Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whethe...Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whether neutrophils can be generated by transdifferentiation strategies is unknown.Here,we show that thymidine induces the conversion of mouse fibroblasts to neutrophils.Induced neutrophils(iNeus)showed antibacterial effects and did not undergo malignant transformation in vivo.Importantly,iNeu transplantation cured neutropenia in mice in vivo.Mechanistically,thymidine mediates iNeu conversion by enhancing Tet3 activity.Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils.Therefore,the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.展开更多
Inflammasomes play important roles in resisting infections caused by various pathogens.HSV-1 is a highly contagious virus among humans.The process by which HSV-1 particles bud from the nucleus is unique to herpes viru...Inflammasomes play important roles in resisting infections caused by various pathogens.HSV-1 is a highly contagious virus among humans.The process by which HSV-1 particles bud from the nucleus is unique to herpes viruses,but the specific mechanism is still unclear.Here,we screened genes involved in HSV-1 replication.We found that TET3 plays an essential role in HSV-1 infection.TET3 recognizes the UL proteins of HSV-1 and,upon activation,can directly bind to caspase-1 to activate an ASC-independent inflammasome in the nucleus.The subsequent cleavage of GSDMD in the nucleus is crucial for the budding of HSV-1 particles from the nucleus.Inhibiting the perforation ability of GSDMD on the nuclear membrane can significantly reduce the maturation and spread of HSV-1.Our results may provide a new approach for the treatment of HSV-1 in the future.展开更多
The methylcytosine dioxygenases TET proteins （TET1, TET2, and TET3） play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro...The methylcytosine dioxygenases TET proteins （TET1, TET2, and TET3） play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro2a cells as a model. We observed that knockdown of TET1, TET2 or TET3 promoted neuronal differentiation of Neuro2a cells, and their overexpression inhibited VPA （valproic acid）-induced neuronal differentiation, suggesting all three TET proteins negatively regulate neu- ronal differentiation of Neuro2a cells. Interestingly, the inducing activity of TET protein is independent of its enzymatic activity. Our previous studies have demon- strated that srGAP3 can negatively regulate neuronal differentiation of Neuro2a cells. Furthermore, we revealed that TET1 could positively regulate srGAP3 expression independent of its catalytic activity, and srGAP3 is required for TET-mediated neuronal differentiation of Neuro2a cells. The results presented here may facilitate better understanding of the role of TET proteins in neuronal differentiation, and provide a possible therapy target for neuroblastoma.展开更多
The emergence of mobile Tigecycline-resistant tet(X3)and tet(X4)is believed to be a global threat to public health.Here,we investigated the prevalence of tet(X3)and tet(X4)in our metagenomic data of migratory birds.Wh...The emergence of mobile Tigecycline-resistant tet(X3)and tet(X4)is believed to be a global threat to public health.Here,we investigated the prevalence of tet(X3)and tet(X4)in our metagenomic data of migratory birds.While tet(X4)was not identified in our samples,tet(X3)was found in two gut microbiomes of bird fecal samples,with 100%amino acid identity of sites 150–387.These results suggest that tet(X3)has been spreading into the environment for a long period of time and that there is an urgent need to control its further transmission.展开更多
The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical e...The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat.Herein,versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance.2-methoxy-1,4-naphthoquinone(MNQ)exhib-ited the potent potentiation(4 to 32-fold)with tetracyclines,along with effective inhibition on biofilm formation.Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4)proteins through interaction with their active residues.Furthermore,exposure to MNQ significantly dissipate the proton motive force,leading to a cascade of membrane structural damage and metabolic homeostasis imbalance.Encouragingly,the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models,as evidenced by the reduced bacterial burden and mitigated pathological injury.Our find-ings propose a potential therapeutic option and a novel tetracyclines’adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).展开更多
基金supported by the National Key R&D Program of China (2020YFA0803501,2019YFA0508501,2021YFF0702802)the National Natural Science Foundation of China (82130088,31930036,81921003,31871494,92042302,91940305,32070533,81772646)+2 种基金the Beijing Natural Science Foundation (5192018)the Biological Resources Program of Chinese Academy of Sciences (KFJ-BRP-017)the Strategic Priority Research Programs of the Chinese Academy of Sciences (XDB19030203).
文摘Neutrophils are derived from bone marrow hematopoietic stem cells(HSCs)and are the largest population among circulating white blood cells in humans,acting as the first line of defense against invading pathogens.Whether neutrophils can be generated by transdifferentiation strategies is unknown.Here,we show that thymidine induces the conversion of mouse fibroblasts to neutrophils.Induced neutrophils(iNeus)showed antibacterial effects and did not undergo malignant transformation in vivo.Importantly,iNeu transplantation cured neutropenia in mice in vivo.Mechanistically,thymidine mediates iNeu conversion by enhancing Tet3 activity.Tet3 initiates the expression of the neutrophil fate decision factors Cebpδ and Rfx1 that drive the transdifferentiation of mouse fibroblasts to neutrophils.Therefore,the induction of functional neutrophils by chemicals may provide a potential therapeutic strategy for patients with neutropenia patients and infectious diseases.
