods, with KGE values ranging from 0.73 to 0.85 at calibration and 0.62 to 0.81 at validation. These KGE values reflect the good performance of the GR4J model in simulating flood flows in the watershed. However, a deterioration in the KGE value was observed over the second validation period. Under these conditions, there may be false or missed alerts for flood prediction, and the use of this model should be treated with the utmost caution for decision-support purposes.展开更多
Turbulent nonpremixed CH4/H2 flame has been simulated using several typical differential secondmoment turbulence closure (SMTC) models. To clarify the applicability of the various models, the LRR-IP model,JM model, SS...Turbulent nonpremixed CH4/H2 flame has been simulated using several typical differential secondmoment turbulence closure (SMTC) models. To clarify the applicability of the various models, the LRR-IP model,JM model, SSG model as well as two modified LRR-IP models were tested. Some of above-mentioned SMTC models cannot provide the overall satisfactory predictions of this challenging case. It is confirmed again that the standard LRR-IP model considerably overpredict the centerline velocity decay rate, and therefore performs not well. Also it is interesting to observe that the JM model does not perform well in this challenging test case, although it has already been proved successful in other cases. The SSG model produces quite satisfactory prediction and performs equally well or better than the two modified LRR-IP models in the reacting case. It can be concluded that the modified LRR-IP models as well as the SSG model are superior to the other SMTC models in the turbulent nonpremixed CH4/H2 flame.展开更多
文摘Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.
基金The authors gratefully acknowledge the financial support of the Natural Science Foundation of China,China(Grant No.21975082 and 21736003)the Guangdong Basic and Applied Basic Research Foundation(Grant Number:2019A1515011472 and 2022A1515011341)the Science and Technology Program of Guangzhou(Grant Number:202102080479).
文摘In order to better understand the specific substituent effects on the electrochemical oxidation process of β-O-4 bond, a series of methoxyphenyl type β-O-4 dimer model compounds with different localized methoxyl groups, including 2-(2-methoxyphenoxy)-1-phenylethanone, 2-(2-methoxyphenoxy)-1-phenylethanol, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2-methoxyphenoxy)-1-(4-methoxyphenyl)ethanol, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanone, 2-(2,6-dimethoxyphenoxy)-1-(4-methoxyphenyl)ethanol have been selected and their electrochemical properties have been studied experimentally by cyclic voltammetry, and FT-IR spectroelectrochemistry. Combining with electrolysis products distribution analysis and density functional theory calculations, oxidation mechanisms of all six model dimers have been explored. In particular, a total effect from substituents of both para-methoxy(on the aryl ring closing to Cα) and Cα-OH on the oxidation mechanisms has been clearly observed, showing a significant selectivity on the Cα-Cβbond cleavage induced by electrochemical oxidations.
基金support from the State Key Program of the National Natural Science Foundation of China (No. 51534008)
文摘A comparative study is conducted to compare the theory and application effect of two accident causation models, the human factors analysis and classification system（HFACS） and the accident causation ＂2-4＂ model（24 Model）, as well as to provide a reference for safety researchers and accident investigators to select an appropriate accident analysis method. The two models are compared in terms of their theoretical foundations, cause classifications, accident analysis processes, application ranges, and accident prevention strategies. A coal and gas outburst accident is then analyzed using both models, and the application results are compared. This study shows that both the 24 Model and HFACS have strong theoretical foundations, and they can each be applied in various domains. In addition, the cause classification in HFACS is more practical, and its accident analysis process is more convenient. On the other hand, the 24 Model includes external factors, which makes the cause analysis more systematic and comprehensive. Moreover, the 24 Model puts forward more corresponding measures to prevent accidents.
