Catalytic methylative coupling of internal alkynes and aldehydes/aldimines through regioselective oxidative cyclization promoted by a phosphine–Co complex is presented.Such process constitutes an unprecedented and un...Catalytic methylative coupling of internal alkynes and aldehydes/aldimines through regioselective oxidative cyclization promoted by a phosphine–Co complex is presented.Such process constitutes an unprecedented and unique approach for Co-catalyzed generation of metallacycles that reversed inherent regiochemical biases to furnish a wide range of allylic alcohols and allylic amides bearing a tetrasubstituted alkene in up to 98%yield with high regioselectivity,representing a novel and general strategy for reversal of substrate-controlled regioselectivity in metal-catalyzed oxidative cyclization.展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytoki...Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.展开更多
BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma me...BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.展开更多
Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells...Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.展开更多
Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the m...Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.展开更多
During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipit...During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.展开更多
Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long ...Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.展开更多
Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain...Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.展开更多
Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its impor...Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its importance,the lack of a complete genome assembly has been a stumbling block in its biological breeding process.Therefore,we generated deep coverage ultralong Oxford Nanopore Technology(ONT)and PacBio HiFi reads to construct a telomere-to-telomere(T2T)genome assembly.The final assembly spans 537.27 Mb with no gaps,demonstrating a remarkable completeness of 98.1%.We utilized a combination of transcriptome data and homologous proteins to annotate the genome,identifying 36018 protein-coding genes.Furthermore,we profiled global cytosine DNA methylations using ONT sequencing data.Global methylome analysis revealed high methylation levels in transposable element(TE)-rich chromosomal regions juxtaposed with comparatively lower methylation in gene-rich areas.By integrating a detailed multi-omics data analysis,we obtained valuable insights into the mechanism underlying endopleura coloration.This investigation led to the identification of eight candidate genes(e.g.ANR)involved in anthocyanin biosynthesis pathways,which are crucial for the development of color in plants.The comprehensive genome assembly and the understanding of the genetic basis of important traits like endopleura coloration will open avenues for more efficient breeding programs and improved crop quality.展开更多
N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis a...N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.展开更多
Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulat...Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.展开更多
Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcript...Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcriptional landscapes across fetal and adult bovine tissues as well as pluripotent stem cells.Among the extensive methylation differences across various stages and tissues,we identify tissue-specific differentially methylated regions(tsDMRs)unique to the rumen,which are crucial for regulating epithelial development and energy metabolism.These tsDMRs cluster within super-enhancer regions that overlap with transcription factor(TF)binding sites.Regression models indicate that DNA methylation,along with H3K27me3 and H3K27ac,can be used to predict enhancer activity.Key upstream TFs,including SOX2,FOSL1/2,and SMAD2/3,primarily maintain an inhibitory state through bivalent modifications during fetal development.Downstream functional genes are maintained mainly in a stable repressive state via DNA methylation until differentiation is complete.Our study underscores the critical role of tsDMRs in regulating distal components of rumen morphology and function,providing key insights into the epigenetic regulatory mechanisms that may influence bovine production traits.展开更多
Gas-phase synthesis of glycolide(GL)from methyl glycolate(MG)is of great significance for producing biodegradable polyglycolic acid.Here,we report a detailed thermodynamics study for the gas-phase synthesis of GL from...Gas-phase synthesis of glycolide(GL)from methyl glycolate(MG)is of great significance for producing biodegradable polyglycolic acid.Here,we report a detailed thermodynamics study for the gas-phase synthesis of GL from MG,which involves complex reaction pathways,by utilizing the Gibbs free energy minimization method.The results indicate that the decompositions of MG and GL and the polymerization of MG are thermodynamically favorable as compared with the target pathway,i.e.,the cyclization of MG.Effects of the reaction conditions including temperature,pressure and feed composition on the formation of GL and linear polymers have also been addressed,which demonstrate that the higher temperature and lower pressure can effectively inhibit the formation of linear methyl ester dimer and improve the selectivity to GL.In addition,the higher N_(2)/MG ratio is beneficial for the formation of GL in the process promoted by catalysts.These thermodynamics results indicate that the process promoted by catalysts would benefit from the kinetics control by high-performance catalysts and the operation at high temperature,low pressure and high N_(2)/MG ratio to enhance the yield of targeted GL.The insights demonstrated here from thermodynamics are valuable for guiding the design of catalysts and/or optimization of reaction conditions for the gas-phase synthesis of GL from MG.展开更多
AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening o...AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening of the GSE24673 and GSE125903 datasets,combined with GeneCards database analysis.A total of 102 RB patients and 62 traumaenucleated controls between January 2018 and December 2023 were enrolled,with their clinicopathological data and retinal tissues collected.The mRNA and methylation levels of MSH6 in retinal tissues were detected using real-time quantitative polymerase chain reaction(PCR)and methylation-specific PCR.Western blot analysis was conducted in one pair of RB and control tissues for preliminary protein-level validation of MSH6 expression.Based on the methylation status of MSH6,RB patients were categorized into two groups:low-methylation and highmethylation.Both univariate and multivariate analyses were conducted to identify independent factors influencing the methylation levels using clinicopathological data.Receiver operating characteristic(ROC)curves were applied to evaluate the diagnostic potential of MSH6 methylation in RB.RESULTS:Bioinformatics analysis of public datasets revealed that MSH6 expression was downregulated across multiple cancers,RB.Consistently,in clinical RB tissues,MSH6 mRNA expression was significantly lower than that in control retinal tissues,whereas the promoter methylation level of MSH6 was markedly higher(both P<0.001),indicating that promoter hypermethylation may contribute to transcriptional silencing of MSH6 in RB.Patients with higher MSH6 methylation levels showed more advanced pathological classification and a higher frequency of metastasis.Multivariate logistic regression confirmed that metastatic status(P=0.008,OR=3.51)and pathological classification(P=0.005,OR=3.7)were independent factors associated with MSH6 methylation.Receiver operating characteristic(ROC)analysis demonstrated that MSH6 methylation could effectively distinguish RB tissues from non-tumorous controls(AUC=0.847,sensitivity=78.43%,specificity=80.65%),suggesting that MSH6 hypermethylation may serve as a potential diagnostic biomarker for RB.CONCLUSION:The methylation level of the MSH6 gene may be a key factor in RB pathogenesis.The methylation status of the MSH6 gene is closely associated with clinicopathological features and shows diagnostic potential.展开更多
Background Thidiazuron(TDZ)is a widely used chemical defoliant in commercial cotton production and is often combined with the herbicide Diuron to form the commercial defoliant mixture known as TDZ·Diuron(T·D...Background Thidiazuron(TDZ)is a widely used chemical defoliant in commercial cotton production and is often combined with the herbicide Diuron to form the commercial defoliant mixture known as TDZ·Diuron(T·D,540 g·L^(-1)suspension).However,due to increasing concerns about the environmental and biological risks posed by Diuron,there is an urgent need to develop safer and more effective alternatives.Jasmonic acid(JA)and its derivatives are key phytohormones in organ senescence and abscission.Results Greenhouse experiments at the seedling stage revealed that Me-JA(0.8 mmol·L^(-1))alone did not induce defoliation.However,its co-application with TDZ(0.45 mmol·L^(-1))at concentrations of 0.6,0.8,and 1.0 mmol·L^(-1)significantly enhanced defoliation efficacy.The most effective combination—TDZ with 0.8 mmol·L^(-1)Me-JA—achieved a 100%defoliation rate at 5 days after treatment(DAT),23.7 percentage points higher than TDZ alone,and comparable to the commercial TDZ·Diuron formulation with equivalent TDZ content.Field trials conducted in Beijing(Shangzhuang),Hebei(Hejian),and Xinjiang(Shihezi)confirmed that the combination of 0.6 mmol·L^(-1)Me-JA with 1.70 mmol·L^(-1)TDZ provided optimal defoliation performance.At 21 DAT,the defoliation rate increased by 13.5–16.3 percentage points compared with TDZ alone.Furthermore,boll opening rates improved by 5.7–12.7 percentage points relative to TDZ-only treatments.Phytohormonal analyses from the Shangzhuang site showed that the combined treatment significantly altered hormone levels in both leaves and petioles.Compared with TDZ alone,the mixture reduced concentrations of auxin(IAA),cytokinins(Z+ZR,iP+iPA,DHZ+DHZR),and gibberellic acid(GA3),while increasing levels of JA,abscisic acid(ABA),and brassinosteroids(BR).These hormonal shifts may underlie the enhanced defoliation observed with the combined treatment.Importantly,the TDZ-Me-JA combination did not adversely affect cotton yield,yield components,or fiber quality.Conclusion The combination of Me-JA and TDZ has a good defoliation effect without affecting crop yield or fiber quality.And it provides a promising foundation for the development of novel,environmentally friendly cotton defoliants.展开更多
Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylat...Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.展开更多
Lymphomas represent one of the most common malignant diseases in young men and an important issue is how treatments will affect their reproductive health.It has been hypothesized that chemotherapies,similarly to envir...Lymphomas represent one of the most common malignant diseases in young men and an important issue is how treatments will affect their reproductive health.It has been hypothesized that chemotherapies,similarly to environmental chemicals,may alter the spermatogenic epigenome.Here,we report the genomic and epigenomic profiling of the sperm DNA from a 31-year-old Hodgkin lymphoma patient who faced recurrent spontaneous miscarriages in his couple 11-26 months after receiving chemotherapy with adriamycin,bleomycin,vinblastine,and dacarbazine(ABVD).In order to capture the potential deleterious impact of the ABVD treatment on mutational and methylation changes,we compared sperm DNA before and 26 months after chemotherapy with whole-genome sequencing(WGS)and reduced representation bisulfite sequencing(RRBS).The WGS analysis identified 403 variants following ABVD treatment,including 28 linked to genes crucial for embryogenesis.However,none were found in coding regions,indicating no impact of chemotherapy on protein function.The RRBS analysis identified 99high-quality differentially methylated regions(hqDMRs)for which methylation status changed upon chemotherapy.Those hqDRMs were associated with 87 differentially methylated genes,among which 14 are known to be important or expressed during embryo development.While no variants were detected in coding regions,promoter regions of several genes potentially important for embryo development contained variants or displayed an altered methylated status.These might in turn modify the corresponding gene expression and thus affect their function during key stages of embryogenesis,leading to potential developmental disorders or miscarriages.展开更多
