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
Objective Recent studies have highlighted the critical role of NUDT19 in the initiation,progression,and prognosis of specific cancer types.However,its involvement in pan-cancer analysis has not been fully characterize...Objective Recent studies have highlighted the critical role of NUDT19 in the initiation,progression,and prognosis of specific cancer types.However,its involvement in pan-cancer analysis has not been fully characterized.This study aims to systematically explore the expression patterns,clinical significance,and immune-related functions of NUDT19 in various cancer types through multi-omics analysis,further revealing its potential role in cancer,particularly its functional and therapeutic target value in leukemia.Methods To achieve this goal,various bioinformatics approaches were employed to evaluate the expression patterns,clinical significance,and immune-related functions of NUDT19 in tumors and normal tissues.Additionally,we analyzed the mutation characteristics of NUDT19 and its relationship with epigenetic modifications.Using the single-cell analysis tool SingleCellBase,we explored the distribution of NUDT19 across different cell subpopulations in tumors.To validate these findings,qRT-PCR was used to measure NUDT19 expression levels in specific tumor cell lines,and we established acute myeloid leukemia(AML)cell lines(HL-60 and THP-1)to conduct NUDT19 knockdown and overexpression experiments,assessing its effects on leukemia cell proliferation,apoptosis,and invasion.Results Pan-cancer analysis revealed the dysregulated expression of NUDT19 across multiple cancer types,which was closely associated with poor prognosis,clinical staging,and diagnostic markers.Furthermore,NUDT19 was significantly correlated with tumor biomarkers,immune-related genes,and immune cell infiltration in different cancers.Mutation analysis showed that multiple mutations in NUDT19 were significantly associated with epigenetic changes.Single-cell analysis revealed the heterogeneity of NUDT19 expression in cancer cells,suggesting its potentially diverse functional roles in different cell subpopulations.qRT-PCR experiments confirmed the significant upregulation of NUDT19 in various tumor cell lines.In AML cell lines,NUDT19 knockdown led to reduced cell proliferation and invasion,with increased apoptosis,while NUDT19 overexpression significantly enhanced cell proliferation and invasion while reducing apoptosis.Conclusion This study demonstrates the diverse roles of NUDT19 in various cancer types,with a particularly prominent functional role in leukemia.NUDT19 is not only associated with tumor initiation and progression but may also influence cancer progression through the regulation of immune microenvironment and epigenetic mechanisms.Our research highlights the potential of NUDT19 as a therapeutic target,particularly for targeted therapies in malignancies such as leukemia,with significant clinical application prospects.展开更多
Increasing evidence implicates disruptions in testicular fatty acid metabolism as a contributing factor in nonobstructive azoospermia(NOA),a severe form of male infertility.However,the precise mechanisms linking fatty...Increasing evidence implicates disruptions in testicular fatty acid metabolism as a contributing factor in nonobstructive azoospermia(NOA),a severe form of male infertility.However,the precise mechanisms linking fatty acid metabolism to NOA pathogenesis have not yet been fully elucidated.Multi-omics analyses,including microarray analysis,single-cell RNA sequencing(scRNA-seq),and metabolomics,were utilized to investigate disruptions in fatty acid metabolism associated with NOA using data from public databases.Results identified ACSL6,ACSBG2,and OLAH as key genes linked to fatty acid metabolism dysregulation,suggesting their potential causative roles in NOA.A marked reduction in omega-3 polyunsaturated fatty acids,especially docosahexaenoic acid(DHA),was observed,potentially contributing to the pathological process of NOA.Sertoli cells in NOA patients exhibited apparent fatty acid metabolic dysfunction,with PPARG identified as a key transcription factor(TF)regulating this process.Functional analyses demonstrated that PPARG is crucial for maintaining blood-testis barrier(BTB)integrity and promoting spermatogenesis via regulation of fatty acid metabolism.These findings reveal the pivotal role of fatty acid metabolism in NOA and identify PPARG as a potential therapeutic target.展开更多
Background:Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations,such as firefighting,law enforcement,mili...Background:Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations,such as firefighting,law enforcement,military,and sports.A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work environment.Methods:To study regulatory processes in intense physical activity simulating real-life conditions,we performed a multi-omics analysis of 3 biofluids(blood plasma,urine,and saliva)collected from 11 wildland firefighters before and after a 45 min,intense exercise regimen.Omics profiles post-vs.pre-exercise were compared by Student’s t-test followed by pathway analysis and comparison between the different omics modalities.Results:Our multi-omics analysis identified and quantified 3835 proteins,730 lipids and 182 metabolites combining the 3 different types of samples.The blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy demands.The urine analysis showed a strong,concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites,reabsorption of nutrients and maintenance of fluid balance.In saliva,we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides.A systematic literature review identified 6 papers that support an altered susceptibility to respiratory infection.Conclusions:This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility,suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.展开更多
Accurate genomic information is essential for advancing genetic breeding research in specific rice varieties.This study presented a gapless genome assembly of the indica rice cultivar Zhonghui 8015(ZH8015)using Pac Bi...Accurate genomic information is essential for advancing genetic breeding research in specific rice varieties.This study presented a gapless genome assembly of the indica rice cultivar Zhonghui 8015(ZH8015)using Pac Bio HiFi,Hi-C,and ONT(Oxford Nanopore Technologies)ultra-long sequencing technologies,annotating 43037 gene structures.Subsequently,utilizing this genome along with transcriptomic and metabolomic techniques,we explored ZH8015's response to brown planthopper(BPH)infestation.Continuous transcriptomic sampling indicated significant changes in gene expression levels around 48 h after BPH feeding.Enrichment analysis revealed particularly significant alterations in genes related to reactive oxygen species scavenging and cell wall formation.Metabolomic results demonstrated marked increases in levels of several monosaccharides,which are components of the cell wall and dramatic changes in flavonoid contents.Omics association analysis identified differentially expressed genes associated with key metabolites,shedding light on ZH8015's response to BPH infestation.In summary,this study constructed a reliable genome sequence resource for ZH8015,and the preliminary multi-omics results will guide future insect-resistant breeding research.展开更多
Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies,resulting in severe disability.Macrophages are widely recogni...Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies,resulting in severe disability.Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation.However,different clusters of macrophages have various functions and receive multiple regulation,which are both still unknown.In our current study,multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury.The transcriptomes of over 74000 human single cells were profiled.As results,we found that SPP1^(+)macrophages,RGCC^(+)endothelial cells,ACKR1^(+)endothelial cells and ADAM12^(+)fibroblasts participated in tendon adhesion formation.Interestingly,despite specific fibrotic clusters in tendon adhesion,FOLR2^(+)macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells.Furthermore,ACKR1 was verified to regulate FOLR2^(+)macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26R^(tdTomato) mice to lethally irradiated Ackr1^(-/-)mice(Ackr1^(-/-)chimeras;deficient in ACKR1)and control mice(WT chimeras).Compared with WT chimeras,the decline of FOLR2^(+)macrophages was also observed,indicating that ACKR1 was specifically involved in FOLR2^(+)macrophages migration.Taken together,our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis,but also uncovered a novel antifibrotic cluster of macrophages and their origin.These results provide potential therapeutic targets against human tendon adhesion.展开更多
