Dear Editor,Influenza viruses cause significant mortality and morbidity in humans.Vaccination is currently the most effective way to combat the virus(Perofsky and Nelson,2020).Unfortunately,the influenza virus frequen...Dear Editor,Influenza viruses cause significant mortality and morbidity in humans.Vaccination is currently the most effective way to combat the virus(Perofsky and Nelson,2020).Unfortunately,the influenza virus frequently changes its antigenicity through rapid mutations,leading to decreased vaccine efficacy or even failure.To improve vaccine effectiveness,it is necessary to monitor antigenic variation and update vaccine strains when significant antigenic variation occurs(Perofsky and Nelson,2020;Malik et al.,2024).展开更多
During the final proofing stage of the paper,the wrong version of Fig.2 was accidently used when replacing it with a high-resolution version.The star and circle marks were missing in the published version.
Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein(RIP)kinases RIPK1 and RIPK3,as well as the RIPK3 substrate mixed lineage kinase domain-like protein(MLKL...Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein(RIP)kinases RIPK1 and RIPK3,as well as the RIPK3 substrate mixed lineage kinase domain-like protein(MLKL).Because of membrane rupture,necroptotic cells release damage-associated molecular patterns(DAMPs)that evoke immune responses.Necroptosis is emerging as an important cellular response in the modulation of cancer initiation,progression,and metastasis.Necroptosis of cancer cells is considered to be an immunogenic cell death capable of activating anti-tumor immunity.Necroptosis also participates in the promotion of myeloid cell-induced adaptive immune suppression and thus contributes to oncogenesis.In addition,necroptosis of endothelial cells and tumor cells is conducive to tumor metastasis.In this review,we summarize the current knowledge of the complex role of necroptosis in cancer and discuss the potential of targeting necroptosis components for cancer therapies.展开更多
The virus receptors are key for the viral infection of host cells.Identification of the virus receptors is still challenging at present.Our previous study has shown that human virus receptor proteins have some unique ...The virus receptors are key for the viral infection of host cells.Identification of the virus receptors is still challenging at present.Our previous study has shown that human virus receptor proteins have some unique features including high N-glycosylation level,high number of interaction partners and high expression level.Here,a random-forest model was built to identify human virus receptorome from human cell membrane proteins with an accepted accuracy based on the combination of the unique features of human virus receptors and protein sequences.A total of 1424 human cell membrane proteins were predicted to constitute the receptorome of the human-infecting virome.In addition,the combination of the random-forest model with protein–protein interactions between human and viruses predicted in previous studies enabled further prediction of the receptors for 693 human-infecting viruses,such as the enterovirus,norovirus and West Nile virus.Finally,the candidate alternative receptors of the SARS-Co V-2 were also predicted in this study.As far as we know,this study is the first attempt to predict the receptorome for the human-infecting virome and would greatly facilitate the identification of the receptors for viruses.展开更多
Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza viru...Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza virus genomes,which may cause flu endemics and epidemics within or even across hosts.Due to the safety and ethical limitations of the experimental studies on influenza virus reassortment,numerous computational researches on the influenza virus reassortment have been done with the explosion of the influenza virus genomic data.A great amount of computational methods and bioinformatics databases were developed to facilitate the identification of influenza virus reassortments.In this review,we summarized the progress and challenge of the bioinformatics research on influenza virus reassortment,which can guide the researchers to investigate the influenza virus reassortment events reasonably and provide valuable insight to develop the related computational identification tools.展开更多
The Influenza A(H1N1)pdm09 virus caused a global pandemic in 2009 and has circulated seasonally ever since.As the continual genetic evolution of hemagglutinin in this virus leads to antigenic drift,rapid identificatio...The Influenza A(H1N1)pdm09 virus caused a global pandemic in 2009 and has circulated seasonally ever since.As the continual genetic evolution of hemagglutinin in this virus leads to antigenic drift,rapid identification of antigenic variants and characterization of the antigenic evolution are needed.In this study,we developed PREDAC-H1pdm,a model to predict antigenic relationships between H1N1pdm viruses and identify antigenic clusters for post-2009 pandemic H1N1 strains.Our model performed well in predicting antigenic variants,which was helpful in influenza surveillance.By mapping the antigenic clusters for H1N1pdm,we found that substitutions on the Sa epitope were common for H1N1pdm,whereas for the former seasonal H1N1,substitutions on the Sb epitope were more common in antigenic evolution.Additionally,the localized epidemic pattern of H1N1pdm was more obvious than that of the former seasonal H1N1,which could make vaccine recommendation more sophisticated.Overall,the antigenic relationship prediction model we developed provides a rapid determination method for identifying antigenic variants,and the further analysis of evolutionary and epidemic characteristics can facilitate vaccine recommendations and influenza surveillance for H1N1pdm.展开更多
Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy ...Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown.Here,we report that the regimen of 25 HC combined with antiretroviral therapy(ART),provides profound immunological modulation towards inhibiting viral replication in chronically SIVmac239-infected rhesus macaques(RMs).Compared to the ART alone,this regimen more effectively controlled SIV replication,enhanced SIVspecific cellular immune responses,restored the ratio of CD4/CD8 cells,reversed the hyperactivation state of CD4^(+)T cells,and inhibited the secretion of proinflammatory cytokines by CD4^(^(+))and CD8^(+)T lymphocytes in chronically SIVinfected RMs.Furthermore,the in vivo safety and the preliminary pharmacokinetics of the 25 HC compound were assessed in this RM model.Taken together,these assessments help explain the profound relationship between cholesterol metabolism,immune modulation,and antiviral activities by 25 HC.These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases.展开更多
