Citation:Liu J,Zhu N,Huo W,et al.Advancing virology research with a human brain organoid platform.hLife 2025;3:237–242.The occurrence of viral infections causing central nervous system(CNS)diseases is significant,oft...Citation:Liu J,Zhu N,Huo W,et al.Advancing virology research with a human brain organoid platform.hLife 2025;3:237–242.The occurrence of viral infections causing central nervous system(CNS)diseases is significant,often accompanied by short-term or long-term sequelae and a high mortality rate.Typical clinical manifestations of viral infections that impact the CNS encompass encephalitis,meningitis,myelitis,and seizures[1].Treatments specific to most viral infections are generally limited.展开更多
High altitudes are one type of extreme environment characterized by hypobaric hypoxia,extreme cold,strong ultraviolet radiation,and low energy availabilty that present tremendous challenges to human and wildlife inhab...High altitudes are one type of extreme environment characterized by hypobaric hypoxia,extreme cold,strong ultraviolet radiation,and low energy availabilty that present tremendous challenges to human and wildlife inhabiting these environs.These extreme environments serve as a unique natural laboratory for delving into the impact of selective pressures on species variation and adaptation.This narrative review compiles the latest research on high-altitude adaptation,with a specific focus on the crucial role of gut microbiota in this process.Evidence indicates that gut microbiota significantly impacts an organism’s ability to adapt to high-altitude conditions by adjusting its composition,and hence impacting its function and ability to release microbial metabolites.We explore the link between gut microbiota and highaltitude environments,the microbial signatures,and their effects on adaptation,as well as the potential for targeted modulation of gut microbiota to enhance acclimatization to high altitudes.By examining the interaction between microbiota and host adaptation,this review aims to promote further mechanistic studies and support strategies for improving high-altitude acclimatization through gut microbiota modulation.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.H...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.However,the mAb escaped from the variant of concern(VOC)ever since the emergence of Beta VOC,with a complete loss of efficacy against the Omicron subvariants.Here,we developed a broad-spectrum and affinity-mature antibody design(BAADesign)procedure to design CB6,enabling it to bind to the receptor-binding domains(RBDs)of multiple important Omicron subvariants,including the recent variant KP.2.Structural analysis confirmed the desired CB6-RBD interactions.Additionally,identical mutations in the complementarity determining regions(CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies.Overall,the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection,and the BAADesign method has implications for the design of other antibodies.展开更多
The 778th Xiangshan Science Conference,themed“Regional Immunity in the Lung and Respiratory Tract:Challenges and Opportunities”,convened in Beijing on April 8–9,2025.Co-chaired by four leading scientists-ProfessorG...The 778th Xiangshan Science Conference,themed“Regional Immunity in the Lung and Respiratory Tract:Challenges and Opportunities”,convened in Beijing on April 8–9,2025.Co-chaired by four leading scientists-ProfessorGeorge FuGao(Institute of Microbiology,Chinese Academy of Sciences),Professor Chen Dong(Westlake University School of Medicine),Professor Zhigang Tian(University of Science and Technology of China).展开更多
The intratumor microbiome,one of the hallmarks of cancer,plays a crucial role in cancer progression through its interaction with the host.However,the underlying mechanisms remain poorly understood.In this study,six pu...The intratumor microbiome,one of the hallmarks of cancer,plays a crucial role in cancer progression through its interaction with the host.However,the underlying mechanisms remain poorly understood.In this study,six publicly available single-cell transcriptomic lung cancer datasets(comprising 178 samples)from multiple centers(Shanghai,New York,Seoul)were integrated to investigate the heterogeneity of host-microbiome interactions at the single-cell level using single-cell analysis of host-microbiome interactions(SAHMI).The results indicate that primary tumor tissues have a high proportion of fungi-associated cells,whereas metastatic brain tissues predominantly contain bacteria-associated cells.There are also distinct microbial distributions across cell types.Notably,the presence of specific bacteria significantly influences the transcriptome of resident host cells,including T cells and macrophages,by modulating pathways related to ribosomal RNA(rRNA)processing,cellular responses to stress and stimuli,and RNA and protein metabolism.Finally,specific cell-associated bacteria are significantly correlated with clinical features,such as lung cancer stages and smoking frequency.These single-cell insights into microbiome-host interactions improve current understanding about lung cancer development and progression and offer potential micro-ecological and diagnostic insights.展开更多
