Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifyi...Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.展开更多
The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of famil...The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.展开更多
Respiratory infectious diseases frequently erupt on a global scale,with RNA viruses,such as SARS-CoV-2,RSV,and influenza viruses,posing challenges to vaccine development due to their high mutation rates.Traditional va...Respiratory infectious diseases frequently erupt on a global scale,with RNA viruses,such as SARS-CoV-2,RSV,and influenza viruses,posing challenges to vaccine development due to their high mutation rates.Traditional vaccine development cycles are lengthy and struggle to keep pace with rapidly evolving viruses,whereas messenger RNA(mRNA)vaccines have demonstrated significant advantages due to their short development periods,straightforward production,and low costs.After the outbreak of the COVID-19 pandemic,multiple mRNA vaccines,including Pfizer-BioNTech and Moderna,rapidly received emergency use authorization,validating their feasibility.The Nobel Prize in Physiology or Medicine in 2023 was awarded to Katalin Karikóand Drew Weissman,underscoring the efficacy of mRNA vaccine technology.In 2024,the U.S.Food and Drug Administration(FDA)approval of Moderna's respiratory syncytial virus(RSV)mRNA vaccine marked the immense potential of mRNA technology in vaccine innovation.This review article summarizes the design,clinical research,and future challenges of mRNA vaccines for respiratory viruses,delving into antigen design,mRNA delivery systems,and advancements in vaccines for multiple respiratory viruses,including innovations in self-amplifying mRNA and circular mRNA vaccines.Additionally,the development of combination vaccines is underway,aiming to provide protection against multiple viruses through a single administration.Despite the significant progress in mRNA vaccine development,challenges remain regarding raw material costs,stability,and delivery efficiency.In the future,with technological advancements and the accumulation of clinical experience,the design strategies and delivery systems of mRNA vaccines are expected to be continuously optimized,thereby enhancing their safety and efficacy.展开更多
The World Health Organization has declared that COVID-19 no longer constitutes a“public health emergency of international concern,”yet the long-term impact of SARSCoV-2 infection on bone health continues to pose new...The World Health Organization has declared that COVID-19 no longer constitutes a“public health emergency of international concern,”yet the long-term impact of SARSCoV-2 infection on bone health continues to pose new challenges for global public health.In recent years,numerous animal model and clinical studies have revealed that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can lead to secondary osteoporosis.The mechanisms involved are related to the virus's direct effects on bone tissue,dysregulation of the body's inflammatory response,hypoxia,noncoding RNA imbalance,and metabolic abnormalities.Although these studies have unveiled the connection between SARS-CoV-2 infection and osteoporosis,current research is not comprehensive and in depth.Future studies are needed to evaluate the long-term effects of SARS-CoV-2 on bone density and metabolism,elucidate the specific mechanisms of pathogenesis,and explore potential interventions.This review aims to collate existing research literature on SARS-CoV-2 infection-induced secondary osteoporosis,summarize the underlying mechanisms,and provide direction for future research.展开更多
BACKGROUND Autoimmune liver diseases,including primary biliary cholangitis(PBC),autoi-mmune hepatitis(AIH),and their overlap syndrome(OS),involve immune-mediated liver injury,with OS occurring in 1.2%-25%of PBC patien...BACKGROUND Autoimmune liver diseases,including primary biliary cholangitis(PBC),autoi-mmune hepatitis(AIH),and their overlap syndrome(OS),involve immune-mediated liver injury,with OS occurring in 1.2%-25%of PBC patients.OS carries a higher risk of cirrhosis,hepatocellular carcinoma,and reduced survival.While its pathogenesis remains unclear,gut microbiota dysbiosis and serum metabolite alterations may play key roles.This study uses 16S rRNA sequencing and liquid chromatography-mass spec-trometry(LC-MS)metabolomics to compare gut microbiota and serum metabolites among PBC,AIH,and OS patients,and explores their associations with liver function.AIM To differentiate OS from PBC and AIH based on gut microbiota,serum metabolites,and liver function.METHODS Gut microbiota profiles were analyzed using 16S rRNA sequencing,while untargeted serum metabolomics was conducted via LC-MS.Comparative analyses were performed to identify differences in microbial composition and serum metabolite levels among PBC,AIH,and OS groups.Correlation analyses and network visualization tech-niques were applied to elucidate the interactions among liver function parameters,gut microbiota,and serum metabolites in OS patients.RESULTS Compared to patients with PBC or AIH,OS patients demonstrated significantly reduced microbial diversity and richness.Notable taxonomic shifts included decreased abundances of Firmicutes,Bacteroidetes,and Actinobacteria,alongside increased levels of Proteobacteria and Verrucomicrobia.Distinct serum metabolites,such as pentadecanoic acid and aminoimidazole carboxamide ribonucleotide,were identified in OS patients.Correlation analysis revealed that aspartate aminotransferase(AST)levels were negatively associated with the bacterial genus Fusicatenibacter and the metabolite L-Tyrosine.A microbial-metabolite network diagram further confirmed a strong association between Fusicatenibacter and L-Tyrosine in OS patients.CONCLUSION OS patients show decreased gut microbiota diversity and unique serum metabolites.Multi-omics linked AST,Fusicatenibacter,and L-Tyrosine,revealing OS mechanisms and diagnostic potential.展开更多
Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising f...Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising from the neuroectoderm,microglia are derived from erythromyeloid progenitors in the embryonic yolk sac[2].展开更多
Autism Spectrum Disorders(ASDs)are reported as a group of neurodevelopmental disorders.The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with ...Autism Spectrum Disorders(ASDs)are reported as a group of neurodevelopmental disorders.The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes,but the underlying mechanisms are not fully understood.Here,we report that deletion of Trio,a high-susceptibility gene of ASDs,causes a postnatal dentate gyrus(DG)hypoplasia with a zigzagged suprapyramidal blade,and the Trio-defcient mice display autism-like behaviors.The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells(GCs),which further results in a migration defcit of neural progenitors.Furthermore,we reveal that Trio plays diferent roles in various excitatory neural cells by spatial transcriptomic sequencing,especially the role of regulating the migration of postmitotic GCs.In summary,our fndings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.展开更多
Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exh...Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exhibit a reduced risk of developing cancer and vice versa.However,the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.Methods:To this end,we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane.We visualized and quantified surface lung tumor colonies,assessed pathological parameters associated with lung cancer and AD using histopathological analysis,and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.Results:Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type(WT)group.The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress.Moreover,greater CD8^(+)T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8^(+)T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.Conclusion:This study identified essential mechanisms through which AD suppresses lung tumorigenesis,thereby providing targets for potential therapeutic interventions in these diseases.展开更多
Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have ...Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.展开更多
Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a...Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a large proportion and play roles as key regulators in a variety of functions,ranging from immune-mediated tumor killing to tumor immune evasion.Understanding the heterogeneity of TIMs will provide valuable insights for new therapeutic targeting of myeloid cells.Single-cell genomic technologies deciphering cell composition and gene expression at single-cell resolution have largely improved our understanding of the cellular heterogeneity of TIMs and highlighted several novel cell subtypes contributing to the variation of patient survival and treatment response.However,these cell subtypes were defined based on limited data without a concordant nomenclature,which makes it difficult to understand whether they exist in different studies.Thus,in this review,we comprehensively summarized the common agreements and current different opinions on the heterogeneity of TIMs gained from single-cell studies;evaluated the feasibility of current myeloid cell targets at single-cell level and proposed a uniform nomenclature for TIM subsets.展开更多
As of December 2022,2603 laboratory-identified Middle East respiratory syndrome coronavirus(MERS-CoV)infections and 935 associated deaths,with a mortality rate of 36%,had been reported to the World Health Organization...As of December 2022,2603 laboratory-identified Middle East respiratory syndrome coronavirus(MERS-CoV)infections and 935 associated deaths,with a mortality rate of 36%,had been reported to the World Health Organization(WHO).However,there are still no vaccines for MERS-CoV,which makes the prevention and control of MERS-CoV difficult.In this study,we generated two DNA vaccine candidates by integrating MERS-CoV Spike(S)gene into a replicating Vaccinia Tian Tan(VTT)vector.Compared to homologous immunization with either vaccine,mice immunized with DNA vaccine prime and VTT vaccine boost exhibited much stronger and durable humoral and cellular immune responses.The immunized mice produced robust binding antibodies and broad neutralizing antibodies against the EMC2012,England1 and KNIH strains of MERS-CoV.Prime-Boost immunization also induced strong MERS-S specific T cells responses,with high memory and poly-functional(CD107a-IFN-γ-TNF-α)effector CD8t T cells.In conclusion,the research demonstrated that DNA-Prime/VTT-Boost strategy could elicit robust and balanced humoral and cellular immune responses against MERS-CoV-S.This study not only provides a promising set of MERS-CoV vaccine candidates,but also proposes a heterologous sequential immunization strategy worthy of further development.展开更多
Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-assoc...Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may involve the induction of central and peripheral lipid metabolism disorders.Therefore,modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression.This study also provided a better animal model for studying AD comorbid with depression.展开更多
Background:The number of medical research publications by Chinese clinical investigators has risen substantially,contributing to 14.63%of the global total in 2019;however,their tangible impact on clinical decisionmaki...Background:The number of medical research publications by Chinese clinical investigators has risen substantially,contributing to 14.63%of the global total in 2019;however,their tangible impact on clinical decisionmaking remains limited.Various evaluation methods have been developed to measure hospital research competence in China,such as Fudan University's China hospital ranking and Science and Technology Evaluation Metrics(STEM)ranking,which predominantly focuses on factors such as academic reputation,volume of publications and patents,and research resources.However,composite indices may not fully capture the actual clinical value generated by medical research.To address this gap,we introduced the“Clinical Influence and Timeliness Evaluation(CITE)”metric to assess both the clinical importance of a given medical research study and the clinical influence of the hospital where it originated.The methodology used relies on the premise that influential medical research would be referenced in clinical guidelines,which serve as critical resources for clinicians.Methods:The CITE metric was applied for 78,636 medical studies concerning chronic obstructive pulmonary disease(COPD)published between 2000 and 2020 and referenced in both Chinese and international clinical guidelines for COPD.Specific indexes and formulas were derived to quantify the clinical weight of a medical research study(W)and its timeliness(T),enabling a dynamic assessment of the clinical value of each study and the overall contribution of a particular hospital.Results:In this analysis,we incorporated 499 hospitals in China and quantitatively identified their dynamic clinical influence in COPD from 2000 to 2020.Our findings offer objective and targeted evaluation metrics by focusing on clinical relevance and recognizing the collaborative nature of medical research.Conclusion:The CITE metric provides an innovative method to gauge the true impact of medical research in China,with potential applications across different medical specialties.CITE can serve as a useful tool for understanding the relationship between research input and practical clinical outcomes,ultimately promoting more clinically relevant research endeavors.展开更多