China's dynamic zero-COVID policy has effectively curbed the spread of SARS-CoV-2,while inadvertently creating immunity gaps within its population.Subsequent surges in COVID-19 cases linked to various SARS-CoV-2 l...China's dynamic zero-COVID policy has effectively curbed the spread of SARS-CoV-2,while inadvertently creating immunity gaps within its population.Subsequent surges in COVID-19 cases linked to various SARS-CoV-2 lineages post-policy termination necessitate a thorough investigation into the epidemiological landscape.This study addresses this issue by analyzing a comprehensive dataset of 39,456 high-quality genomes collected nationwide over an 11-month period since policy termination.Through lineage assignment,phylogenetic analysis,pandemic pattern comparison,phylodynamic reconstruction,and recombination detection,we found that China's postepidemic period could be divided into three stages,along with dynamic changes in dominant lineages.Geographical clustering of similar lineages implies the importance of cross-border cooperation among neighboring regions.Compared to the USA,UK,and Japan,China exhibits unique trajectories of lineage epidemics,characterized by initial lagging followed by subsequent advancement,indicating the potential influence of diverse prevention and control policies on lineage epidemic patterns.Hong Kong,Shanghai,and Hubei emerge as pivotal nodes in the nationwide spread,marking a shift in the transmission center from east to central regions of China.Although China hasn't experienced significant variant emergence,the detection and validation of the novel recombination event,XCN lineage,underscore the ongoing virus evolution.Overall,this study systematically analyzes the spatiotemporal transmission of SARS-CoV-2 virus in China since the termination of the dynamic zeroCOVID policy,offering valuable insights for regional surveillance and evidence-based public health policymaking.展开更多
Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission....Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission.This causes global pandemics and seasonal flu outbreaks,posing sustained threats worldwide.Thus,studying all IAVs'evolutionary patterns and underlying mechanisms is crucial for effective prevention and control.We developed FluTyping to identify IAV genotypes,to explore overall genetic diversity patterns and their restriction factors.FluTyping groups isolates based on genetic distance and phylogenetic relationships using whole genomes,enabling identification of each isolate's genotype.Three distinct genetic diversity patterns were observed:one genotype domination pattern comprising only H1N1 and H3N2 seasonal influenza subtypes,multi-genotypes cocirculation pattern including majority avian influenza subtypes and swine influenza H1N2,and hybrid-circulation pattern involving H7N9 and three H5 subtypes of influenza viruses.Furthermore,the IAVs in multi-genotypes cocirculation pattern showed region-specific dominant genotypes,implying the restriction of virus transmission is a key factor contributing to distinct genetic diversity patterns,and the genomic evolution underlying different patterns was more influenced by host-specific factors.In summary,a comprehensive picture of the evolutionary patterns of overall IAVs is provided by the FluTyping's identified genotypes,offering important theoretical foundations for future prevention and control of these viruses.展开更多
The influenza virus changes its antigenicity frequently due to rapid mutations, leading to immune escape and failure of vaccination. Rapid determination of the influenza antigenicity could help identify the antigenic ...The influenza virus changes its antigenicity frequently due to rapid mutations, leading to immune escape and failure of vaccination. Rapid determination of the influenza antigenicity could help identify the antigenic variants in time. Here, we built a stacked auto-encoder (SAE) model for predicting the antigenic variant of human influenza A(H3N2) viruses based on the hemagglutinin (HA) protein sequences. The model achieved an accuracy of 0.95 in five-fold cross-validations, better than the logistic regression model did. Further analysis of the model shows that most of the active nodes in the hidden layer reflected the combined contribution of multiple residues to antigenic variation. Besides, some features (residues on HA protein) in the input layer were observed to take part in multiple active nodes, such as residue 189, 145 and 156, which were also reported to mostly determine the antigenic variation of influenza A(H3N2) viruses. Overall,this work is not only useful for rapidly identifying antigenic variants in influenza prevention, but also an interesting attempt in inferring the mechanisms of biological process through analysis of SAE model, which may give some insights into interpretation of the deep learning展开更多
Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue a...Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue and cell specificity of glycosylation. Here, we built a two-step computational method GlycoCell to predict the cell-specific O-GalNAc glycosylation, the most complex type of O-glycosylation reported so far, in 12 human cell types. The first step predicted whether a site had the potential to be O-glycosylated. The model achieved an accuracy of 0.83. The second step predicted whether a potential glycosite would be O-glycosylated in the given cell type. For 12 cell types, a model was built for each cell type. The accuracies for these models ranged from 0.78 to 0.87. To facilitate the usage of GlycoCell for the public, a web server was built which is available at http://www.biomedcloud.com.cn/GlyoCell/main.htm. It could be useful for investigating the cell-specific O-glycosylation in human.展开更多
BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease tra...BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.展开更多
Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(...Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.展开更多
OBJECTIVE Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis,the underlying mechanisms remain not well understood.Our previous finding that nicotine inh...OBJECTIVE Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis,the underlying mechanisms remain not well understood.Our previous finding that nicotine inhibits inflammatory responses through inducing miRNA-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine on UC.METHODS MiR-124 expres.sion in colon tissues and cells was determined by q-PCR and in situ hybridization.The effect of miR-124 on protective role of nicotine in ulcerative colitis was evaluated in DSS-treated mice and IL-6-treated Caco-2 colon epithelial cells.Expression of p-STAT3/STAT3 was detected by immunohistochemistry and Western-blot analysis.RESULTS miR-124 expression is upregulated in colon tissues from UC patients and DSS-induced colitis mice.Nicotine treatment further elevated miR-124 level in lympho.cytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice,both in infiltrated lymphocytes and epithelial cells.Administration of nicotine also reduced weight loss,improved DAI and decreased HE score in DSS-induced colitis mice.Moreover,knockdown of miR-124 in vivo significantly diminished the beneficial effect of nicotine on murine colitis,and in vitro on IL-6-treated Caco-2 colon epithelial cells.Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6-treated Caco-2 colon epithelial cells and Jurkat human T lymphocytes,in which miR-124 knockdown led to increased activation of STAT3.Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine′s protective effect in this model.CONCLUSION These data indicated that nicotine exerts its protective action in UC through inducing miR-124 and its effect on STAT3,and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC.展开更多
