Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macro...Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.展开更多
Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown ...Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.展开更多
The occurrence of severe thalassemia,an inherited blood disorder that is either blood-transfusiondependent or fatal,can be mitigated through carrier screening.Here,we aim to evaluate the effectiveness and outcomes of ...The occurrence of severe thalassemia,an inherited blood disorder that is either blood-transfusiondependent or fatal,can be mitigated through carrier screening.Here,we aim to evaluate the effectiveness and outcomes of pre-conceptional and early pregnancy screening initiatives for severe thalassemia prevention in a diverse population of 28,043 women.Using next-generation sequencing(NGS),we identify 4,226(15.07%)thalassemia carriers across 29 ethnic groups and categorize them into high-(0.75%),low-(25.86%),and unknown-risk(69.19%)groups based on their spouses'screening results.Post-screening follow-up reveals 59 fetuses with severe thalassemia exclusively in high-risk couples,underscoring the efficacy of risk classification.Among 25,053 live births over 6 months of age,two severe thalassemia infants were born to unknown-risk couples,which was attributed to incomplete screening and late NGS-based testing for a rare variant.Notably,64 rare variants are identified in 287 individuals,highlighting the genetic heterogeneity of thalassemia.We also observe that migrant flow significantly impacts carrier rates,with 93.90%of migrants to Chenzhou originating from high-prevalence regions in southern China.Our study demonstrates that NGS-based screening during pre-conception and early pregnancy is effective for severe thalassemia prevention,emphasizing the need for continuous screening efforts in areas with high and underestimated prevalence.展开更多
Anther is a key male reproductive organ that is essential for the plant life cycle,from the sporophyte to the gametophyte generation.To explore the isoform-level transcriptional landscape of developing anthers in maiz...Anther is a key male reproductive organ that is essential for the plant life cycle,from the sporophyte to the gametophyte generation.To explore the isoform-level transcriptional landscape of developing anthers in maize(Zea mays L.),we analyzed Iso-Seq data from anthers collected at 10 developmental stages,together with strand-specific RNA-seq,CAGE-seq,and PAS-seq data.Of the 152,026 high-confidence full-length isoforms identified,68.8%have not been described;these include 22,365 isoforms that originate from previously unannotated loci and 82,167 novel isoforms that originate from annotated protein-coding genes.Using our newly developed strategy to detect dynamic expression patterns of isoforms,we identify 13,899 differentially variable regions(DVRs);surprisingly,1275 genes contain more than two DVRs,revealing highly efficient utilization of limited genic regions.We identify 7876 long non-coding RNAs(IncRNAs)from 4098 loci,most of which were preferentially expressed during cell differentiation and meiosis.We also detected 371 long-range interactions involving intergenic IncRNAs(lincRNAs);interestingly,243 were lincRNA-gene ones,and the interacting genes were highly expressed in anthers,suggesting that many potential IncRNA regulators of key genes are required for anther development.This study provides valuable resources and fundamental information for studying the essential transcripts of key genes during anther development.展开更多
Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.Ho...Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.展开更多
Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance...Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.展开更多
This study establishes and validates a method for the precise quantification of aquatic microbial loads using microbial diversity absolute quantitative sequencing.By adding synthetic spike-in DNA to water samples from...This study establishes and validates a method for the precise quantification of aquatic microbial loads using microbial diversity absolute quantitative sequencing.By adding synthetic spike-in DNA to water samples from the Dahei River prior to DNA extraction and 16S rRNA gene sequencing,it generates standard curves to convert sequencing data into absolute microbial copy numbers.The method,which is proved highly accurate(R^(2)>0.99),reveals a clear contrast between the river sites:the upstream community has not only a significantly higher total microbial load but also a completely different makeup of species compared to the downstream site.This approach effectively overcomes the limitations of relative abundance analysis,providing a powerful tool for environmental monitoring,and proposes key steps for future standardization to ensure data comparability and integration.展开更多
