Six months after the United Nations General Assembly 2nd high-level meeting in 26 September 2024 to review the progress made at all levels to tackle antimicrobial resistance(AMR)and accelerate progress through One Hea...Six months after the United Nations General Assembly 2nd high-level meeting in 26 September 2024 to review the progress made at all levels to tackle antimicrobial resistance(AMR)and accelerate progress through One Health,Global AMR Innovation Fund(GAMRIF)summit 2025 was held with three aims:“to encourage and foster new collaboration between AMR research and development(R&D)stakeholders,to share learnings and best practices across the wide range of stakeholders,and to envision the future of AMR R&D”.The summit lasted for three days and began with an introduction and overview of the high-level commitment in AMR and the key global policy developments in 2024 and their implications for innovation R&D(http://globalamrhub.org/news/gamrif-summit-2025/).展开更多
Postoperative infection is a major global health concern,affecting 5%-10%of surgical patients and nearly doubling mortality in severe cases[1].Transplant recipients are particularly vulnerable,with 30%-80%developing i...Postoperative infection is a major global health concern,affecting 5%-10%of surgical patients and nearly doubling mortality in severe cases[1].Transplant recipients are particularly vulnerable,with 30%-80%developing infections within 30 days,often from opportunistic pathogens[2,3].Key risk factors include epidemiological exposure,net immunosuppression,age,transplant type,and surgical history[4].Despite known infection risks,current evidence remains transplantation type-specific and neglects behavioral modulators[5].Different types of transplantation may share similar risk factors[6].To identify common factors affecting postoperative infection,this study collected standardized clinical data-including diet,psychological response,medication use,and biochemical indicators-from liver and kidney transplant patients across six hospitals using a unified standard operating procedure(SOP).展开更多
Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical fu...Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical full-length HERV provirus consists of four primary genes:gag,pro,pol,and env,flanked by two long terminal repeats(LTRs).Although some of the HERV proviruses remain intact,the majority of HERVs have undergone truncation,insertions,deletions,or point mutations over evolutionary time.-Recent studies have revealed that epigenetic reprogramming,a hallmark of both cellular senescence and premature aging,can lead to the activation of HERVs[1].This reactivation has also been observed across a range of aging-related diseases,including immunosenescence,neurodegenerative diseases,and certain types of cancer.These findings suggest that HERVs may not only be consequences of aging but also active contributors to aging-related cellular dysfunction.In this perspective,we review emerging evidence linking HERVs to cellular senescence and aging-related diseases,highlight their potential utility as biomarkers and diagnostic indicators,and address both the opportunities and challenges in translating this knowledge into clinical applications.展开更多
The continuous evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)presents ongoing challenges and risks to public health,as it renders most reported monoclonal antibodies(mAbs)ineffective due to i...The continuous evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)presents ongoing challenges and risks to public health,as it renders most reported monoclonal antibodies(mAbs)ineffective due to immune escape[1,2].Unlike conventional strategies that rely on conserved epitopes across known viral subtypes,the extraordinary pace and unpredictability of SARS-CoV-2 mutations have progressively eroded these epitopes,thereby destabilizing the foundations of traditional broadly neutralizing antibody(bnAb)development[3].展开更多
With the growing proportion of older adults globally,aging has emerged as a leading risk factor for a range of chronic diseases and mortality[1].This process is characterized by progressive degeneration and loss of fu...With the growing proportion of older adults globally,aging has emerged as a leading risk factor for a range of chronic diseases and mortality[1].This process is characterized by progressive degeneration and loss of function across multiple physiological systems[2].While chronological age is the most straightforward indicator of aging,the variability in aging across different organ systems[3]results in a wide variation in aging characteristics among individuals of the same chronological age[4,5].Recently,several promising DNA methylation(DNAm)-based algorithms(e,g.,HorvathAge,GrimAge,GrimAge2)have been developed to assess biological age by analyzing age-associated changes in DNAm patterns[6].These algorithms are now widely used in biological age assessment.Some of them have demonstrated robust predictive power for mortality and various age-related conditions[1].However,due to differences in objectives,meth-odologies,and tissue types used across these algorithms[6],it remains uncertain which tool best captures the true state of bio-logical aging.展开更多
A NOBEL FOR METAL-ORGANIC FRAMEWORK The 2025 Nobel Prize in Chemistry was awarded to Susumu Kitagawa,Richard Robson,and Omar M.Yaghi for their groundbreaking contributions to the field of metal-organic frameworks(MOFs...A NOBEL FOR METAL-ORGANIC FRAMEWORK The 2025 Nobel Prize in Chemistry was awarded to Susumu Kitagawa,Richard Robson,and Omar M.Yaghi for their groundbreaking contributions to the field of metal-organic frameworks(MOFs).These molecular-based crystalline porous materials,constructed by the coordination of metal nodes with organic ligands,possess precisely designed porous structures and tunable functionalities[1].展开更多
Modern molecular biology began with the discovery of the DNA double helix,revealing the physical basis of genetics.Whereas genes carry genetic information in one-dimension,living cells'functional activities are pe...Modern molecular biology began with the discovery of the DNA double helix,revealing the physical basis of genetics.Whereas genes carry genetic information in one-dimension,living cells'functional activities are performed by proteins in the form of three-dimensional structures.About 240,000 experimentally determined protein structures have been deposited in the Protein Data Bank(PDB).With the newly developed artificial intelligence(AI)tool Alpha Fold,essentially the whole protein universe has been reliably predicted.This perspective explores the genetic features of protein structures.展开更多