The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has seriously threatened global public health and caused huge economic losses.Omics studies of SARS-...The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has seriously threatened global public health and caused huge economic losses.Omics studies of SARS-CoV-2 can help understand the interaction between the virus and host,thereby providing a new perspective in guiding the intervention and treatment of the SARS-CoV-2 infection.Since large amount of SARS-CoV-2 omics data have been accumulated in public databases,this study aimed to identify key host factors involved in SARSCoV-2 infection through systematic integration of transcriptome and interactome data.By manually curating published studies,we obtained a comprehensive SARS-CoV-2-human protein-protein interactions(PPIs)network,comprising 3591 human proteins interacting with 31 SARS-CoV-2 viral proteins.Using the RobustRankAggregation method,we identified 123 multiple cell line common genes(CLCGs),of which 115 up-regulated CLCGs showed host enhanced innate immunity and chemotactic response signatures.Combined with network analysis,co-expression and functional enrichment analysis,we discovered four key host factors involved in SARS-CoV-2 infection:IFITM1,SERPINE1,DDX60,and TNFAIP2.Furthermore,SERPINE1 was found to facilitate SARSCoV-2 replication,and can alleviate the endoplasmic reticulum(ER)stress induced by ORF8 protein through interaction with ORF8.Our findings highlight the importance of systematic integration analysis in understanding SARS-CoV-2-human interactions and provide valuable insights for future research on potential therapeutic targets against SARS-CoV-2 infection.展开更多
Nanotechnology provides various nanomaterials with tremendous functionalities for cancer diagnostics and therapeutics.Recently, theranostics has been developed as an alternative strategy for efficient cancer treatment...Nanotechnology provides various nanomaterials with tremendous functionalities for cancer diagnostics and therapeutics.Recently, theranostics has been developed as an alternative strategy for efficient cancer treatment through combination of imaging diagnosis and therapeutic interventions under the guidance of diagnostic results. Ultrasound(US) imaging shows unique advantages with excellent features of real-time imaging, low cost, high safety and portability, making US contrast agents(UCAs)an ideal platform for construction of cancer theranostic agents. This review focuses on the development of nanomaterials incorporated multifunctional UCAs serving as theranostic agents for cancer diagnostics and therapeutics, via conjugation of superparamagnetic iron oxide nanoparticles(SPIOs), Cu S nanoparticles, DNA, si RNA, gold nanoparticles(GNPs), gold nanorods(GNRs), gold nanoshell(GNS), graphene oxides(GOs), polypyrrole(PPy) nanocapsules, Prussian blue(PB) nanoparticles and so on to different types of UCAs. The cancer treatment could be more effectively and accurately carried out under the guidance and monitoring with the help of the achieved theranostic agents. Furthermore, nanomaterials incorporated theranostic agents based on UCAs can be designed and constructed by demand for personalized and accurate treatment of cancer, demonstrating their great potential to address the challenges of cancer heterogeneity and adaptation, which can provide alternative strategies for cancer diagnosis and therapeutics.展开更多
Dear Editor, The influenza viruses cause continual epidemics in human society. As is reported by the World Health Organization （WHO）, each year the seasonal influenza viruses, i.e., human influenza A （H1N1）, A （H...Dear Editor, The influenza viruses cause continual epidemics in human society. As is reported by the World Health Organization （WHO）, each year the seasonal influenza viruses, i.e., human influenza A （H1N1）, A （H3N2） and B viruses, infected 5%- 15% of the world＇s population, leading to about 3 to 5 million cases of severe illness and about 250000 to 500000 deaths worldwide （WHO, 2014）. Vaccination is currently the most effective way to fight against it. Due to the frequent mutations on the HA protein, the virus often changes its antigen, which may lead to the ineffectiveness of the influenza vaccines （Carrat and Flahault, 2007; Taubenberger and Kash, 2010）.展开更多
Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.I...Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.In this study,we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues.By incorporating chromatin immunoprecipitation sequencing data,we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways.Among these,lactotransferrin-eRNA(LTFe)was markedly downregulated in prostate cancer tissues,with functional analyses revealing its tumor-suppressive role.Mechanistically,LTFe promotes the transcription of its target gene,lactotransferrin(LTF),by interacting with heterogeneous nuclear ribonucleoprotein F(HNRNPF)and facilitating enhancer-promoter chromatin interactions.Furthermore,we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport.Notably,androgen receptor(AR)signaling disrupts LTFe-associated chromatin looping,leading to ferroptosis resistance.Therapeutically,co-administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth,offering a promising strategy for castrationresistant prostate cancer.Collectively,this study provides novel insights into the mechanistic role of eRNAs in prostate cancer,highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.展开更多
Introduction:Human influenza A/H3N2 imposes a substantial global disease burden.Beyond hemagglutinin(HA),neuraminidase(NA)also plays a critical role in the antigenic evolution of influenza viruses.However,a comprehens...Introduction:Human influenza A/H3N2 imposes a substantial global disease burden.Beyond hemagglutinin(HA),neuraminidase(NA)also plays a critical role in the antigenic evolution of influenza viruses.However,a comprehensive understanding of NA antigenic evolution remains lacking.Methods:NA inhibition(NAI)data were collected and structural epitopes for A/H3N2 NA were identified.A machine learning model was developed to accurately predict antigenic relationships by integrating four feature groups:epitopes,physicochemical properties,N-glycosylation,and catalytic sites.An antigenic correlation network(ACNet)was constructed and antigenic clusters were identified using the Markov clustering algorithm.Results:The best random forest model(PREDEC-N2)achieved an accuracy of 0.904 in crossvalidation and 0.867 in independent testing.Eight main antigenic clusters were identified on the ACNet.Spatiotemporal analysis revealed the continuous replacement and rapid global spread of new antigenic clusters for human influenza A/H3N2 NA.Conclusions:This study developed a timely and accurate computational model to map the antigenic landscape of A/H3N2 NA,revealing both its relative antigenic conservation and continuous evolution.These insights provide valuable guidance for improved antigenic surveillance,vaccine recommendations,and prevention and control strategies for human influenza viruses.展开更多