Marchantia polymorpha,a model liverwort,provides a valuable system for investigating the evolution of plant sexual reproduction.To explore the cellular landscape of its reproductive structures,we generate a single-nuc...Marchantia polymorpha,a model liverwort,provides a valuable system for investigating the evolution of plant sexual reproduction.To explore the cellular landscape of its reproductive structures,we generate a single-nucleus transcriptomic atlas of the antheridiophore,archegoniophore,and sporophyte.Using singlenucleus RNA sequencing(snRNA-seq),we capture over 30,000 high-quality nuclei and identify distinct cel populations.In the male organ,we characterize stages of spermatogenesis from early antheridium cells to mature sperm,revealing dynamic transcriptional programs including cell cycle regulation,chromatin remodeling,and calcium signaling.In the female organ,we define cell types including archegonial layers and secondary central cells.Sporophyte clusters are annotated as spores,elaters,capsule wall,foot,and seta cells,with transcriptional signatures related to structural support,stress response,and reproductive functions.Cross-species analysis indicates that capsule wall cells in liverworts are similar to tapetum cells.Notably,foot cells exhibit high expression of genes involved in sporopollenin biosynthesis and signaling pathways,serving as a central hub that mediates communication between the maternal gametophyte and the developing sporophyte.This study provides a comprehensive cellular and molecular map of M.polymorpha reproductive organs and sporophyte,establishing a framework for investigating the development and evolution of sexual reproduction in early land plants.展开更多
Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types ...Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types involved in this process,the underlying molecular and cellular mechanisms remain largely unexplored.In this study,we used single-cell RNA sequencing to profile distinct cell populations at different stages of spinal cord injury in zebrafish.Our analysis revealed that multiple subpopulations of neurons showed persistent activation of genes associated with axonal regeneration post injury,while molecular signals promoting growth cone collapse were inhibited.Radial glial cells exhibited significant proliferation and differentiation potential post injury,indicating their intrinsic roles in promoting neurogenesis and axonal regeneration,respectively.Additionally,we found that inflammatory factors rapidly decreased in the early stages following spinal cord injury,creating a microenvironment permissive for tissue repair and regeneration.Furthermore,oligodendrocytes lost maturity markers while exhibiting increased proliferation following injury.These findings demonstrated that the rapid and orderly regulation of inflammation,as well as the efficient proliferation and redifferentiation of new neurons and glial cells,enabled zebrafish to reconstruct the spinal cord.This research provides new insights into the cellular transitions and molecular programs that drive spinal cord regeneration,offering promising avenues for future research and therapeutic strategies.展开更多
Hyperpolarization of nuclear spins is crucial for advancing nuclear magnetic resonance and quantum information technologies,as nuclear spins typically exhibit extremely low polarization at room temperature due to thei...Hyperpolarization of nuclear spins is crucial for advancing nuclear magnetic resonance and quantum information technologies,as nuclear spins typically exhibit extremely low polarization at room temperature due to their small gyromagnetic ratios.A promising approach to achieving high nuclear spin polarization is transferring the polarization of electrons to nuclear spins.The nitrogen-vacancy(NV)center in diamond has emerged as a highly effective medium for this purpose,and various hyperpolarization protocols have been developed.Among these,the pulsed polarization(PulsePol)method has been extensively studied due to its robustness against static energy shifts of the electron spin.In this work,we present a novel polarization protocol and uncover a family of magic sequences for hyperpolarizing nuclear spins,with PulsePol emerging as a special case of our general approach.Notably,we demonstrate that some of these magic sequences exhibit significantly greater robustness compared to the PulsePol protocol in the presence of finite half𝜋pulse duration of the protocol,Rabi and detuning errors.This enhanced robustness positions our protocol as a more suitable candidate for hyper-polarizing nuclear spins species with large gyromagnetic ratios and also ensures better compatibility with high-efficiency readout techniques at high magnetic fields.Additionally,the generality of our protocol allows for its direct application to other solid-state quantum systems beyond the NV center.展开更多
In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome p...In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome prevention,and other reproductive strategies.Despite its availability for three decades,the clinical use of IVM remains limited due to efficacy and safety concerns.This study examines the DNA methylation profile of IVM oocytes collected during laparoscopic/hysteroscopic surgeries compared to in vivo matured oocytes via reduced representation bisulfite sequencing.Results indicate IVM oocytes exhibit a higher global methylation level.Differentially methylated regions(DMRs)analysis reveals that the in vitro group displays more hypermethylated and fewer hypomethylated DMRs compared to the in vivo group.Additionally,the in vitro group exhibits a higher level of non-CpG methylation than the in vivo group.However,no significant correlation between methylation levels and transcriptional activity in these oocytes is found,especially for those specific imprinted genes or genes related to embryonic development.These findings shed light on the epigenetic landscape of IvM oocytes,contributing to the ongoing assessment of their clinical feasibility and safety in assisted reproduction.展开更多
Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in m...Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.展开更多
Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways ...Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.展开更多
Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)...Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.展开更多
In the realm of bioinformatics and computational biology, the most rudimentary data upon which all the analysis is built is the sequence data of genes, proteins and RNA. The sequence data of the entire genome is the s...In the realm of bioinformatics and computational biology, the most rudimentary data upon which all the analysis is built is the sequence data of genes, proteins and RNA. The sequence data of the entire genome is the solution to the genome assembly problem. The scope of this contribution is to provide an overview on the art of problem-solving applied within the domain of genome assembly in the next- generation sequencing （NGS） platforms. This article discusses the major genome assemblers that were proposed in the literature during the past decade by outlining their basic working principles. It is intended to act as a qualitative, not a quantitative, tutorial to all working on genome assemblers pertaining to the next generation of sequencers. We discuss the theoretical aspects of various genome assemblers, identifying their working schemes. We also discuss briefly the direction in which the area is headed towards along with discussing core issues on software simplicity.展开更多
Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe n...Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.展开更多
Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage se...Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.展开更多
Helicobacter pylori(H.pylori)infection plays a critical role in gastric diseases,impacting the microbiota structure in gastric and duodenal ulcers.In their study,Jin et al utilized metagenomic sequencing to analyze mu...Helicobacter pylori(H.pylori)infection plays a critical role in gastric diseases,impacting the microbiota structure in gastric and duodenal ulcers.In their study,Jin et al utilized metagenomic sequencing to analyze mucosal samples from patients with ulcers and healthy controls,revealing significant changes in microbial diversity and composition.This article reviews their findings,emphasizing H.pylori’s role in gastric ulcers and the need for further research on its impact on duodenal ulcers.We evaluate the study’s strengths and limitations,suggesting future research directions to enhance our understanding of H.pylori’s contribution to ulcerative diseases.展开更多
基金supported by Qingdao Key Medical and Health Discipline ProjectThe Intramural Research Program of the Affiliated Hospital of Qingdao University,No. 4910Qingdao West Coast New Area Science and Technology Project,No. 2020-55 (all to SW)。
文摘Border-associated macrophages are located at the interface between the brain and the periphery, including the perivascular spaces, choroid plexus, and meninges. Until recently, the functions of border-associated macrophages have been poorly understood and largely overlooked. However, a recent study reported that border-associated macrophages participate in stroke-induced inflammation, although many details and the underlying mechanisms remain unclear. In this study, we performed a comprehensive single-cell analysis of mouse border-associated macrophages using sequencing data obtained from the Gene Expression Omnibus(GEO) database(GSE174574 and GSE225948). Differentially expressed genes were identified, and enrichment analysis was performed to identify the transcription profile of border-associated macrophages. CellChat analysis was conducted to determine the cell communication network of border-associated macrophages. Transcription factors were predicted using the ‘pySCENIC' tool. We found that, in response to hypoxia, borderassociated macrophages underwent dynamic transcriptional changes and participated in the regulation of inflammatory-related pathways. Notably, the tumor necrosis factor pathway was activated by border-associated macrophages following ischemic stroke. The pySCENIC analysis indicated that the activity of signal transducer and activator of transcription 3(Stat3) was obviously upregulated in stroke, suggesting that Stat3 inhibition may be a promising strategy for treating border-associated macrophages-induced neuroinflammation. Finally, we constructed an animal model to investigate the effects of border-associated macrophages depletion following a stroke. Treatment with liposomes containing clodronate significantly reduced infarct volume in the animals and improved neurological scores compared with untreated animals. Taken together, our results demonstrate comprehensive changes in border-associated macrophages following a stroke, providing a theoretical basis for targeting border-associated macrophages-induced neuroinflammation in stroke treatment.
