Cellular thin-shell structures are widely applied in ultralightweight designs due to their high bearing capacity and strength-to-weight ratio.In this paper,a full-scale isogeometric topology optimization(ITO)method ba...Cellular thin-shell structures are widely applied in ultralightweight designs due to their high bearing capacity and strength-to-weight ratio.In this paper,a full-scale isogeometric topology optimization(ITO)method based on Kirchhoff-Love shells for designing cellular tshin-shell structures with excellent damage tolerance ability is proposed.This method utilizes high-order continuous nonuniform rational B-splines(NURBS)as basis functions for Kirchhoff-Love shell elements.The geometric and analysis models of thin shells are unified by isogeometric analysis(IGA)to avoid geometric approximation error and improve computational accuracy.The topological configurations of thin-shell structures are described by constructing the effective density field on the controlmesh.Local volume constraints are imposed in the proximity of each control point to obtain bone-like cellular structures.To facilitate numerical implementation,the p-norm function is used to aggregate local volume constraints into an equivalent global constraint.Several numerical examples are provided to demonstrate the effectiveness of the proposed method.After simulation and comparative analysis,the results indicate that the cellular thin-shell structures optimized by the proposed method exhibit great load-carrying behavior and high damage robustness.展开更多
A novel method for the mechanical simulation of linear and nonlinear Timoshenko-beams has been presented.The beam strains are based on a kinematic assumption where the shear deformation and rotational are considered.A...A novel method for the mechanical simulation of linear and nonlinear Timoshenko-beams has been presented.The beam strains are based on a kinematic assumption where the shear deformation and rotational are considered.Applying the isoparametric concept the kinematic quantities are approximated using NURBS(non-uniform Rational B-spline)functions.This numerical simulation can be called as isogeometric analysis,which can improve the efficiency in CAD(computer aided design).Furthermore,an efficient Code has been developed and the results for two numerical applications are given in the end.展开更多
In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflamm...In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflammation. However, whether eCIRP regulates macrophage bacterial phagocytosis is unknown. Here, we reported that the bacterial loads in the blood and peritoneal fluid were decreased in CIRP^(−/−) mice and anti-eCIRP Ab-treated mice after sepsis. Increased eCIRP levels were correlated with decreased bacterial clearance in septic mice. CIRP−/− mice showed a marked increase in survival after sepsis. Recombinant murine CIRP (rmCIRP) significantly decreased the phagocytosis of bacteria by macrophages in vivo and in vitro. rmCIRP decreased the protein expression of actin-binding proteins, ARP2, and p-cofilin in macrophages. rmCIRP significantly downregulated the protein expression of βPIX, a Rac1 activator. We further demonstrated that STAT3 and βPIX formed a complex following rmCIRP treatment, preventing βPIX from activating Rac1. We also found that eCIRP-induced STAT3 phosphorylation was required for eCIRP’s action in actin remodeling. Inhibition of STAT3 phosphorylation prevented the formation of the STAT3-βPIX complex, restoring ARP2 and p-cofilin expression and membrane protrusion in rmCIRP-treated macrophages. The STAT3 inhibitor stattic rescued the macrophage phagocytic dysfunction induced by rmCIRP. Thus, we identified a novel mechanism of macrophage phagocytic dysfunction caused by eCIRP, which provides a new therapeutic target to ameliorate sepsis.展开更多
Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragment...Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.展开更多
Biopolymer chitin and its derivatives have a wide range of applications in different fields.Chitin is primarily produced from marine crustacean by strong acid and strong alkali treatment.To reduce the environmental ha...Biopolymer chitin and its derivatives have a wide range of applications in different fields.Chitin is primarily produced from marine crustacean by strong acid and strong alkali treatment.To reduce the environmental hazardous in the production of chitin,post-fermentation fungal biomass waste like fungi cell walls provides a viable alternative source for chitin.In this study,improved chitin content in yeast cell wall was achieved by overexpressing chitin biosyntheic pathway related genes.The chitin content was 51.5μg/mg cell wall and 122.9μg/mg cell wall in strain GS-1.10(gfat,uap and chs1 genes overexpression)and strain GS-2.6(gfat,gna1,agm1,uap and chs1 genes overexpression),which were 44.3%and 244.4%higher than that in control strain GS115,respectively.By overexpressing another chitin synthase gene(chs3),the chitin content in strain GS-3.10 was further increased to 136.2μg/mg cell wall,which was 10.8%and 281.6%higher than that in GS-2.6 and in control GS115,respectively.Moreover,chitin yield was further improved by various culture conditions optimization,and reached 162.4μg/mg cell wall,which was 4.43 times of that in the starting strain GS115.The final titer of chitin was 2.23 g/L culture broth in 84 h fed-batch fermentation in a 5 L bioreactor.To our knowledge,this is the first report of chitin production in engineered Pichia pastoris via biosynthetic pathway enhancement.展开更多
Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining g...Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining genetic material.Through cellular evolution of prokaryotic to eukaryotic,nucleases become structure-specific in recognizing its own or foreign genomic DNA/RNA configurations as its substrates,including flaps,bubbles,and Holliday junctions.These special structural configurations are commonly found as intermediates in processes like DNA replication,repair,and recombination.The structure-specific nature and diversified functions make them essential to maintaining genome integrity and evolution in normal and cancer cells.In this article,we review their roles in various pathways,including Okazaki fragment maturation during DNA replication,end resection in homology-directed recombination repair of DNA double-strand breaks,DNA excision repair and apoptosis DNA fragmentation in response to exogenous DNA damage,and HIV life cycle.As the nucleases serve as key points for the DNA dynamics,cellular apoptosis,and cancer cell survival pathways,we discuss the efforts in the field in developing the therapeutic regimens,taking advantage of recently available knowledge of their diversified structures and functions.展开更多
基金supported by the National Key R&D Program of China(Grant Number 2020YFB1708300)China National Postdoctoral Program for Innovative Talents(Grant Number BX20220124)+1 种基金China Postdoctoral Science Foundation(Grant Number 2022M710055)the New Cornerstone Science Foundation through the XPLORER PRIZE,the Knowledge Innovation Program of Wuhan-Shuguang,the Young Top-Notch Talent Cultivation Program of Hubei Province and the Taihu Lake Innovation Fund for Future Technology(Grant Number HUST:2023-B-7).