Innate immunity in host cells must be rapidly activated to combat invading microbes.Upon RIG-I activation,the transcription of type I interferons is induced within one hour in virus-infected cells.Previous studies hav...Innate immunity in host cells must be rapidly activated to combat invading microbes.Upon RIG-I activation,the transcription of type I interferons is induced within one hour in virus-infected cells.Previous studies have shown that endogenous MAVS spreads signals via aggregation on the mitochondrial membrane,whereas truncated recombinant MAVS forms prion-like filaments in vitro.How MAVS transmits signals so quickly,and the molecular architecture of its membrane aggregates,remains elusive.Here,we report that activated MAVS forms fibrils encircling its resident mitochondrion or connecting neighboring mitochondria with a“ladder-like”structure,allowing the activation of dormant MAVS on encountered mitochondria.This“intermitochondrial activation”process promotes a rapid antiviral response in cells to overcome the immediate danger caused by viruses.Moreover,stuck MAVS fibrils between mitochondria have limited cytosolic protein access and thus relay signals poorly.This study demonstrated that prion-like MAVS fibrils cluster in mitochondria to ensure a rapid antiviral response.展开更多
Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is re...Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.Methods:In this study,the dataset GSE132903 was retrieved from the GEO database,encompassing both non-demented(ND)control and AD samples.Through the combination of differential expression gene analysis,weighted gene co-expression network analysis,and intersection with mitochondrial database gene sets,four hub genes associated with AD were identified.These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.Results:The hub genes identified through bioinformatics analysis include SYNJ2BP,VDAC1,NUBPL,and COX19.Within the GSE132903 dataset,the expression levels of SYNJ2BP,NUBPL,and COX19 were significantly elevated in the AD group compared to the non-demented(ND)group,whereas VDAC1 expression was reduced in the AD group relative to the ND group.Furthermore,in the hippocampus of APP/PS1 and 5xFAD mouse models,the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.Conclusion:Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.展开更多
Understanding the acid resistance mechanism of S.mutans is crucial for preventing dental caries.FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis.Our previou...Understanding the acid resistance mechanism of S.mutans is crucial for preventing dental caries.FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis.Our previous study revealed that the FtsZ in S.mutans(SmFtsZ) has higher self-assembly and GTPase activity under acidic stress,which may be responsible for acid resistance and ca riogenesis of S.mutans.However,the functional structure mechanism of SmFtsZ under low pH conditions is still unclear.Here,we further reported the crystal structure of S.mutans FtsZ,revealing a unique lateral interface.Through protein polymerization and GTPase activity assay,we experimentally demonstrated that the mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment.The phenotype assay and rat caries model further showed that the mutation of Arg68 effectively inhibited the acid resistance of S.mutans and the occurrence and progress of dental caries in vivo.By employing a molecular dynamics simulation analysis,we conclude that the mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions.Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S.mutans in acidic environments.展开更多
In the third line of the second paragraph of Section 2.1,“Gaff2”should be“GAFF2”.There is no space between“atomsto”in the first sentence of the last paragraph of Section 2.2.It should be“First,the initial struc...In the third line of the second paragraph of Section 2.1,“Gaff2”should be“GAFF2”.There is no space between“atomsto”in the first sentence of the last paragraph of Section 2.2.It should be“First,the initial structure underwent pre-equilibration by restraining Cαatoms to eliminate unreasonable interactions”.The unit of the last sentence of the first paragraph of Section 2.3 is wrong.It should be“Three independent simulations were run for each system,so 3×500 ns MD simulations at 350 K were performed”.展开更多
T-cell immunotherapy has progressed rapidly,evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer.This review explores eng...T-cell immunotherapy has progressed rapidly,evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer.This review explores engineering strategies,ranging from natural TCRs to synthetic receptors,that increase T-cell activation and therapeutic potential.We begin by highlighting the foundational role of native receptors in the T-cell response,emphasizing how these structural and functional insights inform the design of next-generation synthetic receptors.Comparisons between CAR and TCR-like synthetic receptors underscore their respective advantages in specificity,efficacy,and safety,as well as potential areas for further improvement.In addition,gene editing technologies such as CRISPR-Cas9 enable precise modifications to the T-cell genome,enhancing receptor performance and minimizing immunogenic risks.In addition to tumors,these engineered T cells can be directed against viral infections,autoimmune disorders,and other diseases.We also explore advanced strategies that engage multiple immune cell types to achieve synergistic,durable responses.By demonstrating how native and synthetic receptors collectively drive innovation,this review aims to inspire new research directions and ultimately expand the scope of T-cell engineering for universal therapeutic applications.展开更多
Cancer immunotherapy is a groundbreaking therapeutic strategy,yet it continues to face significant challenges,including limited overall response rates and treatment resistance.Emerging research has demonstrated the pi...Cancer immunotherapy is a groundbreaking therapeutic strategy,yet it continues to face significant challenges,including limited overall response rates and treatment resistance.Emerging research has demonstrated the pivotal role of epigenetic modifications in tumor immune evasion,providing a strong rationale for developing“epi‐immunotherapy”—an innovative approach that combines epigenetic therapy with immunotherapy.This comprehensive review systematically examines how epigenetic regulation mediates tumor immune escape and the mechanisms involved,including suppression of tumor antigen expression and antigen presentation,upregulation of immune checkpoint molecules,inhibition of antitumor immune cell recruitment and function,and enhancement of immunosuppressive cell proliferation and activity.By integrating epigenetic modulation with immunotherapeutic strategies,epi‐immunotherapy demonstrates a remarkable ability to enhance treatment efficacy and reverse therapeutic resistance.We also summarize the current clinical applications of epi‐immunotherapy in both hematological malignancies and solid tumors,with particular emphasis on its mechanisms for overcoming immune checkpoint inhibitor resistance and converting immunologically“cold”tumors into“hot”tumors.Despite its promising potential,epiimmunotherapy faces several challenges that require urgent resolution.This review provides an in‐depth analysis of these limitations,which include the complexity of epigenetic regulation,a lack of reliable biomarkers,and constraints in drug development.As our understanding of epigenetic mechanisms deepens and technologies continue to advance,epiimmunotherapy is poised to become an essential component of cancer treatment,offering patients more effective and personalized therapeutic options.展开更多
Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells.While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activ...Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells.While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activation,recent advancements in antigen discovery and vaccine platform engineering have revitalized the field.This review provides a comprehensive overview of key tumor antigens,including tumor-associated antigens,viral oncoprotein antigens,neoantigens,and cryptic antigens,with a focus on their immunogenicity and therapeutic potential.Advances in our understanding of traditional cancer vaccination targets,in conjunction with the timely identification of novel antigen epitopes,have facilitated the strategic selection of vaccination targets.We also discuss the evolution of cancer vaccine platforms—spanning peptide-based formulations to advanced mRNA vectors—emphasizing innovative strategies to optimize antigen delivery efficiency and adjuvant effects.Efficient antigen delivery and adjuvant selection overcome immune tolerance and tumor-induced immunosuppression.Furthermore,we examine recent clinical trial data and emerging combination approaches that integrate cancer vaccines with other immunotherapies to increase efficacy.While significant progress has been made,challenges remain in improving vaccine-induced T-cell responses,overcoming immune suppression,and translating these advances into effective clinical interventions.Addressing these hurdles will be critical for realizing the full potential of cancer vaccines in immunotherapy.展开更多
文摘Objective:Clinical use of stimulator of interferon genes(STING)agonists has challenges due to poor responsiveness and variable efficacy.Therefore,identifying tumor types that are sensitive to these agents and clarifying the underlying mechanisms are essential.Methods:In vitro screening was performed to identify tumor types that are sensitive to STING agonists.The non-nucleotide agonist,SR-717,and the macrocyclic agonist,E7766,were compared for efficacy.Complementary in vivo and in vitro studies,including gene-knockout models,HMGN2-knockout Neuro-2A and CT-2A cells apoptosis assays,and murine tumor models,were then performed.These experiments focused on the mechanism by which SR-717 mediates antitumor effects and emphasized the role of STING signaling-induced high-mobility group nucleosome-binding protein 2(HMGN2).In addition,the potential of HMGN2 as a prognostic biomarker was assessed.Results:Neuroblastomas and glioblastomas,two nervous system tumors,were shown to be sensitive to STING agonists.SR-717 exhibited greater antitumor efficacy compared to E7766.Mechanistic studies indicated that STING agonists promote apoptosis through activation of the intrinsic STING-signal transducer and activator of transcription 1(STAT1)-HMGN2 axis within tumor cells.Ectopic expression of HMGN2 in melanoma cells,which naturally lack HMGN2,led to significant apoptosis.Furthermore,analysis of The Cancer Genome Atlas and Gene Expression Omnibus databases revealed positive correlation between elevated HMGN2 expression and patient survival,supporting the utility of HMGN2 as a prognostic biomarker.Conclusions:This study clarified the mechanism underlying the potent antitumor activity of SR-717 in nervous system tumors through activation of the STING-STAT1-HMGN2 signaling pathway and demonstrated that SR-717 has superior efficacy compared to E7766.In addition,HMGN2 was shown to exhibit translational potential as a prognostic biomarker for patient survival.
基金supported by the Natural Science Foundation of Beijing,Nos.7244428(to WZ)and 7222215(to JH)the Peking University Medicine Sailing Program forYoung Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+4 种基金the National Natural Science Foundation of China,Nos.81873784,82071426(to DF),and81974197(to JH)the Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(to DF)Beijing Physician-Scientist TrainingProgram,No.BJPSTP-2024-03(to JH)the China Postdoctoral Science Foundation,Nos.2022TQ0014(to LX),2022M720284(to LX)the E-Town Cooperation&Development Foundation,No.YCXJ-JZ-2023-017(to LX).
文摘The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.
基金Grants from the Ministry of Science and Technology of the People's Republic of China,Grant/Award Number:2021YFA1300301 and 2018YFA0507101National Natural Science Foundation of China,Grant/Award Number:31730054 and 31770900Beijing Natural Science Foundation,Grant/Award Number:5212016。
文摘Respiratory infectious diseases frequently erupt on a global scale,with RNA viruses,such as SARS-CoV-2,RSV,and influenza viruses,posing challenges to vaccine development due to their high mutation rates.Traditional vaccine development cycles are lengthy and struggle to keep pace with rapidly evolving viruses,whereas messenger RNA(mRNA)vaccines have demonstrated significant advantages due to their short development periods,straightforward production,and low costs.After the outbreak of the COVID-19 pandemic,multiple mRNA vaccines,including Pfizer-BioNTech and Moderna,rapidly received emergency use authorization,validating their feasibility.The Nobel Prize in Physiology or Medicine in 2023 was awarded to Katalin Karikóand Drew Weissman,underscoring the efficacy of mRNA vaccine technology.In 2024,the U.S.Food and Drug Administration(FDA)approval of Moderna's respiratory syncytial virus(RSV)mRNA vaccine marked the immense potential of mRNA technology in vaccine innovation.This review article summarizes the design,clinical research,and future challenges of mRNA vaccines for respiratory viruses,delving into antigen design,mRNA delivery systems,and advancements in vaccines for multiple respiratory viruses,including innovations in self-amplifying mRNA and circular mRNA vaccines.Additionally,the development of combination vaccines is underway,aiming to provide protection against multiple viruses through a single administration.Despite the significant progress in mRNA vaccine development,challenges remain regarding raw material costs,stability,and delivery efficiency.In the future,with technological advancements and the accumulation of clinical experience,the design strategies and delivery systems of mRNA vaccines are expected to be continuously optimized,thereby enhancing their safety and efficacy.