Recently,the Royal Swedish Academy of Sciences announced that one-half of the 2024 Nobel Prize in Chemistry was awarded to David Baker for computational protein design,and the other half was awarded jointly to Demis H...Recently,the Royal Swedish Academy of Sciences announced that one-half of the 2024 Nobel Prize in Chemistry was awarded to David Baker for computational protein design,and the other half was awarded jointly to Demis Hassabis and John Jumper for protein structure prediction.Proteins are the molecule tools of life.To carry out their functions,many proteins need to fold into particular three-dimensional(3D)structures,which are programmed by the amino acid sequences of the proteins[1].The goal of protein structure prediction is to predict the 3D structures from given amino acid sequences.Conversely,protein design aims to identify amino acid sequences that achieve desired structural or functional goals.展开更多
Microbiology,born to study life forms invisible to the naked eye,owes its origin to Antonie van Leeuwenhoek,who in the 1670s first observed bacteria and other microbes using microscopes of his design.From its inceptio...Microbiology,born to study life forms invisible to the naked eye,owes its origin to Antonie van Leeuwenhoek,who in the 1670s first observed bacteria and other microbes using microscopes of his design.From its inception,microbiology has been an interdisciplinary science,deeply reliant on advances in instrumentation and methodology.A pivotal milestone was reached in the late 19th century when Robert Koch established the germtheory of disease by conclusively linking specific microbes to specific illnesses.展开更多
Nosocomial pathogen carbapenem-resistant Klebsiella pneumoniae(CRKP)poses a heightened risk to public health through carbapenem resistance and virulence convergence,particularly in China’s dominant sequence type 11(S...Nosocomial pathogen carbapenem-resistant Klebsiella pneumoniae(CRKP)poses a heightened risk to public health through carbapenem resistance and virulence convergence,particularly in China’s dominant sequence type 11(ST11)clone[1,2].Monoclonal K.pneumoniae exhibits within-host diversity during prolonged infections[3–5],with certain variants surviving through adaptation[4,6].CRKP strains from the blood of a single patient are heterogeneous in terms of antibiotic susceptibility,capsular polysaccharide production,and mucoviscosity[3].Intra-host evolution drives novel resistance via cumulative mutations(e.g.,the transcriptional regulator gene ramR mutations and the outer membrane porin gene OmpK35 loss)[4].展开更多
Mosquito-borne arboviruses significantly threaten global health,affecting millions of people worldwide.The innate immune system is the primary line of defense against arboviruses in both mammalian hosts and mosquito v...Mosquito-borne arboviruses significantly threaten global health,affecting millions of people worldwide.The innate immune system is the primary line of defense against arboviruses in both mammalian hosts and mosquito vectors,although the innate immune responses of these organisms involve distinct mechanisms.This review compares the innate immune responses of mammals with those of mosquitoes,focusing on their shared reliance on pattern recognition receptors(PRRs),immune signaling pathways,and cellular innate immunity.While mosquitoes utilize RNA interference(RNAi)and melanization to control arboviral replication without inflammation,mammals depend on complement systems,complex interferon(IFN)responses,and cytokine production to rapidly clear arboviral infections.This review provides a comparative analysis of the innate immune responses of mammalian hosts and mosquito vectors,highlighting key differences in the strategies by which these organisms manage arboviral infections.Understanding these distinctions may inform the development of novel interventions to disrupt arboviral transmission and improve disease control.展开更多
Antimicrobial resistance is a global health crisis and carbapenem-resistant Klebsiella pneumoniae(CRKp)is listed as one of the top high-priority pathogens by the World Health Organization.Meanwhile,hypervirulent K.pne...Antimicrobial resistance is a global health crisis and carbapenem-resistant Klebsiella pneumoniae(CRKp)is listed as one of the top high-priority pathogens by the World Health Organization.Meanwhile,hypervirulent K.pneumoniae(hvKp)causes severe community-associated infections,such as liver abscesses and meningitis,in otherwise healthy individuals.Both CRKp and hvKp infections are associated with high mortality rates.The convergence of carbapenem resistance and hypervirulence within a single bacterial strain may lead to significantly more severe clinical outcomes.展开更多
Histoplasmosis is a serious fungal disease commonly reported in the Americas,Southeast Asia,and sub-Saharan Africa[1].The classical or American type is caused by Histoplasma capsulatum var.capsulatum while African his...Histoplasmosis is a serious fungal disease commonly reported in the Americas,Southeast Asia,and sub-Saharan Africa[1].The classical or American type is caused by Histoplasma capsulatum var.capsulatum while African histoplasmosis is caused by H.capsulatum var.duboisii[2].展开更多