Influenza viruses are a major cause of respiratory illness,with significant public health impact due to their ability to cause pandemics.This dialogue brought together experts including Professors George Fu Gao,Stephe...Influenza viruses are a major cause of respiratory illness,with significant public health impact due to their ability to cause pandemics.This dialogue brought together experts including Professors George Fu Gao,Stephen Cusack,Mark von Itzstein,Ervin Fodor,Jonathan Grimes,Aartjan J.W.te Velthuis,and Tao Deng to decode the pressing scientific challenges and future directions in influenza research.They discussed how structural studies of the influenza polymerase have advanced our understanding of viral RNA transcription and replication.These insights are crucial for developing new antiviral drugs,with a particular focus on targeting the polymerase and its interactions with host factors like acidic nuclear phosphoprotein 32(ANP32).The dialogue also highlighted the potential of artificial intelligence(AI)to assist in designing small-molecule drugs,offering new strategies for combating influenza.Future research will continue to unravel the complexities of the polymerase’s role in replication,aiming to translate these findings into effective therapies and resilient public health strategies.展开更多
Exercise,as a non-pharmacological health intervention,has been widely recognized for its beneficial effects,yet its underlying molecular mechanisms remain incompletely understood.The duration,frequency,and intensity o...Exercise,as a non-pharmacological health intervention,has been widely recognized for its beneficial effects,yet its underlying molecular mechanisms remain incompletely understood.The duration,frequency,and intensity of exercise exert distinct physiological impacts on the human body[1].Notably,acute exercise(AE)primarily elicits immediate metabolic responses and immune activation to cope with environmental stimuli,whereas long-term exercise(LE)induces cumulative health benefits across multiple organ systems[2‒4].Aging represents a complex biological process that persists throughout the ontogenetic continuum and serves as a pivotal etiological determinant for numerous chronic pathologies.In the context of accelerating global demographic aging,the development of interventions to promote healthspan extension and modulate aging trajectories has become a paramount research imperative in geroscience.Currently,research on the relationship between exercise and aging is a hot topic.For example,exercise has been shown to modulate aging through pathways such as AMP-activated protein kinase(AMPK)[5].However,the precise molecular links remain elusive.In a recent breakthrough study,Geng et al.used a novel multi-omics strategy to pinpoint betaine,a glycine derivative from choline/diet that serves as both a hepatic methyl donor and a renal osmoprotectant,as a key exercise-induced molecule with anti-inflammatory and geroprotective effects mediated partially via TANK-binding kinase 1(TBK1)inhibition[6,7].This work represents a significant advance as it systematically maps the molecular divergence between acute and long-term exercise while establishing a direct link between renal metabolism and systemic senescence-delaying benefits.展开更多
“The Dao begets One,One begets Two,Two begets Three,Three begets all things.”-The Tao-te Ching We are delighted to present the first issue of the fourth volume of hLife and would like to extend our heartfelt thanks ...“The Dao begets One,One begets Two,Two begets Three,Three begets all things.”-The Tao-te Ching We are delighted to present the first issue of the fourth volume of hLife and would like to extend our heartfelt thanks to our global community for their strong support in the last three years.This moment signifies more than just a milestone in our calendar,it is an opportunity to unite our enduring scientific vision with our shared aspirations for universal health.Health,as defined by the World Health Organization(WHO)in 1948,encompasses a state of complete physical,mental,and social well-being and not merely the absence of disease or infirmity.In an era of interconnected challenges-from pandemics to psychosocial stressors-the integration of these three aspects is more critical than ever.展开更多
Bats are critical viral reservoirs that harbor viromes with high cross-species transmission risks,yet their virome diversity in the mainland Southeast Asia and adjacent regions remains underexplored.Here,we characteri...Bats are critical viral reservoirs that harbor viromes with high cross-species transmission risks,yet their virome diversity in the mainland Southeast Asia and adjacent regions remains underexplored.Here,we characterized the bat viromes from 659 samples(197 individuals,16 species)from Yunnan province and Guangxi Zhuang autonomous region,China,as well as from Cambodia,using next-generation sequencing(NGS).RNA sequencing,viral classification,phylogenetic analyses,and deep learning-based host adaptability analysis were performed to reveal the viral composition and cross-species transmission risks.We identified 137 viral strains,including 40 novel species spanning 18 families.Viral richness was highest in Vespertilionidae bats(12 viral families found)along China's southwestern border,where Middle Eastern respiratory syndrome(MERS)-like coronavirus(Co V)was found.Cambodian bat viruses were evolutionarily more distant from those of known viruses.A porcine epidemic diarrhea virus(PEDV)-related Co V was found in Cambodia,showing 90.36%genome homology with PEDV CV777 and exhibiting recombinant features between Suidae-adapted ORF1ab and Chiroptera-adapted Spike genes,suggesting that bats are the evolutionary source of PEDV.These findings illuminate the undercharacterized bat viral diversity in biogeographic transition zones and highlight the mainland Southeast Asia and adjacent regions as a hotspot for Co V recombination.We advocate for enhanced One Health-aligned surveillance targeting viral recombination hotspots and human±bat interfaces in this ecologically critical region.展开更多
Trained immunity is essential for innate immune cells to retain a memory of previously encountered pathogens,strengthening the hosts’response against these pathogens.However,the mechanisms governing trained immunity ...Trained immunity is essential for innate immune cells to retain a memory of previously encountered pathogens,strengthening the hosts’response against these pathogens.However,the mechanisms governing trained immunity have not been well elucidated.In this study,flies of different genotypes were trained with heat-killed gram-negative(G)bacteria and subsequently reinfected with live pathogens.The innate immune responses against reinfection were evaluated through assessments of survival rates,antimicrobial peptide expression levels,and bacterial loads,complemented by transcriptomic and chromatin immunoprecipitation(ChIP)analyses.We found that flies trained with heat-killed gram-negative bacteria exhibited a higher survival rate upon secondary infection compared to unprimed flies,which was associated with increased expression of antimicrobial peptides.Priming with Gbacteria increased the sensitivity of the immune deficiency pathway to a second bacterial infection owing to lower levels of peptidoglycan recognition protein SC(PGRP-SC)after the first infection.The gut was the major tissue involved in the downregulation of PGRP-SC expression.The histone H3 lysine 9 trimethylation(H3K9me3)levels were higher at the PGRP-SC loci in immune-trained flies compared to untrained flies,contributing to the suppression of PGRP-SC expression.PGRP-SC overexpression in the fly gut abolished the effect of trained immunity.Taken together,our studies identify an innate immune memory in Drosophila that is regulated by gut-derived PGRP-SC through H3K9me3-mediated epigenetic repression of the PGRP-SC.展开更多