Background Mitochondrial diseases are among the most common metabolic disorders caused by mitochondrial dysfunction.Analyzing mitochondrial respiratory chain enzyme activity is essential for diagnosis.However,clinical...Background Mitochondrial diseases are among the most common metabolic disorders caused by mitochondrial dysfunction.Analyzing mitochondrial respiratory chain enzyme activity is essential for diagnosis.However,clinical laboratories often rely on mitochondria isolated from muscle biopsies or cultured skin fibroblasts,which may be unacceptable for some pediatric patients.This highlights the need for improved blood-based diagnostic methods.Methods This paper describes spectrophotometric assays to evaluate mitochondrial respiratory chain enzyme activity in peripheral blood monocytes.Sample preparation methods and assays for respiratory complexes I–IV and the mitochondrial matrix enzyme citrate synthase are detailed.The assays were validated via samples from a panel of 28 healthy children and validated in patients with combined and isolated mitochondrial oxidative phosphorylation system(OXPHOS)deficiency.Results The citrate synthase-normalized activities were 0.23±0.08 for complex I,0.22±0.081 for complex II,0.16±0.07 for complex III,and 0.22±0.07 for complex IV.All patients with mitochondrial disease exhibited the expected reductions in respiratory complex activity.Conclusions We established a method to analyze the respiratory complex activities via blood samples.The normal enzymatic activity ranges were established from healthy Chinese pediatric populations.We also validated the assay via samples from patients with mitochondrial disease.By establishing the first pediatric-specific reference ranges for mitochondrial respiratory chain complex activities in a Chinese population and validating this minimally invasive blood-based assay in patients with mitochondrial disease,our study enabled earlier detection,precise monitoring,and personalized management of mitochondrial disorders while avoiding the need for invasive tissue biopsies.展开更多
基金upported by the Major Project of Guangzhou National Laboratory(GZNL2024A01002)National Key Plan for Scientific Research and Development of China(2022YFC2303802)+1 种基金National Natural Science Foundation of China(32170651&32370700)Hunan Provincial Natural Science Foundation of China(2024JJ2015).
文摘Dear Editor,Influenza viruses cause significant mortality and morbidity in humans.Vaccination is currently the most effective way to combat the virus(Perofsky and Nelson,2020).Unfortunately,the influenza virus frequently changes its antigenicity through rapid mutations,leading to decreased vaccine efficacy or even failure.To improve vaccine effectiveness,it is necessary to monitor antigenic variation and update vaccine strains when significant antigenic variation occurs(Perofsky and Nelson,2020;Malik et al.,2024).
文摘During the final proofing stage of the paper,the wrong version of Fig.2 was accidently used when replacing it with a high-resolution version.The star and circle marks were missing in the published version.
基金supported by the National Natural Science Foundation of China(Nos.31671436,31600133,31771533,and 31830051)the Priority Academic Program Development of Jiangsu Higher Education Institutions,the Natural Science Foundation of Jiangsu Province(No.BK20160314)+1 种基金the Fok Ying Tung Education Foundation for Young Teachers(No.151020)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Nos.2017NL31002 and 2017NL31004)
文摘Necroptosis is a tightly regulated form of necrosis that requires the activation of receptor-interacting protein(RIP)kinases RIPK1 and RIPK3,as well as the RIPK3 substrate mixed lineage kinase domain-like protein(MLKL).Because of membrane rupture,necroptotic cells release damage-associated molecular patterns(DAMPs)that evoke immune responses.Necroptosis is emerging as an important cellular response in the modulation of cancer initiation,progression,and metastasis.Necroptosis of cancer cells is considered to be an immunogenic cell death capable of activating anti-tumor immunity.Necroptosis also participates in the promotion of myeloid cell-induced adaptive immune suppression and thus contributes to oncogenesis.In addition,necroptosis of endothelial cells and tumor cells is conducive to tumor metastasis.In this review,we summarize the current knowledge of the complex role of necroptosis in cancer and discuss the potential of targeting necroptosis components for cancer therapies.
基金supported by the National Key Plan for Scientific Research and Development of China(2016YFD0500300)Hunan Provincial Natural Science Foundation of China(2018JJ3039)+1 种基金the Chinese Academy of Medical Sciences(2016-I2M-1-005)the special project for COVID-19 of Guangzhou Regenerative Medicine and Health Guangdong Laboratory(2020GZR110406001)
文摘The virus receptors are key for the viral infection of host cells.Identification of the virus receptors is still challenging at present.Our previous study has shown that human virus receptor proteins have some unique features including high N-glycosylation level,high number of interaction partners and high expression level.Here,a random-forest model was built to identify human virus receptorome from human cell membrane proteins with an accepted accuracy based on the combination of the unique features of human virus receptors and protein sequences.A total of 1424 human cell membrane proteins were predicted to constitute the receptorome of the human-infecting virome.In addition,the combination of the random-forest model with protein–protein interactions between human and viruses predicted in previous studies enabled further prediction of the receptors for 693 human-infecting viruses,such as the enterovirus,norovirus and West Nile virus.Finally,the candidate alternative receptors of the SARS-Co V-2 were also predicted in this study.As far as we know,this study is the first attempt to predict the receptorome for the human-infecting virome and would greatly facilitate the identification of the receptors for viruses.
基金This work was supported by the National Natural Science Foundation of China(31801101 to X.D.,31671371,32070678 to T.J.)the CAMS Initiative for Innovative Medicine(CAMS-I2M,2016-I2M-1-005,2020-I2M-2-003 to T.J.)。
文摘Genomic reassortment is an important evolutionary mechanism for influenza viruses.In this process,the novel viruses acquire new characteristics by the exchange of the intact gene segments among multiple influenza virus genomes,which may cause flu endemics and epidemics within or even across hosts.Due to the safety and ethical limitations of the experimental studies on influenza virus reassortment,numerous computational researches on the influenza virus reassortment have been done with the explosion of the influenza virus genomic data.A great amount of computational methods and bioinformatics databases were developed to facilitate the identification of influenza virus reassortments.In this review,we summarized the progress and challenge of the bioinformatics research on influenza virus reassortment,which can guide the researchers to investigate the influenza virus reassortment events reasonably and provide valuable insight to develop the related computational identification tools.
