Background:Genome-wide association studies(GWAS)have identified thousands of genomic non-coding variants statistically associated with many human traits and diseases,including cancer.However,the functional interpretat...Background:Genome-wide association studies(GWAS)have identified thousands of genomic non-coding variants statistically associated with many human traits and diseases,including cancer.However,the functional interpretation of these non-coding variants remains a significant challenge in the post-GWAS era.Alternative polyadenylation(APA)plays an essential role in post-transcriptional regulation for most human genes.By employing different poly(A)sites,genes can either shorten or extend the 3'-UTRs that contain cu-regulatory elements such as miRNAs or RNA-binding protein binding sites.Therefore,APA can affect the mRNA stability,translation,and cellular localization of proteins.Population-scale studies have revealed many inherited genetic variants that potentially impact APA to further influence disease susceptibility and phenotypic diversity,but systematic computational investigations to delineate the connections are in their earliest states.Results:Here,we discuss the evolving definitions of the genetic basis of APA and the modern genomics tools to identify,characterize,and validate the genetic influences of APA events in human populations.We also explore the emerging and surprisingly complex molecular mechanisms that regulate APA and summarize the genetic control of APA that is associated with complex human diseases and traits.Conclusion:APA is an intermediate molecular phenotype that can translate human common non-coding variants to individual phenotypic variability and disease susceptibility.展开更多
Dendritic cells （DCs） comprise two functionally distinct subsets： plasmacytoid DCs （pDCs） and myeloid DCs （mDCs）. pDCs are specialized in rapid and massive se- cretion of type I interferon （IFN-I） in response...Dendritic cells （DCs） comprise two functionally distinct subsets： plasmacytoid DCs （pDCs） and myeloid DCs （mDCs）. pDCs are specialized in rapid and massive se- cretion of type I interferon （IFN-I） in response to nucleic acids through Toll like receptor （TLR）-7 or TLR-9. In this report, we characterized a CD56^＋ DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56^＋ DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56^＋ DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naive T cells without prior activation. These data suggest that the CD56^＋ DCs represent a novel mDC subset mixed with some pDC features. A CD4^＋CD56^＋ hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm （BPDCN） due to its expression of characteristic molecules of pDCs.However, we demonstrated that BPDCN is closer to CD56^＋ DCs than pDCs by global gene-expression pro- filing. Thus, we propose that the CD4^＋CD56^＋ neoplasm may be a tumor counterpart of CD56^＋ mDCs but not pDCs.展开更多
Mesoporous bioactive glasses(MBGs),which belong to the category of modern porous nanomaterials,have garnered significant attention due to their impressive biological activities,appealing physicochemical properties,and...Mesoporous bioactive glasses(MBGs),which belong to the category of modern porous nanomaterials,have garnered significant attention due to their impressive biological activities,appealing physicochemical properties,and desirable morphological features.They hold immense potential for utilization in diverse fields,including adsorption,separation,catalysis,bioengineering,and medicine.Despite possessing interior porous structures,excellent morphological characteristics,and superior biocompatibility,primitive MBGs face challenges related to weak encapsulation efficiency,drug loading,and mechanical strength when applied in biomedical fields.It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies,miscellaneous metal species,and their conjugates into the material surfaces or intrinsic mesoporous networks.The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications,such as stimuli-responsive drug delivery,with exceptional in-vivo performances.In view of the above,we outline the fabrication process of calcium-silicon-phosphorus based MBGs,followed by discussions on their significant progress in various engineered strategies involving surface functionalization,nanostructures,and network modification.Furthermore,we emphasize the recent advancements in the textural and physicochemical properties of MBGs,along with their theranostic potentials in multiple cancerous and non-cancerous diseases.Lastly,we recapitulate compelling viewpoints,with specific considerations given from bench to bedside.展开更多
Underlying the regulation of mammalian gene expression at the level of transcription is the structure and modifications of chromatin. Understanding the twisting structures of DNA wrapped around histones and their high...Underlying the regulation of mammalian gene expression at the level of transcription is the structure and modifications of chromatin. Understanding the twisting structures of DNA wrapped around histones and their higher-level ordering allows us to peek into a vast regulatory landscape.展开更多
Tandem repeats(TRs)are DNA sequences where specific nucleotide patterns are repeated consecutively along the DNA strand.TRs(~8.1%of the genome)constitute a substantial source of genetic diversity within the human geno...Tandem repeats(TRs)are DNA sequences where specific nucleotide patterns are repeated consecutively along the DNA strand.TRs(~8.1%of the genome)constitute a substantial source of genetic diversity within the human genome[1],influencing complex traits and disease susceptibilities across populations[2,3].Over the past 30 years,TR expansions have been linked to over 60 human diseases,predominantly neurological,including Huntington’s disease,fragile X syndrome,and frontotemporal dementia[3–5].The length of TRs varies,ranging from a few base pairs(bp)to thousands.They are typically categorized into two main types based on motif length:short tandem repeats(STRs),which consist of repeat units of 1–6 bp;and variable number tandem repeats,which have longer repeat units(≥7 bp)[1,4,5].TRs exhibit high levels of polymorphism,with mutation rates decreasing as motif length increases[6–8].TR variation can manifest in both coding and non-coding regions;notably,more than 90%of polymorphic TR loci are concentrated within intronic and intergenic regions[6].Although TRs significantly contribute to genetic variation,they have largely been overlooked in genomic research due to technical challenges in sequencing and analysis,a historical focus on single nucleotide variants(SNVs),limitations of bioinformatic tools,biased database representation,and underappreciated biological significance[2–6,9,10].This paper aims to describe the advancement of TR research in humans,focusing on large-scale characterizations,current resources,and limitations.展开更多
基金support from the National Institutes of Health grant R01-GM134539(EJ.W).