Seasonal influenza activity significantly decreased in China during the coronavirus disease 2019(COVID-19)pandemic,yet the H3N2 virus led to three epidemic waves.Understanding the characteristics of H3N2 epidemic viru...Seasonal influenza activity significantly decreased in China during the coronavirus disease 2019(COVID-19)pandemic,yet the H3N2 virus led to three epidemic waves.Understanding the characteristics of H3N2 epidemic viruses is essential for recognizing influenza during COVID-19 and for updating vaccines.In this study,we analyzed 579 respiratory samples from patients exhibiting influenza-like symptoms,collected in 2019–2022,leading to the successful sequencing of 36 complete H3N2 genomes.Genomic analysis indicated that the epidemic strains from these periods belonged to different hemagglutinin(HA)clades and exhibited phylogenetic divergence from the concurrently used vaccine strains.Significant antigenic differences were identified through cross-hemagglutination inhibition(HI)and cross-microneutralization(MN)assays.Furthermore,pathogenicity studies showed that representative strains replicated in Madin-Darby canine kidney(MDCK)cells,with varying abilities,and all replicated more effectively at 37℃ compared to 33℃.These strains also replicated well in the respiratory tracts of mice and guinea pigs.The findings indicate a mismatch between circulating H3N2 viruses and recommended vaccine strains,highlighting the need for improved international cooperation and epidemiological surveillance of influenza viruses post-COVID-19.Optimizing effective vaccine strain update strategy and developing a universal influenza vaccine are crucial for future preparedness.展开更多
The mpox virus(MPXV)is undergoing mutations at an alarmingly rapid pace,necessitating heightened genomic surveil-lance to manage its global spread.However,current assessments lack a comprehensive evaluation of genomic...The mpox virus(MPXV)is undergoing mutations at an alarmingly rapid pace,necessitating heightened genomic surveil-lance to manage its global spread.However,current assessments lack a comprehensive evaluation of genomic varia-tions and the influence of environmental and social factors.To address this gap,we developed the mpox virus variations risk evaluation system(VarEPS-MPXV),which uses a multidimensional strategy to assess observed and virtual varia-tions-those that have yet to occur-thereby mitigating time-lag issues in risk prediction.The system integrates six environmental and four social factors to monitor their impact on genomic variation.By analyzing 17,523 publicly avail-able MPxV sequences,we identified 61,788 unique amino acid variants and highlighted five significant mutations.Notably,OPG118:K606E is predicted to play a critical role in MPXV survival and transmission.Our assessment revealed that most key mutations involved amino acid substitutions with low mutational bariers.Variations in the OPG190 gene may alter antibody affinity,while the mutation at site 127 in the OPG038 gene may influence immune protein binding sta-bility.The VarEPS-MPXV offers vital support for managing MPXV outbreaks and other viral diseases,contributing to global public health research and practice.Researchers can freely access the database at https://nmdc.cn/mpox/.展开更多
Alzheimer’s disease(AD)and associated cognitive dysfunction are major healthcare challenges globally.Various mechanisms of pathogenesis and signaling molecules have been studied for their plausible role in disease in...Alzheimer’s disease(AD)and associated cognitive dysfunction are major healthcare challenges globally.Various mechanisms of pathogenesis and signaling molecules have been studied for their plausible role in disease initiation and progression.Neuroinflammation has been considered a major hallmark of AD.Amyloid beta(Ab),hyperphosphorylated tau protein,and formed neurofibrillary tangles(NFT)are positively correlated with neuroinflammation.Microglial activation was found to be a key contributor to neuroinflammation,AD pathogenesis,and progression.The mechanism of microglial activation has been studied in detail,and looking into its pivotal role in disease etiology,various drugs have been developed,and many are in the clinical phases of development.These drugs either inhibit the microglial activation or neuroinflammatory event postmicroglial activation.Considering these facts,in the present study,we herein discuss the mechanism of microglial activation and the mechanism of neuroinflammation related to microglial activation and dementia.Here we also discussed the various drugs that either act at tau protein or mitigate neuroinflammation,along with their status in clinical trials.In brief,this review provides an in-depth mechanism of microglial activation and updates on drugs that can inhibit this activation,leading to significant anti-Alzheimer effect and mitigation of cognitive dysfunction.展开更多
Leucine-rich repeat kinase 2(Lrrk2)has received widespread attention as a risk gene associated with Parkinson’s disease.As the immune response attributes of Parkinson’s disease have been gradually revealed,the link ...Leucine-rich repeat kinase 2(Lrrk2)has received widespread attention as a risk gene associated with Parkinson’s disease.As the immune response attributes of Parkinson’s disease have been gradually revealed,the link between Lrrk2 and the immune system has emerged.Here,we demonstrated that Lrrk2 regulates macrophage function by promoting M1 polarization.Transcriptome and immunological analyses revealed that deletion of Lrrk2 in macrophages leads to blunted interferon(IFN)-γ and lipopolysaccharide(LPS)-stimulated M1 macrophage-associated gene expression and function.Mechanistically,Lrrk2 supports M1-associated immune effector signatures,including chemokines and inducible nitric oxide synthase(iNOS)expression,by enhancing signal transducer and activator of transcription 1(STAT1)transcription factor signaling.The effect of Lrrk2 on macrophages is dependent on its kinase activity.These results revealed a previously uncharacterized role of Lrrk2 in M1 macrophage polarization by modulating cellular responses to cytokines and toll-like receptors(TLRs),such as IFN-γ and LPS.展开更多