基金National High Technology Research and Development Program 863(Grant No.2012AA020308)National Natural Science Foundation of China(Grant No.21272017)
文摘ATP-binding cassette（ABC） transporter multidrug resistance protein 4（MRP4, ABCC4） is involved in multidrug resistance（MDR）, which is an increasing challenge to the treatment of cancers and infections. MRP4 is overexpressed in several types of cancers, and MRP4 inhibition shows striking effects against cancer progression and drug resistance. However, the structural knowledge of this protein remains unclear due to lack of an MRP4 X-ray structure, and homology modeling approach is an effective way to obtain three-dimensional structure of MRP4. We constructed three molecular models of human MRP4 mainly based on the inward facing Caenorhabditis elegans P-glycoprotein（P-gp）, the Thermotoga maritima heterodimeric ABC transporter TM287-TM288（TM287/288） and the outward facing Staphylococcus aureus Sav1866 crystal structures, which represented substrate uptake, transport and release state, respectively. The structures were further energy minimized and optimized by molecular dynamic simulations（MDS）. All the models were validated by various tools and servers, and the results showed that the quality of the models was reasonable and acceptable. These MRP4 models could be used as working tools for experimental studies on the structure and functions of MRP4 and designing more specific membrane transport modulating agents（MTMA）.
基金supported by the National Natural Science Foundation of China(#92254302 and#32293202 to S.J.)National Key Research and Development(#2019YFA0801403 to S.J.).
文摘Mitochondrial dysfunction is a critical factor leading to a wide range of clinically heterogeneous and often severe disorders due to its central role in generating cellular energy.Mutations in the TUFM gene are known to cause combined oxidative phosphorylation deficiency 4(COXPD4),a rare mitochondrial disorder characterized by a comprehensive quantitative deficiency in mitochondrial respiratory chain(MRC)complexes.The development of a reliable animal model for COXPD4 is crucial for elucidating the roles and mechanisms of TUFM in disease pathogenesis and benefiting its medical management.In this study,we construct a zebrafish tufm−/−mutant that closely resembles the COXPD4 syndrome,exhibiting compromised mitochondrial protein translation,dysfunctional mitochondria with oxidative phosphorylation defects,and significant metabolic suppression of the tricarboxylic acid cycle.Leveraging this COXPD4 zebrafish model,we comprehensively validate the clinical relevance of TUFM mutations and identify probucol as a promising therapeutic approach for managing COXPD4.Our data offer valuable insights for understanding mitochondrial diseases and developing effective treatments.
基金financially supported by the National Natural Science Foundation of China(Nos.51275415 and50905144)the Natural Science Basic Research Plan in Shanxi Province(No.2011JQ6004)the Program of the Ministry of Education of China for Introducing Talents of Discipline to Universities(No.B08040)
文摘Warm rotary draw bending provides a feasible method to form the large-diameter thin-walled（LDTW）TC4 bent tubes, which are widely used in the pneumatic system of aircrafts. An accurate prediction of flow behavior of TC4 tubes considering the couple effects of temperature,strain rate and strain is critical for understanding the deformation behavior of metals and optimizing the processing parameters in warm rotary draw bending of TC4 tubes. In this study, isothermal compression tests of TC4 tube alloy were performed from 573 to 873 K with an interval of 100 K and strain rates of 0.001, 0.010 and0.100 s^（-1）. The prediction of flow behavior was done using two constitutive models, namely modified Arrhenius model and artificial neural network（ANN） model. The predictions of these constitutive models were compared using statistical measures like correlation coefficient（R）, average absolute relative error（AARE） and its variation with the deformation parameters（temperature, strain rate and strain）. Analysis of statistical measures reveals that the two models show high predicted accuracy in terms of R and AARE. Comparatively speaking, the ANN model presents higher predicted accuracy than the modified Arrhenius model. In addition, the predicted accuracy of ANN model presents high stability at the whole deformation parameter ranges, whereas the predictability of the modified Arrhenius model has some fluctuation at different deformation conditions. It presents higher predicted accuracy at temperatures of 573-773 K, strain rates of 0.010-0.100 s^（-1）and strain of 0.04-0.32, while low accuracy at temperature of 873 K, strain rates of 0.001 s^（-1）and strain of 0.36-0.48.Thus, the application of modified Arrhenius model is limited by its relatively low predicted accuracy at some deformation conditions, while the ANN model presents very high predicted accuracy at all deformation conditions,which can be used to study the compression behavior of TC4 tube at the temperature range of 573-873 K and the strain rate of 0.001-0.100 s^（-1）. It can provide guideline for the design of processing parameters in warm rotary draw bending of LDTW TC4 tubes.