基金funded by the National Natural Science Foundation of China (32070678)the National Key Research and Development Program of China (2021YFC2302001).
文摘The Influenza A(H1N1)pdm09 virus caused a global pandemic in 2009 and has circulated seasonally ever since.As the continual genetic evolution of hemagglutinin in this virus leads to antigenic drift,rapid identification of antigenic variants and characterization of the antigenic evolution are needed.In this study,we developed PREDAC-H1pdm,a model to predict antigenic relationships between H1N1pdm viruses and identify antigenic clusters for post-2009 pandemic H1N1 strains.Our model performed well in predicting antigenic variants,which was helpful in influenza surveillance.By mapping the antigenic clusters for H1N1pdm,we found that substitutions on the Sa epitope were common for H1N1pdm,whereas for the former seasonal H1N1,substitutions on the Sb epitope were more common in antigenic evolution.Additionally,the localized epidemic pattern of H1N1pdm was more obvious than that of the former seasonal H1N1,which could make vaccine recommendation more sophisticated.Overall,the antigenic relationship prediction model we developed provides a rapid determination method for identifying antigenic variants,and the further analysis of evolutionary and epidemic characteristics can facilitate vaccine recommendations and influenza surveillance for H1N1pdm.
基金supported by the National Natural Science Foundation of China(81971927,31870912,32000124)the National Science and Technology Major Project of China(2018ZX10731101-002)+4 种基金the National Key Research and Development Program of China(2018YFA0900803)the Science and Technology Planning Project of Shenzhen City(20190804095916056,JCYJ20200109142601702)the High Level Project of Medicine in Longhua,Shenzhen(HLPM201907020105)China Postdoctoral Science Foundation(Grant No.2019M663140)the Municipal Health and Medical cooperation innovation Major Project of Guangzhou City(201704020219,201803040002)。
文摘Cholesterol-25-hydroxylase(CH25 H)and its enzymatic product 25-hydroxy cholesterol(25 HC)exert broadly antiviral activity including inhibiting HIV-1 infection.However,their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown.Here,we report that the regimen of 25 HC combined with antiretroviral therapy(ART),provides profound immunological modulation towards inhibiting viral replication in chronically SIVmac239-infected rhesus macaques(RMs).Compared to the ART alone,this regimen more effectively controlled SIV replication,enhanced SIVspecific cellular immune responses,restored the ratio of CD4/CD8 cells,reversed the hyperactivation state of CD4^(+)T cells,and inhibited the secretion of proinflammatory cytokines by CD4^(^(+))and CD8^(+)T lymphocytes in chronically SIVinfected RMs.Furthermore,the in vivo safety and the preliminary pharmacokinetics of the 25 HC compound were assessed in this RM model.Taken together,these assessments help explain the profound relationship between cholesterol metabolism,immune modulation,and antiviral activities by 25 HC.These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases.
基金supported by the National Key Plan for Scientific Research and Development of China(2021YFC2301305)the National Natural Science Foundation of China(92169106)+6 种基金the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-PT180-001)Capital's Funds for health Improvement and Research(shoufa-1G-1131)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1-061,2022-I2M-2-004,2023-PT330-01,2023-I2M-2-005)Suzhou science and technology development plan(szs2020311)Natural Science Foundation of Jiangsu Province(Grants No.BK20220278)Jiangsu Provincial Key Project of Science and Technology Plan(Grants No.BE2023601),Scientific research project of Jiangsu health commission(DX202301)the NCTIB Fund for R&D Platform for Cell and Gene Therapy.We gratefully acknowledge the CNCB,CoV-Spectrum,and GISAID databases,as well as all the authors who originated and submitted the SARS-CoV-2 sequences,for generously sharing their work through open databases.
文摘China's dynamic zero-COVID policy has effectively curbed the spread of SARS-CoV-2,while inadvertently creating immunity gaps within its population.Subsequent surges in COVID-19 cases linked to various SARS-CoV-2 lineages post-policy termination necessitate a thorough investigation into the epidemiological landscape.This study addresses this issue by analyzing a comprehensive dataset of 39,456 high-quality genomes collected nationwide over an 11-month period since policy termination.Through lineage assignment,phylogenetic analysis,pandemic pattern comparison,phylodynamic reconstruction,and recombination detection,we found that China's postepidemic period could be divided into three stages,along with dynamic changes in dominant lineages.Geographical clustering of similar lineages implies the importance of cross-border cooperation among neighboring regions.Compared to the USA,UK,and Japan,China exhibits unique trajectories of lineage epidemics,characterized by initial lagging followed by subsequent advancement,indicating the potential influence of diverse prevention and control policies on lineage epidemic patterns.Hong Kong,Shanghai,and Hubei emerge as pivotal nodes in the nationwide spread,marking a shift in the transmission center from east to central regions of China.Although China hasn't experienced significant variant emergence,the detection and validation of the novel recombination event,XCN lineage,underscore the ongoing virus evolution.Overall,this study systematically analyzes the spatiotemporal transmission of SARS-CoV-2 virus in China since the termination of the dynamic zeroCOVID policy,offering valuable insights for regional surveillance and evidence-based public health policymaking.
基金supported by the National Key Plan for Scientific Research and Development of China(2021YFC2301305 and 2021YFC2302001)the National Natural Science Foundation of China(32370703,92169106,9216910042 and 32070678)+2 种基金the CAMS Innovation Fund for Medical Science(2022-I2M-1-021,2021-I2M-1-051)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-PT180-001)the Emergency Key Program of Guangzhou Laboratory(grant EKPG21-12).
