The amniote pallium,a vital component of the forebrain,exhibits considerable evolutionary divergence across species and mediates diverse functions,including sensory processing,memory formation,and learning.However,the...The amniote pallium,a vital component of the forebrain,exhibits considerable evolutionary divergence across species and mediates diverse functions,including sensory processing,memory formation,and learning.However,the relationships among pallial subregions in different species remain poorly characterized,particularly regarding the identification of homologous neurons and their transcriptional signatures.In this study,we utilized singlenucleus RNA sequencing to examine over 130?000 nuclei from the macaque(Macaca fascicularis)neocortex,complemented by datasets from humans(Homo sapiens),mice(Mus musculus),zebra finches(Taeniopygia guttata),turtles(Chrysemys picta bellii),and lizards(Pogona vitticeps),enablingcomprehensivecross-species comparison.Results revealed transcriptomic conservation and species-specific distinctions within the amniote pallium.Notable similarities were observed among cell subtypes,particularly within PVALB+inhibitory neurons,which exhibited species-preferred subtypes.Furthermore,correlations between pallial subregions and several transcription factor candidates were identified,including RARB,DLX2,STAT6,NR3C1,and THRB,with potential regulatory roles in gene expression in mammalian pallial neurons compared to their avian and reptilian counterparts.These results highlight the conserved nature of inhibitory neurons,remarkable regional divergence of excitatory neurons,and species-specific gene expression and regulation in amniote pallial neurons.Collectively,these findings provide valuable insights into the evolutionary dynamics of the amniote pallium.展开更多
CRISPR-Cas technology has revolutionized our ability to understand and engineer organisms,evolving from a singular Cas9 model to a diverse CRISPR toolbox.A critical bottleneck in developing new Cas proteins is identif...CRISPR-Cas technology has revolutionized our ability to understand and engineer organisms,evolving from a singular Cas9 model to a diverse CRISPR toolbox.A critical bottleneck in developing new Cas proteins is identifying protospacer adjacent motif(PAM)sequences.Due to the limitations of experimental methods,bioinformatics approaches have become essential.However,existing PAM prediction programs are limited by the small number of spacers in CRISPR-Cas systems,resulting in low accuracy.To address this,we develop PAMPHLET,a pipeline that uses homology searches to identify additional spacers,significantly increasing the number of spacers up to 18-fold.PAMPHLET is validated on 20 CRISPR-Cas systems and successfully predicts PAM sequences for 18 protospacers.These predictions are further validated using the DocMF platform,which characterizes protein-DNA recognition patterns via next-generation sequencing.The high consistency between PAMPHLET predictions and DocMF results for Cas proteins demonstrates the potential of PAMPHLET to enhance PAM sequence prediction accuracy,expedite the discovery process,and accelerate the development of CRISPR tools.展开更多
Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small population...Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.展开更多
Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking micr...Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking microbiota absence to systemic immune deficits remain incompletely defined.Here,droplet-based single-cell RNA sequencing of bone marrow and peripheral blood from both germ-free and specific pathogen-free mice was performed,identifying 25 transcriptionally distinct cell types.Neutrophil apoptosis was elevated in germ-free mice,potentially due to the absence of niacin dehydrogenase,a metabolite primarily produced by Pseudomonas.In addition,germ-free mice exhibited increased excretion of 5’-methylthioadenosine,enhanced ERK activation driven by reactive oxygen species,and disruption of bone marrow stromal antigen 2 signaling.Monocytes and CD8^(+)T cells from germ-free mice showed diminished responses to interferon-β and interferon-γ,consistent with heightened viral susceptibility.These findings establish a microbiota-dependent regulatory pathway linking immunodeficiency to microbial absence in germ-free mice,confirmed through complementary validation techniques.展开更多
Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health....Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health.The development of innovative tools for enhancing early CRC screening and diagnosis,along with novel treatments and therapies for improved management,remains an urgent necessity.CRC is intricately associated with the gut microbiota,which is integral to food digestion,nutrient generation,drug metabolism,metabolite production,immune enhancement,endocrine regulation,neurogenesis modulation,and the maintenance of physiologic and psychological equilibrium.Dysbiosis or imbalances in the gut microbiome have been implicated in various disorders,including CRC.Emerging evidence highlights the critical role of the gut microbiome in CRC pathogenesis and treatment,which presents potential opportunities for early detection and diagnosis.Despite substantial advances in understanding the relationship between the gut microbiota and CRC,significant challenges persist.Gaining a deeper and more detailed understanding of the interactions between the human microbiota and cancer is essential to fully realize the potential of the microbiota in cancer management.Unlike genetic factors,the gut microbiome is subject to modification,offering a promising avenue for the development of CRC treatments and drug discovery.This review provides an overview of the interactions between the human gut microbiome and CRC,while examining prospects for precision management of CRC.展开更多
基金supported by the National Key Research and Development Program (2022YEF0203200)National Science and Technology Innovation 2030 Major Program (STI2030-2021ZD0200100)National Key Research and Development Program (2018YFA0801400,2021YFA0805100)。
文摘The amniote pallium,a vital component of the forebrain,exhibits considerable evolutionary divergence across species and mediates diverse functions,including sensory processing,memory formation,and learning.However,the relationships among pallial subregions in different species remain poorly characterized,particularly regarding the identification of homologous neurons and their transcriptional signatures.In this study,we utilized singlenucleus RNA sequencing to examine over 130?000 nuclei from the macaque(Macaca fascicularis)neocortex,complemented by datasets from humans(Homo sapiens),mice(Mus musculus),zebra finches(Taeniopygia guttata),turtles(Chrysemys picta bellii),and lizards(Pogona vitticeps),enablingcomprehensivecross-species comparison.Results revealed transcriptomic conservation and species-specific distinctions within the amniote pallium.Notable similarities were observed among cell subtypes,particularly within PVALB+inhibitory neurons,which exhibited species-preferred subtypes.Furthermore,correlations between pallial subregions and several transcription factor candidates were identified,including RARB,DLX2,STAT6,NR3C1,and THRB,with potential regulatory roles in gene expression in mammalian pallial neurons compared to their avian and reptilian counterparts.These results highlight the conserved nature of inhibitory neurons,remarkable regional divergence of excitatory neurons,and species-specific gene expression and regulation in amniote pallial neurons.Collectively,these findings provide valuable insights into the evolutionary dynamics of the amniote pallium.
