Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a ...Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a key role in promoting the mesodermal differentiation of hESCs.In this study,an epigenome-wide analysis of hESCs and MSCs revealed that growth differentiation factor 6(GDF6),which is involved in bone formation,was the most upregulated gene associated with MSCs compared to hESCs.Furthermore,we identified GDF6 as a repressive target of EZH2 and found that ectopic GDF6 selectively promoted hESC differentiation towards the mesodermal lineage and enriched the MSC population.Our results provide molecular insights governing the mesenchymal commitment of hESCs and identify an inducing factor that offers strong promise for the future of regenerative medicine.展开更多
Dear Editor,Japanese encephalitis(JE)is a mosquito-borne acute neurological infectious disease caused by the Japanese encephalitis virus(JEV).Globally,68,000 cases of the disease are estimated each year,with a fatalit...Dear Editor,Japanese encephalitis(JE)is a mosquito-borne acute neurological infectious disease caused by the Japanese encephalitis virus(JEV).Globally,68,000 cases of the disease are estimated each year,with a fatality rate of as high as 30%and with approximately 30%-50%of survivors suffering from severe neurological sequelae(WHO,2015).展开更多
In the course of isolating the attenuated Japanese encephalitis vaccine SA14-14-2,two attenuated strains SA14-9-7 and SA14-5-3 were also obtained that elicited low antibody responses in humans(o10%and 62%,respectively...In the course of isolating the attenuated Japanese encephalitis vaccine SA14-14-2,two attenuated strains SA14-9-7 and SA14-5-3 were also obtained that elicited low antibody responses in humans(o10%and 62%,respectively)and exerted much weaker immune protection in animal challenge experiments.However,the reason for these differences remains unknown.In order to understand why SA14-14-2 is superior to SA14-9-7 and SA14-5-3,we employed a reverse genetics method to identify the key mutations in the virus genome that determine the immunogenicity of live attenuated Japanese encephalitis viruses.We first sequenced the full genomic sequences of SA14-9-7 and SA14-5-3 and found mutations that changed four amino-acid base pairs when compared to the envelope gene of SA14-14-2.We mutated the genome of SA14-14-2 to generate these mutations both singly(E-177,E-264,E-279 and E-315)and in combination(E-177/264,E-279/315 and E-177/264/279/315)and tested these mutants along with parental strains SA14-14-2,SA14-9-7 and SA14-5-3 for their immunogenicity in vivo.When mice were immunized with SA14-9-7 and SA14-5-3,lower levels of neutralizing antibodies were generated compared with the immune response to SA14-14-2.Furthermore,SA14-5-3 was more immunogenic than SA14-9-7,which replicated the results previously seen in humans.Point mutations E-177,E-264,E-279 and E-315 diminished the immunogenicity of SA14-14-2 with E-264 and E-315,contributing the most to this phenotype.The mutant rJEV(E-177/E-264/E-279/E-315)containing all four point mutations exhibited the lowest immunogenicity with a seroconversion rate of 0 at an inoculation dose of 103 PFU(plaque-forming unit).We have identified the key amino acids in the envelope protein that account for the superior immunogenicity of SA14-14-2.展开更多
HCV genotypes have been documented in clinical practice.The aim of this study was to determine the replication priority of different HCV genotypes in a Chinese HCV positive cohort.Serum samples from 491 apparently hea...HCV genotypes have been documented in clinical practice.The aim of this study was to determine the replication priority of different HCV genotypes in a Chinese HCV positive cohort.Serum samples from 491 apparently healthy Chinese blood donors testing positive for HCV antibodies and naive to antiviral drug therapy were tested.Genotyping analysis showed that genotypes 1b and 2a were predominant and accounted for 77.6%of the HCV infections.Among the genotype groups,individuals infected with genotype 2a had an HCV RNA viral load(108 copies/mL)about 200-fold(lg,2.3)greater than those infected with other genotypes(10^(4)–10^(5)copies/mL)indicating a replication priority of genotype 2a.However,there was no correlation between HCV genotype and antibody response suggesting that the amplification advantage of genotype 2a results from a favorable interaction with the host cellular environment.In conclusion,HCV genotypes 1b and 2a are the predominant genotypes in China and genotype 2a possesses a significant replication priority compared with the other genotypes.This suggests the existence of host cellular factors that may act as drug-targets for entirely clearing HCV infection in the future.展开更多
基金supported by the National Natural Science Foundation of China(grant numbers:81602688,81773245,and 81972858)the Natural Science Foundation of Chongqing(cstc2016jcyjA0531)+2 种基金the Science and Technology Innovation Special Project of Chongqing Social Undertak ings and Livelihood Security(cstc2017shmsA130108)the Chongqing Innovation Leading Talents Program(cstccxljrc201910)the Cultivation Program for Clinical Research Talents of Army Medical University(2018XLC1010)。
基金the NIH/NIDCR grant R01DE16513(C.Y.W.),NIH/NIDCR K08DE024603(C.H.)the Shapiro family Charitable Funds.The Flow cytometry was performed in the UCLA Flow Cytometry Core Facility that is supported by NIH awards P30CA016042 and 5P30AI028697.