文摘Influenza A virus(IAV)shows an extensive host range and rapid genomic variations,leading to continuous emergence of novel viruses with significant antigenic variations and the potential for cross-species transmission.This causes global pandemics and seasonal flu outbreaks,posing sustained threats worldwide.Thus,studying all IAVs'evolutionary patterns and underlying mechanisms is crucial for effective prevention and control.We developed FluTyping to identify IAV genotypes,to explore overall genetic diversity patterns and their restriction factors.FluTyping groups isolates based on genetic distance and phylogenetic relationships using whole genomes,enabling identification of each isolate's genotype.Three distinct genetic diversity patterns were observed:one genotype domination pattern comprising only H1N1 and H3N2 seasonal influenza subtypes,multi-genotypes cocirculation pattern including majority avian influenza subtypes and swine influenza H1N2,and hybrid-circulation pattern involving H7N9 and three H5 subtypes of influenza viruses.Furthermore,the IAVs in multi-genotypes cocirculation pattern showed region-specific dominant genotypes,implying the restriction of virus transmission is a key factor contributing to distinct genetic diversity patterns,and the genomic evolution underlying different patterns was more influenced by host-specific factors.In summary,a comprehensive picture of the evolutionary patterns of overall IAVs is provided by the FluTyping's identified genotypes,offering important theoretical foundations for future prevention and control of these viruses.
文摘The influenza virus changes its antigenicity frequently due to rapid mutations, leading to immune escape and failure of vaccination. Rapid determination of the influenza antigenicity could help identify the antigenic variants in time. Here, we built a stacked auto-encoder (SAE) model for predicting the antigenic variant of human influenza A(H3N2) viruses based on the hemagglutinin (HA) protein sequences. The model achieved an accuracy of 0.95 in five-fold cross-validations, better than the logistic regression model did. Further analysis of the model shows that most of the active nodes in the hidden layer reflected the combined contribution of multiple residues to antigenic variation. Besides, some features (residues on HA protein) in the input layer were observed to take part in multiple active nodes, such as residue 189, 145 and 156, which were also reported to mostly determine the antigenic variation of influenza A(H3N2) viruses. Overall,this work is not only useful for rapidly identifying antigenic variants in influenza prevention, but also an interesting attempt in inferring the mechanisms of biological process through analysis of SAE model, which may give some insights into interpretation of the deep learning
文摘Glycosylation is one of the most extensive post-translation modifications of proteins. Although lots of computational models have been developed to predict the glycosylation sites, none of them considered the tissue and cell specificity of glycosylation. Here, we built a two-step computational method GlycoCell to predict the cell-specific O-GalNAc glycosylation, the most complex type of O-glycosylation reported so far, in 12 human cell types. The first step predicted whether a site had the potential to be O-glycosylated. The model achieved an accuracy of 0.83. The second step predicted whether a potential glycosite would be O-glycosylated in the given cell type. For 12 cell types, a model was built for each cell type. The accuracies for these models ranged from 0.78 to 0.87. To facilitate the usage of GlycoCell for the public, a web server was built which is available at http://www.biomedcloud.com.cn/GlyoCell/main.htm. It could be useful for investigating the cell-specific O-glycosylation in human.
基金Supported by the Zhejiang Provincial Natural Science Foundation,No.LZ22H270001.
文摘BACKGROUND Hepatic fibrosis(HF)represents a pivotal stage in the progression and potential reversal of cirrhosis,underscoring the importance of early identification and therapeutic intervention to modulate disease trajectory.AIM To explore the complex relationship between chronic hepatitis B(CHB)-related HF and gut microbiota to identify microbiota signatures significantly associated with HF progression in CHB patients using advanced machine learning algorithms.METHODS This study included patients diagnosed with CHB and classified them into HF and non-HF groups based on liver stiffness measurements.The HF group was further subdivided into four subgroups:F1,F2,F3,and F4.Data on clinical indicators were collected.Stool samples were collected for 16S rRNA sequencing to assess the gut microbiome.Microbiota diversity,relative abundance,and linear discriminant analysis effect size(LEfSe)were analyzed in different groups.Correlation analysis between clinical indicators and the relative abundance of gut microbiota was performed.The random forest and eXtreme gradient boosting algorithms were used to identify key differential gut microbiota.The Shapley additive explanations were used to evaluate microbiota importance.RESULTS Integrating the results from univariate analysis,LEfSe,and machine learning,we identified that the presence of Dorea in gut microbiota may be a key feature associated with CHB-related HF.Dorea possibly serves as a core differential feature of the gut microbiota that distinguishes HF from non-HF patients,and the presence of Dorea shows significant variations across different stages of HF(P<0.05).The relative abundance of Dorea significantly decreases with increasing HF severity(P=0.041).Moreover,the gut microbiota composition in patients with different stages of HF was found to correlate with several liver function indicators,such asγ-glutamyl transferase,alkaline phosphatase,total bilirubin,and the aspartate aminotransferase/alanine transaminase ratio(P<0.05).The associated pathways were predominantly enriched in biosynthesis,degradation/utilization/assimilation,generation of precursors,metabolites,and energy,among other categories.CONCLUSION HF affects the composition of the gut microbiota,indicating that the gut microbiota plays a crucial role in its pathophysiological processes.The abundance of Dorea varies significantly across various stages of HF,making it a potential microbial marker for identifying HF onset and progression.
基金supported by the National Science and Technology Major Project (2018ZX097110003-005-002)the Key-Area Research and Development Program of Guangdong Province (2022B1111020002)+3 种基金the National Natural Science Foundation of China (NSFC) (32170159,and 82174055)supported by the National Science Fund for Distinguished Young Scholars (81925025)the Innovative Research Group (81621005)of the NSFCthe Innovation Fund for Medical Sciences (2019-I2M-5-049)of the Chinese Academy of Medical Sciences.
文摘Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.