The prevalence of stunting in Indonesian children under five years of age is approximately 20%.Chronic maternal malnutrition contributes to the risk of stunting by affecting global DNA methylation.In the present study...The prevalence of stunting in Indonesian children under five years of age is approximately 20%.Chronic maternal malnutrition contributes to the risk of stunting by affecting global DNA methylation.In the present study,we aimed to evaluate the levels of 5-methyl-cytosine(5mC)as a surrogate marker of global DNA methylation in buccal swabs and its potential association with the risk of stunting and cognitive performance.The levels of 5mC were measured using an enzyme-linked immunosorbent assay.The Wechsler Preschool and Primary Scale of Intelligence(WPPSI)was used to measure cognitive function.Buccal swab DNA samples and anthropometric data were collected from a total of 231 children aged zero to five years.In this cross-sectional cohort,the prevalence of stunting was 37%in 138 children aged zero to two years and 30%in 93 children aged over two years.The univariable analysis revealed that the levels of 5mC in buccal swab DNA were significantly lower in severely stunted children(median,2.84;interquartile range[IQR],2.39–4.62)and children aged less than two years(median,2.81;IQR,2.53–4.62)than those in normal children(median,3.75;IQR,2.80–4.74;P-value,0.028)and children aged over four years(median,4.01;IQR,3.39–4.87;P-value<0.001),respectively.We also found that the average cognitive scores tended to be low in boys and stunted children,although the differences were not statistically significant.Furthermore,the levels of 5mC found in buccal swab and mouthwash DNA were not associated with cognitive scores.展开更多
Background:Kidney renal clear cell carcinoma(KIRC),a prevalent urological malignancy,represents about 3%of all adult malignancies.KIRC,accounting for~75%of renal malignancies,has poor prognosis in metastatic stages.Id...Background:Kidney renal clear cell carcinoma(KIRC),a prevalent urological malignancy,represents about 3%of all adult malignancies.KIRC,accounting for~75%of renal malignancies,has poor prognosis in metastatic stages.Identifying robust prognostic markers remains urgent.Block of proliferation 1(BOP1),a WD40-repeat protein,is implicated in cancer pathogenesis,but its role in KIRC is unclear.This study aimed to characterize BOP1 expression in KIRC and evaluate its prognostic value.Methods:BOP1 transcriptional levels were assessed through TCGA-KIRC RNA sequencing datasets.ROC curve construction was implemented via R statistical packages for diagnostic evaluation.Patient survival outcomes were visualized through Kaplan-Meier plotting with log-rank testing.Multivariate logistic regression models quantified associations between BOP1 expression and clinicopathological parameters.TIMER algorithm analyzed immune microenvironment composition.Genomic alterations and epigenetic modifications were investigated using cBioPortal and MethSurv platforms respectively.BOP1 protein levels in 786-O clear cell renal cell carcinoma(ccRCC)versus HK-2(normal renal)cell lines were validated by immunoblotting.Results:Evaluation of the TCGA database demonstrated that BOP1 mRNA abundance was higher in tumor specimens than in corresponding adjacent tissues.Patients with KIRC who had high BOP1 expression had differential overall survival(OS),disease-specific survival(DSS),and disease-free interval(DFI).BOP1 expression accurately recognised tumour tissues versus normal tissues(AUC=0.858),and the area under the ROCs for survival at 1,3,and 5 years were all greater than 0.6.The BOP1 gene variant rate was<1%.Out of the 15 DNA methylation CpG sites examined,7 exhibited prognostic significance in KIRC.BOP1 displayed a distinct relationship with immune cell infiltration in KIRC.The 786-O experimental group exhibited substantially higher BOP1 expression,as confirmed by Western blot detection.Conclusion:This study indicates that heightened BOP1 expression is linked to an adverse prognosis in KIRC,establishing it as an independent risk factor for this disease.These findings establish BOP1 as a novel and independent prognostic biomarker for KIRC,offering potential clinical utility for risk stratification and personalized therapeutic strategies.展开更多
基金supported by the National Key R&D Program of China(2022YFA1506100)National Natural Science Foundation of China(Grant Nos.22371294,and 21821002)+1 种基金the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0610000)Beijing National Laboratory for Molecular Sciences(BNLMS202304).
文摘Catalytic methylative coupling of internal alkynes and aldehydes/aldimines through regioselective oxidative cyclization promoted by a phosphine–Co complex is presented.Such process constitutes an unprecedented and unique approach for Co-catalyzed generation of metallacycles that reversed inherent regiochemical biases to furnish a wide range of allylic alcohols and allylic amides bearing a tetrasubstituted alkene in up to 98%yield with high regioselectivity,representing a novel and general strategy for reversal of substrate-controlled regioselectivity in metal-catalyzed oxidative cyclization.
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金supported by the National Natural Science Foundation of China,Nos.32070735(to QL),82371321(to QL),82171270(to ZL)Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People's Republic of China,No.2020-0103-3-1(to ZL)+2 种基金the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)。
文摘Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.
基金Supported by the Medical Talents of Wuhan Health and Family Planning Commission,No.2017[51](to Yu J)the Medical Talents of Wuhan Hospital of Traditional Chinese and Western Medicine(to Yu J)+1 种基金the Hubei Natural Science Foundation,No.2023AFB1091Wuhan Medical Research Project,No.WX23A36(to Yu J).