Biliary tract infections(BTIs)present a significant therapeutic challenge,particularly in the face of increasing antimicrobial resistance.Bacteriophages,viruses that target and destroy bacteria,offer the potential for...Biliary tract infections(BTIs)present a significant therapeutic challenge,particularly in the face of increasing antimicrobial resistance.Bacteriophages,viruses that target and destroy bacteria,offer the potential for treating severe bacterial infections,although their use in BTIs has been limited.We describe an 88-year-old female with a complex and recurrent BTI caused by multiple bacteria,including multidrug-resistant Pseudomonas aeruginosa.Despite treatment with various antibiotics and percutaneous transhepatic cholangiodrainage(PTCD),her condition did not improve.As a final measure,we implemented personalized phage therapy in combination with antibiotics.An initial 9-day antibiotic treatment combined with a P.aeruginosa phage cocktail administered via PTCD fluid resulted in significant symptom relief.However,phage-resistant pathogens emerged,exhibiting resistance to all 100 double-stranded DNA(dsDNA)phages in our library due to genetic mutations affecting lipopolysaccharides biosynthesis.A second round of therapy with a double-stranded RNA(dsRNA)phage,phiYY,which targets O-antigen deficient mutants,was subsequently administered.Although complete eradication of P.aeruginosa was not achieved,the patient’s clinical symptoms were markedly improved.This case demonstrated the safety and efficacy of phage therapy in the treatment of BTIs and showcased the feasibility of employing dsRNA phages to combat the emergence of O-antigen-deficient bacterial mutants.However,it also underscores the considerable challenges in completely eradicating persistent P.aeruginosa infections,which may be attributed to bacterial heterogeneity,biofilm formation,and phage-resistant genetic mutations.展开更多
Chimeric antigen receptor-T(CAR-T)cell therapy has revolutionized cancer treatment,yet its application to autoimmune diseases remains in its infancy.In 2024,Professor Huji Xu and his colleagues achieved a groundbreaki...Chimeric antigen receptor-T(CAR-T)cell therapy has revolutionized cancer treatment,yet its application to autoimmune diseases remains in its infancy.In 2024,Professor Huji Xu and his colleagues achieved a groundbreaking milestone in allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.In this dialogue,Professor Xu elaborated on the rationale and development of allogeneic CAR-T therapy as a cost-effective,scalable alternative to autologous approaches.By utilizing multiplex genome-edited CD19-targeted CAR-T cells derived from healthy donors,his team aims to address critical challenges in manufacturing,accessibility,and long-term efficacy.Professor Xu also discussed strategies for cost reduction,regulatory hurdles,and the broader implications for immunotherapy.Drawing on his extensive experience,he envisions allogeneic CAR-T therapy emerging as a transformative treatment for autoimmune diseases,with the potential to achieve widespread accessibility and profound clinical impact.展开更多
Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for h...Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.展开更多
The 2025 Nobel Prize in Physiology or Medicine,awarded for groundbreaking research on regulatory T cells(Tregs)and peripheral immune regulation,marks a major milestone in our understanding of immune homeostasis.At the...The 2025 Nobel Prize in Physiology or Medicine,awarded for groundbreaking research on regulatory T cells(Tregs)and peripheral immune regulation,marks a major milestone in our understanding of immune homeostasis.At the same time,this achievement highlights the broader framework of signal transducer and activator of transcription(STAT)protein-mediated regulation,which orchestrates the differentiation and balance of multiple T helper(Th)cell subsets.Each Th lineage is guided by distinct cytokines that activate specific STAT proteins,thereby shaping the overall equilibrium of the peripheral immune system[1,2].展开更多
hLife proudly announced the addition of two distinguished scholars to the editorial board:Professor Peter Piot,the celebrated microbiologist,and Professor Heidi Larson,the pioneering anthropologist of vaccine confiden...hLife proudly announced the addition of two distinguished scholars to the editorial board:Professor Peter Piot,the celebrated microbiologist,and Professor Heidi Larson,the pioneering anthropologist of vaccine confidence.Their appointments came during an important visit to the Institute of Microbiology,Chinese Academy of Sciences(CAS)on April 1,2025,at the invitation of hLife Editor-in-Chief Professor George Fu Gao(Figure 1).展开更多
基金funded by the National Key Research and Development Program of China(2022YFC2304100 to W.T.)Beijing Natural Science Foundation(M23014 to N.Z.).
文摘Citation:Liu J,Zhu N,Huo W,et al.Advancing virology research with a human brain organoid platform.hLife 2025;3:237–242.The occurrence of viral infections causing central nervous system(CNS)diseases is significant,often accompanied by short-term or long-term sequelae and a high mortality rate.Typical clinical manifestations of viral infections that impact the CNS encompass encephalitis,meningitis,myelitis,and seizures[1].Treatments specific to most viral infections are generally limited.
基金supported by the National Natural Science Foundation for Key Programs of China Grants(No.32394054)the National Key R&D Program of China(No.2022YFC2601200).