基金State Key Laboratory Special FundGrant/Award Number:2060204+5 种基金Key-Area Research and Development Program of Guangdong ProvinceGrant/Award Number:2022B1111020005Chinese Academy of Medical Sciences Innovation Fund for Medical SciencesGrant/Award Number:2021-I2M-1-034,2023-I2M-2-001The Foundation for Innovative Research Groups of the National Natural Science Foundation of ChinaGrant/Award Number:82221004。
文摘The World Health Organization has declared that COVID-19 no longer constitutes a“public health emergency of international concern,”yet the long-term impact of SARSCoV-2 infection on bone health continues to pose new challenges for global public health.In recent years,numerous animal model and clinical studies have revealed that severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection can lead to secondary osteoporosis.The mechanisms involved are related to the virus's direct effects on bone tissue,dysregulation of the body's inflammatory response,hypoxia,noncoding RNA imbalance,and metabolic abnormalities.Although these studies have unveiled the connection between SARS-CoV-2 infection and osteoporosis,current research is not comprehensive and in depth.Future studies are needed to evaluate the long-term effects of SARS-CoV-2 on bone density and metabolism,elucidate the specific mechanisms of pathogenesis,and explore potential interventions.This review aims to collate existing research literature on SARS-CoV-2 infection-induced secondary osteoporosis,summarize the underlying mechanisms,and provide direction for future research.
基金Supported by WBE Liver Foundation,No.WBE20220182022 Young and Middle-aged Talents Incubation Project(Youth Innovation)of Beijing Youan Hospital,Capital Medical University,No.BJYAYY-YN-2022-092023 Young and Middle-aged Talents Incubation Project(Youth Innovation)of Beijing Youan Hospital,Capital Medical University,No.BJYAYYYN2023-14.
文摘BACKGROUND Autoimmune liver diseases,including primary biliary cholangitis(PBC),autoi-mmune hepatitis(AIH),and their overlap syndrome(OS),involve immune-mediated liver injury,with OS occurring in 1.2%-25%of PBC patients.OS carries a higher risk of cirrhosis,hepatocellular carcinoma,and reduced survival.While its pathogenesis remains unclear,gut microbiota dysbiosis and serum metabolite alterations may play key roles.This study uses 16S rRNA sequencing and liquid chromatography-mass spec-trometry(LC-MS)metabolomics to compare gut microbiota and serum metabolites among PBC,AIH,and OS patients,and explores their associations with liver function.AIM To differentiate OS from PBC and AIH based on gut microbiota,serum metabolites,and liver function.METHODS Gut microbiota profiles were analyzed using 16S rRNA sequencing,while untargeted serum metabolomics was conducted via LC-MS.Comparative analyses were performed to identify differences in microbial composition and serum metabolite levels among PBC,AIH,and OS groups.Correlation analyses and network visualization tech-niques were applied to elucidate the interactions among liver function parameters,gut microbiota,and serum metabolites in OS patients.RESULTS Compared to patients with PBC or AIH,OS patients demonstrated significantly reduced microbial diversity and richness.Notable taxonomic shifts included decreased abundances of Firmicutes,Bacteroidetes,and Actinobacteria,alongside increased levels of Proteobacteria and Verrucomicrobia.Distinct serum metabolites,such as pentadecanoic acid and aminoimidazole carboxamide ribonucleotide,were identified in OS patients.Correlation analysis revealed that aspartate aminotransferase(AST)levels were negatively associated with the bacterial genus Fusicatenibacter and the metabolite L-Tyrosine.A microbial-metabolite network diagram further confirmed a strong association between Fusicatenibacter and L-Tyrosine in OS patients.CONCLUSION OS patients show decreased gut microbiota diversity and unique serum metabolites.Multi-omics linked AST,Fusicatenibacter,and L-Tyrosine,revealing OS mechanisms and diagnostic potential.
基金supported in part by National Science and Technology Major Project of National Health Commission of China(2023ZD0520300)the National Natural Science Foundation of China(32130037 and 32370953)the Tsinghua University Initiative Scientific Research Program,SXMU-Tsinghua Collaborative Innovation Center for Frontier Medicine and the Research Fund of Vanke School of Public Health,Tsinghua University.H.Q.is a New Cornerstone Investigator.
文摘Microglia have been recognized as a unique cell population in the central nervous system(CNS)for more than a century[1].However,it was not until 2010 that their developmental origin was clarified.Rather than arising from the neuroectoderm,microglia are derived from erythromyeloid progenitors in the embryonic yolk sac[2].
基金supported by grants from the Key Realm R&D Program of Guangdong Province(2019B030335001)the National Natural Science Foundation of China(82071541,81971283,82271576,and 82101570)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2023-PT320-08).
文摘Autism Spectrum Disorders(ASDs)are reported as a group of neurodevelopmental disorders.The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes,but the underlying mechanisms are not fully understood.Here,we report that deletion of Trio,a high-susceptibility gene of ASDs,causes a postnatal dentate gyrus(DG)hypoplasia with a zigzagged suprapyramidal blade,and the Trio-defcient mice display autism-like behaviors.The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells(GCs),which further results in a migration defcit of neural progenitors.Furthermore,we reveal that Trio plays diferent roles in various excitatory neural cells by spatial transcriptomic sequencing,especially the role of regulating the migration of postmitotic GCs.In summary,our fndings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
基金CAMS Innovation Fund for Medical Science,Grant/Award Number:2021-I2M-1-034The Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01。
文摘Background:Alzheimer's disease(AD)and lung cancer are leading causes of mortality among the older population.Epidemiological evidence suggests an antagonistic relationship between them,whereby patients with AD exhibit a reduced risk of developing cancer and vice versa.However,the precise mechanism by which AD antagonizes lung cancer progression warrants further elucidation.Methods:To this end,we established a co-morbidity model using 5xFAD transgenic mice induced with the carcinogen urethane.We visualized and quantified surface lung tumor colonies,assessed pathological parameters associated with lung cancer and AD using histopathological analysis,and employed single-cell sequencing and molecular pathological analyses to explore the mechanisms by which AD confers resistance to lung cancer.Results:Our findings revealed a significant reduction in lung tumor incidence in the AD group compared with that in the wild-type(WT)group.The results indicated a close association between AD-induced inhibition of lung tumor progression and iron homeostasis imbalance and increased oxidative stress.Moreover,greater CD8^(+)T cytotoxic lymphocyte and effector natural killer cell infiltration in the lung tumor tissues of AD mice and enhanced CD8^(+)T cytotoxic lymphocyte-mediated killing of target cells may be the primary factors contributing to the inhibition of lung tumor growth in the presence of AD.Conclusion:This study identified essential mechanisms through which AD suppresses lung tumorigenesis,thereby providing targets for potential therapeutic interventions in these diseases.