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金supported by the National Natural Science Foundation of China,Nos.82471123,82171053the Jilin Province Special Project for Talent in Medical and Health Sciences,No.2024WSXK-E01the Natural Science Foundation of Jilin Province,YDZJ202501ZYTS318(all to GL).
文摘Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.
基金supported by the National Natural Science Foundation of China(81760037)Yunling Scholar Project of Yunnan Province(YNWR-YLXZ-2019-0005)+1 种基金Hunan Provincial Innovation Platform and Talent Program(2018SK4004)Hunan Provincial Natural Science Foundation(2019JJ80048).
文摘The occurrence of severe thalassemia,an inherited blood disorder that is either blood-transfusiondependent or fatal,can be mitigated through carrier screening.Here,we aim to evaluate the effectiveness and outcomes of pre-conceptional and early pregnancy screening initiatives for severe thalassemia prevention in a diverse population of 28,043 women.Using next-generation sequencing(NGS),we identify 4,226(15.07%)thalassemia carriers across 29 ethnic groups and categorize them into high-(0.75%),low-(25.86%),and unknown-risk(69.19%)groups based on their spouses'screening results.Post-screening follow-up reveals 59 fetuses with severe thalassemia exclusively in high-risk couples,underscoring the efficacy of risk classification.Among 25,053 live births over 6 months of age,two severe thalassemia infants were born to unknown-risk couples,which was attributed to incomplete screening and late NGS-based testing for a rare variant.Notably,64 rare variants are identified in 287 individuals,highlighting the genetic heterogeneity of thalassemia.We also observe that migrant flow significantly impacts carrier rates,with 93.90%of migrants to Chenzhou originating from high-prevalence regions in southern China.Our study demonstrates that NGS-based screening during pre-conception and early pregnancy is effective for severe thalassemia prevention,emphasizing the need for continuous screening efforts in areas with high and underestimated prevalence.
基金supported by the Excellent Young Scientists Fund(Category B)(32422063)the National Key Research and Development Program of China(2022YFF1003500)the Zhengzhou University Qiushi Postdoctoral Research Funding Program.For open access,the authors have applied for a Creative Commons Attribution(CC BY)license for any Author Accepted Manuscript version arising from this submission.
文摘Anther is a key male reproductive organ that is essential for the plant life cycle,from the sporophyte to the gametophyte generation.To explore the isoform-level transcriptional landscape of developing anthers in maize(Zea mays L.),we analyzed Iso-Seq data from anthers collected at 10 developmental stages,together with strand-specific RNA-seq,CAGE-seq,and PAS-seq data.Of the 152,026 high-confidence full-length isoforms identified,68.8%have not been described;these include 22,365 isoforms that originate from previously unannotated loci and 82,167 novel isoforms that originate from annotated protein-coding genes.Using our newly developed strategy to detect dynamic expression patterns of isoforms,we identify 13,899 differentially variable regions(DVRs);surprisingly,1275 genes contain more than two DVRs,revealing highly efficient utilization of limited genic regions.We identify 7876 long non-coding RNAs(IncRNAs)from 4098 loci,most of which were preferentially expressed during cell differentiation and meiosis.We also detected 371 long-range interactions involving intergenic IncRNAs(lincRNAs);interestingly,243 were lincRNA-gene ones,and the interacting genes were highly expressed in anthers,suggesting that many potential IncRNA regulators of key genes are required for anther development.This study provides valuable resources and fundamental information for studying the essential transcripts of key genes during anther development.