Accurate prediction and monitoring of acute graft-versus-host disease(aGVHD)remain challenging in allogeneic hematopoietic stem cell transplantation(allo-HSCT)as current diagnostic approaches rely on symptomatic prese...Accurate prediction and monitoring of acute graft-versus-host disease(aGVHD)remain challenging in allogeneic hematopoietic stem cell transplantation(allo-HSCT)as current diagnostic approaches rely on symptomatic presentation.Therefore,this study sought to identify predictive biomarkers and therapeutic targets for aGVHD through longitudinal immune monitoring and mechanistic investigations.In this study,peripheral blood samples were collected weekly for 100 days from a group of 115 allo-HSCT recipients.CD38^(+)HLA-DR^(+)CD8^(+)T(activated CD8^(+)T)cells were analyzed using the t-distributed stochastic neighbor embedding(t-SNE)algorithm for high-dimensional data visualization and population identification.Clinical data integration was used to assess biomarker utility.Mechanistic studies included interleukin-15(IL-15)stimulation,signaling pathway inhibition,cytotoxicity assays,and xenogeneic GVHD modeling with anti-CD38(daratumumab)intervention.Our results revealed that sustained elevation of activated CD8^(+)T cells(>36.6%)within the first month post-transplantation predicted aGVHD onset with high accuracy(AUC=0.84,P<0.001).Cell frequency dynamically correlated with treatment outcome,decreasing substantially in responders.Mechanistically,IL-15 drove T-cell receptor(TCR)-independent cytotoxicity via PI3K/mTOR activation,mediated by natural killer group 2D(NKG2D)and major histocompatibility complex class I chain related proteins A(MIC-α)interactions,validated by reduced K562 cell lysis following antibody blockade.In an 8-10-week-old NSG mouse model for xenogeneic transplantation,treatment with daratumumab(5 mg/kg)effectively lowered histopathological damage and increased survival.In conclusion,activated CD8+T cells can serve as dual-purpose biomarkers for early aGVHD prediction and treatment monitoring.Their IL-15-driven cytotoxicity represents a targetable pathway,with daratumumab demonstrating therapeutic efficacy.展开更多
Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we inves...Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we investigated whether the gut microbiota mediates the radioprotective effects of BBR using a C57BL/6 RILI mouse model with 20 Gy thoracic irradiation(n=6 per group).BBR(100 mg/kg)and inosine(INO,300 mg/kg)were administered orally in vivo.Antibiotic depletion and fecal microbiota transplantation were performed to assess microbiota dependence.Lung injury was assessed by histology,pulmonary function,and cytokine levels.Gut microbiota was analyzed by 16S rRNA sequencing,and metabolites were profiled using LC-MS/MS.Transcriptomic and epigenomic alterations were assessed by RNA sequencing,ATAC sequencing,and CUT&Tag analysis.Molecular docking and surface plasmon resonance were used to assess metabolite-protein interactions.We demonstrated that BBR alleviated RILI in a microbiota-dependent manner.BBR increased Akkermansia muciniphila abundance and metabolite INO levels.Mechanistically,INO was associated with reduced neuron navigator 3(NAV3)expression,accompanied by decreased chromatin accessibility and increased histone H3 lysine 27 trimethylation(H3K27me3)at the NAV3 locus.Together,these findings reveal a gut microbiota-mediated mechanism underlying BBR-mediated protection against RILI,and suggest microbiota-informed biomarkers for risk stratification.展开更多
Rabies,a persistent and historic global zoonosis,continues to impose a significant public health burden,particularly in resource-limited regions.The causative agent,rabies virus(RABV;genus Lyssavirus,family Rhabdoviri...Rabies,a persistent and historic global zoonosis,continues to impose a significant public health burden,particularly in resource-limited regions.The causative agent,rabies virus(RABV;genus Lyssavirus,family Rhabdoviridae),possesses a surface glycoprotein(G)that is pivotal for virus entry and pathogenesis.Rabies virus glycoprotein(RABV-G)mediates binding to host cell receptor(s)and acidic-pH-dependent membrane fusion,enabling the release of RNA genome into the host cytoplasm.It is also the main target for neutralizing antibodies and the major component of rabies vaccines.In this review,we systematically summarize the structural features,functional mechanisms,and antiviral targeting strategies of RABV-G,emphasizing recent structural insights into its conformational dynamics.Key neutralizing epitopes and their recognition by monoclonal antibodies are discussed,along with antiviral strategies,including entry inhibitors,antibody therapies,and advanced vaccine platforms.Accumulating structural analyses indicate that the pH-dependent and reversible conformational transitions of this classⅢviral fusion protein underlie both viral infectivity and vulnerability to immune intervention.Collectively,available data establish that neutralizing epitopes on RABV-G are conformationally defined and dynamically regulated during fusion,thereby constraining viral entry and dictating the effectiveness of antibody-and entry inhibitor–mediated neutralization.Together,these findings establish RABV-G as the primary determinant of rabies virus virulence and immune control.By exploring the structural framework and prospective treatment modalities,we aim to enhance our understanding of rabies virus,particularly the glycoprotein G,and support ongoing initiatives to alleviate the burden of rabies,offering renewed optimism in the battle against this formidable infectious disease.展开更多
Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 1...Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.展开更多