基金supported by grants from the Foundation for Distinguished Young Talents in Higher Education of Guangdong,China(2024KQNCX157)Our work was also supported in part by the Guangdong Provincial Key Laboratory of Interdisciplinary Research and Application for Data Science,BNU-HKBU United International College(2022B1212010006)+1 种基金in part by the Guangdong Higher Education Upgrading Plan(2021-2025)of“Rushing to the Top,Making Up Shortcomings and Strengthening Special Features”(R0400001-22)Additionally,we acknowledge support from the Zhuhai Basic and Applied Basic ResearchFoundation(2220004002717).
文摘CRISPR-Cas technology has revolutionized our ability to understand and engineer organisms,evolving from a singular Cas9 model to a diverse CRISPR toolbox.A critical bottleneck in developing new Cas proteins is identifying protospacer adjacent motif(PAM)sequences.Due to the limitations of experimental methods,bioinformatics approaches have become essential.However,existing PAM prediction programs are limited by the small number of spacers in CRISPR-Cas systems,resulting in low accuracy.To address this,we develop PAMPHLET,a pipeline that uses homology searches to identify additional spacers,significantly increasing the number of spacers up to 18-fold.PAMPHLET is validated on 20 CRISPR-Cas systems and successfully predicts PAM sequences for 18 protospacers.These predictions are further validated using the DocMF platform,which characterizes protein-DNA recognition patterns via next-generation sequencing.The high consistency between PAMPHLET predictions and DocMF results for Cas proteins demonstrates the potential of PAMPHLET to enhance PAM sequence prediction accuracy,expedite the discovery process,and accelerate the development of CRISPR tools.
基金supported by the Fundamental Research Funds for the Central Universities of China(2572022DQ03)the National Natural Science Foundation of China(32170517)+2 种基金the Guangdong Provincial Key Laboratory of Genome Read and Write(2017B030301011)the Start-up Scientific Foundation of Northeast Forestry University(60201524043)supported by China National GeneBank(CNGB).
文摘Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.
基金supported by the Science Technology and Innovation Commission of Shenzhen Municipality,China(SGCX20190919142801722)。
文摘Germ-free mice exhibit profound immunological immaturity.Despite recent studies emphasizing the role of specific bacterium-derived metabolites in immune cell development and differentiation,the mechanisms linking microbiota absence to systemic immune deficits remain incompletely defined.Here,droplet-based single-cell RNA sequencing of bone marrow and peripheral blood from both germ-free and specific pathogen-free mice was performed,identifying 25 transcriptionally distinct cell types.Neutrophil apoptosis was elevated in germ-free mice,potentially due to the absence of niacin dehydrogenase,a metabolite primarily produced by Pseudomonas.In addition,germ-free mice exhibited increased excretion of 5’-methylthioadenosine,enhanced ERK activation driven by reactive oxygen species,and disruption of bone marrow stromal antigen 2 signaling.Monocytes and CD8^(+)T cells from germ-free mice showed diminished responses to interferon-β and interferon-γ,consistent with heightened viral susceptibility.These findings establish a microbiota-dependent regulatory pathway linking immunodeficiency to microbial absence in germ-free mice,confirmed through complementary validation techniques.
基金the Hangzhou Institute of Medicine(HIM)and Chinese Academy of Sciences for supporting work of this article。
文摘Colorectal cancer(CRC)is a major contributor to global cancer-related mortality with increasing incidence rates in both developed and developing regions.Therefore,CRC presents a significant challenge to global health.The development of innovative tools for enhancing early CRC screening and diagnosis,along with novel treatments and therapies for improved management,remains an urgent necessity.CRC is intricately associated with the gut microbiota,which is integral to food digestion,nutrient generation,drug metabolism,metabolite production,immune enhancement,endocrine regulation,neurogenesis modulation,and the maintenance of physiologic and psychological equilibrium.Dysbiosis or imbalances in the gut microbiome have been implicated in various disorders,including CRC.Emerging evidence highlights the critical role of the gut microbiome in CRC pathogenesis and treatment,which presents potential opportunities for early detection and diagnosis.Despite substantial advances in understanding the relationship between the gut microbiota and CRC,significant challenges persist.Gaining a deeper and more detailed understanding of the interactions between the human microbiota and cancer is essential to fully realize the potential of the microbiota in cancer management.Unlike genetic factors,the gut microbiome is subject to modification,offering a promising avenue for the development of CRC treatments and drug discovery.This review provides an overview of the interactions between the human gut microbiome and CRC,while examining prospects for precision management of CRC.