基金supported by the Fundamental Research Funds for the Central Universities(226-2022-00035)the National Natural Science Foundation of China(81600986).
文摘Down syndrome(DS)is caused by an extra copy of chromosome 21(Hsa21).Children with DS have an increased frequency of respiratory tract infections,impaired alveolar and vascular development,and pulmonary hypertension.How trisomy 21 causes lung diseases remains poorly understood.In this study,we use the Dp16 mouse model,which contains a segmental chromosomal duplication of the entire Hsa21 syntenic region on mouse chromosome 16,to explore the gene dosage effects on DS-related lung diseases.The Dp16 mice present impaired alveolar development and inflammatory-like pathological changes.Single-cell RNA sequencing(scRNA-seq)analysis highlights increased APP-related interactions among male Dp16 lung cells.Specifically,altered antigen processing and presentation with increased MHC-II signaling are found in Dp16 immune cells.Reduced angiogenesis and altered inflammatory responses of Dp16 endothelial cells are also suggested.Moreover,scRNA-seq indicates hyperplasia of Dp16 vascular smooth muscle cells,which is validated by tissue immunofluorescence assessment.Transthoracic echocardiography further shows the existence of pulmonary hypertension in young Dp16 mice.Independent scRNA-seq analysis of the female lung cells recapitulates the majority of key findings identified in male mice,confirming the reproducibility of the results.Collectively,our results provide important clues for the further development of therapeutic approaches for DS-related lung diseases.
基金supported by Ministry of Science and Technology China Brain Initiative Grant,No.2022ZD0204702(to ZY)the National Natural Science Foundation of China,No.82371357(to LC)+2 种基金Foundation for Military Medicine,No.16QNP085(to ZY)Navy Medical University Basic Medical College“Yi Zhang”Basic Medical Talent Development and Support Program,Nos.JCYZRC-D-022(to TC)and JCYZRC-D-024(to HD)Science and Technology Innovation Special Fund of Shanghai Baoshan District,No.2023-E-05(to YW).
文摘Macrophages in the brain barrier system include microglia in the brain parenchyma,border-associated macrophages at the brain’s borders,and recruited macrophages.They are responsible for neural development,maintenance of homeostasis,and orchestrating immune responses.With the rapid exploitation and development of new technologies,there is a deeper understanding of macrophages in the brain barrier system.Here we review the origin,development,important molecules,and functions of macrophages,mainly focusing on microglia and border-associated macrophages.We also highlight some advances in single-cell sequencing and significant cell markers.We anticipate that more advanced methods will emerge to study resident and recruited macrophages in the future,opening new horizons for neuroimmunology and related peripheral immune fields.
基金supported by the National Natural Science Foundation of China(Grant No.32160172)the Key Science-Technology Project of Inner Mongolia(2023KYPT0010)+1 种基金the Natural Science Foundation of Inner Mongolia Autonomous Region of China(Grant No.2025QN03006)the 2023 Inner Mongolia Public Institution High-level Talent Introduction Scientific Research Support Project.
文摘This study establishes and validates a method for the precise quantification of aquatic microbial loads using microbial diversity absolute quantitative sequencing.By adding synthetic spike-in DNA to water samples from the Dahei River prior to DNA extraction and 16S rRNA gene sequencing,it generates standard curves to convert sequencing data into absolute microbial copy numbers.The method,which is proved highly accurate(R^(2)>0.99),reveals a clear contrast between the river sites:the upstream community has not only a significantly higher total microbial load but also a completely different makeup of species compared to the downstream site.This approach effectively overcomes the limitations of relative abundance analysis,providing a powerful tool for environmental monitoring,and proposes key steps for future standardization to ensure data comparability and integration.
基金supported by the 10 KP project(https://db.cngb.org/1Okp/)and the Scientific Foundation of the Urban Management Bureau of Shenzhen(202403).