文摘Mesenchymal stem cells(MSCs)derived from human embryonic stem cells(hESCs)have significant potential for cell-mediated bone regeneration.Our recent study revealed that inhibiting the epigenetic regulator EZH2 plays a key role in promoting the mesodermal differentiation of hESCs.In this study,an epigenome-wide analysis of hESCs and MSCs revealed that growth differentiation factor 6(GDF6),which is involved in bone formation,was the most upregulated gene associated with MSCs compared to hESCs.Furthermore,we identified GDF6 as a repressive target of EZH2 and found that ectopic GDF6 selectively promoted hESC differentiation towards the mesodermal lineage and enriched the MSC population.Our results provide molecular insights governing the mesenchymal commitment of hESCs and identify an inducing factor that offers strong promise for the future of regenerative medicine.
文摘Dear Editor,Japanese encephalitis(JE)is a mosquito-borne acute neurological infectious disease caused by the Japanese encephalitis virus(JEV).Globally,68,000 cases of the disease are estimated each year,with a fatality rate of as high as 30%and with approximately 30%-50%of survivors suffering from severe neurological sequelae(WHO,2015).
基金This study was funded by the Chinese mega project of science research for major new drugs innovationdevelopment research for quality control of JE live attenuated vaccine and polio vaccine(Grant No.20142014ZX09304316-003).
文摘In the course of isolating the attenuated Japanese encephalitis vaccine SA14-14-2,two attenuated strains SA14-9-7 and SA14-5-3 were also obtained that elicited low antibody responses in humans(o10%and 62%,respectively)and exerted much weaker immune protection in animal challenge experiments.However,the reason for these differences remains unknown.In order to understand why SA14-14-2 is superior to SA14-9-7 and SA14-5-3,we employed a reverse genetics method to identify the key mutations in the virus genome that determine the immunogenicity of live attenuated Japanese encephalitis viruses.We first sequenced the full genomic sequences of SA14-9-7 and SA14-5-3 and found mutations that changed four amino-acid base pairs when compared to the envelope gene of SA14-14-2.We mutated the genome of SA14-14-2 to generate these mutations both singly(E-177,E-264,E-279 and E-315)and in combination(E-177/264,E-279/315 and E-177/264/279/315)and tested these mutants along with parental strains SA14-14-2,SA14-9-7 and SA14-5-3 for their immunogenicity in vivo.When mice were immunized with SA14-9-7 and SA14-5-3,lower levels of neutralizing antibodies were generated compared with the immune response to SA14-14-2.Furthermore,SA14-5-3 was more immunogenic than SA14-9-7,which replicated the results previously seen in humans.Point mutations E-177,E-264,E-279 and E-315 diminished the immunogenicity of SA14-14-2 with E-264 and E-315,contributing the most to this phenotype.The mutant rJEV(E-177/E-264/E-279/E-315)containing all four point mutations exhibited the lowest immunogenicity with a seroconversion rate of 0 at an inoculation dose of 103 PFU(plaque-forming unit).We have identified the key amino acids in the envelope protein that account for the superior immunogenicity of SA14-14-2.
基金This study was supported by the“Key Program for the Control of Infectious Diseases”(Grant No.2005DIB1J090)the 973 Program of the Ministry of Science and Technology of the People's Republic of China(Grant No.2004CB518901,Jian-Dong Jiang).
文摘HCV genotypes have been documented in clinical practice.The aim of this study was to determine the replication priority of different HCV genotypes in a Chinese HCV positive cohort.Serum samples from 491 apparently healthy Chinese blood donors testing positive for HCV antibodies and naive to antiviral drug therapy were tested.Genotyping analysis showed that genotypes 1b and 2a were predominant and accounted for 77.6%of the HCV infections.Among the genotype groups,individuals infected with genotype 2a had an HCV RNA viral load(108 copies/mL)about 200-fold(lg,2.3)greater than those infected with other genotypes(10^(4)–10^(5)copies/mL)indicating a replication priority of genotype 2a.However,there was no correlation between HCV genotype and antibody response suggesting that the amplification advantage of genotype 2a results from a favorable interaction with the host cellular environment.In conclusion,HCV genotypes 1b and 2a are the predominant genotypes in China and genotype 2a possesses a significant replication priority compared with the other genotypes.This suggests the existence of host cellular factors that may act as drug-targets for entirely clearing HCV infection in the future.