Human fungal infections represent a rapidly emerging global health threat,especially threatening immunocompromised populations,highlighting the urgent need for accurate and timely diagnostic approaches to reduce morbi...Human fungal infections represent a rapidly emerging global health threat,especially threatening immunocompromised populations,highlighting the urgent need for accurate and timely diagnostic approaches to reduce morbidity and mortality.This review synthesizes recent advances in diagnostic methodologies,including serological assays,point-of-care diagnostics,polymerase chain reaction(PCR)-based and sequencing technologies,as well as artificial intelligence(AI)-and machine learning(ML)-powered tools.Emerging diagnostic approaches have demonstrated notable improvements in detection accuracy,turnaround time,and antifungal resistance profiling capabilities,especially for drug-resistant strains.Nevertheless,substantial challenges persist in terms of standardization,scalability,cost-effectiveness,and implementation,particularly in resource-constrained settings.Future efforts should be directed toward the continuous innovation of rapid,sensitive,and multiplex diagnostic platforms for the simultaneous detection of fungi,bacteria,and viruses.Such advances may accelerate result acquisition,enhance diagnostic accuracy,support the development of more targeted therapeutic strategies,and ultimately improve clinical outcomes for patients.展开更多
The high polymorphism of histocompatibility complex class Ⅱ(MHC-Ⅱ)alleles and limited immunopeptidomic data hinder pan-species epitope prediction.In this study,leveraging the predictive power of AlphaFold(AF)and the...The high polymorphism of histocompatibility complex class Ⅱ(MHC-Ⅱ)alleles and limited immunopeptidomic data hinder pan-species epitope prediction.In this study,leveraging the predictive power of AlphaFold(AF)and the conserved structural features of the core region of MHC-Ⅱ-binding peptides,derived from a comprehensive analysis of MHC-Ⅱ structure data in the PDB database,we developed a new tool,AF-prediction(AF-pred),with explicit quantitative criteria for MHC-Ⅱ-restricted epitope prediction.We validated AF-pred across human,porcine,bovine,and bat MHC-Ⅱ molecules through large-scale in silico analyses using known immunopeptidome datasets(1000 positive and 1000 negative antigenic peptides),together with in vitro binding assays and crystallographic characterization of newly predicted epitopes.Using uncharacterized bat MHC-Ⅱ structures,we demonstrated that AF-pred’s amino-acid interaction prediction underpins its pan-prediction capability and the underlying rationale of the method.Conversely,this characteristic limits the prediction of atypical MHC-Ⅱ peptide-binding modes.Compared with sequence-based tools,AF-pred demonstrates enhanced cross-species MHC-Ⅱ binding prediction,with higher accuracy and interpretability,and further reveals that iterative AF updates improve AF-pred performance.AF-pred has the potential to facilitate the development of novel T-cell epitope vaccines and advance the“One Health”initiative.展开更多
The local immune system of the lungs is essential for the defense against pathogens,and respiratory bacterial infections remain a major cause of mortality in patients with lower respiratory tract diseases.However,the ...The local immune system of the lungs is essential for the defense against pathogens,and respiratory bacterial infections remain a major cause of mortality in patients with lower respiratory tract diseases.However,the precise mechanisms underlying immune-pathogen interactions and the modulatory roles of commensal bacteria remain incompletely understood.This review discusses the mechanisms of immune recognition and inflammatory responses during bacterial respiratory bacterial infections,highlighting the importance of pattern recognition receptors,including toll-like receptors,nucleotide oligomerization domain-like receptors,and C-type lectin receptors in detecting pathogens and triggering immune signaling pathways.We also explore how commensal bacteria influence the respiratory immune microenvironment and discuss the complex interplay among pathogenic bacteria,commensals,and the host pulmonary immune system.This analysis provides a theoretical foundation for the development of targeted therapeutics against bacterial respiratory infections.展开更多
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
基金C.I.received a fungal AMR innovations for LMICs:solutions and access for everyone(FAILSAFE)research grant cofunded by the UK Department of HealthSocial Care(DHSC)as part of the Global AMR Innovation Fund(GAMRIF).One Health UK aid fund that supports research and development around the world to reduce the threat of antimicrobial resistance(AMR)in humans,animals,and the environment for the benefit of people in lowand middle-income countries(LMICs).
文摘Six months after the United Nations General Assembly 2nd high-level meeting in 26 September 2024 to review the progress made at all levels to tackle antimicrobial resistance(AMR)and accelerate progress through One Health,Global AMR Innovation Fund(GAMRIF)summit 2025 was held with three aims:“to encourage and foster new collaboration between AMR research and development(R&D)stakeholders,to share learnings and best practices across the wide range of stakeholders,and to envision the future of AMR R&D”.The summit lasted for three days and began with an introduction and overview of the high-level commitment in AMR and the key global policy developments in 2024 and their implications for innovation R&D(http://globalamrhub.org/news/gamrif-summit-2025/).
基金the MOST Key Research and Development Program of China(grant number 2022YFC2304703)the Natural Science Foundation of China(grant number 32422004)+5 种基金The Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University(grant number 24X010301328)the Natural Science Foundation of China(grant number 32270202)the Computational Biology Program of Science and Technology Commission of Shanghai Municipality(STCSM)(grant number 25JS2810200)the MOST Key Research and Development Program of China(grant number 2020YFA0907200)Program of Shanghai Academic Research Leader(grant number 23XD1422300)Innovative research team of high-level local universities in Shanghai.All funding sources are attributed to N.N.L.
文摘Postoperative infection is a major global health concern,affecting 5%-10%of surgical patients and nearly doubling mortality in severe cases[1].Transplant recipients are particularly vulnerable,with 30%-80%developing infections within 30 days,often from opportunistic pathogens[2,3].Key risk factors include epidemiological exposure,net immunosuppression,age,transplant type,and surgical history[4].Despite known infection risks,current evidence remains transplantation type-specific and neglects behavioral modulators[5].Different types of transplantation may share similar risk factors[6].To identify common factors affecting postoperative infection,this study collected standardized clinical data-including diet,psychological response,medication use,and biochemical indicators-from liver and kidney transplant patients across six hospitals using a unified standard operating procedure(SOP).
