To promote efficient screening of active angiogenic drugs from traditional medicines, we constructed a humanembryonic kidney-293 cell model using vascular endothelial growth factor (VEGF) gene promoter as the drug t...To promote efficient screening of active angiogenic drugs from traditional medicines, we constructed a humanembryonic kidney-293 cell model using vascular endothelial growth factor (VEGF) gene promoter as the drug target. Inthis model, VEGF gene promoter may regulate the expression of the luciferase reporter gene by responding to thestimulation of drug molecules. This cell model allows rapid and efficient screening of vascular-inducing activecomponents from several drug monomer molecules. Furthermore, we used rat bone marrow mesenchymal stem cells(rMSCs) to conduct a preliminary study on the activity of alantolactone. Using simvastatin as a positive control, weinvestigated the effects of alantolactone on the expression of vascular-related cell marker molecules such as VEGF andα-smooth muscle actin (α-SMA) in rMSCs. According to our results, 0.1, 1, 3 and 5 μM of alantolactone upregulated thetranscriptional luciferase gene activity of VEGF promoter, and a significant difference from that in the control group wasobserved. Among them, 3μM of alantolactone showed the better effect than that of 3 μM of simvastatin (P = 0.036) andother concentrations of alantolactone and simvastatin showed similar effects. Compared with that in the control group,rMSCs induced with 1μM alantolactone for 3 days showed a significant increase in the relative mRNA expressions ofVEGF and α-SMA genes. However, these effect of 5 μM alantolactone were weaker than those of 5 μM simvastatin (P 〈0.05); rMSCs treated with 1 μM alantolactone for 3 days showed brighter green fluorescence (FITC marker) of α-SMAand VEGF in situ expression than that observed in the control group and similar fluorescence intensity than that ofsimvastatin group in an immunoradiometric assay. The above results demonstrate the reliability of the highly efficientsystem for screening of active drug molecules and confirmed the vascular induction function of alantolactone at the geneand protein levels.展开更多
Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses ...Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses and fatalities.Although the H1N1 gene segments have three origins in terms of host species,the virus has been named swine-origin influenza virus(S-OIV)due to a predominant swine origin.2009 S-OIV has been shown to highly resemble the 1918 pandemic virus in many aspects.Hemagglutinin is responsible for the host range and receptor binding of the virus and is therefore a primary indicator for the potential of infection.Primary sequence analysis of the 2009 S-OIV hemagglutinin(HA)reveals its closest relationship to that of the 1918 pandemic influenza virus,however,analysis at the structural level is necessary to critically assess the functional significance.In this report,we report the crystal structure of soluble hemagglutinin H1(09H1)at 2.9Å,illustrating that the 09H1 is very similar to the 1918 pandemic HA(18H1)in overall structure and the structural modules,including the five defined antiboby(Ab)-binding epitopes.Our results provide an explanation as to why sera from the survivors of the 1918 pandemics can neutralize the 2009 S-OIV,and people born around the 1918 are resistant to the current pandemic,yet younger generations are more susceptible to the 2009 pandemic.展开更多
A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability.To evaluate its antigenicity relationship with other variants,antisera from guinea pigs immunized with spike pr...A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability.To evaluate its antigenicity relationship with other variants,antisera from guinea pigs immunized with spike protein of SARS-CoV-2 variants of concern(VOCs)and variants of interest(VOIs)were cross-tested against pseudotyped variants.The neutralization activity against Omicron was markedly reduced when other VOCs or VOIs were used as immunogens,and Omicron(BA.1)-elicited sera did not efficiently neutralize the other variants.However,a Beta or Omicron booster,when administered as the 4th dose 3-months after the 3rd dose of any of the variants,could elicit broad neutralizing antibodies against all of the current variants including Omicron BA.1.Further analysis with 280 available antigen–antibody structures and quantification of immune escape from 715 reported neutralizing antibodies provide explanations for the observed differential immunogenicity.Three distinct clades predicted using an in silico algorithm for clustering of sarbecoviruses based on immune escape provide key information for rational design of vaccines.展开更多