文摘Cellular thin-shell structures are widely applied in ultralightweight designs due to their high bearing capacity and strength-to-weight ratio.In this paper,a full-scale isogeometric topology optimization(ITO)method based on Kirchhoff-Love shells for designing cellular tshin-shell structures with excellent damage tolerance ability is proposed.This method utilizes high-order continuous nonuniform rational B-splines(NURBS)as basis functions for Kirchhoff-Love shell elements.The geometric and analysis models of thin shells are unified by isogeometric analysis(IGA)to avoid geometric approximation error and improve computational accuracy.The topological configurations of thin-shell structures are described by constructing the effective density field on the controlmesh.Local volume constraints are imposed in the proximity of each control point to obtain bone-like cellular structures.To facilitate numerical implementation,the p-norm function is used to aggregate local volume constraints into an equivalent global constraint.Several numerical examples are provided to demonstrate the effectiveness of the proposed method.After simulation and comparative analysis,the results indicate that the cellular thin-shell structures optimized by the proposed method exhibit great load-carrying behavior and high damage robustness.
文摘A novel method for the mechanical simulation of linear and nonlinear Timoshenko-beams has been presented.The beam strains are based on a kinematic assumption where the shear deformation and rotational are considered.Applying the isoparametric concept the kinematic quantities are approximated using NURBS(non-uniform Rational B-spline)functions.This numerical simulation can be called as isogeometric analysis,which can improve the efficiency in CAD(computer aided design).Furthermore,an efficient Code has been developed and the results for two numerical applications are given in the end.
基金supported by the National Natural Science Foundation of China(32370288)Capital Normal University,and the Support Project of Highlevel Teachers in Beijing Municipal Universities in the Period of 14th Five-year Plan(BPHR20220114).
文摘In the intricate molecular warfare between plants and pathogens,bacteria deploy sophisticated strategies to subvert host defenses.Xanthomonas oryzae pathogens,which cause devastating bacterial blight(BB)and bacterial leaf streak(BLS)in rice,utilize transcription activator-like effectors(TALEs)to manipulate host gene expression.
基金supported by the US National Institutes of Health(NIH)grants R35GM118337,R01HL076179,R01AA028947,U01AI133655 and U01AI170018MA is supported by the US NIH grants R01GM129633 and U01AI170018.
文摘In sepsis, macrophage bacterial phagocytosis is impaired, but the mechanism is not well elucidated. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that causes inflammation. However, whether eCIRP regulates macrophage bacterial phagocytosis is unknown. Here, we reported that the bacterial loads in the blood and peritoneal fluid were decreased in CIRP^(−/−) mice and anti-eCIRP Ab-treated mice after sepsis. Increased eCIRP levels were correlated with decreased bacterial clearance in septic mice. CIRP−/− mice showed a marked increase in survival after sepsis. Recombinant murine CIRP (rmCIRP) significantly decreased the phagocytosis of bacteria by macrophages in vivo and in vitro. rmCIRP decreased the protein expression of actin-binding proteins, ARP2, and p-cofilin in macrophages. rmCIRP significantly downregulated the protein expression of βPIX, a Rac1 activator. We further demonstrated that STAT3 and βPIX formed a complex following rmCIRP treatment, preventing βPIX from activating Rac1. We also found that eCIRP-induced STAT3 phosphorylation was required for eCIRP’s action in actin remodeling. Inhibition of STAT3 phosphorylation prevented the formation of the STAT3-βPIX complex, restoring ARP2 and p-cofilin expression and membrane protrusion in rmCIRP-treated macrophages. The STAT3 inhibitor stattic rescued the macrophage phagocytic dysfunction induced by rmCIRP. Thus, we identified a novel mechanism of macrophage phagocytic dysfunction caused by eCIRP, which provides a new therapeutic target to ameliorate sepsis.