基金the National Natural Science Foundation of China(grant number 32470151 to J.C.).
文摘Human endogenous retroviruses(HERVs)are remnants of ancient retroviral infections that have become permanently integrated into the human genome,collectively accounting for approximately 8%of the human DNA.A typical full-length HERV provirus consists of four primary genes:gag,pro,pol,and env,flanked by two long terminal repeats(LTRs).Although some of the HERV proviruses remain intact,the majority of HERVs have undergone truncation,insertions,deletions,or point mutations over evolutionary time.-Recent studies have revealed that epigenetic reprogramming,a hallmark of both cellular senescence and premature aging,can lead to the activation of HERVs[1].This reactivation has also been observed across a range of aging-related diseases,including immunosenescence,neurodegenerative diseases,and certain types of cancer.These findings suggest that HERVs may not only be consequences of aging but also active contributors to aging-related cellular dysfunction.In this perspective,we review emerging evidence linking HERVs to cellular senescence and aging-related diseases,highlight their potential utility as biomarkers and diagnostic indicators,and address both the opportunities and challenges in translating this knowledge into clinical applications.
基金funded by the External Cooperation Program of CAS(grant number 180GJHZ2023017MI)to G.F.G.
文摘The continuous evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)presents ongoing challenges and risks to public health,as it renders most reported monoclonal antibodies(mAbs)ineffective due to immune escape[1,2].Unlike conventional strategies that rely on conserved epitopes across known viral subtypes,the extraordinary pace and unpredictability of SARS-CoV-2 mutations have progressively eroded these epitopes,thereby destabilizing the foundations of traditional broadly neutralizing antibody(bnAb)development[3].
基金supported by grants from the National Natural Science Foundation of China (grant number 82301768 to H.Z.)the International Joint Laboratory on Tropical Diseases Control in Greater Mekong Subregion (grant number 21410750200 to X.L.)
文摘With the growing proportion of older adults globally,aging has emerged as a leading risk factor for a range of chronic diseases and mortality[1].This process is characterized by progressive degeneration and loss of function across multiple physiological systems[2].While chronological age is the most straightforward indicator of aging,the variability in aging across different organ systems[3]results in a wide variation in aging characteristics among individuals of the same chronological age[4,5].Recently,several promising DNA methylation(DNAm)-based algorithms(e,g.,HorvathAge,GrimAge,GrimAge2)have been developed to assess biological age by analyzing age-associated changes in DNAm patterns[6].These algorithms are now widely used in biological age assessment.Some of them have demonstrated robust predictive power for mortality and various age-related conditions[1].However,due to differences in objectives,meth-odologies,and tissue types used across these algorithms[6],it remains uncertain which tool best captures the true state of bio-logical aging.
基金support from the National Natural Science Foundation of China(grant numbers 22401281 and 22494631 to J.G.,22494633 and 22571304 to M.S.Y.)CAS President’s International Fellowship for Visiting Scientists(grant number 2024VBC0002 to K.O.and M.S.Y.)+1 种基金Fujian Provincial Natural Science Foundation of China(grant number 2024N0059 to M.S.Y.)the research fund of State Key Laboratory of Mesoscience and Engineering(grant number MESO-25-E04 to J.G.)。
文摘A NOBEL FOR METAL-ORGANIC FRAMEWORK The 2025 Nobel Prize in Chemistry was awarded to Susumu Kitagawa,Richard Robson,and Omar M.Yaghi for their groundbreaking contributions to the field of metal-organic frameworks(MOFs).These molecular-based crystalline porous materials,constructed by the coordination of metal nodes with organic ligands,possess precisely designed porous structures and tunable functionalities[1].
文摘Modern molecular biology began with the discovery of the DNA double helix,revealing the physical basis of genetics.Whereas genes carry genetic information in one-dimension,living cells'functional activities are performed by proteins in the form of three-dimensional structures.About 240,000 experimentally determined protein structures have been deposited in the Protein Data Bank(PDB).With the newly developed artificial intelligence(AI)tool Alpha Fold,essentially the whole protein universe has been reliably predicted.This perspective explores the genetic features of protein structures.
文摘Influenza viruses are a major cause of respiratory illness,with significant public health impact due to their ability to cause pandemics.This dialogue brought together experts including Professors George Fu Gao,Stephen Cusack,Mark von Itzstein,Ervin Fodor,Jonathan Grimes,Aartjan J.W.te Velthuis,and Tao Deng to decode the pressing scientific challenges and future directions in influenza research.They discussed how structural studies of the influenza polymerase have advanced our understanding of viral RNA transcription and replication.These insights are crucial for developing new antiviral drugs,with a particular focus on targeting the polymerase and its interactions with host factors like acidic nuclear phosphoprotein 32(ANP32).The dialogue also highlighted the potential of artificial intelligence(AI)to assist in designing small-molecule drugs,offering new strategies for combating influenza.Future research will continue to unravel the complexities of the polymerase’s role in replication,aiming to translate these findings into effective therapies and resilient public health strategies.