文摘BACKGROUND Cholangiocarcinoma(CCA),also known as bile duct cancer,is a devastating malignancy primarily affecting the biliary tract.AIM To assess their performance in clinical diagnosis and monitoring of CCA,plasma methylation and circulating tumor cells were detected.METHODS Plasma samples were collected from Hubei Cancer Hospital(n=156).Plasma DNA was tested to detect SHOX2,HOXA9,SEPTIN9,and RASSF1A methylation using TaqMan PCR.Circulating tumor cells(CTCs)were detected in the peripheral blood of patients using the United States Food and Drug Administration-approved cell search system before and after clinical therapy.The CCA diagnostic value was estimated using the area under the curve.The independent prognosis risk factors for patients with CCA were estimated using Cox and logistic regression analyses.RESULTS The sensitivity and specificity of the four DNA plasma methylations exhibited 64.74%sensitivity and 93.88%specificity for detecting CCA.The receiver operating characteristic curve of the combined value for CCA diagnosis in plasma was 0.828±0.032.RASSF1A plasma methylation was related to the prognosis of patients with CCA.We determined the prognostic hazard ratio for CCA using CTC count,tumor stage,methylation,and carbohydrate antigen 19-9 levels as key factors.Our overall survival nomogram achieved a C-index of 0.705(0.605-0.805).CONCLUSION SHOX2,HOXA9,SEPTIN9,and RASSF1A plasma methylation demonstrated increased sensitivity for diagnosing CCA.RASSF1A plasma methylation and CTCs were valuable predictors to assess CCA prognosis and recurrence.
基金supported by grants from the National Key R&D Program of China(2022YFC2403000 and 2021YFC2400500)the National Natural Science Foundation of China(32200728 and 32170925)+3 种基金the Clinical Research Project of Shenzhen Medical Academy of Research and Translation(C2301008)Shenzhen Science and Technology Program(JCYJ20220531100406014,JCYJ2022081800807016,RCBS20221008093336088,KQTD20210811090115019)Guangdong Basic and Applied Basic Research Foundation(2021A1515110375)the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20210601).
文摘Regulatory T(Treg)cells are pivotal for maintaining immune homeostasis and play essential roles in various diseases,such as autoimmune diseases,graft-versus-host disease(GVHD),tumors,and infectious diseases.Treg cells exert suppressive function via distinct mechanisms,including inhibitory cytokines,granzyme or perforin-mediated cytolysis,metabolic disruption,and suppression of dendritic cells.Forkhead Box P3(FOXP3),the characteristic transcription factor,is essential for Treg cell function and plasticity.Cumulative evidence has demonstrated that FOXP3 activity and Treg cell function are modulated by a variety of post-translational modifications(PTMs),including ubiquitination,acetylation,phosphorylation,methylation,glycosylation,poly(ADP-ribosyl)ation,and uncharacterized modifications.This review describes Treg cell suppressive mechanisms and summarizes the current evidence on PTM regulation of FOXP3 and Treg cell function.Understanding the regulatory role of PTMs in Treg cell plasticity and function will be helpful in designing therapeutic strategies for autoimmune diseases,GVHD,tumors,and infectious diseases.
基金supported by the Shandong Province Natural Science Foundation of Major Basic Research Program (No.ZR2020ZD34)the Key Projects of the National Natural Science Foundation of China (No.42230706)+3 种基金the National Natural Science Foundation of China (No.42307164)the China Postdoctoral Science Foundation (Nos.2023TQ0191 and 2023M732060)the Shandong Postdoctoral Science Foundation (No.SDBX2023041)and the Qingdao Postdoctoral Science Foundation (No.QDBSH20230202052).
文摘Arsenic(As)methylation in soils affects the environmental behavior of As,excessive accumulation of dimethylarsenate(DMA)in rice plants leads to straighthead disease and a serious drop in crop yield.Understanding the mobility and transformation of methylated arsenic in redox-changing paddy fields is crucial for food security.Here,soils including unarsenic contaminated(N-As),low-arsenic(L-As),medium-arsenic(M-As),and high-arsenic(H-As)soils were incubated under continuous anoxic,continuous oxic,and consecutive anoxic/oxic treatments respectively,to profile arsenic methylating process and microbial species involved in the As cycle.Under anoxic-oxic(A-O)treatment,methylated arsenic was significantly increased once oxygen was introduced into the incubation system.The methylated arsenic concentrations were up to 2-24 times higher than those in anoxic(A),oxic(O),and oxic-anoxic(O-A)treatments,under which arsenic was methylated slightly and then decreased in all four As concentration soils.In fact,the most plentiful arsenite S-adenosylmethionine methyltransferase genes(arsM)contributed to the increase in As methylation.Proteobacteria(40.8%-62.4%),Firmicutes(3.5%-15.7%),and Desulfobacterota(5.3%-13.3%)were the major microorganisms related to this process.These microbial increasedmarkedly and played more important roles after oxygen was introduced,indicating that they were potential keystone microbial groups for As methylation in the alternating anoxic(flooding)and oxic(drainage)environment.The novel findings provided newinsights into the reoxidation-driven arsenic methylation processes and the model could be used for further risk estimation in periodically flooded paddy fields.
基金supported by the National Key R&D Program of China(2022YFE0131000)the National Natural Science Foundation of China(82220108012,82271306,and 82071307)+1 种基金The Science and Education for Health Foundation of Suzhou for Youth(KJXW2023001)the Boxi Youth Natural Science Foundation(BXQN2023028).