Enolase is a conserved cytoplasmic metalloenzyme existing universally in both eukaryotic and prokaryotic cells.The enzyme can also locate on the cell surface and bind to plasminogen,via which contributing to the mucos...Enolase is a conserved cytoplasmic metalloenzyme existing universally in both eukaryotic and prokaryotic cells.The enzyme can also locate on the cell surface and bind to plasminogen,via which contributing to the mucosal surface localization of the bacterial pathogens and assisting the invasion into the host cells.The functions of the eukaryotic enzymes on the cell surface expression(including T cells,B cells,neutrophils,monocytoes,neuronal cells and epithelial cells)are not known.Streptococcus suis serotype 2(S.suis 2,SS2)is an important zoonotic pathogen which has recently caused two large-scale outbreaks in southern China with severe streptococcal toxic shock syndrome(STSS)never seen before in human sufferers.We recently identified the SS2 enolase as an important protective antigen which could protect mice from fatal S.suis 2 infection.In this study,a 2.4-angstrom structure of the SS2 enolase is solved,revealing an octameric arrangement in the crystal.We further demonstrated that the enzyme exists exclusively as an octamer in solution via a sedimentation assay.These results indicate that the octamer is the biological unit of SS2 enolase at least in vitro and most likely in vivo as well.This is,to our knowledge,the first comprehensive characterization of the SS2 enolase octamer both structurally and biophysically,and the second octamer enolase structure in addition to that of Streptococcus pneumoniae.We also investigated the plasminogen binding property of the SS2 enzyme.展开更多
There is keen interest in using Ti alloys as lightweight structural materials for aerospace and automotive industries.However,a long-standing problem for these materials is their poor oxidation resistance.Herein,we de...There is keen interest in using Ti alloys as lightweight structural materials for aerospace and automotive industries.However,a long-standing problem for these materials is their poor oxidation resistance.Herein,we designed and fabricated a Ti_(5)Si_(3) reinforced Ti-4(wt.%)Mo composite with two-scale network architecture by low energy milling and spark plasma sintering.It displays superior oxidation resistance at 800°C owing to the in-situ formation of a multi-component surface layer.This oxide layer has a dense grain size gradient structure that consists of an outer TiO_(2)layer and an inner SiO_(2)-padding-TiO_(2) layer,which has remarkable oxidation resistance and thermal stability.Furthermore,it was revealed that the hitherto unknown interaction between Ti_(5)Si_(3) reinforcement and nitrogen during oxidation would contribute to the formation of a TiN nano-twin interface layer,which accommodates the thermal mismatch strain between the oxide layer and matrix.This,along with high adhesion,confers excellent thermal cycling life with no cracking or spallation during long-term oxidation.In this regard,the secure operating temperature of this new composite can be increased to 800°C,which provides a design pathway for a new family of Ti matrix composites for high-temperature applications.展开更多
Dear Editor,The spread of antibiotic resistance genes among bacteria is a serious and growing threat to global health (Peleg and Hoopet,2010).One emerging case is transferable genes found in bacteria-encoding enzymes ...Dear Editor,The spread of antibiotic resistance genes among bacteria is a serious and growing threat to global health (Peleg and Hoopet,2010).One emerging case is transferable genes found in bacteria-encoding enzymes resistant to colistin.Colistin is a cationic polypeptide antibiotic with broadspectrum activity against Gram-negative bacteria through interactions with the lipid A moiety of bacterial lipopoly-saccharide(LPS),subsequently destroying the cell envelope.During late 2015,a plasmid-mediated gene,mcr-1,was first reported from Escherichia coli(E.coli)in China to confer resistance to colistin(Liu et a1.,2016),and detected world-wide soon afterwards(Gao et a1.,2016;Hu et a1.,2016).展开更多