BACKGROUND Angiogenesis plays an important role in colon cancer(CC)progression.AIM To investigate the tumor microenvironment(TME)and intratumor microbes of angiogenesis subtypes(AGSs)and explore potential targets for ...BACKGROUND Angiogenesis plays an important role in colon cancer(CC)progression.AIM To investigate the tumor microenvironment(TME)and intratumor microbes of angiogenesis subtypes(AGSs)and explore potential targets for antiangiogenic therapy in CC.METHODS The data were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database.K-means clustering was used to construct the AGSs.The prognostic model was constructed based on the differential genes between two subtypes.Single-cell analysis was used to analyze the expression level of SLC2A3 on different cells in CC,which was validated by immunofluorescence.Its biological functions were further explored in HUVECs.RESULTS CC samples were grouped into two AGSs(AGS-A and AGS-B)groups and patients in the AGS-B group had poor prognosis.Further analysis revealed that the AGS-B group had high infiltration of TME immune cells,but also exhibited high immune escape.The intratumor microbes were also different between the two subtypes.A convenient 6-gene angiogenesis-related signature(ARS),was established to identify AGSs and predict the prognosis in CC patients.SLC2A3 was selected as the representative gene of ARS,which was higher expressed in endothelial cells and promoted the migration of HUVECs.CONCLUSION Our study identified two AGSs with distinct prognoses,TME,and intratumor microbial compositions,which could provide potential explanations for the impact on the prognosis of CC.The reliable ARS model was further constructed,which could guide the personalized treatment.The SLC2A3 might be a potential target for antiangiogenic therapy.展开更多
Sesquiterpene valencene is dominant in flavedo tissues of sweet oranges and imparts a unique woody aroma.However,the interaction between the biosynthetic pathways of valencene and other nutritional compounds is less s...Sesquiterpene valencene is dominant in flavedo tissues of sweet oranges and imparts a unique woody aroma.However,the interaction between the biosynthetic pathways of valencene and other nutritional compounds is less studied.Sesquiterpenoids were significantly accumulated in a previously reported glossy mutant of orange(MT)than the wild type(WT),especially valencene and caryophyllene.In addition,we identified several other pathways with variations at both the transcriptional and metabolic levels in MT.It’s interesting to found those upregulated metabolites in MT,such as eukaryotic lipids,kaempferol and proline also showed strong positive correlation with valencene along with fruit maturation while those down-regulated metabolites,such as phenylpropanoid coumarins and most of the modified flavonoids exhibited negative correlation.We then categorized these shifted pathways into the‘sesquitepenoid-identical shunt’and the sesquitepenoid-opposite shunt’and confirmed the classification result at transcriptional level.Our results provide important insights into the connections between various fruit quality-related properties.展开更多
BACKGROUND Esophageal cancer is one of the most poorly diagnosed and fatal cancers in the world.Although a series of studies on esophageal cancer have been reported,the molecular pathogenesis of the disease remains el...BACKGROUND Esophageal cancer is one of the most poorly diagnosed and fatal cancers in the world.Although a series of studies on esophageal cancer have been reported,the molecular pathogenesis of the disease remains elusive.AIM To investigate comprehensively the molecular process of esophageal cancer.METHODS Differential expression analysis was performed to identify differentially expressed genes(DEGs)in different stages of esophageal cancer from The Cancer Genome Atlas data.Exacting gene interaction modules were generated,and hub genes in the module interaction network were found.Further,through survival analysis,methylation analysis,pivot analysis,and enrichment analysis,some important molecules and related functions/pathways were identified to elucidate potential mechanisms in esophageal cancer.RESULTS A total of 7457 DEGs and 14 gene interaction modules were identified.These module genes were significantly involved in the positive regulation of protein transport,gastric acid secretion,insulin-like growth factor receptor binding,and other biological processes as well as p53 signaling pathway,epidermal growth factor signaling pathway,and epidermal growth factor receptor signaling pathway.Transcription factors(including hypoxia inducible factor 1A)and noncoding RNAs(including colorectal differentially expressed and hsa-miR-330-3p)that significantly regulate dysfunction modules were identified.Survival analysis showed that G protein subunit gamma transducin 2(GNGT2)was closely related to survival of esophageal cancer.DEGs with strong methylation regulation ability were identified,including SST and SH3GL2.Furthermore,the expression of GNGT2 was evaluated by quantitative real time polymerase chain reaction,and the results showed that GNGT2 expression was significantly upregulated in esophageal cancer patient samples and cell lines.Moreover,cell counting kit-8 assay revealed that GNGT2 could promote the proliferation of esophageal cancer cell lines.CONCLUSION This study not only revealed the potential regulatory factors involved in the development of esophageal cancer but also deepens our understanding of its underlying mechanism.展开更多
Prior exposure to microbial-associated molecular patterns or specific chemical compounds can promote plants into a primed state with stronger defence responses.β-aminobutyric acid(BABA)is an endogenous stress metabol...Prior exposure to microbial-associated molecular patterns or specific chemical compounds can promote plants into a primed state with stronger defence responses.β-aminobutyric acid(BABA)is an endogenous stress metabolite that induces resistance protecting various plants towards diverse stresses.In this study,by integrating BABA-induced changes in selected metabolites with transcriptome and proteome data,we generated a global map of the molecular processes operating in BABA-induced resistance(BABA-IR)in tomato.BABA significantly restricts the growth of the pathogens Oidium neolycopersici and Phytophthora parasitica but not Botrytis cinerea.A cluster analysis of the upregulated processes showed that BABA acts mainly as a stress factor in tomato.The main factor distinguishing BABA-IR from other stress conditions was the extensive induction of signaling and perception machinery playing a key role in effective resistance against pathogens.Interestingly,the signalling processes and immune response activated during BABA-IR in tomato differed from those in Arabidopsis with substantial enrichment of genes associated with jasmonic acid(JA)and ethylene(ET)signalling and no change in Asp levels.Our results revealed key differences between the effect of BABA on tomato and other model plants studied until now.Surprisingly,salicylic acid(SA)is not involved in BABA downstream signalization whereas ET and JA play a crucial role.展开更多