文摘Background:Genome-wide association studies(GWAS)have identified thousands of genomic non-coding variants statistically associated with many human traits and diseases,including cancer.However,the functional interpretation of these non-coding variants remains a significant challenge in the post-GWAS era.Alternative polyadenylation(APA)plays an essential role in post-transcriptional regulation for most human genes.By employing different poly(A)sites,genes can either shorten or extend the 3'-UTRs that contain cu-regulatory elements such as miRNAs or RNA-binding protein binding sites.Therefore,APA can affect the mRNA stability,translation,and cellular localization of proteins.Population-scale studies have revealed many inherited genetic variants that potentially impact APA to further influence disease susceptibility and phenotypic diversity,but systematic computational investigations to delineate the connections are in their earliest states.Results:Here,we discuss the evolving definitions of the genetic basis of APA and the modern genomics tools to identify,characterize,and validate the genetic influences of APA events in human populations.We also explore the emerging and surprisingly complex molecular mechanisms that regulate APA and summarize the genetic control of APA that is associated with complex human diseases and traits.Conclusion:APA is an intermediate molecular phenotype that can translate human common non-coding variants to individual phenotypic variability and disease susceptibility.
文摘Dendritic cells （DCs） comprise two functionally distinct subsets： plasmacytoid DCs （pDCs） and myeloid DCs （mDCs）. pDCs are specialized in rapid and massive se- cretion of type I interferon （IFN-I） in response to nucleic acids through Toll like receptor （TLR）-7 or TLR-9. In this report, we characterized a CD56^＋ DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56^＋ DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56^＋ DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naive T cells without prior activation. These data suggest that the CD56^＋ DCs represent a novel mDC subset mixed with some pDC features. A CD4^＋CD56^＋ hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm （BPDCN） due to its expression of characteristic molecules of pDCs.However, we demonstrated that BPDCN is closer to CD56^＋ DCs than pDCs by global gene-expression pro- filing. Thus, we propose that the CD4^＋CD56^＋ neoplasm may be a tumor counterpart of CD56^＋ mDCs but not pDCs.
基金funded by National Natural Science Foundation of China,grant 81701020National Natural Science Foundation of China,grant 82071081+1 种基金Shanghai Municipal Health and Family Planning Commission,grant 201740035China Postdoctoral Science Foundation,grant 2023M742318。
文摘Mesoporous bioactive glasses(MBGs),which belong to the category of modern porous nanomaterials,have garnered significant attention due to their impressive biological activities,appealing physicochemical properties,and desirable morphological features.They hold immense potential for utilization in diverse fields,including adsorption,separation,catalysis,bioengineering,and medicine.Despite possessing interior porous structures,excellent morphological characteristics,and superior biocompatibility,primitive MBGs face challenges related to weak encapsulation efficiency,drug loading,and mechanical strength when applied in biomedical fields.It is important to note that the advantageous attributes of MBGs can be effectively preserved by incorporating supramolecular assemblies,miscellaneous metal species,and their conjugates into the material surfaces or intrinsic mesoporous networks.The innovative advancements in these modified colloidal inorganic nanocarriers inspire researchers to explore novel applications,such as stimuli-responsive drug delivery,with exceptional in-vivo performances.In view of the above,we outline the fabrication process of calcium-silicon-phosphorus based MBGs,followed by discussions on their significant progress in various engineered strategies involving surface functionalization,nanostructures,and network modification.Furthermore,we emphasize the recent advancements in the textural and physicochemical properties of MBGs,along with their theranostic potentials in multiple cancerous and non-cancerous diseases.Lastly,we recapitulate compelling viewpoints,with specific considerations given from bench to bedside.
基金supported by the National Institutes of Health,United States,to Wei Li(Grant Nos.R01HG007538,R01CA193466,and R01CA228140)。
文摘Underlying the regulation of mammalian gene expression at the level of transcription is the structure and modifications of chromatin. Understanding the twisting structures of DNA wrapped around histones and their higher-level ordering allows us to peek into a vast regulatory landscape.
文摘Tandem repeats(TRs)are DNA sequences where specific nucleotide patterns are repeated consecutively along the DNA strand.TRs(~8.1%of the genome)constitute a substantial source of genetic diversity within the human genome[1],influencing complex traits and disease susceptibilities across populations[2,3].Over the past 30 years,TR expansions have been linked to over 60 human diseases,predominantly neurological,including Huntington’s disease,fragile X syndrome,and frontotemporal dementia[3–5].The length of TRs varies,ranging from a few base pairs(bp)to thousands.They are typically categorized into two main types based on motif length:short tandem repeats(STRs),which consist of repeat units of 1–6 bp;and variable number tandem repeats,which have longer repeat units(≥7 bp)[1,4,5].TRs exhibit high levels of polymorphism,with mutation rates decreasing as motif length increases[6–8].TR variation can manifest in both coding and non-coding regions;notably,more than 90%of polymorphic TR loci are concentrated within intronic and intergenic regions[6].Although TRs significantly contribute to genetic variation,they have largely been overlooked in genomic research due to technical challenges in sequencing and analysis,a historical focus on single nucleotide variants(SNVs),limitations of bioinformatic tools,biased database representation,and underappreciated biological significance[2–6,9,10].This paper aims to describe the advancement of TR research in humans,focusing on large-scale characterizations,current resources,and limitations.