文摘High altitudes are one type of extreme environment characterized by hypobaric hypoxia,extreme cold,strong ultraviolet radiation,and low energy availabilty that present tremendous challenges to human and wildlife inhabiting these environs.These extreme environments serve as a unique natural laboratory for delving into the impact of selective pressures on species variation and adaptation.This narrative review compiles the latest research on high-altitude adaptation,with a specific focus on the crucial role of gut microbiota in this process.Evidence indicates that gut microbiota significantly impacts an organism’s ability to adapt to high-altitude conditions by adjusting its composition,and hence impacting its function and ability to release microbial metabolites.We explore the link between gut microbiota and highaltitude environments,the microbial signatures,and their effects on adaptation,as well as the potential for targeted modulation of gut microbiota to enhance acclimatization to high altitudes.By examining the interaction between microbiota and host adaptation,this review aims to promote further mechanistic studies and support strategies for improving high-altitude acclimatization through gut microbiota modulation.
基金supported by the National Natural Science Foundation of China(82225021)the National Key R&D Program of China(2022YFC2303403,2021YFA1300803,2021YFA1301404).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is continuously evolving since 2019.Some monoclonal antibodies(mAbs)have been developed and widely used,such as etesevimab(CB6)developed by Eli-Lilly/Junshi.However,the mAb escaped from the variant of concern(VOC)ever since the emergence of Beta VOC,with a complete loss of efficacy against the Omicron subvariants.Here,we developed a broad-spectrum and affinity-mature antibody design(BAADesign)procedure to design CB6,enabling it to bind to the receptor-binding domains(RBDs)of multiple important Omicron subvariants,including the recent variant KP.2.Structural analysis confirmed the desired CB6-RBD interactions.Additionally,identical mutations in the complementarity determining regions(CDR)1 and CDR2 of the CB6 mutants also restored neutralizing potency for some RBD-1 group antibodies.Overall,the enhanced CB6 neutralizing capacity makes it a promising candidate against SARS-CoV-2 infection,and the BAADesign method has implications for the design of other antibodies.
文摘The 778th Xiangshan Science Conference,themed“Regional Immunity in the Lung and Respiratory Tract:Challenges and Opportunities”,convened in Beijing on April 8–9,2025.Co-chaired by four leading scientists-ProfessorGeorge FuGao(Institute of Microbiology,Chinese Academy of Sciences),Professor Chen Dong(Westlake University School of Medicine),Professor Zhigang Tian(University of Science and Technology of China).
基金funding from the MOST Key R&D Program of China(Grant numbers 2022YFC2304703 and 2020YFA0907200)the Natural Science Foundation of China(Grant numbers 32270202 and 62372286)+2 种基金Program of Shanghai Academic/Technology Research Leader(Grant number 23XD1422300)Science and Technology Innovation Plan of Shanghai(Grant number 23JC1403200)Innovative research team of high-level local universities in Shanghai are greatly appreciated by all the authors.
文摘The intratumor microbiome,one of the hallmarks of cancer,plays a crucial role in cancer progression through its interaction with the host.However,the underlying mechanisms remain poorly understood.In this study,six publicly available single-cell transcriptomic lung cancer datasets(comprising 178 samples)from multiple centers(Shanghai,New York,Seoul)were integrated to investigate the heterogeneity of host-microbiome interactions at the single-cell level using single-cell analysis of host-microbiome interactions(SAHMI).The results indicate that primary tumor tissues have a high proportion of fungi-associated cells,whereas metastatic brain tissues predominantly contain bacteria-associated cells.There are also distinct microbial distributions across cell types.Notably,the presence of specific bacteria significantly influences the transcriptome of resident host cells,including T cells and macrophages,by modulating pathways related to ribosomal RNA(rRNA)processing,cellular responses to stress and stimuli,and RNA and protein metabolism.Finally,specific cell-associated bacteria are significantly correlated with clinical features,such as lung cancer stages and smoking frequency.These single-cell insights into microbiome-host interactions improve current understanding about lung cancer development and progression and offer potential micro-ecological and diagnostic insights.
文摘Recently,the Royal Swedish Academy of Sciences announced that one-half of the 2024 Nobel Prize in Chemistry was awarded to David Baker for computational protein design,and the other half was awarded jointly to Demis Hassabis and John Jumper for protein structure prediction.Proteins are the molecule tools of life.To carry out their functions,many proteins need to fold into particular three-dimensional(3D)structures,which are programmed by the amino acid sequences of the proteins[1].The goal of protein structure prediction is to predict the 3D structures from given amino acid sequences.Conversely,protein design aims to identify amino acid sequences that achieve desired structural or functional goals.
基金supported by theBeijing Natural Science Founda-tion(grant number IS23089 to Y.V.F.)the National Natural Science Foundation ofChina(grant number 52091541 to Y.V.F.).