基金supported by National Natural Science Foundation of China(8147325981603116)
文摘OBJECTIVE Although it is generally believed that nicotine accounts for the beneficial effect of smoking on ulcerative colitis,the underlying mechanisms remain not well understood.Our previous finding that nicotine inhibits inflammatory responses through inducing miRNA-124 prompted us to ask whether the miRNA is involved in the protective action of nicotine on UC.METHODS MiR-124 expres.sion in colon tissues and cells was determined by q-PCR and in situ hybridization.The effect of miR-124 on protective role of nicotine in ulcerative colitis was evaluated in DSS-treated mice and IL-6-treated Caco-2 colon epithelial cells.Expression of p-STAT3/STAT3 was detected by immunohistochemistry and Western-blot analysis.RESULTS miR-124 expression is upregulated in colon tissues from UC patients and DSS-induced colitis mice.Nicotine treatment further elevated miR-124 level in lympho.cytes isolated from human ulcerative colonic mucosa and ulcerative colon tissues from DSS mice,both in infiltrated lymphocytes and epithelial cells.Administration of nicotine also reduced weight loss,improved DAI and decreased HE score in DSS-induced colitis mice.Moreover,knockdown of miR-124 in vivo significantly diminished the beneficial effect of nicotine on murine colitis,and in vitro on IL-6-treated Caco-2 colon epithelial cells.Further analysis indicated that nicotine inhibited STAT3 activation in vivo and in IL-6-treated Caco-2 colon epithelial cells and Jurkat human T lymphocytes,in which miR-124 knockdown led to increased activation of STAT3.Blocking STAT3 activity alone is beneficial for DSS colitis and also abolished nicotine′s protective effect in this model.CONCLUSION These data indicated that nicotine exerts its protective action in UC through inducing miR-124 and its effect on STAT3,and suggest that the miR-124/STAT3 system is a potential target for the therapeutic intervention of UC.
基金supported by the National Natural Science Foundation of China (32070678,82102371 and 31671371)the Emergency Key Program of Guangzhou Laboratory,grant no.EKPG21-12+3 种基金the Selfsupporting Program of Guangzhou Laboratory,Grant No.SRPG22-007,SRPG22-020the National Key Research and Development Program of China (2020YFC0840800)CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-061)the National Key Research and Development Program of China (2021YFC2302000).
文摘The coronavirus disease 2019(COVID-19)pandemic,caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has seriously threatened global public health and caused huge economic losses.Omics studies of SARS-CoV-2 can help understand the interaction between the virus and host,thereby providing a new perspective in guiding the intervention and treatment of the SARS-CoV-2 infection.Since large amount of SARS-CoV-2 omics data have been accumulated in public databases,this study aimed to identify key host factors involved in SARSCoV-2 infection through systematic integration of transcriptome and interactome data.By manually curating published studies,we obtained a comprehensive SARS-CoV-2-human protein-protein interactions(PPIs)network,comprising 3591 human proteins interacting with 31 SARS-CoV-2 viral proteins.Using the RobustRankAggregation method,we identified 123 multiple cell line common genes(CLCGs),of which 115 up-regulated CLCGs showed host enhanced innate immunity and chemotactic response signatures.Combined with network analysis,co-expression and functional enrichment analysis,we discovered four key host factors involved in SARS-CoV-2 infection:IFITM1,SERPINE1,DDX60,and TNFAIP2.Furthermore,SERPINE1 was found to facilitate SARSCoV-2 replication,and can alleviate the endoplasmic reticulum(ER)stress induced by ORF8 protein through interaction with ORF8.Our findings highlight the importance of systematic integration analysis in understanding SARS-CoV-2-human interactions and provide valuable insights for future research on potential therapeutic targets against SARS-CoV-2 infection.
基金financially supported by the National Natural Science Foundation of China(Grant No.81501585)the Natural Science Foundation of Jiangsu Province of China(Grant No.BK20150348)+1 种基金the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(Grant No.15KJB310019)China Postdoctoral Science Foundation(Grant No.2015M570475 and 2016T90496)
文摘Nanotechnology provides various nanomaterials with tremendous functionalities for cancer diagnostics and therapeutics.Recently, theranostics has been developed as an alternative strategy for efficient cancer treatment through combination of imaging diagnosis and therapeutic interventions under the guidance of diagnostic results. Ultrasound(US) imaging shows unique advantages with excellent features of real-time imaging, low cost, high safety and portability, making US contrast agents(UCAs)an ideal platform for construction of cancer theranostic agents. This review focuses on the development of nanomaterials incorporated multifunctional UCAs serving as theranostic agents for cancer diagnostics and therapeutics, via conjugation of superparamagnetic iron oxide nanoparticles(SPIOs), Cu S nanoparticles, DNA, si RNA, gold nanoparticles(GNPs), gold nanorods(GNRs), gold nanoshell(GNS), graphene oxides(GOs), polypyrrole(PPy) nanocapsules, Prussian blue(PB) nanoparticles and so on to different types of UCAs. The cancer treatment could be more effectively and accurately carried out under the guidance and monitoring with the help of the achieved theranostic agents. Furthermore, nanomaterials incorporated theranostic agents based on UCAs can be designed and constructed by demand for personalized and accurate treatment of cancer, demonstrating their great potential to address the challenges of cancer heterogeneity and adaptation, which can provide alternative strategies for cancer diagnosis and therapeutics.
基金supported by the National Natural Science Foundation(31500126 and 31371338)National Key Plan for Scientific Research and Development of China(2016YFD0500300 and 2016YFC1200200)the Young Teacher’s Development Plan of Hunan University to YS(531107040720)
文摘Dear Editor, The influenza viruses cause continual epidemics in human society. As is reported by the World Health Organization （WHO）, each year the seasonal influenza viruses, i.e., human influenza A （H1N1）, A （H3N2） and B viruses, infected 5%- 15% of the world＇s population, leading to about 3 to 5 million cases of severe illness and about 250000 to 500000 deaths worldwide （WHO, 2014）. Vaccination is currently the most effective way to fight against it. Due to the frequent mutations on the HA protein, the virus often changes its antigen, which may lead to the ineffectiveness of the influenza vaccines （Carrat and Flahault, 2007; Taubenberger and Kash, 2010）.