文摘To promote efficient screening of active angiogenic drugs from traditional medicines, we constructed a humanembryonic kidney-293 cell model using vascular endothelial growth factor (VEGF) gene promoter as the drug target. Inthis model, VEGF gene promoter may regulate the expression of the luciferase reporter gene by responding to thestimulation of drug molecules. This cell model allows rapid and efficient screening of vascular-inducing activecomponents from several drug monomer molecules. Furthermore, we used rat bone marrow mesenchymal stem cells(rMSCs) to conduct a preliminary study on the activity of alantolactone. Using simvastatin as a positive control, weinvestigated the effects of alantolactone on the expression of vascular-related cell marker molecules such as VEGF andα-smooth muscle actin (α-SMA) in rMSCs. According to our results, 0.1, 1, 3 and 5 μM of alantolactone upregulated thetranscriptional luciferase gene activity of VEGF promoter, and a significant difference from that in the control group wasobserved. Among them, 3μM of alantolactone showed the better effect than that of 3 μM of simvastatin (P = 0.036) andother concentrations of alantolactone and simvastatin showed similar effects. Compared with that in the control group,rMSCs induced with 1μM alantolactone for 3 days showed a significant increase in the relative mRNA expressions ofVEGF and α-SMA genes. However, these effect of 5 μM alantolactone were weaker than those of 5 μM simvastatin (P 〈0.05); rMSCs treated with 1 μM alantolactone for 3 days showed brighter green fluorescence (FITC marker) of α-SMAand VEGF in situ expression than that observed in the control group and similar fluorescence intensity than that ofsimvastatin group in an immunoradiometric assay. The above results demonstrate the reliability of the highly efficientsystem for screening of active drug molecules and confirmed the vascular induction function of alantolactone at the geneand protein levels.
基金This work is supported by the intramural grant of the Chinese Academy of Sciences(Grant No.KSCX2-YW-R-158)the National Basic Research Program(973 Program)(Grant Nos.2010CB534004 and 2005CB523001)+1 种基金G.F.G.is a distinguished young investigator of the NSFC(Grant No.30525010)Dr.Christopher Vavricka is,partly,supported by the Fellowship for Young International Scientists of the Chinese Academy of Sciences(Grant No.2009Y2BS2).
文摘Influenza virus is the causative agent of the seasonal and occasional pandemic flu.The current H1N1 influenza pandemic,announced by the WHO in June 2009,is highly contagious and responsible for global economic losses and fatalities.Although the H1N1 gene segments have three origins in terms of host species,the virus has been named swine-origin influenza virus(S-OIV)due to a predominant swine origin.2009 S-OIV has been shown to highly resemble the 1918 pandemic virus in many aspects.Hemagglutinin is responsible for the host range and receptor binding of the virus and is therefore a primary indicator for the potential of infection.Primary sequence analysis of the 2009 S-OIV hemagglutinin(HA)reveals its closest relationship to that of the 1918 pandemic influenza virus,however,analysis at the structural level is necessary to critically assess the functional significance.In this report,we report the crystal structure of soluble hemagglutinin H1(09H1)at 2.9Å,illustrating that the 09H1 is very similar to the 1918 pandemic HA(18H1)in overall structure and the structural modules,including the five defined antiboby(Ab)-binding epitopes.Our results provide an explanation as to why sera from the survivors of the 1918 pandemics can neutralize the 2009 S-OIV,and people born around the 1918 are resistant to the current pandemic,yet younger generations are more susceptible to the 2009 pandemic.
基金supported by the National Key Research and Development Program of China(grant number 2021YFC0863300)General Program of the National Natural Science Foundation of China(grant number 82073621,32070678&82172244)+1 种基金Beijing Municipal Science and Technology Project(Z211100002521018)the Bill&Melinda Gates Foundation(Investment ID INV-006379).
文摘A steep rise in Omicron reinfection cases suggests that this variant has increased immune evasion ability.To evaluate its antigenicity relationship with other variants,antisera from guinea pigs immunized with spike protein of SARS-CoV-2 variants of concern(VOCs)and variants of interest(VOIs)were cross-tested against pseudotyped variants.The neutralization activity against Omicron was markedly reduced when other VOCs or VOIs were used as immunogens,and Omicron(BA.1)-elicited sera did not efficiently neutralize the other variants.However,a Beta or Omicron booster,when administered as the 4th dose 3-months after the 3rd dose of any of the variants,could elicit broad neutralizing antibodies against all of the current variants including Omicron BA.1.Further analysis with 280 available antigen–antibody structures and quantification of immune escape from 715 reported neutralizing antibodies provide explanations for the observed differential immunogenicity.Three distinct clades predicted using an in silico algorithm for clustering of sarbecoviruses based on immune escape provide key information for rational design of vaccines.