文摘Microbiology,born to study life forms invisible to the naked eye,owes its origin to Antonie van Leeuwenhoek,who in the 1670s first observed bacteria and other microbes using microscopes of his design.From its inception,microbiology has been an interdisciplinary science,deeply reliant on advances in instrumentation and methodology.A pivotal milestone was reached in the late 19th century when Robert Koch established the germtheory of disease by conclusively linking specific microbes to specific illnesses.
基金Guangdong Basic and Applied Basic Research Foundation(grant number 2024A1515010319 to J.Q.)Science and Technology Program of Shenzhen(grant numbers KCXFZ20230731100901003 to J.Q.and L.L.,KJZD20230923115116032 to J.Q.,JCYJ20190809144005609 to J.Q.)+1 种基金Shenzhen Key Laboratory of Biochip(grant number ZDSYS201504301534057 to J.Q.)Shenzhen High-level Hospital Construction Fund(to J.Q.).
文摘Nosocomial pathogen carbapenem-resistant Klebsiella pneumoniae(CRKP)poses a heightened risk to public health through carbapenem resistance and virulence convergence,particularly in China’s dominant sequence type 11(ST11)clone[1,2].Monoclonal K.pneumoniae exhibits within-host diversity during prolonged infections[3–5],with certain variants surviving through adaptation[4,6].CRKP strains from the blood of a single patient are heterogeneous in terms of antibiotic susceptibility,capsular polysaccharide production,and mucoviscosity[3].Intra-host evolution drives novel resistance via cumulative mutations(e.g.,the transcriptional regulator gene ramR mutations and the outer membrane porin gene OmpK35 loss)[4].
基金supported by grants from the National Key Research and Development Plan of China(2022YFC2303200,2021YFC2302405,and 2022YFC2303400 to G.C.)Shenzhen Medical Research Fund(B2404002 to G.C.)+3 种基金the National Natural Science Foundation of China(82422049 to Y.Z.and 32188101 to G.C.)the Shenzhen San-Ming Project for Prevention and Research on Vector-borne Diseases(SZSM202211023 to G.C.)the Science and Technology Project of Southwest United Graduate School of Yunnan(202302AO370010 to G.C.)supported by the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the XPLORER PRIZE.
文摘Mosquito-borne arboviruses significantly threaten global health,affecting millions of people worldwide.The innate immune system is the primary line of defense against arboviruses in both mammalian hosts and mosquito vectors,although the innate immune responses of these organisms involve distinct mechanisms.This review compares the innate immune responses of mammals with those of mosquitoes,focusing on their shared reliance on pattern recognition receptors(PRRs),immune signaling pathways,and cellular innate immunity.While mosquitoes utilize RNA interference(RNAi)and melanization to control arboviral replication without inflammation,mammals depend on complement systems,complex interferon(IFN)responses,and cytokine production to rapidly clear arboviral infections.This review provides a comparative analysis of the innate immune responses of mammalian hosts and mosquito vectors,highlighting key differences in the strategies by which these organisms manage arboviral infections.Understanding these distinctions may inform the development of novel interventions to disrupt arboviral transmission and improve disease control.
基金supported by the National Natural Science Foundation of China(grant numbers 81991531 to M.W.,82102440 to J.J.,and 32400149 to J.Z.).
文摘Antimicrobial resistance is a global health crisis and carbapenem-resistant Klebsiella pneumoniae(CRKp)is listed as one of the top high-priority pathogens by the World Health Organization.Meanwhile,hypervirulent K.pneumoniae(hvKp)causes severe community-associated infections,such as liver abscesses and meningitis,in otherwise healthy individuals.Both CRKp and hvKp infections are associated with high mortality rates.The convergence of carbapenem resistance and hypervirulence within a single bacterial strain may lead to significantly more severe clinical outcomes.
文摘Histoplasmosis is a serious fungal disease commonly reported in the Americas,Southeast Asia,and sub-Saharan Africa[1].The classical or American type is caused by Histoplasma capsulatum var.capsulatum while African histoplasmosis is caused by H.capsulatum var.duboisii[2].
基金supported by the National Key R&D Program of China(2022YFC3500804 and 2023YFC2307500 to Y.L.and Y.B.)the National Natural Science Foundation of China(NSFC)(32261133524 and 32425053 to Y.B.)+7 种基金the Beijing Research Center for Respiratory Infectious Diseases(BJRID2025-007 to Y.B.)the CAS Southeast Asia Biodiversity Research Institute(151C53KYSB20210023 to Y.B.)the Major Project of Guangzhou National Laboratory(GZNL2023A01001 to Y.B.)the National Science and Technology Infrastructure of China(National Pathogen Resource Center-NPRC-32 to Y.B.)the CAS Project for Young Scientists in Basic Research(YSBR-086 to Y.B.)the Youth Innovation Promotion Association of CAS(Y2021034 to Y.B.)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTD-D-202208 to Y.B.)the Russian Science Foundation(23-44-00026 to M.G.and A.S.).