文摘Marchantia polymorpha,a model liverwort,provides a valuable system for investigating the evolution of plant sexual reproduction.To explore the cellular landscape of its reproductive structures,we generate a single-nucleus transcriptomic atlas of the antheridiophore,archegoniophore,and sporophyte.Using singlenucleus RNA sequencing(snRNA-seq),we capture over 30,000 high-quality nuclei and identify distinct cel populations.In the male organ,we characterize stages of spermatogenesis from early antheridium cells to mature sperm,revealing dynamic transcriptional programs including cell cycle regulation,chromatin remodeling,and calcium signaling.In the female organ,we define cell types including archegonial layers and secondary central cells.Sporophyte clusters are annotated as spores,elaters,capsule wall,foot,and seta cells,with transcriptional signatures related to structural support,stress response,and reproductive functions.Cross-species analysis indicates that capsule wall cells in liverworts are similar to tapetum cells.Notably,foot cells exhibit high expression of genes involved in sporopollenin biosynthesis and signaling pathways,serving as a central hub that mediates communication between the maternal gametophyte and the developing sporophyte.This study provides a comprehensive cellular and molecular map of M.polymorpha reproductive organs and sporophyte,establishing a framework for investigating the development and evolution of sexual reproduction in early land plants.
基金supported by the Jiangsu Province Traditional Chinese Medicine Technology Development Plan Project,Nos.MS2023113(to JC),MS2022090Young and Middle-aged Academic Leaders of Jiangsu Qing-Lan Project(to GL).
文摘Unlike mammals,zebrafish possess a remarkable ability to regenerate their spinal cord after injury,making them an ideal vertebrate model for studying regeneration.While previous research has identified key cell types involved in this process,the underlying molecular and cellular mechanisms remain largely unexplored.In this study,we used single-cell RNA sequencing to profile distinct cell populations at different stages of spinal cord injury in zebrafish.Our analysis revealed that multiple subpopulations of neurons showed persistent activation of genes associated with axonal regeneration post injury,while molecular signals promoting growth cone collapse were inhibited.Radial glial cells exhibited significant proliferation and differentiation potential post injury,indicating their intrinsic roles in promoting neurogenesis and axonal regeneration,respectively.Additionally,we found that inflammatory factors rapidly decreased in the early stages following spinal cord injury,creating a microenvironment permissive for tissue repair and regeneration.Furthermore,oligodendrocytes lost maturity markers while exhibiting increased proliferation following injury.These findings demonstrated that the rapid and orderly regulation of inflammation,as well as the efficient proliferation and redifferentiation of new neurons and glial cells,enabled zebrafish to reconstruct the spinal cord.This research provides new insights into the cellular transitions and molecular programs that drive spinal cord regeneration,offering promising avenues for future research and therapeutic strategies.
基金supported by the National Natural Science Foundation of China (Grant Nos.12475012,62461160263 for P.W.,and 62276171 for H.L.)Quantum Science and Technology-National Science and Technology Major Project of China (Project No.2023ZD0300600 for P.W.)+3 种基金Guangdong Provincial Quantum Science Strategic Initiative (Grant Nos.GDZX240-3009 and GDZX2303005 for P.W.)Guangdong Basic and Applied Basic Research Foundation (Grant No.2024-A1515011938 for H.L.)Shenzhen Fundamental ResearchGeneral Project (Grant No.JCYJ20240813141503005 for H.L.)the Talents Introduction Foundation of Beijing Normal University (Grant No.310432106 for P.W.)。
文摘Hyperpolarization of nuclear spins is crucial for advancing nuclear magnetic resonance and quantum information technologies,as nuclear spins typically exhibit extremely low polarization at room temperature due to their small gyromagnetic ratios.A promising approach to achieving high nuclear spin polarization is transferring the polarization of electrons to nuclear spins.The nitrogen-vacancy(NV)center in diamond has emerged as a highly effective medium for this purpose,and various hyperpolarization protocols have been developed.Among these,the pulsed polarization(PulsePol)method has been extensively studied due to its robustness against static energy shifts of the electron spin.In this work,we present a novel polarization protocol and uncover a family of magic sequences for hyperpolarizing nuclear spins,with PulsePol emerging as a special case of our general approach.Notably,we demonstrate that some of these magic sequences exhibit significantly greater robustness compared to the PulsePol protocol in the presence of finite half𝜋pulse duration of the protocol,Rabi and detuning errors.This enhanced robustness positions our protocol as a more suitable candidate for hyper-polarizing nuclear spins species with large gyromagnetic ratios and also ensures better compatibility with high-efficiency readout techniques at high magnetic fields.Additionally,the generality of our protocol allows for its direct application to other solid-state quantum systems beyond the NV center.