文摘During the hyperacute phase of intracerebral hemorrhage(ICH),the mass effect and blood components mechanically lead to brain damage and neurotoxicity.Our findings revealed that the mass effect and transferrin precipitate neuronal oxidative stress and iron uptake,culminating in ferroptosis in neurons.M6A(N6-methyladenosine)modification,the most prevalent mRNA modification,plays a critical role in various cell death pathways.The Fto(fat mass and obesity-associated protein)demethylase has been implicated in numerous signaling pathways of neurological diseases by modulating m6A mRNA levels.Regulation of Fto protein levels in neurons effectively mitigated mass effect-induced neuronal ferroptosis.Applying nanopore direct RNA sequencing,we identified voltage-dependent anion channel 3(Vdac3)as a potential target associated with ferroptosis.Fto influenced neuronal ferroptosis by regulating the m6A methylation of Vdac3 mRNA.These findings elucidate the intricate interplay between Fto,Vdac3,m6A methylation,and ferroptosis in neurons during the hyperacute phase post-ICH and suggest novel therapeutic strategies for ICH.
基金supported by the National Key R&D Program of China(2023YFD1300103)the Science and Technology Plan Project of Yantai City(2023ZDCX024)+5 种基金the National Natural Science Foundation of China(32372852)the Science Fund for Distinguished Young Scholars of Shaanxi Province(2024JC-JCQN-30)Shaanxi Provincial Innovation Leadership Program in Sciences and Technologies for Young and Middle-aged Scientists(2023SR205)the China Agriculture Research System-beef(CARS-37)the Innovation Team of Cattle Industry in Technological System of Shandong Modern Agriculture Industry(SDAIT-09-03)the Key Research and Development Project in Shandong Province(Competitive Innovation Platform)(2022CXPT010).
文摘Background N^(6)-methyladenosine(m^(6)A)methylation is a key epigenetic modification that can modulate gene expression and strongly affect mammalian developmental processes.However,the genome-wide methylation of long non-coding RNAs(lncRNAs)and its implications for the development of skeletal muscle remain poorly understood.Bovine skeletal muscle samples from five developmental stages were analyzed in this study to establish lncRNA methylome and transcriptomic maps.Results Globally,59.67%of lncRNAs in skeletal muscle with m^(6)A modifications,and this percentage decreased progressively during development.lncRNA expression levels were positively associated with the number of m^(6)A peaks,with lncRNAs possessing 3 or more peaks showing significantly higher expression levels than those with 1 or 2 peaks.Specific lncRNAs involved in skeletal muscle development were identified through two analytical approaches.The first approach employed weighted gene co-expression network analysis(WGCNA)of transcriptomic data to identify correlations between annotated lncRNAs and growth-related traits,resulting in 21 candidate hub lncRNAs.The intersection of these 21 hub lncRNAs with 151 differentially methylated lncRNAs(DM-lncRNAs)identified 10 shared candidate lncRNAs.The second approach integrated MeRIP-seq and RNA-seq data to identify 36 lncRNAs that were both differentially m^(6)A modified and differentially expressed(dme-lncRNAs).GO and KEGG enrichment analyses of cis-target genes associated with these dme-lncRNAs identified eight candidate lncRNAs.Combining the results from the two approaches identified 16 key m^(6)A-modified lncRNAs likely involved in skeletal muscle development.Conclusions These findings highlight the regulatory and functional significance of dynamic lncRNA methylation in skeletal muscle development.
基金supported by the National Key Research and Development Program of China(2023YFD1200403).
文摘Aegilops speltoides,the closest ancestor of the wheat B subgenome,has been well studied genomically.However,the epigenetic landscape of Ae.speltoides and the effects of epigenetics on its growth and development remain poorly understood.Here,we present a comprehensive multi-omics atlas of leaves and roots in Ae.speltoides,encompassing transcriptome,DNA methylation,histone modifications,and small RNA profiling.Divergent DNA methylation levels were detected between leaves and roots,and were associated with differences in accumulated 24-nt siRNAs.DNA methylation changes in promoters and gene bodies showed strong connections with altered expression between leaves and roots.Transcriptional regulatory networks(TRN)reconstructed between leaves and roots were driven by tissue-specific TF families.DNA methylation and histone modification act together as switches that shape root and leaf morphogenesis by modulating the binding of tissue-specific TFs to their target genes.The TRNs in leaves and roots reshaped during wheat polyploidization were associated with alterations in epigenetic modi-fications.Collectively,these results not only shed light on the critical contribution of epigenetic regulation in the morphogenesis of leaves and roots in Ae.speltoides but also provide new insights for future investigations into the complex interplay of genetic and epigenetic factors in the developmental biology of common wheat.
基金supported by the Yunnan Seed Laboratory,China(202205AR070001-15)the National Natural Science Foundation of China,China(Grant No.32160697)。
文摘Juglans sigillata is an economically valuable nut crop renowned for its nutritional richness,including essential nutrients,antioxidants,and healthy fats,which boost human cardial,brain and gut health.Despite its importance,the lack of a complete genome assembly has been a stumbling block in its biological breeding process.Therefore,we generated deep coverage ultralong Oxford Nanopore Technology(ONT)and PacBio HiFi reads to construct a telomere-to-telomere(T2T)genome assembly.The final assembly spans 537.27 Mb with no gaps,demonstrating a remarkable completeness of 98.1%.We utilized a combination of transcriptome data and homologous proteins to annotate the genome,identifying 36018 protein-coding genes.Furthermore,we profiled global cytosine DNA methylations using ONT sequencing data.Global methylome analysis revealed high methylation levels in transposable element(TE)-rich chromosomal regions juxtaposed with comparatively lower methylation in gene-rich areas.By integrating a detailed multi-omics data analysis,we obtained valuable insights into the mechanism underlying endopleura coloration.This investigation led to the identification of eight candidate genes(e.g.ANR)involved in anthocyanin biosynthesis pathways,which are crucial for the development of color in plants.The comprehensive genome assembly and the understanding of the genetic basis of important traits like endopleura coloration will open avenues for more efficient breeding programs and improved crop quality.