基金funded by the National Natural Science Foundation of China(grant numbers 32371244 and 92057118 to M.H.)the 2023 Shanghai Eastern Talent Plan Leading Project(to M.H.)+2 种基金supported by the innovative research team of high-level local universities in Shanghai(grant numbers SHSMUZDCX20212000 and SHSMU-ZDCX20211202 to M.H.)the Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases,and the Fundamental Research Funds for the Central Universities to M.H.labsupported by the Natural Science Foundation of Guangxi Zhuang Autonomous Region(grant number 2025GXNSFAA069105 to M.H.)。
文摘Exercise,as a non-pharmacological health intervention,has been widely recognized for its beneficial effects,yet its underlying molecular mechanisms remain incompletely understood.The duration,frequency,and intensity of exercise exert distinct physiological impacts on the human body[1].Notably,acute exercise(AE)primarily elicits immediate metabolic responses and immune activation to cope with environmental stimuli,whereas long-term exercise(LE)induces cumulative health benefits across multiple organ systems[2‒4].Aging represents a complex biological process that persists throughout the ontogenetic continuum and serves as a pivotal etiological determinant for numerous chronic pathologies.In the context of accelerating global demographic aging,the development of interventions to promote healthspan extension and modulate aging trajectories has become a paramount research imperative in geroscience.Currently,research on the relationship between exercise and aging is a hot topic.For example,exercise has been shown to modulate aging through pathways such as AMP-activated protein kinase(AMPK)[5].However,the precise molecular links remain elusive.In a recent breakthrough study,Geng et al.used a novel multi-omics strategy to pinpoint betaine,a glycine derivative from choline/diet that serves as both a hepatic methyl donor and a renal osmoprotectant,as a key exercise-induced molecule with anti-inflammatory and geroprotective effects mediated partially via TANK-binding kinase 1(TBK1)inhibition[6,7].This work represents a significant advance as it systematically maps the molecular divergence between acute and long-term exercise while establishing a direct link between renal metabolism and systemic senescence-delaying benefits.
文摘“The Dao begets One,One begets Two,Two begets Three,Three begets all things.”-The Tao-te Ching We are delighted to present the first issue of the fourth volume of hLife and would like to extend our heartfelt thanks to our global community for their strong support in the last three years.This moment signifies more than just a milestone in our calendar,it is an opportunity to unite our enduring scientific vision with our shared aspirations for universal health.Health,as defined by the World Health Organization(WHO)in 1948,encompasses a state of complete physical,mental,and social well-being and not merely the absence of disease or infirmity.In an era of interconnected challenges-from pandemics to psychosocial stressors-the integration of these three aspects is more critical than ever.
基金supported by the Capital’s Funds for Health Improvement and Research(grant number 2024-1G4421 to Y.T.)the National Key Research and Development Program of China(grant numbers 2024YFC2607500 and 2019YFC1200500 to J.J.)the National Natural Science Foundation of China(grant number U2002219 to J.J.).
文摘Bats are critical viral reservoirs that harbor viromes with high cross-species transmission risks,yet their virome diversity in the mainland Southeast Asia and adjacent regions remains underexplored.Here,we characterized the bat viromes from 659 samples(197 individuals,16 species)from Yunnan province and Guangxi Zhuang autonomous region,China,as well as from Cambodia,using next-generation sequencing(NGS).RNA sequencing,viral classification,phylogenetic analyses,and deep learning-based host adaptability analysis were performed to reveal the viral composition and cross-species transmission risks.We identified 137 viral strains,including 40 novel species spanning 18 families.Viral richness was highest in Vespertilionidae bats(12 viral families found)along China's southwestern border,where Middle Eastern respiratory syndrome(MERS)-like coronavirus(Co V)was found.Cambodian bat viruses were evolutionarily more distant from those of known viruses.A porcine epidemic diarrhea virus(PEDV)-related Co V was found in Cambodia,showing 90.36%genome homology with PEDV CV777 and exhibiting recombinant features between Suidae-adapted ORF1ab and Chiroptera-adapted Spike genes,suggesting that bats are the evolutionary source of PEDV.These findings illuminate the undercharacterized bat viral diversity in biogeographic transition zones and highlight the mainland Southeast Asia and adjacent regions as a hotspot for Co V recombination.We advocate for enhanced One Health-aligned surveillance targeting viral recombination hotspots and human±bat interfaces in this ecologically critical region.
基金funded by the National Key R&D Program of China (grant numbers 2021YFA0805800, 2023YFE0107700, and 2020YFA0803202 to R.J.)the 111 Project (grant number D18010 to R.J.)+3 种基金the National Natural Science Foundation of China (grant number 31970538 to R.J.)the Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (grant number JCXKJS2022A02 to R.J.)the Medical Scientific Research Foundation of Guangdong Province (grant number A2019292 to J.L.)the Natural Science Foundation of Guangdong Province (grant number 2017A030310403 to Z.D.)
文摘Trained immunity is essential for innate immune cells to retain a memory of previously encountered pathogens,strengthening the hosts’response against these pathogens.However,the mechanisms governing trained immunity have not been well elucidated.In this study,flies of different genotypes were trained with heat-killed gram-negative(G)bacteria and subsequently reinfected with live pathogens.The innate immune responses against reinfection were evaluated through assessments of survival rates,antimicrobial peptide expression levels,and bacterial loads,complemented by transcriptomic and chromatin immunoprecipitation(ChIP)analyses.We found that flies trained with heat-killed gram-negative bacteria exhibited a higher survival rate upon secondary infection compared to unprimed flies,which was associated with increased expression of antimicrobial peptides.Priming with Gbacteria increased the sensitivity of the immune deficiency pathway to a second bacterial infection owing to lower levels of peptidoglycan recognition protein SC(PGRP-SC)after the first infection.The gut was the major tissue involved in the downregulation of PGRP-SC expression.The histone H3 lysine 9 trimethylation(H3K9me3)levels were higher at the PGRP-SC loci in immune-trained flies compared to untrained flies,contributing to the suppression of PGRP-SC expression.PGRP-SC overexpression in the fly gut abolished the effect of trained immunity.Taken together,our studies identify an innate immune memory in Drosophila that is regulated by gut-derived PGRP-SC through H3K9me3-mediated epigenetic repression of the PGRP-SC.