基金supported by the National Natural Science Foundation of China(Nos.82373333,82173068)to Z.Wang,and Nos.82073082,82311530050 to G.-H.Wei+2 种基金the Hubei Natural Science Foundation Innovation Development Joint Fund Key Project(2024AFD420 to Z.Wang)the National Key Research and Development Program of China(2022YFC2703600 to G.-H.Wei)Z.X.Wang was supported by the National Natural Science Foundation of China(82203416)。
文摘Enhancer RNAs(eRNAs),a subclass of non-coding RNAs transcribed from enhancer regions,have emerged as critical regulators of gene expression;however,their functional roles in prostate cancer remain largely unexplored.In this study,we performed integrated chromatin accessibility and transcriptomic analyses using ATAC-seq and RNA-seq on twenty pairs of prostate cancer and matched benign tissues.By incorporating chromatin immunoprecipitation sequencing data,we identified a subset of differentially expressed eRNAs significantly associated with genes involved in prostate development and oncogenic signaling pathways.Among these,lactotransferrin-eRNA(LTFe)was markedly downregulated in prostate cancer tissues,with functional analyses revealing its tumor-suppressive role.Mechanistically,LTFe promotes the transcription of its target gene,lactotransferrin(LTF),by interacting with heterogeneous nuclear ribonucleoprotein F(HNRNPF)and facilitating enhancer-promoter chromatin interactions.Furthermore,we demonstrate that the LTFe-LTF axis facilitates ferroptosis by modulating iron transport.Notably,androgen receptor(AR)signaling disrupts LTFe-associated chromatin looping,leading to ferroptosis resistance.Therapeutically,co-administration of the AR inhibitor enzalutamide and the ferroptosis inducer RSL3 significantly suppressed tumor growth,offering a promising strategy for castrationresistant prostate cancer.Collectively,this study provides novel insights into the mechanistic role of eRNAs in prostate cancer,highlighting the LTFe-LTF axis as a critical epigenetic regulator and potential therapeutic target for improved treatment outcomes.
基金Supported by the National Key Research and Development Program under grant 2022YFC2303800the Major Program of Guangzhou National Laboratory under grant GZNL2024A01002+2 种基金the National Natural Science Foundation of China under grant 81961128002the Science and Technology Planning Project of Guangdong Province,China under grant 2021B1212040017the Shenzhen Science and Technology Program under grant ZDSYS20230626091203007.
文摘Introduction:Human influenza A/H3N2 imposes a substantial global disease burden.Beyond hemagglutinin(HA),neuraminidase(NA)also plays a critical role in the antigenic evolution of influenza viruses.However,a comprehensive understanding of NA antigenic evolution remains lacking.Methods:NA inhibition(NAI)data were collected and structural epitopes for A/H3N2 NA were identified.A machine learning model was developed to accurately predict antigenic relationships by integrating four feature groups:epitopes,physicochemical properties,N-glycosylation,and catalytic sites.An antigenic correlation network(ACNet)was constructed and antigenic clusters were identified using the Markov clustering algorithm.Results:The best random forest model(PREDEC-N2)achieved an accuracy of 0.904 in crossvalidation and 0.867 in independent testing.Eight main antigenic clusters were identified on the ACNet.Spatiotemporal analysis revealed the continuous replacement and rapid global spread of new antigenic clusters for human influenza A/H3N2 NA.Conclusions:This study developed a timely and accurate computational model to map the antigenic landscape of A/H3N2 NA,revealing both its relative antigenic conservation and continuous evolution.These insights provide valuable guidance for improved antigenic surveillance,vaccine recommendations,and prevention and control strategies for human influenza viruses.
基金supported by a Suzhou Science and Technology Development Project(SKY2023007)a Research Project of the Jiangsu Commission of Health(M2021082)+4 种基金supported by the National Natural Science Foundation of China(31701251)a Summit Project of Clinical Medicine(ML13100523)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutionssupported by the Project of MOE Key Laboratory of Geriatric Diseases and Immunology(JYN202407)supported by the Undergraduate Training Program for Innovation and Entrepreneurship,Soochow University(202310285065Z).
文摘Background Mitochondrial diseases are among the most common metabolic disorders caused by mitochondrial dysfunction.Analyzing mitochondrial respiratory chain enzyme activity is essential for diagnosis.However,clinical laboratories often rely on mitochondria isolated from muscle biopsies or cultured skin fibroblasts,which may be unacceptable for some pediatric patients.This highlights the need for improved blood-based diagnostic methods.Methods This paper describes spectrophotometric assays to evaluate mitochondrial respiratory chain enzyme activity in peripheral blood monocytes.Sample preparation methods and assays for respiratory complexes I–IV and the mitochondrial matrix enzyme citrate synthase are detailed.The assays were validated via samples from a panel of 28 healthy children and validated in patients with combined and isolated mitochondrial oxidative phosphorylation system(OXPHOS)deficiency.Results The citrate synthase-normalized activities were 0.23±0.08 for complex I,0.22±0.081 for complex II,0.16±0.07 for complex III,and 0.22±0.07 for complex IV.All patients with mitochondrial disease exhibited the expected reductions in respiratory complex activity.Conclusions We established a method to analyze the respiratory complex activities via blood samples.The normal enzymatic activity ranges were established from healthy Chinese pediatric populations.We also validated the assay via samples from patients with mitochondrial disease.By establishing the first pediatric-specific reference ranges for mitochondrial respiratory chain complex activities in a Chinese population and validating this minimally invasive blood-based assay in patients with mitochondrial disease,our study enabled earlier detection,precise monitoring,and personalized management of mitochondrial disorders while avoiding the need for invasive tissue biopsies.