Our understanding of intricate biological systems has been completely transformed by the development of multi-omics approaches,which entail the simultaneous study of several different molecular data types.However,ther...Our understanding of intricate biological systems has been completely transformed by the development of multi-omics approaches,which entail the simultaneous study of several different molecular data types.However,there are many obstacles to overcome when analyzing multi-omics data,including the requirement for sophisticated data processing and analysis tools.The integration of multi-omics research with artificial intelligence(AI)has the potential to fundamentally alter our understanding of biological systems.AI has emerged as an effective tool for evaluating complicated data sets.The application of AI and data processing techniques in multiomics analysis is explored in this study.The present study articulates the diverse categories of information generated by multi-omics methodologies and the intricacies involved in managing and merging these datasets.Additionally,it looks at the various AI techniquesDsuch as machine learning,deep learning,and neural networksDthat have been created for multi-omics analysis.The assessment comes to the conclusion that multiomics analysis has a lot of potential to change with the integration of AI and data processing techniques.AI can speed up the discovery of new biomarkers and therapeutic targets as well as the advancement of personalized medicine strategies by enabling the integration and analysis of massive and complicated data sets.The necessity for high-quality data sets and the creation of useful algorithms and models are some of the difficulties that come with using AI in multi-omics study.In order to fully exploit the promise of AI in multi-omics analysis,more study in this area is required.展开更多
Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely...Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely unknown.Here,we pinpoint GRB10 specificity in muscle tissue and cells between obese and lean pigs by combining genomics,transcriptomics,epigenomics,and single-cell transcriptomics.GRB10 shows notable differences in divergent selection on haplotype blocks and expression levels between obese and lean pig breeds,with its expression profiles varying significantly by tissue and development stage.Notably,we identify a muscle-specific promoter of GRB10 and its transcription factor KLF15.This TF-promoter binding is verified by dual luciferase and chromatin immunoprecipitation(Ch IP)assays,and is suggested to be conserved in humans.Single-nucleus RNA sequencing further highlights differential expression patterns of GRB10 between obese and lean pig breeds across various cell types.Type IIa myonuclei and TTN+FAPs,which are more predominant in lean pigs,play a crucial role in myofibril assembly and muscle tissue development.These findings offer insights into the regulatory mechanisms controlling muscle growth.They highlight the tissue-and cell type-specific effects of GRB10 on muscle heterogeneity,which has potential applications in livestock breeding and human obesity research.展开更多
Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expre...Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.展开更多
Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adeno...Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adenocarcinoma(LUAD)accounts for approximately 40%of all lung cancer cases.1 Due to the heterogeneity of LUAD,accurate categorization is required to create a treatment plan for LUAD patients,while the existing paradigm does not adequately capture the enormously heterogeneous characteristics of LUAD.The rise of epigenetics has brought new perspectives for tumor heterogeneity exploration.Epigenetic modifications,such as aberrant DNA methylation and microRNA(miRNA),are essential in controlling gene expression,heterogeneity,and clinical implication.2 Meanwhile,epigenetic disruptions contribute to lung cancer tumorigenesis,the generation of a malignant phenotype and aggression,and chemoresistance,which could serve as credible biomarkers for lung cancer molecular categorization,early diagnosis,prognosis classification,and treatment efficacy prediction.3 Through integrative clustering of the gene expression profiles regulated by epigenetics,we determined and validated four lung adenocarcinoma epigenetic subtypes(LAESs)with distinct prognoses and biological peculiarities from four independent multi-center lung adenocarcinoma cohorts.展开更多
Dopamine can be used to treat depression,myocardial infarction,and other diseases.However,few reports are available on the de novo microbial synthesis of dopamine from low-cost substrate.In this study,integrated omics...Dopamine can be used to treat depression,myocardial infarction,and other diseases.However,few reports are available on the de novo microbial synthesis of dopamine from low-cost substrate.In this study,integrated omics technology was used to explore the dopamine metabolism of a novel marine multi-stress-tolerant aromatic yeast Meyerozyma guilliermondii GXDK6.GXDK6 was found to have the ability to biosynthesize dopamine when using glucose as the substrate.14 key genes for the biosynthesis of dopamine were identified by whole genome-wide analysis.Transcriptomic and proteomic data showed that the expression levels of gene AAT2 encoding aspartate aminotransferase(regulating dopamine anabolism)were upregulated,while gene AO-I encoding copper amine oxidase(involved in dopamine catabolism)were downregulated under 10%NaCl stress compared with non-NaCl stress,thereby contributing to biosynthesis of dopamine.Further,the amount of dopamine under 10%NaCl stress was 2.51-fold higher than that of zero NaCl,which was consistent with the multi-omics results.Real-time fluorescence quantitative PCR(RT-qPCR)and high-performance liquid chromatography(HPLC)results confirmed the metabolic model of dopamine.Furthermore,by overexpressing AAT2,AST enzyme activity was increased by 24.89%,the expression of genes related to dopamine metabolism was enhanced,and dopamine production was increased by 56.36%in recombinant GXDK6AAT2.In conclusion,Meyerozyma guilliermondii GXDK6 could utilize low-cost carbon source to synthesize dopamine,and NaCl stress promoted the biosynthesis of dopamine.展开更多
Background As an indigenous livestock species on the Tibetan Plateau,Tibetan sheep exhibit remarkable adaptability to low temperatures and nutrient-scarce environments.During the cold season,Tibetan sheep are typicall...Background As an indigenous livestock species on the Tibetan Plateau,Tibetan sheep exhibit remarkable adaptability to low temperatures and nutrient-scarce environments.During the cold season,Tibetan sheep are typically managed under two feeding regimes:barn feeding(BF)and traditional grazing(TG).However,the molecular mechanisms underlying their adaptation to these distinct management strategies remain unclear.This study aimed to investigate the adaptive strategies of rumen function in Tibetan sheep to cold-season feeding regimes by integrating analyses of rumen morphology,microbiome,metabolome,and transcriptome.Twelve healthy Tibetan sheep with similar body weights were assigned into two groups(BF vs.TG).At the end of the experiment,rumen tissues were subjected to histological observation.Multi-omics techniques were employed to evaluate the effects of cold-season feeding regimes on rumen function in Tibetan sheep.Results The ruminal papilla height,width,and muscular thickness were significantly higher in BF group.The relative abundances of Actinobacteria and Succiniclasticum were significantly elevated in the rumen of BF group,whereas Rikenellaceae,Gracilibacteria,and Lachnospiraceae showed higher abundances in the TG group.Metabolomic analysis identified 19 differential metabolites between the two groups,including upregulated compounds in BF group(fumaric acid,maltose,L-phenylalanine,and L-alanine)and TG group(e.g.,phenylacetic acid,salicyluric acid and ferulic acid).These metabolites were predominantly enriched in phenylalanine metabolism,alanine,aspartate and glutamate metabolism,and phenylalanine,tyrosine and tryptophan biosynthesis pathways.Additionally,210 differentially expressed genes(DEGs)were identified in rumen epithelium:100 upregulated DEGs in the BF group were enriched in nutrient metabolism-related pathways(e.g.,fatty acid degradation and PPAR signaling pathway),while 110 upregulated DEGs in the TG group were associated with immune-related pathways(e.g.,p53 signaling pathway and glutathione metabolism).Conclusions Among these,we observed distinct rumen functional responses to different cold-season feeding regimes in Tibetan sheep and revealed energy allocation strategies mediated by host-microbe interactions.In the BF group,Tibetan sheep adopted a"metabolic efficiency-priority"strategy,driving rumen microbiota to maximize energy capture from high-nutrient diets to support host growth.In contrast,the TG group exhibited an"environmental adaptation-priority"strategy,where rumen microbiota prioritized cellulose degradation and anti-inflammatory functions,reallocating energy toward homeostasis maintenance at the expense of rumen development and growth performance.展开更多
Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics...Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.展开更多
SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination.The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping abilit...SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination.The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences.Molecular markers for evaluating the pathogenicity of new variants are therefore needed.By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels,six key molecules on the polyamine biosynthesis pathway including putrescine,SAM,dc-SAM,ODC1,SAMS,and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants.To validate our discovery,human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients.Using ODC1 as a proof-ofconcept,differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system(RAS)and positively associated with ACE2 activity.Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern(VOCs)and was found to be correlated with each VOCs’pathogenic properties.Particularly,the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models.Our work,therefore,presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.展开更多
Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering va...Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering valuable insights into tumor biology and potential treatment strategies.Methods:We conducted a comprehensive multi-omics analysis of 132 patients with American Joint Committee on Cancer(AJCC)stage III TNBC,comprising 36 long-term survivors(RFS≥8 years),62 moderate-term survivors(RFS:3-8 years),and 34 short-term survivors(RFS<3 years).Analyses investigated clinicopathological factors,whole-exome sequencing,germline mutations,copy number alterations(CNAs),RNA sequences,and metabolomic profiles.Results:Long-term survivors exhibited fewer metastatic regional lymph nodes,along with tumors showing reduced stromal fibrosis and lower Ki67 index.Molecularly,these tumors exhibited multiple alterations in genes related to homologous recombination repair,with higher frequencies of germline mutations and somatic CNAs.Additionally,tumors from long-term survivors demonstrated significant downregulation of the RTK-RAS signaling pathway.Metabolomic profiling revealed decreased levels of lipids and carbohydrate,particularly those involved in glycerophospholipid,fructose,and mannose metabolism,in long-term survival group.Multivariate Cox analysis identified fibrosis[hazard ratio(HR):12.70,95%confidence interval(95%CI):2.19-73.54,P=0.005]and RAC1copy number loss/deletion(HR:0.22,95%CI:0.06-0.83,P=0.026)as independent predictors of RFS.Higher fructose/mannose metabolism was associated with worse overall survival(HR:1.30,95%CI:1.01-1.68,P=0.045).Our findings emphasize the association between biological determinants and prolonged survival in patients with TNBC.Conclusions:Our study systematically identified the key molecular and metabolic features associated with prolonged survival in AJCC stage III TNBC,suggesting potential therapeutic targets to improve patient outcomes.展开更多
Background:Early detection,timely diagnosis and rapid response are essential for case management and precautions of burn-associated sepsis.However,studies on indicators for early warning and intervention have rarely b...Background:Early detection,timely diagnosis and rapid response are essential for case management and precautions of burn-associated sepsis.However,studies on indicators for early warning and intervention have rarely been conducted.This study was performed to better understand the pathophysiological changes and targets for prevention of severe burn injuries.Methods:We conducted a multi-center,prospective multi-omics study,including genomics,microRNAomics,proteomics and single-cell transcriptomics,in 60 patients with severe burn injuries.A mouse model of severe burn injuries was also constructed to verify the early warning ability and therapeutic effects of potential markers.Results:Through genomic analysis,we identified seven important susceptibility genes(DNAH11,LAMA2,ABCA2,ZFAND4,CEP290,MUC20 and ENTPD1)in patients with severe burn injuries complicated with sepsis.Through plasma miRNAomics studies,we identified four miRNAs(hsamiR-16-5p,hsa-miR-185-5p,hsa-miR-451a and hsa-miR-423-5p)that may serve as early warning markers of burn-associated sepsis.A proteomic study indicated the changes in abundance of major proteins at different time points after severe burn injury and revealed the candidate early warning markers S100A8 and SERPINA10.In addition,the proteomic analysis indicated that neutrophils play an important role in the pathogenesis of severe burn injuries,as also supported by findings from single-cell transcriptome sequencing of neutrophils.Through further studies on severely burned mice,we determined that S100A8 is also a potential early therapeutic target for severe burn injuries,beyond being an early warning indicator.Conclusions:Our multi-omics study identified seven susceptibility genes,four miRNAs and two proteins as early warning markers for severe burn-associated sepsis.In severe burn-associated sepsis,the protein S100A8 has both warning and therapeutic effects.展开更多
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.
文摘Objective Recent studies have highlighted the critical role of NUDT19 in the initiation,progression,and prognosis of specific cancer types.However,its involvement in pan-cancer analysis has not been fully characterized.This study aims to systematically explore the expression patterns,clinical significance,and immune-related functions of NUDT19 in various cancer types through multi-omics analysis,further revealing its potential role in cancer,particularly its functional and therapeutic target value in leukemia.Methods To achieve this goal,various bioinformatics approaches were employed to evaluate the expression patterns,clinical significance,and immune-related functions of NUDT19 in tumors and normal tissues.Additionally,we analyzed the mutation characteristics of NUDT19 and its relationship with epigenetic modifications.Using the single-cell analysis tool SingleCellBase,we explored the distribution of NUDT19 across different cell subpopulations in tumors.To validate these findings,qRT-PCR was used to measure NUDT19 expression levels in specific tumor cell lines,and we established acute myeloid leukemia(AML)cell lines(HL-60 and THP-1)to conduct NUDT19 knockdown and overexpression experiments,assessing its effects on leukemia cell proliferation,apoptosis,and invasion.Results Pan-cancer analysis revealed the dysregulated expression of NUDT19 across multiple cancer types,which was closely associated with poor prognosis,clinical staging,and diagnostic markers.Furthermore,NUDT19 was significantly correlated with tumor biomarkers,immune-related genes,and immune cell infiltration in different cancers.Mutation analysis showed that multiple mutations in NUDT19 were significantly associated with epigenetic changes.Single-cell analysis revealed the heterogeneity of NUDT19 expression in cancer cells,suggesting its potentially diverse functional roles in different cell subpopulations.qRT-PCR experiments confirmed the significant upregulation of NUDT19 in various tumor cell lines.In AML cell lines,NUDT19 knockdown led to reduced cell proliferation and invasion,with increased apoptosis,while NUDT19 overexpression significantly enhanced cell proliferation and invasion while reducing apoptosis.Conclusion This study demonstrates the diverse roles of NUDT19 in various cancer types,with a particularly prominent functional role in leukemia.NUDT19 is not only associated with tumor initiation and progression but may also influence cancer progression through the regulation of immune microenvironment and epigenetic mechanisms.Our research highlights the potential of NUDT19 as a therapeutic target,particularly for targeted therapies in malignancies such as leukemia,with significant clinical application prospects.