基金This work was supported by grants from the National Basic Research Program of China （2015CB910600）, the National Natural Science Foundation of China （31700688）, the National Key Research and Development Program of China （2017YFA0503900）, and the Natural Science Foundation of Zhejiang Province （LY16C050003） to Y.I.H. and H.X. A part of the work presented in the current article was supported by the National Institutes of Health grants ROICA073764 to B.H.S and R50CA211397 to L.Z.
文摘Human flap endonuclease 1 （FEN1） is a structure-specific, multi-functional endonuclease essential for DNA replication and repair. We and others have shown that during DNA replication, FEN1 processes Okazaki fragments via its interaction with the proliferating cell nuclear antigen （PCNA）. Alternatively, in response to DNA damage, FEN1 interacts with the PCNA-like Radg-Radl-Husl complex instead of PCNA to engage in DNA repair activities, such as homology-directed repair of stalled DNA replication forks. However, it is unclear how FEN1 is able to switch between these interactions and its roles in DNA replication and DNA repair. Here, we report that FEN1 undergoes SUMOylation by SUMO-1 in response to DNA replication fork-staUing agents, such as UV irradiation, hydroxyurea, and mitomycin C. This DNA damage-induced SUMO-1 modification promotes the interaction of FEN1 with the Radg-Rad1-Husl complex. Furthermore, we found that FEN1 mutations that prevent its SUMO-1 modification also impair its ability to interact with HUS1 and to rescue stalled replication forks. These impairments lead to the accumulation of DNA damage and heightened sensitivity to fork-staUing agents. Altogether, our findings suggest an important role of the SUMO-1 modification of FEN1 in regulating its roles in DNA replication and repair.
基金supported by the National Key R&D Program of China(2019YFD0901805)the 111 Project(B18022)the Fundamental Research Funds for the Central Universities(22221818014).
文摘Biopolymer chitin and its derivatives have a wide range of applications in different fields.Chitin is primarily produced from marine crustacean by strong acid and strong alkali treatment.To reduce the environmental hazardous in the production of chitin,post-fermentation fungal biomass waste like fungi cell walls provides a viable alternative source for chitin.In this study,improved chitin content in yeast cell wall was achieved by overexpressing chitin biosyntheic pathway related genes.The chitin content was 51.5μg/mg cell wall and 122.9μg/mg cell wall in strain GS-1.10(gfat,uap and chs1 genes overexpression)and strain GS-2.6(gfat,gna1,agm1,uap and chs1 genes overexpression),which were 44.3%and 244.4%higher than that in control strain GS115,respectively.By overexpressing another chitin synthase gene(chs3),the chitin content in strain GS-3.10 was further increased to 136.2μg/mg cell wall,which was 10.8%and 281.6%higher than that in GS-2.6 and in control GS115,respectively.Moreover,chitin yield was further improved by various culture conditions optimization,and reached 162.4μg/mg cell wall,which was 4.43 times of that in the starting strain GS115.The final titer of chitin was 2.23 g/L culture broth in 84 h fed-batch fermentation in a 5 L bioreactor.To our knowledge,this is the first report of chitin production in engineered Pichia pastoris via biosynthetic pathway enhancement.
基金This work was supported by National Institutes of Health(NIH)/National Cancer Institute(NCI)grants(R01CA073764,R01CA085344,and R01CA233664 to B.S.and R50CA211397 to L.Z.)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS,2023-I2M-3-006 to H.S.).
文摘Nucleases are a super family of enzymes that hydrolyze phosphodiester bonds present in genomes.They widely vary in substrates,causing differentiation in cleavage patterns and having a diversified role in maintaining genetic material.Through cellular evolution of prokaryotic to eukaryotic,nucleases become structure-specific in recognizing its own or foreign genomic DNA/RNA configurations as its substrates,including flaps,bubbles,and Holliday junctions.These special structural configurations are commonly found as intermediates in processes like DNA replication,repair,and recombination.The structure-specific nature and diversified functions make them essential to maintaining genome integrity and evolution in normal and cancer cells.In this article,we review their roles in various pathways,including Okazaki fragment maturation during DNA replication,end resection in homology-directed recombination repair of DNA double-strand breaks,DNA excision repair and apoptosis DNA fragmentation in response to exogenous DNA damage,and HIV life cycle.As the nucleases serve as key points for the DNA dynamics,cellular apoptosis,and cancer cell survival pathways,we discuss the efforts in the field in developing the therapeutic regimens,taking advantage of recently available knowledge of their diversified structures and functions.