基金supported by funding from the National Natural Science Foundation of China(81971349 and 81300456).
文摘In vitro maturation(IvM)of human oocytes offers cost efficiency and minimal invasiveness,serving as a valuable supplementary tool in assisted reproduction for fertility preservation,ovarian hyperstimulation syndrome prevention,and other reproductive strategies.Despite its availability for three decades,the clinical use of IVM remains limited due to efficacy and safety concerns.This study examines the DNA methylation profile of IVM oocytes collected during laparoscopic/hysteroscopic surgeries compared to in vivo matured oocytes via reduced representation bisulfite sequencing.Results indicate IVM oocytes exhibit a higher global methylation level.Differentially methylated regions(DMRs)analysis reveals that the in vitro group displays more hypermethylated and fewer hypomethylated DMRs compared to the in vivo group.Additionally,the in vitro group exhibits a higher level of non-CpG methylation than the in vivo group.However,no significant correlation between methylation levels and transcriptional activity in these oocytes is found,especially for those specific imprinted genes or genes related to embryonic development.These findings shed light on the epigenetic landscape of IvM oocytes,contributing to the ongoing assessment of their clinical feasibility and safety in assisted reproduction.
基金supported by the National Science Foundation of China(No.82405004,82474253)the Natural Science Foundation postdoctoral project of Chongqing(CSTB2022NSCQ-BHX0709)+2 种基金Chongqing Wanzhou District doctoral“through train”scientific research project(wzstc-20220124)Natural Science Foundation of Chongqing,China(No.Cstc2021jcyj-msxmX0996)Chongqing Wanzhou District Science and Health Joint Medical Research Project(wzstc-kw2023032)。
文摘Background:ZhiZi-BoPi Decoction(ZZBPD),a traditional prescription for liver and gallbladder protection,has garnered significant clinical interest due to its hepatoprotective properties.Despite its proven efficacy in mitigating intrahepatic cholestasis,the precise mechanisms underlying its therapeutic effects remain inadequately understood.This study aims to comprehensively investigate the pharmacological mechanisms underlying the therapeutic effects of ZZBPD in cholestatic liver injury(CLI).Methods:Firstly,we evaluated the hepatoprotective effects of ZZBPD on mice with CLI induced byα-naphthylisothiocyanate(ANIT),by measuring biochemical markers,inflammatory factors,and bile acid levels.Subsequently,we employed network pharmacology and single-cell RNA sequencing(scRNA-seq)to identify key targets and potential signaling pathways for the prevention and treatment of CLI.Finally,we further validated the mechanism of action of ZZBPD on these key targets through molecular docking,western blotting,and immunofluorescence techniques.Results:ZZBPD notably improved serum liver function,reduced hepatic inflammation,and restored bile acid balance.Through network pharmacology and scRNA-seq analysis,48 core targets were identified,including TNF,IL-6,and NFKB1,all of which are linked to the IL-17 and NF-κB signaling pathways,as shown by KEGG enrichment analysis.Molecular docking further confirmed stable interactions between ZZBPD’s key active components and molecules such as IL-6,IL-17,and NF-κB.Additionally,western blotting and immunofluorescence validated the downregulation of IL-17 and NF-κB protein expression in liver tissue.Conclusion:ZZBPD effectively treats CLI by activating pathways related to the bile acid receptor FXR,while also modulating the IL-17/NF-κB signaling pathway.This dual action enhances bile secretion and alleviates liver inflammation.These findings offer important insights into the pharmacological mechanisms of ZZBPD and underscore its potential as a promising therapeutic for CLI.