基金supported by the Natural Science Foundation of Heilongjiang Province of China,Outstanding Youth Foundation,No.YQ2022H003 (to DW)。
文摘N6-methyladenosine(m^(6)A), the most prevalent and conserved RNA modification in eukaryotic cells, profoundly influences virtually all aspects of mRNA metabolism. mRNA plays crucial roles in neural stem cell genesis and neural regeneration, where it is highly concentrated and actively involved in these processes. Changes in m^(6)A modification levels and the expression levels of related enzymatic proteins can lead to neurological dysfunction and contribute to the development of neurological diseases. Furthermore, the proliferation and differentiation of neural stem cells, as well as nerve regeneration, are intimately linked to memory function and neurodegenerative diseases. This paper presents a comprehensive review of the roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, as well as its implications in memory and neurodegenerative diseases. m^(6)A has demonstrated divergent effects on the proliferation and differentiation of neural stem cells. These observed contradictions may arise from the time-specific nature of m^(6)A and its differential impact on neural stem cells across various stages of development. Similarly, the diverse effects of m^(6)A on distinct types of memory could be attributed to the involvement of specific brain regions in memory formation and recall. Inconsistencies in m^(6)A levels across different models of neurodegenerative disease, particularly Alzheimer's disease and Parkinson's disease, suggest that these disparities are linked to variations in the affected brain regions. Notably, the opposing changes in m^(6)A levels observed in Parkinson's disease models exposed to manganese compared to normal Parkinson's disease models further underscore the complexity of m^(6)A's role in neurodegenerative processes. The roles of m^(6)A in neural stem cell proliferation, differentiation, and self-renewal, and its implications in memory and neurodegenerative diseases, appear contradictory. These inconsistencies may be attributed to the timespecific nature of m^(6)A and its varying effects on distinct brain regions and in different environments.
基金supported by a grant from the Massachusetts Alzheimer’s Disease Research Center(5P50 AG 005134)(to SL).
文摘Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia.Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-βoligomers in the brain,influenced by complex genetic and environmental factors.The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction.Throughout life,environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders.These changes,known as epigenetic modifications,also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity.In this context,we highlight recent advances in understanding the roles played by key components of the epigenetic machinery,specifically DNA methylation,histone modification,and microRNAs,in the development of Alzheimer’s disease,synaptic function,and activity-dependent synaptic plasticity.Moreover,we explore various strategies,including enriched environments,exposure to non-invasive brain stimulation,and the use of pharmacological agents,aimed at improving synaptic function and enhancing long-term potentiation,a process integral to epigenetic mechanisms.Lastly,we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease.We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.
基金funded by the Science and Technology Major Project of the Inner Mongolia Autonomous Region of China to the State Key Laboratory of Reproductive Regulation(2023KYPT0010 and 2021ZD0048)STI 2030-Major Projects(2023ZD0407504)of China+1 种基金the development plan for young scientific and technological talents in colleges and universities of Inner Mongolia Autonomous Region of China(NMGIRT2204)the National Natural Science Foundation of China(32160172).
文摘Epigenetic regulation in the rumen,a unique ruminant organ,remains largely unexplored compared with other tissues studied in model species.In this study,we perform an in-depth analysis of the epigenetic and transcriptional landscapes across fetal and adult bovine tissues as well as pluripotent stem cells.Among the extensive methylation differences across various stages and tissues,we identify tissue-specific differentially methylated regions(tsDMRs)unique to the rumen,which are crucial for regulating epithelial development and energy metabolism.These tsDMRs cluster within super-enhancer regions that overlap with transcription factor(TF)binding sites.Regression models indicate that DNA methylation,along with H3K27me3 and H3K27ac,can be used to predict enhancer activity.Key upstream TFs,including SOX2,FOSL1/2,and SMAD2/3,primarily maintain an inhibitory state through bivalent modifications during fetal development.Downstream functional genes are maintained mainly in a stable repressive state via DNA methylation until differentiation is complete.Our study underscores the critical role of tsDMRs in regulating distal components of rumen morphology and function,providing key insights into the epigenetic regulatory mechanisms that may influence bovine production traits.
基金supported by the National Natural Science Foundation of China(22478106,22178102,and 22332003)Shanghai Rising-Star Program(23QA1401900)+1 种基金Young Elite Scientists Sponsorship Programby CAST(2023QNRC001)the Open Project of Yunnan Precious Metals Laboratory Co.,Ltd(YPML-2023050272).
文摘Gas-phase synthesis of glycolide(GL)from methyl glycolate(MG)is of great significance for producing biodegradable polyglycolic acid.Here,we report a detailed thermodynamics study for the gas-phase synthesis of GL from MG,which involves complex reaction pathways,by utilizing the Gibbs free energy minimization method.The results indicate that the decompositions of MG and GL and the polymerization of MG are thermodynamically favorable as compared with the target pathway,i.e.,the cyclization of MG.Effects of the reaction conditions including temperature,pressure and feed composition on the formation of GL and linear polymers have also been addressed,which demonstrate that the higher temperature and lower pressure can effectively inhibit the formation of linear methyl ester dimer and improve the selectivity to GL.In addition,the higher N_(2)/MG ratio is beneficial for the formation of GL in the process promoted by catalysts.These thermodynamics results indicate that the process promoted by catalysts would benefit from the kinetics control by high-performance catalysts and the operation at high temperature,low pressure and high N_(2)/MG ratio to enhance the yield of targeted GL.The insights demonstrated here from thermodynamics are valuable for guiding the design of catalysts and/or optimization of reaction conditions for the gas-phase synthesis of GL from MG.