基金The financial support received for this research work from Department of Science and Technology (DST), Government of India, SERB-DST, SR/FTP/ETA0056/2011
文摘Forming limit diagram (FLD) is an important performance index to describe the maximum limit of principal strains that can be sustained by sheet metals till to the onset of localized necking. It offers a convenient and useful tool to predict the forming limit in the sheet metal forming processes. In the present study, FLD has been determined experimentally for Ti?6Al?4V alloy at 400 °C by conducting a Nakazima test with specimens of different widths. Additionally, for theoretical FLD prediction, various anisotropic yield criteria (Barlat 1989, Barlat 1996, Hill 1993) and different hardening models viz., Hollomon power law (HPL), Johnson?Cook (JC), modified Zerilli–Armstrong (m-ZA), modified Arrhenius (m-Arr) models have been developed. Theoretical FLDs have been determined using Marciniak and Kuczynski (M?K) theory incorporating the developed yield criteria and constitutive models. It has been observed that the effect of yield model is more pronounced than the effect of constitutive model for theoretical FLDs prediction. However, the value of thickness imperfection factor (f0) is solely dependent on hardening model. Hill (1993) yield criterion is best suited for FLD prediction in the right hand side region. Moreover, Barlat (1989) yield criterion is best suited for FLD prediction in left hand side region. Therefore, the proposed hybrid FLD in combination with Barlat (1989) and Hill (1993) yield models with m-Arr hardening model is in the best agreement with experimental FLD.
文摘In recent years, West Africa has been confronted with hydro-climatic disasters causing crises in both urban and rural areas. The tragedy in the occurrence of such events lies in the recurrent aspect of high water and associated floods. The devastating floods observed in Africa’s major rivers have revealed the need to understand the causes of these phenomena and to predict their behavior in order to improve the safety of exposed people and property. The aim of this study is to reproduce flood flows using the GR4J (Rural Engineering Four Daily Parameters) model to analyze flood risk in the Oti watershed in Togo. Daily data on flows (m3/s), potential evapotranspiration (mm/day) and average precipitation (mm) over the basin from 1961-2022 collected at the National Meteorological Agency of Togo (ANAMET) and the Department of Water Resources in Lome, were used with the R software package airGR. The Data from the West African Cordex program from 1961-2100 were used to analyze projected flows. The results obtained show the GR4J model’s effectiveness in reproducing flood flows, indicating that observed flows are well simulated during the calibration and validation periods, with KGE values ranging from 0.73 to 0.85 at calibration and 0.62 to 0.81 at validation. These KGE values reflect the good performance of the GR4J model in simulating flood flows in the watershed. However, a deterioration in the KGE value was observed over the second validation period. Under these conditions, there may be false or missed alerts for flood prediction, and the use of this model should be treated with the utmost caution for decision-support purposes.
文摘Turbulent nonpremixed CH4/H2 flame has been simulated using several typical differential secondmoment turbulence closure (SMTC) models. To clarify the applicability of the various models, the LRR-IP model,JM model, SSG model as well as two modified LRR-IP models were tested. Some of above-mentioned SMTC models cannot provide the overall satisfactory predictions of this challenging case. It is confirmed again that the standard LRR-IP model considerably overpredict the centerline velocity decay rate, and therefore performs not well. Also it is interesting to observe that the JM model does not perform well in this challenging test case, although it has already been proved successful in other cases. The SSG model produces quite satisfactory prediction and performs equally well or better than the two modified LRR-IP models in the reacting case. It can be concluded that the modified LRR-IP models as well as the SSG model are superior to the other SMTC models in the turbulent nonpremixed CH4/H2 flame.