基金Peking Union Medical CollegeCAMS initiative for Innovative Medicine of ChinaGrant/Award Number:2021-I2M-1-034
文摘Background:Pathological angiogenesis and blood–brain barrier damage may play an important role in Alzheimer's disease(AD).ACE2 is mainly expressed on the surface of endothelial cells in brain.Recent studies have shown that the expression of ACE2 in AD is reduced,but its role in AD is still unclear.Method:We induced AD damage in endothelial cells using Aβ25-35 and overexpressed ACE2 in bEend.3 cells through lentiviral transfection.We detected the effect of Aβ25-35 on cell viability using the CCK-8 assay and examined the effect of overexpressing ACE2 on angiogenesis using an angiogenesis assay.We used western blot and cell immunofluorescence to detect changes in the expression of the VEGF/VEGFR2 pathway,tight junction protein,and NF-κB pathway.Results:Aβ25-35 treatment significantly decreased the expression of ACE2 and reduced cell viability.ACE2 overexpression(1)reduced the number of branches and junctions in tube formation,(2)inhibited the activation of the VEGF/VEGFR2 pathway induced by Aβ25-35,(3)increased the expression of TJPs,including ZO-1 and claudin-5,and(4)restored Aβ25-35-induced activation of the NF-κB pathway.Conclusion:Overexpression of ACE2 can improve pathological angiogenesis and blood–brain barrier damage in AD models in vitro by inhibiting NF-κB/VEGF/VEGFR2 pathway activity.ACE2 may therefore represent a therapeutic target for endothelial cell dysfunction in AD.
文摘Tumor microenvironment(TME)is highly heterogeneous and composed of complex cellular components,including multiple kinds of immune cells.Among all immune cells in TME,tumor-infiltrating myeloid cells(TIMs)account for a large proportion and play roles as key regulators in a variety of functions,ranging from immune-mediated tumor killing to tumor immune evasion.Understanding the heterogeneity of TIMs will provide valuable insights for new therapeutic targeting of myeloid cells.Single-cell genomic technologies deciphering cell composition and gene expression at single-cell resolution have largely improved our understanding of the cellular heterogeneity of TIMs and highlighted several novel cell subtypes contributing to the variation of patient survival and treatment response.However,these cell subtypes were defined based on limited data without a concordant nomenclature,which makes it difficult to understand whether they exist in different studies.Thus,in this review,we comprehensively summarized the common agreements and current different opinions on the heterogeneity of TIMs gained from single-cell studies;evaluated the feasibility of current myeloid cell targets at single-cell level and proposed a uniform nomenclature for TIM subsets.
基金financially supported by National Nature Science Foundation of China(U20A20362)the Subject of SKLID(2020SKLID102).
文摘As of December 2022,2603 laboratory-identified Middle East respiratory syndrome coronavirus(MERS-CoV)infections and 935 associated deaths,with a mortality rate of 36%,had been reported to the World Health Organization(WHO).However,there are still no vaccines for MERS-CoV,which makes the prevention and control of MERS-CoV difficult.In this study,we generated two DNA vaccine candidates by integrating MERS-CoV Spike(S)gene into a replicating Vaccinia Tian Tan(VTT)vector.Compared to homologous immunization with either vaccine,mice immunized with DNA vaccine prime and VTT vaccine boost exhibited much stronger and durable humoral and cellular immune responses.The immunized mice produced robust binding antibodies and broad neutralizing antibodies against the EMC2012,England1 and KNIH strains of MERS-CoV.Prime-Boost immunization also induced strong MERS-S specific T cells responses,with high memory and poly-functional(CD107a-IFN-γ-TNF-α)effector CD8t T cells.In conclusion,the research demonstrated that DNA-Prime/VTT-Boost strategy could elicit robust and balanced humoral and cellular immune responses against MERS-CoV-S.This study not only provides a promising set of MERS-CoV vaccine candidates,but also proposes a heterologous sequential immunization strategy worthy of further development.
基金CAMS initiative for Innovative Medicine of China,Grant/Award Number:2021-I2M-1-034。
文摘Background:Apolipoprotein E4(ApoE4)allele is the strongest genetic risk factor for late-onset Alzheimer's disease,and it can aggravate depressive symptoms in non-AD patients.However,the impact of ApoE4 on AD-associated depression-l ike behaviors and its underlying pathogenic mechanisms remain unclear.Methods:This study developed a 5xFAD mouse model overexpressing human ApoE4(E4FAD).Behavioral assessments and synaptic function tests were conducted to explore the effects of ApoE4 on cognition and depression in 5xFAD mice.Changes in peripheral and central lipid metabolism,as well as the levels of serotonin(5-HT)andγ-aminobutyric acid(GABA)neurotransmitters in the prefrontal cortex,were examined.In addition,the protein levels of 24-dehydrocholesterol reductase/glycogen synthase kinase-3 beta/mammalian target of rapamycin(DHCR24/GSK3β/m TOR)and postsynaptic density protein 95/calmodulin-dependent protein kinase II/brain-derived neurotrophic factor(PSD95/CaMK-II/BDNF)were measured to investigate the molecular mechanism underlying the effects of ApoE4 on AD mice.Results:Compared with 5xFAD mice,E4FAD mice exhibited more severe depressionlike behaviors and cognitive impairments.These mice also exhibited increased amyloid-beta deposition in the hippocampus,increased astrocyte numbers,and decreased expression of depression-related neurotransmitters 5-HT and GABA in the prefrontal cortex.Furthermore,lipid metabolism disorders were observed in E4FAD,manifesting as elevated low-density lipoprotein cholesterol and reduced high-density lipoprotein cholesterol in peripheral blood,decreased cholesterol level in the prefrontal cortex,and reduced expression of key enzymes and proteins related to cholesterol synthesis and homeostasis.Abnormal expression of proteins related to the DHCR24/GSK3β/m TOR and PSD95/CaMK-II/BDNF pathways was also observed.Conclusion:This study found that ApoE4 overexpression exacerbates depressionlike behaviors in 5xFAD mice and confirmed that ApoE4 reduces cognitive function in these mice.The mechanism may involve the induction of central and peripheral lipid metabolism disorders.Therefore,modulating ApoE expression or function to restore cellular lipid homeostasis may be a promising therapeutic target for AD comorbid with depression.This study also provided a better animal model for studying AD comorbid with depression.