基金supported by the National Natural Science Foundation of China (U22A20277,81971373)Jiangsu Provincial Medical Key Discipline Cultivation Unit (JSDW202215)+1 种基金333 High-level Personnel Training Project of Jiangsu Province (BRA2019109)Postgraduate Research&Practice Innovation Program of Jiangsu Province (KYCX22_1826)。
文摘Increasing evidence implicates disruptions in testicular fatty acid metabolism as a contributing factor in nonobstructive azoospermia(NOA),a severe form of male infertility.However,the precise mechanisms linking fatty acid metabolism to NOA pathogenesis have not yet been fully elucidated.Multi-omics analyses,including microarray analysis,single-cell RNA sequencing(scRNA-seq),and metabolomics,were utilized to investigate disruptions in fatty acid metabolism associated with NOA using data from public databases.Results identified ACSL6,ACSBG2,and OLAH as key genes linked to fatty acid metabolism dysregulation,suggesting their potential causative roles in NOA.A marked reduction in omega-3 polyunsaturated fatty acids,especially docosahexaenoic acid(DHA),was observed,potentially contributing to the pathological process of NOA.Sertoli cells in NOA patients exhibited apparent fatty acid metabolic dysfunction,with PPARG identified as a key transcription factor(TF)regulating this process.Functional analyses demonstrated that PPARG is crucial for maintaining blood-testis barrier(BTB)integrity and promoting spermatogenesis via regulation of fatty acid metabolism.These findings reveal the pivotal role of fatty acid metabolism in NOA and identify PPARG as a potential therapeutic target.
基金supported by the BRAVE Agile Investment from the PNNL
文摘Background:Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations,such as firefighting,law enforcement,military,and sports.A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work environment.Methods:To study regulatory processes in intense physical activity simulating real-life conditions,we performed a multi-omics analysis of 3 biofluids(blood plasma,urine,and saliva)collected from 11 wildland firefighters before and after a 45 min,intense exercise regimen.Omics profiles post-vs.pre-exercise were compared by Student’s t-test followed by pathway analysis and comparison between the different omics modalities.Results:Our multi-omics analysis identified and quantified 3835 proteins,730 lipids and 182 metabolites combining the 3 different types of samples.The blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy demands.The urine analysis showed a strong,concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites,reabsorption of nutrients and maintenance of fluid balance.In saliva,we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides.A systematic literature review identified 6 papers that support an altered susceptibility to respiratory infection.Conclusions:This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility,suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.
基金supported by the Chinese Academy of Agricultural Sciences Innovation Project(Grant No.CAASASTIP-2013CNRRI)Fundamental Research Funds for Central Public Welfare Research Institutes of Chinese Rice Research Institute(Grant No.CPSIBRF-CNRRI-202102)。
文摘Accurate genomic information is essential for advancing genetic breeding research in specific rice varieties.This study presented a gapless genome assembly of the indica rice cultivar Zhonghui 8015(ZH8015)using Pac Bio HiFi,Hi-C,and ONT(Oxford Nanopore Technologies)ultra-long sequencing technologies,annotating 43037 gene structures.Subsequently,utilizing this genome along with transcriptomic and metabolomic techniques,we explored ZH8015's response to brown planthopper(BPH)infestation.Continuous transcriptomic sampling indicated significant changes in gene expression levels around 48 h after BPH feeding.Enrichment analysis revealed particularly significant alterations in genes related to reactive oxygen species scavenging and cell wall formation.Metabolomic results demonstrated marked increases in levels of several monosaccharides,which are components of the cell wall and dramatic changes in flavonoid contents.Omics association analysis identified differentially expressed genes associated with key metabolites,shedding light on ZH8015's response to BPH infestation.In summary,this study constructed a reliable genome sequence resource for ZH8015,and the preliminary multi-omics results will guide future insect-resistant breeding research.
基金supported by the National Natural Science Foundation of China(No.82172408)Shanghai Jiao Tong University Medical College“Two-hundred Talent”Program(No.20191829)+1 种基金The Second Three-Year Action Plan for Promoting Clinical Skills and Clinical Innovation in Municipal Hospitals of Shanghai Shenkang(No.SHDC2020CR4032)Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration(No.20DZ2254100).
文摘Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies,resulting in severe disability.Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation.However,different clusters of macrophages have various functions and receive multiple regulation,which are both still unknown.In our current study,multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury.The transcriptomes of over 74000 human single cells were profiled.As results,we found that SPP1^(+)macrophages,RGCC^(+)endothelial cells,ACKR1^(+)endothelial cells and ADAM12^(+)fibroblasts participated in tendon adhesion formation.Interestingly,despite specific fibrotic clusters in tendon adhesion,FOLR2^(+)macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells.Furthermore,ACKR1 was verified to regulate FOLR2^(+)macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26R^(tdTomato) mice to lethally irradiated Ackr1^(-/-)mice(Ackr1^(-/-)chimeras;deficient in ACKR1)and control mice(WT chimeras).Compared with WT chimeras,the decline of FOLR2^(+)macrophages was also observed,indicating that ACKR1 was specifically involved in FOLR2^(+)macrophages migration.Taken together,our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis,but also uncovered a novel antifibrotic cluster of macrophages and their origin.These results provide potential therapeutic targets against human tendon adhesion.
基金Supported by Beijing Science and Technology Program,No.Z211100002921028Capital’s Funds for Health Improvement and Research,No.CFH2022-2-2025。
文摘BACKGROUND Angiogenesis plays an important role in colon cancer(CC)progression.AIM To investigate the tumor microenvironment(TME)and intratumor microbes of angiogenesis subtypes(AGSs)and explore potential targets for antiangiogenic therapy in CC.METHODS The data were obtained from The Cancer Genome Atlas database and Gene Expression Omnibus database.K-means clustering was used to construct the AGSs.The prognostic model was constructed based on the differential genes between two subtypes.Single-cell analysis was used to analyze the expression level of SLC2A3 on different cells in CC,which was validated by immunofluorescence.Its biological functions were further explored in HUVECs.RESULTS CC samples were grouped into two AGSs(AGS-A and AGS-B)groups and patients in the AGS-B group had poor prognosis.Further analysis revealed that the AGS-B group had high infiltration of TME immune cells,but also exhibited high immune escape.The intratumor microbes were also different between the two subtypes.A convenient 6-gene angiogenesis-related signature(ARS),was established to identify AGSs and predict the prognosis in CC patients.SLC2A3 was selected as the representative gene of ARS,which was higher expressed in endothelial cells and promoted the migration of HUVECs.CONCLUSION Our study identified two AGSs with distinct prognoses,TME,and intratumor microbial compositions,which could provide potential explanations for the impact on the prognosis of CC.The reliable ARS model was further constructed,which could guide the personalized treatment.The SLC2A3 might be a potential target for antiangiogenic therapy.