文摘Seasonal influenza activity significantly decreased in China during the coronavirus disease 2019(COVID-19)pandemic,yet the H3N2 virus led to three epidemic waves.Understanding the characteristics of H3N2 epidemic viruses is essential for recognizing influenza during COVID-19 and for updating vaccines.In this study,we analyzed 579 respiratory samples from patients exhibiting influenza-like symptoms,collected in 2019–2022,leading to the successful sequencing of 36 complete H3N2 genomes.Genomic analysis indicated that the epidemic strains from these periods belonged to different hemagglutinin(HA)clades and exhibited phylogenetic divergence from the concurrently used vaccine strains.Significant antigenic differences were identified through cross-hemagglutination inhibition(HI)and cross-microneutralization(MN)assays.Furthermore,pathogenicity studies showed that representative strains replicated in Madin-Darby canine kidney(MDCK)cells,with varying abilities,and all replicated more effectively at 37℃ compared to 33℃.These strains also replicated well in the respiratory tracts of mice and guinea pigs.The findings indicate a mismatch between circulating H3N2 viruses and recommended vaccine strains,highlighting the need for improved international cooperation and epidemiological surveillance of influenza viruses post-COVID-19.Optimizing effective vaccine strain update strategy and developing a universal influenza vaccine are crucial for future preparedness.
基金work was supported by various funding sources,including the National Key Research Program of China(2022YFC2303400 to C.S.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0830000 to L.W.)+1 种基金the Key Research Programof the Chi-nese Academy of Sciences(KFZD-SW-219 to L.W.)the Shenzhen Medical Research Fund(E24010010 to Z.L.and E24010011 to Z.L.).
文摘The mpox virus(MPXV)is undergoing mutations at an alarmingly rapid pace,necessitating heightened genomic surveil-lance to manage its global spread.However,current assessments lack a comprehensive evaluation of genomic varia-tions and the influence of environmental and social factors.To address this gap,we developed the mpox virus variations risk evaluation system(VarEPS-MPXV),which uses a multidimensional strategy to assess observed and virtual varia-tions-those that have yet to occur-thereby mitigating time-lag issues in risk prediction.The system integrates six environmental and four social factors to monitor their impact on genomic variation.By analyzing 17,523 publicly avail-able MPxV sequences,we identified 61,788 unique amino acid variants and highlighted five significant mutations.Notably,OPG118:K606E is predicted to play a critical role in MPXV survival and transmission.Our assessment revealed that most key mutations involved amino acid substitutions with low mutational bariers.Variations in the OPG190 gene may alter antibody affinity,while the mutation at site 127 in the OPG038 gene may influence immune protein binding sta-bility.The VarEPS-MPXV offers vital support for managing MPXV outbreaks and other viral diseases,contributing to global public health research and practice.Researchers can freely access the database at https://nmdc.cn/mpox/.
文摘Alzheimer’s disease(AD)and associated cognitive dysfunction are major healthcare challenges globally.Various mechanisms of pathogenesis and signaling molecules have been studied for their plausible role in disease initiation and progression.Neuroinflammation has been considered a major hallmark of AD.Amyloid beta(Ab),hyperphosphorylated tau protein,and formed neurofibrillary tangles(NFT)are positively correlated with neuroinflammation.Microglial activation was found to be a key contributor to neuroinflammation,AD pathogenesis,and progression.The mechanism of microglial activation has been studied in detail,and looking into its pivotal role in disease etiology,various drugs have been developed,and many are in the clinical phases of development.These drugs either inhibit the microglial activation or neuroinflammatory event postmicroglial activation.Considering these facts,in the present study,we herein discuss the mechanism of microglial activation and the mechanism of neuroinflammation related to microglial activation and dementia.Here we also discussed the various drugs that either act at tau protein or mitigate neuroinflammation,along with their status in clinical trials.In brief,this review provides an in-depth mechanism of microglial activation and updates on drugs that can inhibit this activation,leading to significant anti-Alzheimer effect and mitigation of cognitive dysfunction.
基金supported by a National Key Research and Development Project Grant(2021YFC2300502)the National Natural Science Foundation of China Grants(32370930 and 32360176).
文摘Leucine-rich repeat kinase 2(Lrrk2)has received widespread attention as a risk gene associated with Parkinson’s disease.As the immune response attributes of Parkinson’s disease have been gradually revealed,the link between Lrrk2 and the immune system has emerged.Here,we demonstrated that Lrrk2 regulates macrophage function by promoting M1 polarization.Transcriptome and immunological analyses revealed that deletion of Lrrk2 in macrophages leads to blunted interferon(IFN)-γ and lipopolysaccharide(LPS)-stimulated M1 macrophage-associated gene expression and function.Mechanistically,Lrrk2 supports M1-associated immune effector signatures,including chemokines and inducible nitric oxide synthase(iNOS)expression,by enhancing signal transducer and activator of transcription 1(STAT1)transcription factor signaling.The effect of Lrrk2 on macrophages is dependent on its kinase activity.These results revealed a previously uncharacterized role of Lrrk2 in M1 macrophage polarization by modulating cellular responses to cytokines and toll-like receptors(TLRs),such as IFN-γ and LPS.
