A new method of system failure analysis was proposed. First, considering the relationships between the failure subsystems,the decision making trial and evaluation laboratory(DEMATEL) method was used to calculate the d...A new method of system failure analysis was proposed. First, considering the relationships between the failure subsystems,the decision making trial and evaluation laboratory(DEMATEL) method was used to calculate the degree of correlation between the failure subsystems, analyze the combined effect of related failures, and obtain the degree of correlation by using the directed graph and matrix operations. Then, the interpretative structural modeling(ISM) method was combined to intuitively show the logical relationship of many failure subsystems and their influences on each other by using multilevel hierarchical structure model and obtaining the critical subsystems. Finally, failure mode effects and criticality analysis(FMECA) was used to perform a qualitative hazard analysis of critical subsystems, determine the critical failure mode, and clarify the direction of reliability improvement.Through an example, the result demonstrates that the proposed method can be efficiently applied to system failure analysis problems.展开更多
Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving int...Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.展开更多
The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the ...The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the SRP68-SRP72 （SRP68/72） heterodimer plays an essen- tial role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, espe- cially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91A. and 1.7A resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats （TPR） and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodi- mer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended sur- face. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68-SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68-SRP72 inter- action in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.展开更多
基金Project(51275205)supported by the National Natural Science Foundation of China
文摘A new method of system failure analysis was proposed. First, considering the relationships between the failure subsystems,the decision making trial and evaluation laboratory(DEMATEL) method was used to calculate the degree of correlation between the failure subsystems, analyze the combined effect of related failures, and obtain the degree of correlation by using the directed graph and matrix operations. Then, the interpretative structural modeling(ISM) method was combined to intuitively show the logical relationship of many failure subsystems and their influences on each other by using multilevel hierarchical structure model and obtaining the critical subsystems. Finally, failure mode effects and criticality analysis(FMECA) was used to perform a qualitative hazard analysis of critical subsystems, determine the critical failure mode, and clarify the direction of reliability improvement.Through an example, the result demonstrates that the proposed method can be efficiently applied to system failure analysis problems.
文摘Innate immunity offers the first line of defense against infections and other types of danger such as tumorigenesis. Its discovery provides tremendous therapeutic opportunities for numerous human diseases. Delving into the structural basis of signal transduction by innate immune receptors, our lab has recently helped to establish the new paradigm in which innate immune receptors transduce ligand-binding signals through formation of higher-order assemblies containing intracellular adapters, signaling enzymes and their substrates. These large signalosome assemblies may be visible under light microscopy as punctate structures in the μm scale, connecting to the underlying molecular structures in the nm scale. They drive proximity-induced enzyme activation, and provide a mechanism for signaling amplification by nucleated polymerization. These supramolecular signaling complexes also open new questions on their cellular organization and mode of regulation, pose challenges to our methodology, and afford valuable implications in drug discovery against these medically important pathways.
文摘The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum （ER） is a key biological process mediated by the signal recognition particle （SRP）. In eukaryotes, the SRP68-SRP72 （SRP68/72） heterodimer plays an essen- tial role in protein translocation. However, structural information on the two largest SRP proteins, SRP68 and SRP72, is limited, espe- cially regarding their interaction. Herein, we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91A. and 1.7A resolution, respectively. The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats （TPR） and a flexible C-terminal cap. Apo-SRP72 exists mainly as dimers in solution. To bind to SRP68, the SRP72 homodimer disassociates, and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodi- mer. A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended sur- face. Structural, biophysical, and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68-SRP72 interaction and their co-localization with ER in mammalian cells. The results highlight the essential role of the SRP68-SRP72 inter- action in SRP-mediated protein translocation and provide a structural basis for disease diagnosis, pathophysiology, and drug design.