文摘AIM:To explore the methylation status of MSH6 in retinoblastoma(RB)and its impact on clinicopathological features and diagnosis.METHODS:Differentially expressed genes were identified through bioinformatics screening of the GSE24673 and GSE125903 datasets,combined with GeneCards database analysis.A total of 102 RB patients and 62 traumaenucleated controls between January 2018 and December 2023 were enrolled,with their clinicopathological data and retinal tissues collected.The mRNA and methylation levels of MSH6 in retinal tissues were detected using real-time quantitative polymerase chain reaction(PCR)and methylation-specific PCR.Western blot analysis was conducted in one pair of RB and control tissues for preliminary protein-level validation of MSH6 expression.Based on the methylation status of MSH6,RB patients were categorized into two groups:low-methylation and highmethylation.Both univariate and multivariate analyses were conducted to identify independent factors influencing the methylation levels using clinicopathological data.Receiver operating characteristic(ROC)curves were applied to evaluate the diagnostic potential of MSH6 methylation in RB.RESULTS:Bioinformatics analysis of public datasets revealed that MSH6 expression was downregulated across multiple cancers,RB.Consistently,in clinical RB tissues,MSH6 mRNA expression was significantly lower than that in control retinal tissues,whereas the promoter methylation level of MSH6 was markedly higher(both P<0.001),indicating that promoter hypermethylation may contribute to transcriptional silencing of MSH6 in RB.Patients with higher MSH6 methylation levels showed more advanced pathological classification and a higher frequency of metastasis.Multivariate logistic regression confirmed that metastatic status(P=0.008,OR=3.51)and pathological classification(P=0.005,OR=3.7)were independent factors associated with MSH6 methylation.Receiver operating characteristic(ROC)analysis demonstrated that MSH6 methylation could effectively distinguish RB tissues from non-tumorous controls(AUC=0.847,sensitivity=78.43%,specificity=80.65%),suggesting that MSH6 hypermethylation may serve as a potential diagnostic biomarker for RB.CONCLUSION:The methylation level of the MSH6 gene may be a key factor in RB pathogenesis.The methylation status of the MSH6 gene is closely associated with clinicopathological features and shows diagnostic potential.
基金funded by the China Agriculture Research System(CARS–15–16)。
文摘Background Thidiazuron(TDZ)is a widely used chemical defoliant in commercial cotton production and is often combined with the herbicide Diuron to form the commercial defoliant mixture known as TDZ·Diuron(T·D,540 g·L^(-1)suspension).However,due to increasing concerns about the environmental and biological risks posed by Diuron,there is an urgent need to develop safer and more effective alternatives.Jasmonic acid(JA)and its derivatives are key phytohormones in organ senescence and abscission.Results Greenhouse experiments at the seedling stage revealed that Me-JA(0.8 mmol·L^(-1))alone did not induce defoliation.However,its co-application with TDZ(0.45 mmol·L^(-1))at concentrations of 0.6,0.8,and 1.0 mmol·L^(-1)significantly enhanced defoliation efficacy.The most effective combination—TDZ with 0.8 mmol·L^(-1)Me-JA—achieved a 100%defoliation rate at 5 days after treatment(DAT),23.7 percentage points higher than TDZ alone,and comparable to the commercial TDZ·Diuron formulation with equivalent TDZ content.Field trials conducted in Beijing(Shangzhuang),Hebei(Hejian),and Xinjiang(Shihezi)confirmed that the combination of 0.6 mmol·L^(-1)Me-JA with 1.70 mmol·L^(-1)TDZ provided optimal defoliation performance.At 21 DAT,the defoliation rate increased by 13.5–16.3 percentage points compared with TDZ alone.Furthermore,boll opening rates improved by 5.7–12.7 percentage points relative to TDZ-only treatments.Phytohormonal analyses from the Shangzhuang site showed that the combined treatment significantly altered hormone levels in both leaves and petioles.Compared with TDZ alone,the mixture reduced concentrations of auxin(IAA),cytokinins(Z+ZR,iP+iPA,DHZ+DHZR),and gibberellic acid(GA3),while increasing levels of JA,abscisic acid(ABA),and brassinosteroids(BR).These hormonal shifts may underlie the enhanced defoliation observed with the combined treatment.Importantly,the TDZ-Me-JA combination did not adversely affect cotton yield,yield components,or fiber quality.Conclusion The combination of Me-JA and TDZ has a good defoliation effect without affecting crop yield or fiber quality.And it provides a promising foundation for the development of novel,environmentally friendly cotton defoliants.
文摘Epidemiological studies indicate a strong correlation between various types of human cancer and dietary factors,whereas the specific mechanisms remain to be fully elucidated.Epigenetic alterations,such as DNA methylation,histone modifications,and noncoding RNA,are influenced by dietary components,especially phytochemicals and nutrients that participate in one-carbon metabolism.These alterations significantly impact cancer occurrence and progression.Consequently,epigenetic pathways may mediate the effects of diet on cancer risk.This review synthesizes the current information regarding the association of epigenetic alterations with cancer initiation and development,as well as the mechanisms by which diet exerts its influence on these changes.The goal of this minireview is to enhance the understanding of the roles of diet on epigenetic alterations to improve cancer prevention and treatment through diet.