基金the National Key Research and Development Program of China(grant number 2024YFC2510502 to W.S.)the National Natural Science Foundation of China(grant number 8217060280 to L.Y.)+2 种基金the Natural Science Foundation of Guang dong Province(grant number 2114050002084 to L.Y.)the Innovative Clinical Technique of Guangzhou(grant number 2023CGX01 to W.S.)the Science and Technology Key Project of Guangzhou(grant numbers 02102010037 to W.S.,SL2024A03J01319,SL2024A04J00240 to L.Y.).
文摘Accurate prediction and monitoring of acute graft-versus-host disease(aGVHD)remain challenging in allogeneic hematopoietic stem cell transplantation(allo-HSCT)as current diagnostic approaches rely on symptomatic presentation.Therefore,this study sought to identify predictive biomarkers and therapeutic targets for aGVHD through longitudinal immune monitoring and mechanistic investigations.In this study,peripheral blood samples were collected weekly for 100 days from a group of 115 allo-HSCT recipients.CD38^(+)HLA-DR^(+)CD8^(+)T(activated CD8^(+)T)cells were analyzed using the t-distributed stochastic neighbor embedding(t-SNE)algorithm for high-dimensional data visualization and population identification.Clinical data integration was used to assess biomarker utility.Mechanistic studies included interleukin-15(IL-15)stimulation,signaling pathway inhibition,cytotoxicity assays,and xenogeneic GVHD modeling with anti-CD38(daratumumab)intervention.Our results revealed that sustained elevation of activated CD8^(+)T cells(>36.6%)within the first month post-transplantation predicted aGVHD onset with high accuracy(AUC=0.84,P<0.001).Cell frequency dynamically correlated with treatment outcome,decreasing substantially in responders.Mechanistically,IL-15 drove T-cell receptor(TCR)-independent cytotoxicity via PI3K/mTOR activation,mediated by natural killer group 2D(NKG2D)and major histocompatibility complex class I chain related proteins A(MIC-α)interactions,validated by reduced K562 cell lysis following antibody blockade.In an 8-10-week-old NSG mouse model for xenogeneic transplantation,treatment with daratumumab(5 mg/kg)effectively lowered histopathological damage and increased survival.In conclusion,activated CD8+T cells can serve as dual-purpose biomarkers for early aGVHD prediction and treatment monitoring.Their IL-15-driven cytotoxicity represents a targetable pathway,with daratumumab demonstrating therapeutic efficacy.
基金supported by the National Natural Science Foundation of China(grant number 82373515 to J.L.).
文摘Radiation-induced lung injury(RILI)is a common complication of radiotherapy.Although berberine(BBR)has been suggested to be associated with reduced RILI incidence,the underlying mechanisms remain unknown.Here,we investigated whether the gut microbiota mediates the radioprotective effects of BBR using a C57BL/6 RILI mouse model with 20 Gy thoracic irradiation(n=6 per group).BBR(100 mg/kg)and inosine(INO,300 mg/kg)were administered orally in vivo.Antibiotic depletion and fecal microbiota transplantation were performed to assess microbiota dependence.Lung injury was assessed by histology,pulmonary function,and cytokine levels.Gut microbiota was analyzed by 16S rRNA sequencing,and metabolites were profiled using LC-MS/MS.Transcriptomic and epigenomic alterations were assessed by RNA sequencing,ATAC sequencing,and CUT&Tag analysis.Molecular docking and surface plasmon resonance were used to assess metabolite-protein interactions.We demonstrated that BBR alleviated RILI in a microbiota-dependent manner.BBR increased Akkermansia muciniphila abundance and metabolite INO levels.Mechanistically,INO was associated with reduced neuron navigator 3(NAV3)expression,accompanied by decreased chromatin accessibility and increased histone H3 lysine 27 trimethylation(H3K27me3)at the NAV3 locus.Together,these findings reveal a gut microbiota-mediated mechanism underlying BBR-mediated protection against RILI,and suggest microbiota-informed biomarkers for risk stratification.
基金supported by the National Natural Science Foundation of China(grant numbers 82272333 to G.L.and 32100114 to F.Y.)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(grant number ZYGD23022 to G.L.)the National Postdoctoral Program for Innovative Talents of China(grant number BX20230243 to S.L.)。
文摘Rabies,a persistent and historic global zoonosis,continues to impose a significant public health burden,particularly in resource-limited regions.The causative agent,rabies virus(RABV;genus Lyssavirus,family Rhabdoviridae),possesses a surface glycoprotein(G)that is pivotal for virus entry and pathogenesis.Rabies virus glycoprotein(RABV-G)mediates binding to host cell receptor(s)and acidic-pH-dependent membrane fusion,enabling the release of RNA genome into the host cytoplasm.It is also the main target for neutralizing antibodies and the major component of rabies vaccines.In this review,we systematically summarize the structural features,functional mechanisms,and antiviral targeting strategies of RABV-G,emphasizing recent structural insights into its conformational dynamics.Key neutralizing epitopes and their recognition by monoclonal antibodies are discussed,along with antiviral strategies,including entry inhibitors,antibody therapies,and advanced vaccine platforms.Accumulating structural analyses indicate that the pH-dependent and reversible conformational transitions of this classⅢviral fusion protein underlie both viral infectivity and vulnerability to immune intervention.Collectively,available data establish that neutralizing epitopes on RABV-G are conformationally defined and dynamically regulated during fusion,thereby constraining viral entry and dictating the effectiveness of antibody-and entry inhibitor–mediated neutralization.Together,these findings establish RABV-G as the primary determinant of rabies virus virulence and immune control.By exploring the structural framework and prospective treatment modalities,we aim to enhance our understanding of rabies virus,particularly the glycoprotein G,and support ongoing initiatives to alleviate the burden of rabies,offering renewed optimism in the battle against this formidable infectious disease.