基金supported by the National Natural Science Foundation of China(92369104,82271790,92169113)the Beijing Natural Science Foundation(JQ23028,7212067)+4 种基金the National Key R&D Program of China(2021YFA1300202,2022YFC2302900)the Strategic Priority Research Programs of the Chinese Academy of Sciences(XDB29020000)the Key Research Program of Frontier Sciences of Chinese Academy of Sciences(ZDBS-LY-SM025)the CAS Project for Young Scientists in Basic Research(YSBR-010)the Fok Ying Tung Education Foundation to P.X.,the Youth Innovation Promotion Association of CAS to S.W.
文摘Inflammasomes play important roles in resisting infections caused by various pathogens.HSV-1 is a highly contagious virus among humans.The process by which HSV-1 particles bud from the nucleus is unique to herpes viruses,but the specific mechanism is still unclear.Here,we screened genes involved in HSV-1 replication.We found that TET3 plays an essential role in HSV-1 infection.TET3 recognizes the UL proteins of HSV-1 and,upon activation,can directly bind to caspase-1 to activate an ASC-independent inflammasome in the nucleus.The subsequent cleavage of GSDMD in the nucleus is crucial for the budding of HSV-1 particles from the nucleus.Inhibiting the perforation ability of GSDMD on the nuclear membrane can significantly reduce the maturation and spread of HSV-1.Our results may provide a new approach for the treatment of HSV-1 in the future.
文摘The methylcytosine dioxygenases TET proteins （TET1, TET2, and TET3） play important regulatory roles in neural function. In this study, we investigated the role of TET proteins in neuronal differentiation using Neuro2a cells as a model. We observed that knockdown of TET1, TET2 or TET3 promoted neuronal differentiation of Neuro2a cells, and their overexpression inhibited VPA （valproic acid）-induced neuronal differentiation, suggesting all three TET proteins negatively regulate neu- ronal differentiation of Neuro2a cells. Interestingly, the inducing activity of TET protein is independent of its enzymatic activity. Our previous studies have demon- strated that srGAP3 can negatively regulate neuronal differentiation of Neuro2a cells. Furthermore, we revealed that TET1 could positively regulate srGAP3 expression independent of its catalytic activity, and srGAP3 is required for TET-mediated neuronal differentiation of Neuro2a cells. The results presented here may facilitate better understanding of the role of TET proteins in neuronal differentiation, and provide a possible therapy target for neuroblastoma.
基金This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(CAS,XDB29010202)the External Cooperation Program of CAS(153211KYSB20160001).
文摘The emergence of mobile Tigecycline-resistant tet(X3)and tet(X4)is believed to be a global threat to public health.Here,we investigated the prevalence of tet(X3)and tet(X4)in our metagenomic data of migratory birds.While tet(X4)was not identified in our samples,tet(X3)was found in two gut microbiomes of bird fecal samples,with 100%amino acid identity of sites 150–387.These results suggest that tet(X3)has been spreading into the environment for a long period of time and that there is an urgent need to control its further transmission.
基金supported by the National Natural Science Foundation of China(grant No.U22A20523,32202856,32172912 and 32102723)the Postdoctoral Research Foundation of China(Certificate Number:2023 M731291)+1 种基金Interdisciplinary Integration and Innovation Project of JLU(JLUXKJC2021QZ04)the Graduate Innovation Fund of Jilin University(No.2022001).
文摘The emergence and worldwide dissemination of mobile tigecycline resistance genes tet(X3)/tet(X4)posed an enor-mous threat to the public health.Urgently,feasible strategies must be implemented to restore the clinical efficacy of tetracyclines and prolong the lifespan of existing drugs to address the emerging global antimicrobial resistance threat.Herein,versatile structural scaffolds of quinones for antibiotic adjuvants discovery enlightened a promising and underappreciated reservoir to circumvent the antibiotic resistance.2-methoxy-1,4-naphthoquinone(MNQ)exhib-ited the potent potentiation(4 to 32-fold)with tetracyclines,along with effective inhibition on biofilm formation.Mechanistic studies revealed that MNQ synergistically operates with tetracyclines by inhibiting the enzymatic activity of Tet(X3)/Tet(X4)proteins through interaction with their active residues.Furthermore,exposure to MNQ significantly dissipate the proton motive force,leading to a cascade of membrane structural damage and metabolic homeostasis imbalance.Encouragingly,the MNQ-tetracyclines combination showcased substantial therapeutic benefits in two in vivo infection models,as evidenced by the reduced bacterial burden and mitigated pathological injury.Our find-ings propose a potential therapeutic option and a novel tetracyclines’adjuvant against drug-resistant pathogens carrying Tet(X3)/Tet(X4).
