Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-ca...Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-canonical role in adaptive immunity,particularly in regulating B-cell immune functions,is poorly characterized.Here,we demonstrate that MDA5 is critical for the marginal zone(MZ)B-cell differentiation,B-cell receptor(BCR)signal transduction,and cytoskeletal dynamics.We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout(KO)B cells can be rescued by the treatment with the dynamin1(DNM1)activator Bis-T-23.Furthermore,MDA5 deficiency induces metabolic perturbations in B cells,characterized by a reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR),excessive reactive oxygen species(ROS)accumulation,and increased mitochondrial fission.Notably,taurine levels are decreased in Mda5 KO B cells,and in vitro taurine supplementation rescues impaired BCR signaling.Finally,MDA5-deficient mice exhibit a blunted humoral immune response.Overall,this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation,BCR signaling,and the humoral immune response.展开更多
The C–H formylation of pyridines represents a valuable strategy for pyridine functionalization,as the resulting formylated pyridines can serve as versatile synthetic linchpins,enabling diverse transformations via the...The C–H formylation of pyridines represents a valuable strategy for pyridine functionalization,as the resulting formylated pyridines can serve as versatile synthetic linchpins,enabling diverse transformations via the formyl group.However,methods for regioselective meta-and para-formylation of pyridine have remained unexplored,and site-switchable strategies for introducing the same functional group are still scarce.Herein,we report a site-switchable metaand para-C–H formylation of pyridines proceeding via oxazino pyridine intermediates.The regioselectivity was precisely dictated by employing CHBr_(3)or CH_(3)OH as masked formyl equivalents under readily tunable conditions.This strategy enabled regioselective access to a structurally diverse array of formylated pyridines,while offering operational simplicity,broad functional group tolerance,scalability,and compatibility with late-stage modifications.Furthermore,the broad synthetic utility of formylated pyridines significantly enhanced the value of this method beyond mere formylation.Together with established ortho-formylation protocols,this work expands the synthetic toolbox for regioselective pyridine formylation,further broadening the accessible pyridine chemical space for applications in drug discovery and materials science.展开更多
Accurate individual identification is required to estimate survival rates in avian populations.For endangered species,non-invasive methods of obtaining individual identification,such as using molted feathers as a sour...Accurate individual identification is required to estimate survival rates in avian populations.For endangered species,non-invasive methods of obtaining individual identification,such as using molted feathers as a source of DNA for microsatellite markers,are preferred because of less disturbance,easy sample preparation and high efficiency.With the availability of many avian genomes,a few pipelines isolating genome-wide microsatellites have been published,but it is still a challenge to isolate microsatellites from the reference genome efficiently.Here,we have developed an integrated tool comprising a bioinformatic pipeline and experimental procedures for microsatellite isolation and validation based on the reference genome.We have identified over 95000 microsatellite loci and established a system comprising 10 highly polymorphic markers(PIC value:0.49–0.93,mean:0.79)for an endangered species,saker falcon(Falco cherrug).These markers(except 1)were successfully amplified in 126 molted feathers,exhibiting high amplification success rates(83.9–99.7%),high quality index(0.90–0.97)and low allelic dropout rates(1–9.5%).To further assess the efficiency of this marker system in a population study,we identified individual sakers using these molted feathers(adult)and 146 plucked feathers(offspring).The use of parent and offspring samples enabled us to infer the genotype of missing samples(N=28),and all adult genotypes were used to ascertain that breeding turnover is a useful proxy for survival estimation in sakers.Our study presents a cost-effective tool for microsatellite isolation based on publicly available reference genomes and demonstrates the power of this tool in estimating key parameters of avian population dynamics.展开更多
基金supported by the National Natural Science Foundation of China(82371784,32311530061)the National Key Research and Development Program of China(2023YFC2507900,2023YFC2706300)+2 种基金R&D Program of Guangzhou Laboratory(SRPG22-006)State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases(2024ZZ10014)the Hubei Provincial Natural Science Foundation of China(Grant number:2024AFB634).