基金supported by grants from Prevention and Control of Emerging and Major Infectious Diseases-National Science and Technology Major Project(grant number 2025ZD01903602 to L.Z.)Shandong Provincial Natural Science Foundation(grant number ZR2024MH017 to L.Z.)+2 种基金National Natural Science Foundation of China(grant numbers 82272306 and 82072270 to L.Z.)Taishan Scholars Program(grant number tstp20221142 to L.Z.)Joint Innovation Team for Clinical&Basic Research(grant number 202409 to L.Z.)。
文摘Chikungunya virus(CHIKV)infection induces the formation of migrasomes,yet their specific role in CHIKV pathogenesis remains unclear.This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25(CHIKV 181/25)and the role of migrasomes in mitigating this damage.Using cultured cell lines,we assessed the impact of CHIKV infection on mitochondrial integrity and function,with particular emphasis on the viroporin proteins transframe(TF)and 6K.We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria.Additionally,calcium imaging assays were conducted to evaluate intracellular calcium levels,and RNA sequencing was performed to examine gene expression.Our results demonstrated that CHIKV infection leads to mitochondrial damage,mediated by the action of TF and 6K.Notably,migrasomes induced by nonstructural protein 1(nsP1)effectively clearing impaired mitochondria through mitocytosis.Furthermore,we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels.Importantly,R37 within TF from other alphaviruses is also critical for mitochondrial damage.In conclusion,our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction,positioning migrasomes as potential mediators in alleviating CHIKVinduced mitochondrial damage.
基金supported by the MOST Key R&D Program of China(grant number 2022YFC2303500 to X.H.)the National Natural Science Foundation of China(grant numbers 32570236,32170195,and 32311530119 to C.C.and 32470200 to X.H.)+1 种基金Shanghai Science and Technology Innovation Action Plan 2023“Basic Research Project”(grant number 23JC1404200 to C.C.)the Foundation of State Key Laboratory of Pathogen and Biosecurity(grant number SKLPBS2236 to C.C.).
文摘Human fungal infections represent a rapidly emerging global health threat,especially threatening immunocompromised populations,highlighting the urgent need for accurate and timely diagnostic approaches to reduce morbidity and mortality.This review synthesizes recent advances in diagnostic methodologies,including serological assays,point-of-care diagnostics,polymerase chain reaction(PCR)-based and sequencing technologies,as well as artificial intelligence(AI)-and machine learning(ML)-powered tools.Emerging diagnostic approaches have demonstrated notable improvements in detection accuracy,turnaround time,and antifungal resistance profiling capabilities,especially for drug-resistant strains.Nevertheless,substantial challenges persist in terms of standardization,scalability,cost-effectiveness,and implementation,particularly in resource-constrained settings.Future efforts should be directed toward the continuous innovation of rapid,sensitive,and multiplex diagnostic platforms for the simultaneous detection of fungi,bacteria,and viruses.Such advances may accelerate result acquisition,enhance diagnostic accuracy,support the development of more targeted therapeutic strategies,and ultimately improve clinical outcomes for patients.
基金supported by the National Key Research and Development Program of China(grant number 2021YFD1800100 to N.Z.)the National Natural Science Foundation of China(grant number 32172871 to N.Z.)+1 种基金the 2115 Talent Development Program of China Agricultural University to N.Zsupported by High-performance Computing Platform of China Agricultural University。
文摘The high polymorphism of histocompatibility complex class Ⅱ(MHC-Ⅱ)alleles and limited immunopeptidomic data hinder pan-species epitope prediction.In this study,leveraging the predictive power of AlphaFold(AF)and the conserved structural features of the core region of MHC-Ⅱ-binding peptides,derived from a comprehensive analysis of MHC-Ⅱ structure data in the PDB database,we developed a new tool,AF-prediction(AF-pred),with explicit quantitative criteria for MHC-Ⅱ-restricted epitope prediction.We validated AF-pred across human,porcine,bovine,and bat MHC-Ⅱ molecules through large-scale in silico analyses using known immunopeptidome datasets(1000 positive and 1000 negative antigenic peptides),together with in vitro binding assays and crystallographic characterization of newly predicted epitopes.Using uncharacterized bat MHC-Ⅱ structures,we demonstrated that AF-pred’s amino-acid interaction prediction underpins its pan-prediction capability and the underlying rationale of the method.Conversely,this characteristic limits the prediction of atypical MHC-Ⅱ peptide-binding modes.Compared with sequence-based tools,AF-pred demonstrates enhanced cross-species MHC-Ⅱ binding prediction,with higher accuracy and interpretability,and further reveals that iterative AF updates improve AF-pred performance.AF-pred has the potential to facilitate the development of novel T-cell epitope vaccines and advance the“One Health”initiative.
基金supported by the National Key R&D Program of China (grant number 2023YFC2306204)Natural Science Foundation of China (grant numbers 92569301, 82595923, U25A20654)+1 种基金Beijing Natural Science Foundation (grant number JQ24043)CAS Project for Young Scientists in Basic Research (grant number YSBR-010) to S.W
文摘The local immune system of the lungs is essential for the defense against pathogens,and respiratory bacterial infections remain a major cause of mortality in patients with lower respiratory tract diseases.However,the precise mechanisms underlying immune-pathogen interactions and the modulatory roles of commensal bacteria remain incompletely understood.This review discusses the mechanisms of immune recognition and inflammatory responses during bacterial respiratory bacterial infections,highlighting the importance of pattern recognition receptors,including toll-like receptors,nucleotide oligomerization domain-like receptors,and C-type lectin receptors in detecting pathogens and triggering immune signaling pathways.We also explore how commensal bacteria influence the respiratory immune microenvironment and discuss the complex interplay among pathogenic bacteria,commensals,and the host pulmonary immune system.This analysis provides a theoretical foundation for the development of targeted therapeutics against bacterial respiratory infections.
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.