文摘Lymphomas represent one of the most common malignant diseases in young men and an important issue is how treatments will affect their reproductive health.It has been hypothesized that chemotherapies,similarly to environmental chemicals,may alter the spermatogenic epigenome.Here,we report the genomic and epigenomic profiling of the sperm DNA from a 31-year-old Hodgkin lymphoma patient who faced recurrent spontaneous miscarriages in his couple 11-26 months after receiving chemotherapy with adriamycin,bleomycin,vinblastine,and dacarbazine(ABVD).In order to capture the potential deleterious impact of the ABVD treatment on mutational and methylation changes,we compared sperm DNA before and 26 months after chemotherapy with whole-genome sequencing(WGS)and reduced representation bisulfite sequencing(RRBS).The WGS analysis identified 403 variants following ABVD treatment,including 28 linked to genes crucial for embryogenesis.However,none were found in coding regions,indicating no impact of chemotherapy on protein function.The RRBS analysis identified 99high-quality differentially methylated regions(hqDMRs)for which methylation status changed upon chemotherapy.Those hqDRMs were associated with 87 differentially methylated genes,among which 14 are known to be important or expressed during embryo development.While no variants were detected in coding regions,promoter regions of several genes potentially important for embryo development contained variants or displayed an altered methylated status.These might in turn modify the corresponding gene expression and thus affect their function during key stages of embryogenesis,leading to potential developmental disorders or miscarriages.
基金Ministry of Education,Culture,Research,and Technology of the Republic of Indonesia through the Kedaireka 2022 Matching Fund Programme(Grant No.282/E1/KS.060.02/2022)。
文摘The prevalence of stunting in Indonesian children under five years of age is approximately 20%.Chronic maternal malnutrition contributes to the risk of stunting by affecting global DNA methylation.In the present study,we aimed to evaluate the levels of 5-methyl-cytosine(5mC)as a surrogate marker of global DNA methylation in buccal swabs and its potential association with the risk of stunting and cognitive performance.The levels of 5mC were measured using an enzyme-linked immunosorbent assay.The Wechsler Preschool and Primary Scale of Intelligence(WPPSI)was used to measure cognitive function.Buccal swab DNA samples and anthropometric data were collected from a total of 231 children aged zero to five years.In this cross-sectional cohort,the prevalence of stunting was 37%in 138 children aged zero to two years and 30%in 93 children aged over two years.The univariable analysis revealed that the levels of 5mC in buccal swab DNA were significantly lower in severely stunted children(median,2.84;interquartile range[IQR],2.39–4.62)and children aged less than two years(median,2.81;IQR,2.53–4.62)than those in normal children(median,3.75;IQR,2.80–4.74;P-value,0.028)and children aged over four years(median,4.01;IQR,3.39–4.87;P-value<0.001),respectively.We also found that the average cognitive scores tended to be low in boys and stunted children,although the differences were not statistically significant.Furthermore,the levels of 5mC found in buccal swab and mouthwash DNA were not associated with cognitive scores.
基金supported by Young Talents Cultivation Program of Xianning City,the Natural Science Foundation of Hubei Province,China(No.2024AFB502)Ph.D.Start-up Funding(No.BK202413)Medical Fund(No.2023YKY04)of Hubei University of Science and Technology.
文摘Background:Kidney renal clear cell carcinoma(KIRC),a prevalent urological malignancy,represents about 3%of all adult malignancies.KIRC,accounting for~75%of renal malignancies,has poor prognosis in metastatic stages.Identifying robust prognostic markers remains urgent.Block of proliferation 1(BOP1),a WD40-repeat protein,is implicated in cancer pathogenesis,but its role in KIRC is unclear.This study aimed to characterize BOP1 expression in KIRC and evaluate its prognostic value.Methods:BOP1 transcriptional levels were assessed through TCGA-KIRC RNA sequencing datasets.ROC curve construction was implemented via R statistical packages for diagnostic evaluation.Patient survival outcomes were visualized through Kaplan-Meier plotting with log-rank testing.Multivariate logistic regression models quantified associations between BOP1 expression and clinicopathological parameters.TIMER algorithm analyzed immune microenvironment composition.Genomic alterations and epigenetic modifications were investigated using cBioPortal and MethSurv platforms respectively.BOP1 protein levels in 786-O clear cell renal cell carcinoma(ccRCC)versus HK-2(normal renal)cell lines were validated by immunoblotting.Results:Evaluation of the TCGA database demonstrated that BOP1 mRNA abundance was higher in tumor specimens than in corresponding adjacent tissues.Patients with KIRC who had high BOP1 expression had differential overall survival(OS),disease-specific survival(DSS),and disease-free interval(DFI).BOP1 expression accurately recognised tumour tissues versus normal tissues(AUC=0.858),and the area under the ROCs for survival at 1,3,and 5 years were all greater than 0.6.The BOP1 gene variant rate was<1%.Out of the 15 DNA methylation CpG sites examined,7 exhibited prognostic significance in KIRC.BOP1 displayed a distinct relationship with immune cell infiltration in KIRC.The 786-O experimental group exhibited substantially higher BOP1 expression,as confirmed by Western blot detection.Conclusion:This study indicates that heightened BOP1 expression is linked to an adverse prognosis in KIRC,establishing it as an independent risk factor for this disease.These findings establish BOP1 as a novel and independent prognostic biomarker for KIRC,offering potential clinical utility for risk stratification and personalized therapeutic strategies.