文摘Melanoma Differentiation-Associated gene 5(MDA5)serves as a pattern recognition receptor(PRR)that identifies pathogen-associated molecular patterns(PAMPs),making it instrumental in antiviral defense.However,its non-canonical role in adaptive immunity,particularly in regulating B-cell immune functions,is poorly characterized.Here,we demonstrate that MDA5 is critical for the marginal zone(MZ)B-cell differentiation,B-cell receptor(BCR)signal transduction,and cytoskeletal dynamics.We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout(KO)B cells can be rescued by the treatment with the dynamin1(DNM1)activator Bis-T-23.Furthermore,MDA5 deficiency induces metabolic perturbations in B cells,characterized by a reduced extracellular acidification rate(ECAR)and oxygen consumption rate(OCR),excessive reactive oxygen species(ROS)accumulation,and increased mitochondrial fission.Notably,taurine levels are decreased in Mda5 KO B cells,and in vitro taurine supplementation rescues impaired BCR signaling.Finally,MDA5-deficient mice exhibit a blunted humoral immune response.Overall,this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation,BCR signaling,and the humoral immune response.
基金grant from Deutsche Forschungsgemeinschaft(DFG),Germany(grant no.STU 280/31-1)the Alexander von Humboldt Foundation,Germany(post-doctoral fellowship to S.-M.Guo).
文摘The C–H formylation of pyridines represents a valuable strategy for pyridine functionalization,as the resulting formylated pyridines can serve as versatile synthetic linchpins,enabling diverse transformations via the formyl group.However,methods for regioselective meta-and para-formylation of pyridine have remained unexplored,and site-switchable strategies for introducing the same functional group are still scarce.Herein,we report a site-switchable metaand para-C–H formylation of pyridines proceeding via oxazino pyridine intermediates.The regioselectivity was precisely dictated by employing CHBr_(3)or CH_(3)OH as masked formyl equivalents under readily tunable conditions.This strategy enabled regioselective access to a structurally diverse array of formylated pyridines,while offering operational simplicity,broad functional group tolerance,scalability,and compatibility with late-stage modifications.Furthermore,the broad synthetic utility of formylated pyridines significantly enhanced the value of this method beyond mere formylation.Together with established ortho-formylation protocols,this work expands the synthetic toolbox for regioselective pyridine formylation,further broadening the accessible pyridine chemical space for applications in drug discovery and materials science.
基金Stipend and research expenses of Xian Hou were provided by the National Key Program of Research and Development,Ministry of Science and Technology,China(2016YFC0503200)the National Natural Science Foundation of China(Nos.31522052 and 31471993)+1 种基金This project was funded by the Environment Agency of Abu DhabiThe fieldwork was partially supported by the Science and Technology Service Network Initiative of Chinese Academy of Sciences(KFJ_STSZDTP-013-1).
文摘Accurate individual identification is required to estimate survival rates in avian populations.For endangered species,non-invasive methods of obtaining individual identification,such as using molted feathers as a source of DNA for microsatellite markers,are preferred because of less disturbance,easy sample preparation and high efficiency.With the availability of many avian genomes,a few pipelines isolating genome-wide microsatellites have been published,but it is still a challenge to isolate microsatellites from the reference genome efficiently.Here,we have developed an integrated tool comprising a bioinformatic pipeline and experimental procedures for microsatellite isolation and validation based on the reference genome.We have identified over 95000 microsatellite loci and established a system comprising 10 highly polymorphic markers(PIC value:0.49–0.93,mean:0.79)for an endangered species,saker falcon(Falco cherrug).These markers(except 1)were successfully amplified in 126 molted feathers,exhibiting high amplification success rates(83.9–99.7%),high quality index(0.90–0.97)and low allelic dropout rates(1–9.5%).To further assess the efficiency of this marker system in a population study,we identified individual sakers using these molted feathers(adult)and 146 plucked feathers(offspring).The use of parent and offspring samples enabled us to infer the genotype of missing samples(N=28),and all adult genotypes were used to ascertain that breeding turnover is a useful proxy for survival estimation in sakers.Our study presents a cost-effective tool for microsatellite isolation based on publicly available reference genomes and demonstrates the power of this tool in estimating key parameters of avian population dynamics.