基金financed by the National Natural Science Foundation of China (31772261)the Huazhong Agricultural University Scientific & Technological Self-Innovation Foundation (Program No.2017RC002) to Dr. Weiwei Wen
文摘Sesquiterpene valencene is dominant in flavedo tissues of sweet oranges and imparts a unique woody aroma.However,the interaction between the biosynthetic pathways of valencene and other nutritional compounds is less studied.Sesquiterpenoids were significantly accumulated in a previously reported glossy mutant of orange(MT)than the wild type(WT),especially valencene and caryophyllene.In addition,we identified several other pathways with variations at both the transcriptional and metabolic levels in MT.It’s interesting to found those upregulated metabolites in MT,such as eukaryotic lipids,kaempferol and proline also showed strong positive correlation with valencene along with fruit maturation while those down-regulated metabolites,such as phenylpropanoid coumarins and most of the modified flavonoids exhibited negative correlation.We then categorized these shifted pathways into the‘sesquitepenoid-identical shunt’and the sesquitepenoid-opposite shunt’and confirmed the classification result at transcriptional level.Our results provide important insights into the connections between various fruit quality-related properties.
基金Supported by Construction of Engineering Laboratory of Jilin Development and Reform Commission(grant no.3J115AK93429)Jilin Provincial Science and Technology Department Medical Health Project(grant no.3D5195001429)
文摘BACKGROUND Esophageal cancer is one of the most poorly diagnosed and fatal cancers in the world.Although a series of studies on esophageal cancer have been reported,the molecular pathogenesis of the disease remains elusive.AIM To investigate comprehensively the molecular process of esophageal cancer.METHODS Differential expression analysis was performed to identify differentially expressed genes(DEGs)in different stages of esophageal cancer from The Cancer Genome Atlas data.Exacting gene interaction modules were generated,and hub genes in the module interaction network were found.Further,through survival analysis,methylation analysis,pivot analysis,and enrichment analysis,some important molecules and related functions/pathways were identified to elucidate potential mechanisms in esophageal cancer.RESULTS A total of 7457 DEGs and 14 gene interaction modules were identified.These module genes were significantly involved in the positive regulation of protein transport,gastric acid secretion,insulin-like growth factor receptor binding,and other biological processes as well as p53 signaling pathway,epidermal growth factor signaling pathway,and epidermal growth factor receptor signaling pathway.Transcription factors(including hypoxia inducible factor 1A)and noncoding RNAs(including colorectal differentially expressed and hsa-miR-330-3p)that significantly regulate dysfunction modules were identified.Survival analysis showed that G protein subunit gamma transducin 2(GNGT2)was closely related to survival of esophageal cancer.DEGs with strong methylation regulation ability were identified,including SST and SH3GL2.Furthermore,the expression of GNGT2 was evaluated by quantitative real time polymerase chain reaction,and the results showed that GNGT2 expression was significantly upregulated in esophageal cancer patient samples and cell lines.Moreover,cell counting kit-8 assay revealed that GNGT2 could promote the proliferation of esophageal cancer cell lines.CONCLUSION This study not only revealed the potential regulatory factors involved in the development of esophageal cancer but also deepens our understanding of its underlying mechanism.
基金This project was supported by the National Infrastructure France Genomique(Commissariat aux Grands Investissements,ANR-10-INBS-09-03,ANR-10-INBS-09-02).
文摘Prior exposure to microbial-associated molecular patterns or specific chemical compounds can promote plants into a primed state with stronger defence responses.β-aminobutyric acid(BABA)is an endogenous stress metabolite that induces resistance protecting various plants towards diverse stresses.In this study,by integrating BABA-induced changes in selected metabolites with transcriptome and proteome data,we generated a global map of the molecular processes operating in BABA-induced resistance(BABA-IR)in tomato.BABA significantly restricts the growth of the pathogens Oidium neolycopersici and Phytophthora parasitica but not Botrytis cinerea.A cluster analysis of the upregulated processes showed that BABA acts mainly as a stress factor in tomato.The main factor distinguishing BABA-IR from other stress conditions was the extensive induction of signaling and perception machinery playing a key role in effective resistance against pathogens.Interestingly,the signalling processes and immune response activated during BABA-IR in tomato differed from those in Arabidopsis with substantial enrichment of genes associated with jasmonic acid(JA)and ethylene(ET)signalling and no change in Asp levels.Our results revealed key differences between the effect of BABA on tomato and other model plants studied until now.Surprisingly,salicylic acid(SA)is not involved in BABA downstream signalization whereas ET and JA play a crucial role.
文摘Our understanding of intricate biological systems has been completely transformed by the development of multi-omics approaches,which entail the simultaneous study of several different molecular data types.However,there are many obstacles to overcome when analyzing multi-omics data,including the requirement for sophisticated data processing and analysis tools.The integration of multi-omics research with artificial intelligence(AI)has the potential to fundamentally alter our understanding of biological systems.AI has emerged as an effective tool for evaluating complicated data sets.The application of AI and data processing techniques in multiomics analysis is explored in this study.The present study articulates the diverse categories of information generated by multi-omics methodologies and the intricacies involved in managing and merging these datasets.Additionally,it looks at the various AI techniquesDsuch as machine learning,deep learning,and neural networksDthat have been created for multi-omics analysis.The assessment comes to the conclusion that multiomics analysis has a lot of potential to change with the integration of AI and data processing techniques.AI can speed up the discovery of new biomarkers and therapeutic targets as well as the advancement of personalized medicine strategies by enabling the integration and analysis of massive and complicated data sets.The necessity for high-quality data sets and the creation of useful algorithms and models are some of the difficulties that come with using AI in multi-omics study.In order to fully exploit the promise of AI in multi-omics analysis,more study in this area is required.
基金supported by the National Natural Science Foundation of China(32172765)。
文摘Domestic pigs are shaped by artificial and natural selection into obese and lean types that are closely related to muscle tissue.However,the key genes and regulatory mechanisms behind these developments remain largely unknown.Here,we pinpoint GRB10 specificity in muscle tissue and cells between obese and lean pigs by combining genomics,transcriptomics,epigenomics,and single-cell transcriptomics.GRB10 shows notable differences in divergent selection on haplotype blocks and expression levels between obese and lean pig breeds,with its expression profiles varying significantly by tissue and development stage.Notably,we identify a muscle-specific promoter of GRB10 and its transcription factor KLF15.This TF-promoter binding is verified by dual luciferase and chromatin immunoprecipitation(Ch IP)assays,and is suggested to be conserved in humans.Single-nucleus RNA sequencing further highlights differential expression patterns of GRB10 between obese and lean pig breeds across various cell types.Type IIa myonuclei and TTN+FAPs,which are more predominant in lean pigs,play a crucial role in myofibril assembly and muscle tissue development.These findings offer insights into the regulatory mechanisms controlling muscle growth.They highlight the tissue-and cell type-specific effects of GRB10 on muscle heterogeneity,which has potential applications in livestock breeding and human obesity research.