基金supported by National Natural Science Foundation of China(NSFC)a leading principal investigator of the NSFC Innovative Research Group(Grant No.81021003).
文摘Enolase is a conserved cytoplasmic metalloenzyme existing universally in both eukaryotic and prokaryotic cells.The enzyme can also locate on the cell surface and bind to plasminogen,via which contributing to the mucosal surface localization of the bacterial pathogens and assisting the invasion into the host cells.The functions of the eukaryotic enzymes on the cell surface expression(including T cells,B cells,neutrophils,monocytoes,neuronal cells and epithelial cells)are not known.Streptococcus suis serotype 2(S.suis 2,SS2)is an important zoonotic pathogen which has recently caused two large-scale outbreaks in southern China with severe streptococcal toxic shock syndrome(STSS)never seen before in human sufferers.We recently identified the SS2 enolase as an important protective antigen which could protect mice from fatal S.suis 2 infection.In this study,a 2.4-angstrom structure of the SS2 enolase is solved,revealing an octameric arrangement in the crystal.We further demonstrated that the enzyme exists exclusively as an octamer in solution via a sedimentation assay.These results indicate that the octamer is the biological unit of SS2 enolase at least in vitro and most likely in vivo as well.This is,to our knowledge,the first comprehensive characterization of the SS2 enolase octamer both structurally and biophysically,and the second octamer enolase structure in addition to that of Streptococcus pneumoniae.We also investigated the plasminogen binding property of the SS2 enzyme.
基金financially supported by the National Natural Science Foundation of China(NSFC)[Grant No.51534009]National Key R&D Program of China[Grant No.2017YFB0306001]Natural Science Foundation of Hunan Province China(Grant No.2021JJ40750)。
文摘There is keen interest in using Ti alloys as lightweight structural materials for aerospace and automotive industries.However,a long-standing problem for these materials is their poor oxidation resistance.Herein,we designed and fabricated a Ti_(5)Si_(3) reinforced Ti-4(wt.%)Mo composite with two-scale network architecture by low energy milling and spark plasma sintering.It displays superior oxidation resistance at 800°C owing to the in-situ formation of a multi-component surface layer.This oxide layer has a dense grain size gradient structure that consists of an outer TiO_(2)layer and an inner SiO_(2)-padding-TiO_(2) layer,which has remarkable oxidation resistance and thermal stability.Furthermore,it was revealed that the hitherto unknown interaction between Ti_(5)Si_(3) reinforcement and nitrogen during oxidation would contribute to the formation of a TiN nano-twin interface layer,which accommodates the thermal mismatch strain between the oxide layer and matrix.This,along with high adhesion,confers excellent thermal cycling life with no cracking or spallation during long-term oxidation.In this regard,the secure operating temperature of this new composite can be increased to 800°C,which provides a design pathway for a new family of Ti matrix composites for high-temperature applications.
基金supported by the Chinese Academy of Sciences (CAS) Strategic Priority Research Program (XDB08020100)the External Cooperation Program of Chinese Academy of Sciences (153211KYSB20160001)the National Key Plan for Scientific Research and Development of China (2016YFD0500305)
文摘Dear Editor,The spread of antibiotic resistance genes among bacteria is a serious and growing threat to global health (Peleg and Hoopet,2010).One emerging case is transferable genes found in bacteria-encoding enzymes resistant to colistin.Colistin is a cationic polypeptide antibiotic with broadspectrum activity against Gram-negative bacteria through interactions with the lipid A moiety of bacterial lipopoly-saccharide(LPS),subsequently destroying the cell envelope.During late 2015,a plasmid-mediated gene,mcr-1,was first reported from Escherichia coli(E.coli)in China to confer resistance to colistin(Liu et a1.,2016),and detected world-wide soon afterwards(Gao et a1.,2016;Hu et a1.,2016).