基金supported by grants from the National Natural Science Foundation of China(82402679 to N.L.,82072325 to B.H.,82070772 to T.Z.,32470145 to N.W.)the Shanghai Sailing Program(23YF1443700 to N.L.)the Clinical Research Plan of Shanghai Municipal Health Commission(20224Y0287 to N.L.).
文摘Biliary tract infections(BTIs)present a significant therapeutic challenge,particularly in the face of increasing antimicrobial resistance.Bacteriophages,viruses that target and destroy bacteria,offer the potential for treating severe bacterial infections,although their use in BTIs has been limited.We describe an 88-year-old female with a complex and recurrent BTI caused by multiple bacteria,including multidrug-resistant Pseudomonas aeruginosa.Despite treatment with various antibiotics and percutaneous transhepatic cholangiodrainage(PTCD),her condition did not improve.As a final measure,we implemented personalized phage therapy in combination with antibiotics.An initial 9-day antibiotic treatment combined with a P.aeruginosa phage cocktail administered via PTCD fluid resulted in significant symptom relief.However,phage-resistant pathogens emerged,exhibiting resistance to all 100 double-stranded DNA(dsDNA)phages in our library due to genetic mutations affecting lipopolysaccharides biosynthesis.A second round of therapy with a double-stranded RNA(dsRNA)phage,phiYY,which targets O-antigen deficient mutants,was subsequently administered.Although complete eradication of P.aeruginosa was not achieved,the patient’s clinical symptoms were markedly improved.This case demonstrated the safety and efficacy of phage therapy in the treatment of BTIs and showcased the feasibility of employing dsRNA phages to combat the emergence of O-antigen-deficient bacterial mutants.However,it also underscores the considerable challenges in completely eradicating persistent P.aeruginosa infections,which may be attributed to bacterial heterogeneity,biofilm formation,and phage-resistant genetic mutations.
文摘Chimeric antigen receptor-T(CAR-T)cell therapy has revolutionized cancer treatment,yet its application to autoimmune diseases remains in its infancy.In 2024,Professor Huji Xu and his colleagues achieved a groundbreaking milestone in allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.In this dialogue,Professor Xu elaborated on the rationale and development of allogeneic CAR-T therapy as a cost-effective,scalable alternative to autologous approaches.By utilizing multiplex genome-edited CD19-targeted CAR-T cells derived from healthy donors,his team aims to address critical challenges in manufacturing,accessibility,and long-term efficacy.Professor Xu also discussed strategies for cost reduction,regulatory hurdles,and the broader implications for immunotherapy.Drawing on his extensive experience,he envisions allogeneic CAR-T therapy emerging as a transformative treatment for autoimmune diseases,with the potential to achieve widespread accessibility and profound clinical impact.
文摘Prof.Zhijian James Chen,a distinguished scientist in the field of innate immunity,has been honored with the 2025 Paul Ehrlich and Ludwig Darmstaedter Prize and the 2024 Albert Lasker Basic Medical Research Award for his groundbreaking discovery of the enzyme cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS).His research has transformed the understanding of innate immune responses,particularly the role of cGAS as a cytosolic DNA sensor that triggers an interferon response.In this dialogue,Prof.Chen reflects on his research journey,from his initial exploration of ubiquitin and nuclear factor-kB(NF-kB)signaling to his discoveries of mitochondrial antiviral-signaling protein(MAVS)and cGAS,highlighting his lifelong interest in cell signaling and human diseases.The interview underscores the importance of perseverance and the pursuit of impactful research questions in scientific endeavors.This scholarly exchange offers a mentor-like perspective for aspiring scientists,encapsulating the essence of a successful career in biomedical research.
基金supported by start-up funds for X.Y.F.sponsored by the West China Hospital,Sichuan University(grant number 139170082).
文摘The 2025 Nobel Prize in Physiology or Medicine,awarded for groundbreaking research on regulatory T cells(Tregs)and peripheral immune regulation,marks a major milestone in our understanding of immune homeostasis.At the same time,this achievement highlights the broader framework of signal transducer and activator of transcription(STAT)protein-mediated regulation,which orchestrates the differentiation and balance of multiple T helper(Th)cell subsets.Each Th lineage is guided by distinct cytokines that activate specific STAT proteins,thereby shaping the overall equilibrium of the peripheral immune system[1,2].
文摘hLife proudly announced the addition of two distinguished scholars to the editorial board:Professor Peter Piot,the celebrated microbiologist,and Professor Heidi Larson,the pioneering anthropologist of vaccine confidence.Their appointments came during an important visit to the Institute of Microbiology,Chinese Academy of Sciences(CAS)on April 1,2025,at the invitation of hLife Editor-in-Chief Professor George Fu Gao(Figure 1).