基金supported by the Foundation Project:National Natural Science.Foundation of China(Nos.:82460249,82100417,81760094)The Foundation of Jiangxi Provincial Department of Science and Technology Outstanding Youth Fund Project(20212BAB206022,20242BAB23080).
文摘Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.
基金supported by Guangdong Province Basic and Applied Basic Research Fund Project(2023A1515220104)Open Fund of Key Laboratory of Hepatoaplenic Surgery,Ministry of Education(Award Number:GPKF202407).
文摘Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.
基金funded by the University of Engineering and Technology,Lahore,Pakistan (Grant No. Estab/DBS/411)National Science Foundation(Grant No. 0915444)
文摘In the realm of bioinformatics and computational biology, the most rudimentary data upon which all the analysis is built is the sequence data of genes, proteins and RNA. The sequence data of the entire genome is the solution to the genome assembly problem. The scope of this contribution is to provide an overview on the art of problem-solving applied within the domain of genome assembly in the next- generation sequencing （NGS） platforms. This article discusses the major genome assemblers that were proposed in the literature during the past decade by outlining their basic working principles. It is intended to act as a qualitative, not a quantitative, tutorial to all working on genome assemblers pertaining to the next generation of sequencers. We discuss the theoretical aspects of various genome assemblers, identifying their working schemes. We also discuss briefly the direction in which the area is headed towards along with discussing core issues on software simplicity.
基金supported by the National Natural Science Foundation of China,Nos.82071307(to HL),82271362(to HL),82171294(to JW),82371303(to JW),and 82301460(to PX)the Natural Science Foundation of Jiangsu Province,No.BK20211552(to HL)+1 种基金Suzhou Medical Technology Innovation Project-Clinical Frontier,No.SKY2022002(to ZY)the Science and Education Foundation for Health of Suzhou for Youth,No.KJXW2023001(to XL)。
文摘Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.
基金supported by the National Natural Science Foundation of China, No.61932008Natural Science Foundation of Shanghai, No.21ZR1403200 (both to JC)。
文摘Neurodegenerative diseases cause great medical and economic burdens for both patients and society;however, the complex molecular mechanisms thereof are not yet well understood. With the development of high-coverage sequencing technology, researchers have started to notice that genomic repeat regions, previously neglected in search of disease culprits, are active contributors to multiple neurodegenerative diseases. In this review, we describe the association between repeat element variants and multiple degenerative diseases through genome-wide association studies and targeted sequencing. We discuss the identification of disease-relevant repeat element variants, further powered by the advancement of long-read sequencing technologies and their related tools, and summarize recent findings in the molecular mechanisms of repeat element variants in brain degeneration, such as those causing transcriptional silencing or RNA-mediated gain of toxic function. Furthermore, we describe how in silico predictions using innovative computational models, such as deep learning language models, could enhance and accelerate our understanding of the functional impact of repeat element variants. Finally, we discuss future directions to advance current findings for a better understanding of neurodegenerative diseases and the clinical applications of genomic repeat elements.
文摘Helicobacter pylori(H.pylori)infection plays a critical role in gastric diseases,impacting the microbiota structure in gastric and duodenal ulcers.In their study,Jin et al utilized metagenomic sequencing to analyze mucosal samples from patients with ulcers and healthy controls,revealing significant changes in microbial diversity and composition.This article reviews their findings,emphasizing H.pylori’s role in gastric ulcers and the need for further research on its impact on duodenal ulcers.We evaluate the study’s strengths and limitations,suggesting future research directions to enhance our understanding of H.pylori’s contribution to ulcerative diseases.