文摘Background:The number of medical research publications by Chinese clinical investigators has risen substantially,contributing to 14.63%of the global total in 2019;however,their tangible impact on clinical decisionmaking remains limited.Various evaluation methods have been developed to measure hospital research competence in China,such as Fudan University's China hospital ranking and Science and Technology Evaluation Metrics(STEM)ranking,which predominantly focuses on factors such as academic reputation,volume of publications and patents,and research resources.However,composite indices may not fully capture the actual clinical value generated by medical research.To address this gap,we introduced the“Clinical Influence and Timeliness Evaluation(CITE)”metric to assess both the clinical importance of a given medical research study and the clinical influence of the hospital where it originated.The methodology used relies on the premise that influential medical research would be referenced in clinical guidelines,which serve as critical resources for clinicians.Methods:The CITE metric was applied for 78,636 medical studies concerning chronic obstructive pulmonary disease(COPD)published between 2000 and 2020 and referenced in both Chinese and international clinical guidelines for COPD.Specific indexes and formulas were derived to quantify the clinical weight of a medical research study(W)and its timeliness(T),enabling a dynamic assessment of the clinical value of each study and the overall contribution of a particular hospital.Results:In this analysis,we incorporated 499 hospitals in China and quantitatively identified their dynamic clinical influence in COPD from 2000 to 2020.Our findings offer objective and targeted evaluation metrics by focusing on clinical relevance and recognizing the collaborative nature of medical research.Conclusion:The CITE metric provides an innovative method to gauge the true impact of medical research in China,with potential applications across different medical specialties.CITE can serve as a useful tool for understanding the relationship between research input and practical clinical outcomes,ultimately promoting more clinically relevant research endeavors.
基金supported by the National Natural Science Foundation of China(32130038)the Chinese Ministry of Science and Technology(2024YFA1306501 and 2022YFC2303700)+1 种基金the China Postdoctoral Science Foundation(2021M700242 and 2022T150017)the Young Elite Scientists Sponsorship Program by CAST(2022QNRC001).
文摘Innate immunity in host cells must be rapidly activated to combat invading microbes.Upon RIG-I activation,the transcription of type I interferons is induced within one hour in virus-infected cells.Previous studies have shown that endogenous MAVS spreads signals via aggregation on the mitochondrial membrane,whereas truncated recombinant MAVS forms prion-like filaments in vitro.How MAVS transmits signals so quickly,and the molecular architecture of its membrane aggregates,remains elusive.Here,we report that activated MAVS forms fibrils encircling its resident mitochondrion or connecting neighboring mitochondria with a“ladder-like”structure,allowing the activation of dormant MAVS on encountered mitochondria.This“intermitochondrial activation”process promotes a rapid antiviral response in cells to overcome the immediate danger caused by viruses.Moreover,stuck MAVS fibrils between mitochondria have limited cytosolic protein access and thus relay signals poorly.This study demonstrated that prion-like MAVS fibrils cluster in mitochondria to ensure a rapid antiviral response.
基金Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2023-PT180-01 and 2023-PT330-01Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-034National Natural Science Foundation of China,Grant/Award Number:82161138027。
文摘Background:Alzheimer's disease(AD)represents the most prevalent neurodegenerative disorder,with mitochondrial dysfunction being observed in both AD patients and mouse models.Nonetheless,further investigation is required to elucidate the pathogenic genes associated with AD and to develop early diagnostic methodologies centered on mitochondrial function.Methods:In this study,the dataset GSE132903 was retrieved from the GEO database,encompassing both non-demented(ND)control and AD samples.Through the combination of differential expression gene analysis,weighted gene co-expression network analysis,and intersection with mitochondrial database gene sets,four hub genes associated with AD were identified.These four hub genes were subsequently validated in APP/PS1 and 5xFAD mouse models using molecular biology techniques.Results:The hub genes identified through bioinformatics analysis include SYNJ2BP,VDAC1,NUBPL,and COX19.Within the GSE132903 dataset,the expression levels of SYNJ2BP,NUBPL,and COX19 were significantly elevated in the AD group compared to the non-demented(ND)group,whereas VDAC1 expression was reduced in the AD group relative to the ND group.Furthermore,in the hippocampus of APP/PS1 and 5xFAD mouse models,the expression patterns of SYNJ2BP and NUBPL were consistent with the bioinformatics analysis results.Conclusion:Hub genes identified here through bioinformatics and molecular biology may help early diagnosis of AD patients and may also help build new AD models to explore its pathogenesis.