基金the Central Guidance for Regional Science and Technology Development Projects(YDZJSX2024B010)Research project of Shanxi Provincial Health Commission(2024067)。
文摘Objective Pneumoconiosis,a lung disease caused by irreversible fibrosis,represents a significant public health burden.This study investigates the causal relationships between gut microbiota,gene methylation,gene expression,protein levels,and pneumoconiosis using a multi-omics approach and Mendelian randomization(MR).Methods We analyzed gut microbiota data from MiBioGen and Esteban et al.to assess their potential causal effects on pneumoconiosis subtypes(asbestosis,silicosis,and inorganic pneumoconiosis)using conventional and summary-data-based MR(SMR).Gene methylation and expression data from Genotype-Tissue Expression and eQTLGen,along with protein level data from deCODE and UK Biobank Pharma Proteomics Project,were examined in relation to pneumoconiosis data from FinnGen.To validate our findings,we assessed self-measured gut flora from a pneumoconiosis cohort and performed fine mapping,drug prediction,molecular docking,and Phenome-Wide Association Studies to explore relevant phenotypes of key genes.Results Three core gut microorganisms were identified:Romboutsia(OR=0.249)as a protective factor against silicosis,Pasteurellaceae(OR=3.207)and Haemophilus parainfluenzae(OR=2.343)as risk factors for inorganic pneumoconiosis.Additionally,mapping and quantitative trait loci analyses revealed that the genes VIM,STX8,and MIF were significantly associated with pneumoconiosis risk.Conclusions This multi-omics study highlights the associations between gut microbiota and key genes(VIM,STX8,MIF)with pneumoconiosis,offering insights into potential therapeutic targets and personalized treatment strategies.
基金supported by Henan Provincial Key Laboratory of Medicine and Henan Provincial Clinical Medical Research Center for Respiratory Diseases.
文摘Lung cancer is the leading cause of cancer-related mortality globally,including small-cell lung cancer and non-small-cell lung cancer.As the most prevalent histological subtype of non-small-cell lung cancer,lung adenocarcinoma(LUAD)accounts for approximately 40%of all lung cancer cases.1 Due to the heterogeneity of LUAD,accurate categorization is required to create a treatment plan for LUAD patients,while the existing paradigm does not adequately capture the enormously heterogeneous characteristics of LUAD.The rise of epigenetics has brought new perspectives for tumor heterogeneity exploration.Epigenetic modifications,such as aberrant DNA methylation and microRNA(miRNA),are essential in controlling gene expression,heterogeneity,and clinical implication.2 Meanwhile,epigenetic disruptions contribute to lung cancer tumorigenesis,the generation of a malignant phenotype and aggression,and chemoresistance,which could serve as credible biomarkers for lung cancer molecular categorization,early diagnosis,prognosis classification,and treatment efficacy prediction.3 Through integrative clustering of the gene expression profiles regulated by epigenetics,we determined and validated four lung adenocarcinoma epigenetic subtypes(LAESs)with distinct prognoses and biological peculiarities from four independent multi-center lung adenocarcinoma cohorts.
基金supported by the Funding Project of Chinese Central Government Guiding to the Guangxi Local Science and Technology Development(Grant No.GUIKEZY21195021)the Natural Science Fund for Distinguished Young Scholars of Guangxi Zhuang Autonomous Region of China(Grant No.2019GXNSFFA245011)+2 种基金the Funding Project of Chinese Central Government Guiding to the Nanning Local Science and Technology Development(Grant No.20231012)the Funding Projects of Guangxi Key Research and Development Plan(GUIKE AB23075173)the Funding Project of Technological Development from Angel Yeast(Chongzuo)Co.,Ltd.(Grant No.JS1006020230722019).
文摘Dopamine can be used to treat depression,myocardial infarction,and other diseases.However,few reports are available on the de novo microbial synthesis of dopamine from low-cost substrate.In this study,integrated omics technology was used to explore the dopamine metabolism of a novel marine multi-stress-tolerant aromatic yeast Meyerozyma guilliermondii GXDK6.GXDK6 was found to have the ability to biosynthesize dopamine when using glucose as the substrate.14 key genes for the biosynthesis of dopamine were identified by whole genome-wide analysis.Transcriptomic and proteomic data showed that the expression levels of gene AAT2 encoding aspartate aminotransferase(regulating dopamine anabolism)were upregulated,while gene AO-I encoding copper amine oxidase(involved in dopamine catabolism)were downregulated under 10%NaCl stress compared with non-NaCl stress,thereby contributing to biosynthesis of dopamine.Further,the amount of dopamine under 10%NaCl stress was 2.51-fold higher than that of zero NaCl,which was consistent with the multi-omics results.Real-time fluorescence quantitative PCR(RT-qPCR)and high-performance liquid chromatography(HPLC)results confirmed the metabolic model of dopamine.Furthermore,by overexpressing AAT2,AST enzyme activity was increased by 24.89%,the expression of genes related to dopamine metabolism was enhanced,and dopamine production was increased by 56.36%in recombinant GXDK6AAT2.In conclusion,Meyerozyma guilliermondii GXDK6 could utilize low-cost carbon source to synthesize dopamine,and NaCl stress promoted the biosynthesis of dopamine.
基金funded by the Chief Scientist Program of Qinghai Province(2024-SF-102)the Joint Special Project of Sanjiangyuan National Park(LHZX-2023-02).
文摘Background As an indigenous livestock species on the Tibetan Plateau,Tibetan sheep exhibit remarkable adaptability to low temperatures and nutrient-scarce environments.During the cold season,Tibetan sheep are typically managed under two feeding regimes:barn feeding(BF)and traditional grazing(TG).However,the molecular mechanisms underlying their adaptation to these distinct management strategies remain unclear.This study aimed to investigate the adaptive strategies of rumen function in Tibetan sheep to cold-season feeding regimes by integrating analyses of rumen morphology,microbiome,metabolome,and transcriptome.Twelve healthy Tibetan sheep with similar body weights were assigned into two groups(BF vs.TG).At the end of the experiment,rumen tissues were subjected to histological observation.Multi-omics techniques were employed to evaluate the effects of cold-season feeding regimes on rumen function in Tibetan sheep.Results The ruminal papilla height,width,and muscular thickness were significantly higher in BF group.The relative abundances of Actinobacteria and Succiniclasticum were significantly elevated in the rumen of BF group,whereas Rikenellaceae,Gracilibacteria,and Lachnospiraceae showed higher abundances in the TG group.Metabolomic analysis identified 19 differential metabolites between the two groups,including upregulated compounds in BF group(fumaric acid,maltose,L-phenylalanine,and L-alanine)and TG group(e.g.,phenylacetic acid,salicyluric acid and ferulic acid).These metabolites were predominantly enriched in phenylalanine metabolism,alanine,aspartate and glutamate metabolism,and phenylalanine,tyrosine and tryptophan biosynthesis pathways.Additionally,210 differentially expressed genes(DEGs)were identified in rumen epithelium:100 upregulated DEGs in the BF group were enriched in nutrient metabolism-related pathways(e.g.,fatty acid degradation and PPAR signaling pathway),while 110 upregulated DEGs in the TG group were associated with immune-related pathways(e.g.,p53 signaling pathway and glutathione metabolism).Conclusions Among these,we observed distinct rumen functional responses to different cold-season feeding regimes in Tibetan sheep and revealed energy allocation strategies mediated by host-microbe interactions.In the BF group,Tibetan sheep adopted a"metabolic efficiency-priority"strategy,driving rumen microbiota to maximize energy capture from high-nutrient diets to support host growth.In contrast,the TG group exhibited an"environmental adaptation-priority"strategy,where rumen microbiota prioritized cellulose degradation and anti-inflammatory functions,reallocating energy toward homeostasis maintenance at the expense of rumen development and growth performance.
基金This work received financial support from the National Natural Science Foundation of China(no.82070677 and 82201964)Natural Science and Technology Major Project of the Xiamen(no.3502Z20231034)+1 种基金Natural Science Fund for Distinguished Young Scholars of Fujian Province(no.2023J01310519)Natural Science Foundation of Xiamen(no.3502Z20227283 and 3502Z20227122).
文摘Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation(LT)is critical for precise clinical management strategies.Here,we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells(PBMCs)collected from LT patients(with and without acute cellular rejection[ACR])at 13 time points.Validation was performed in two independent cohorts with additional LT patients and healthy controls.Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition,expression programs,and interactions along this process.The intensity of the immune response differs between the ACR and non-ACR patients.Notably,the newly identified inflamed NK cells,CD14+RNASE2+monocytes,and FOS-expressing monocytes emerged as predictive indicators of ACR.This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery,providing a four-phase framework that aids the clinical management of LT patients.
基金This work was supported by the National Natural Science Foundation of China(21705137)the Theme-based Research Scheme(TRS,T11-709/21-N)+1 种基金the Collaborative Research Fund(CRF,C7042-21G)of the Research Grants Council of the HKSAR governmentthe Tier 1 Research Start-up Grants from Research Committee of Hong Kong Baptist University(162874).
文摘SARS-CoV-2 continues to threaten human society by generating novel variants via mutation and recombination.The high number of mutations that appeared in emerging variants not only enhanced their immune-escaping ability but also made it difficult to predict the pathogenicity and virulence based on viral nucleotide sequences.Molecular markers for evaluating the pathogenicity of new variants are therefore needed.By comparing host responses to wild-type and variants with attenuated pathogenicity at proteome and metabolome levels,six key molecules on the polyamine biosynthesis pathway including putrescine,SAM,dc-SAM,ODC1,SAMS,and SAMDC were found to be differentially upregulated and associated with pathogenicity of variants.To validate our discovery,human airway organoids were subsequently used which recapitulates SARS-CoV-2 replication in the airway epithelial cells of COVID-19 patients.Using ODC1 as a proof-ofconcept,differential activation of polyamine biosynthesis was found to be modulated by the renin-angiotensin system(RAS)and positively associated with ACE2 activity.Further experiments demonstrated that ODC1 expression could be differentially activated upon a panel of SARS-CoV-2 variants of concern(VOCs)and was found to be correlated with each VOCs’pathogenic properties.Particularly,the presented study revealed the discriminative ability of key molecules on polyamine biosynthesis as a predictive marker for virulence evaluation and assessment of SARS-CoV-2 variants in cell or organoid models.Our work,therefore,presented a practical strategy that could be potentially applied as an evaluation tool for the pathogenicity of current and emerging SARS-CoV-2 variants.
基金supported by grants from the Medical Engineering Jiont Fund of the Fudan University(No.IDH2310117)。
文摘Objective:Triple-negative breast cancer(TNBC)is a highly aggressive subtype that lacks targeted therapies,leading to a poorer prognosis.However,some patients achieve long-term recurrence-free survival(RFS),offering valuable insights into tumor biology and potential treatment strategies.Methods:We conducted a comprehensive multi-omics analysis of 132 patients with American Joint Committee on Cancer(AJCC)stage III TNBC,comprising 36 long-term survivors(RFS≥8 years),62 moderate-term survivors(RFS:3-8 years),and 34 short-term survivors(RFS<3 years).Analyses investigated clinicopathological factors,whole-exome sequencing,germline mutations,copy number alterations(CNAs),RNA sequences,and metabolomic profiles.Results:Long-term survivors exhibited fewer metastatic regional lymph nodes,along with tumors showing reduced stromal fibrosis and lower Ki67 index.Molecularly,these tumors exhibited multiple alterations in genes related to homologous recombination repair,with higher frequencies of germline mutations and somatic CNAs.Additionally,tumors from long-term survivors demonstrated significant downregulation of the RTK-RAS signaling pathway.Metabolomic profiling revealed decreased levels of lipids and carbohydrate,particularly those involved in glycerophospholipid,fructose,and mannose metabolism,in long-term survival group.Multivariate Cox analysis identified fibrosis[hazard ratio(HR):12.70,95%confidence interval(95%CI):2.19-73.54,P=0.005]and RAC1copy number loss/deletion(HR:0.22,95%CI:0.06-0.83,P=0.026)as independent predictors of RFS.Higher fructose/mannose metabolism was associated with worse overall survival(HR:1.30,95%CI:1.01-1.68,P=0.045).Our findings emphasize the association between biological determinants and prolonged survival in patients with TNBC.Conclusions:Our study systematically identified the key molecular and metabolic features associated with prolonged survival in AJCC stage III TNBC,suggesting potential therapeutic targets to improve patient outcomes.
基金supported by the National Natural Science Foundation of China,No.82072217,81772135 and U21A20370the Jiangsu Natural Science Foundation,No.BE2017695 and BK20201178.
文摘Background:Early detection,timely diagnosis and rapid response are essential for case management and precautions of burn-associated sepsis.However,studies on indicators for early warning and intervention have rarely been conducted.This study was performed to better understand the pathophysiological changes and targets for prevention of severe burn injuries.Methods:We conducted a multi-center,prospective multi-omics study,including genomics,microRNAomics,proteomics and single-cell transcriptomics,in 60 patients with severe burn injuries.A mouse model of severe burn injuries was also constructed to verify the early warning ability and therapeutic effects of potential markers.Results:Through genomic analysis,we identified seven important susceptibility genes(DNAH11,LAMA2,ABCA2,ZFAND4,CEP290,MUC20 and ENTPD1)in patients with severe burn injuries complicated with sepsis.Through plasma miRNAomics studies,we identified four miRNAs(hsamiR-16-5p,hsa-miR-185-5p,hsa-miR-451a and hsa-miR-423-5p)that may serve as early warning markers of burn-associated sepsis.A proteomic study indicated the changes in abundance of major proteins at different time points after severe burn injury and revealed the candidate early warning markers S100A8 and SERPINA10.In addition,the proteomic analysis indicated that neutrophils play an important role in the pathogenesis of severe burn injuries,as also supported by findings from single-cell transcriptome sequencing of neutrophils.Through further studies on severely burned mice,we determined that S100A8 is also a potential early therapeutic target for severe burn injuries,beyond being an early warning indicator.Conclusions:Our multi-omics study identified seven susceptibility genes,four miRNAs and two proteins as early warning markers for severe burn-associated sepsis.In severe burn-associated sepsis,the protein S100A8 has both warning and therapeutic effects.