基金supported by the Beijing Natural Science Foundation:7222220National Natural Science Foundation of China (82001039)+2 种基金Research Foundation of Peking University School and Hospital of Stomatology:PKUSS20230117The Fundamental Research Funds for the Central UniversitiesYoung Elite Scientist Sponsorship Program by CAST (No.2019QNRC001 to Y.L.L)。
文摘Understanding the acid resistance mechanism of S.mutans is crucial for preventing dental caries.FtsZ is the core protein for cell division in bacteria that can polymerize into Z-rings and drive cytokinesis.Our previous study revealed that the FtsZ in S.mutans(SmFtsZ) has higher self-assembly and GTPase activity under acidic stress,which may be responsible for acid resistance and ca riogenesis of S.mutans.However,the functional structure mechanism of SmFtsZ under low pH conditions is still unclear.Here,we further reported the crystal structure of S.mutans FtsZ,revealing a unique lateral interface.Through protein polymerization and GTPase activity assay,we experimentally demonstrated that the mutation of Arg68 on this lateral interface significantly reduced the functional activity of FtsZ in an acidic environment.The phenotype assay and rat caries model further showed that the mutation of Arg68 effectively inhibited the acid resistance of S.mutans and the occurrence and progress of dental caries in vivo.By employing a molecular dynamics simulation analysis,we conclude that the mutation of Arg68 disrupts the conformation change necessary for SmFtsZ polymerization under acidic conditions.Our study proposes a novel mechanism to maintain FtsZ function in bacteria and could be a potential target for antimicrobial drugs to inhibit the growth of S.mutans in acidic environments.
文摘In the third line of the second paragraph of Section 2.1,“Gaff2”should be“GAFF2”.There is no space between“atomsto”in the first sentence of the last paragraph of Section 2.2.It should be“First,the initial structure underwent pre-equilibration by restraining Cαatoms to eliminate unreasonable interactions”.The unit of the last sentence of the first paragraph of Section 2.3 is wrong.It should be“Three independent simulations were run for each system,so 3×500 ns MD simulations at 350 K were performed”.
文摘T-cell immunotherapy has progressed rapidly,evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer.This review explores engineering strategies,ranging from natural TCRs to synthetic receptors,that increase T-cell activation and therapeutic potential.We begin by highlighting the foundational role of native receptors in the T-cell response,emphasizing how these structural and functional insights inform the design of next-generation synthetic receptors.Comparisons between CAR and TCR-like synthetic receptors underscore their respective advantages in specificity,efficacy,and safety,as well as potential areas for further improvement.In addition,gene editing technologies such as CRISPR-Cas9 enable precise modifications to the T-cell genome,enhancing receptor performance and minimizing immunogenic risks.In addition to tumors,these engineered T cells can be directed against viral infections,autoimmune disorders,and other diseases.We also explore advanced strategies that engage multiple immune cell types to achieve synergistic,durable responses.By demonstrating how native and synthetic receptors collectively drive innovation,this review aims to inspire new research directions and ultimately expand the scope of T-cell engineering for universal therapeutic applications.
基金supported by the National Natural Science Foundation of China(82341208,82430012).
文摘Cancer immunotherapy is a groundbreaking therapeutic strategy,yet it continues to face significant challenges,including limited overall response rates and treatment resistance.Emerging research has demonstrated the pivotal role of epigenetic modifications in tumor immune evasion,providing a strong rationale for developing“epi‐immunotherapy”—an innovative approach that combines epigenetic therapy with immunotherapy.This comprehensive review systematically examines how epigenetic regulation mediates tumor immune escape and the mechanisms involved,including suppression of tumor antigen expression and antigen presentation,upregulation of immune checkpoint molecules,inhibition of antitumor immune cell recruitment and function,and enhancement of immunosuppressive cell proliferation and activity.By integrating epigenetic modulation with immunotherapeutic strategies,epi‐immunotherapy demonstrates a remarkable ability to enhance treatment efficacy and reverse therapeutic resistance.We also summarize the current clinical applications of epi‐immunotherapy in both hematological malignancies and solid tumors,with particular emphasis on its mechanisms for overcoming immune checkpoint inhibitor resistance and converting immunologically“cold”tumors into“hot”tumors.Despite its promising potential,epiimmunotherapy faces several challenges that require urgent resolution.This review provides an in‐depth analysis of these limitations,which include the complexity of epigenetic regulation,a lack of reliable biomarkers,and constraints in drug development.As our understanding of epigenetic mechanisms deepens and technologies continue to advance,epiimmunotherapy is poised to become an essential component of cancer treatment,offering patients more effective and personalized therapeutic options.
基金supported by funding from the National Science and Technology Major Project of the Ministry of Science and Technology of China(2023YFC2508505)grants from the Natural Science Foundation of China(82250710684).
文摘Therapeutic cancer vaccines aim to expand and activate antigen-specific T cells for the targeted elimination of cancer cells.While early clinical trials faced challenges due to suboptimal antigen-specific T-cell activation,recent advancements in antigen discovery and vaccine platform engineering have revitalized the field.This review provides a comprehensive overview of key tumor antigens,including tumor-associated antigens,viral oncoprotein antigens,neoantigens,and cryptic antigens,with a focus on their immunogenicity and therapeutic potential.Advances in our understanding of traditional cancer vaccination targets,in conjunction with the timely identification of novel antigen epitopes,have facilitated the strategic selection of vaccination targets.We also discuss the evolution of cancer vaccine platforms—spanning peptide-based formulations to advanced mRNA vectors—emphasizing innovative strategies to optimize antigen delivery efficiency and adjuvant effects.Efficient antigen delivery and adjuvant selection overcome immune tolerance and tumor-induced immunosuppression.Furthermore,we examine recent clinical trial data and emerging combination approaches that integrate cancer vaccines with other immunotherapies to increase efficacy.While significant progress has been made,challenges remain in improving vaccine-induced T-cell responses,overcoming immune suppression,and translating these advances into effective clinical interventions.Addressing these hurdles will be critical for realizing the full potential of cancer vaccines in immunotherapy.
