Qingke,a staple crop grown on the high-altitude Tibetan Plateau,has evolved a metabolomic profile providing both environmental stress resilience and human nutrition.We review the hypothesis that the metabolites that c...Qingke,a staple crop grown on the high-altitude Tibetan Plateau,has evolved a metabolomic profile providing both environmental stress resilience and human nutrition.We review the hypothesis that the metabolites that confer cold and UV resistance on the crop also facilitate human adaptation to high-altitude stresses.Specifically,β-glucans regulate blood glucose primarily via short-chain fatty acids(SCFAs)produced through gut microbiota fermentation,which directly mediate glucose homeostasis.Phenolamides accumulate via the phenylpropanoid pathway,with chalcone isomerase(CHI)serving as a key enzyme in flavonoid biosynthesis and enhancing UV-B resistance.Under low temperatures,β-glucans improve frost tolerance by modulating osmotic balance and inhibiting ice-nucleating proteins,while lipids maintain membrane fluidity to sustain cellular function during cold stress.Importantly,we explore the hypothesis that these same metabolites,upon consumption,may facilitate human adaptation to high-altitude stresses.This hypothesis is supported by preliminary epidemiological associations between Qingke consumption and favorable health outcomes in high-altitude populations,as well as established bioactivities of the implicated metabolites in vitro and in animal models.However,direct causal evidence in humans and a comprehensive understanding of the underlying molecular mechanisms remain key knowledge gaps that warrant future investigation.Qingke as a unique resource at the interface of agricultural resilience and human nutrition.Understanding its metabolic blueprint will inform the development of functional foods and climate-resilient crops.展开更多
Skeletal muscle injuries are prone to induce fatigue,decrease resistance and imbalances in the body.Although ovalbumin(OVA)has such biological effect as promoting tissue development and immunomodulation,its impact on ...Skeletal muscle injuries are prone to induce fatigue,decrease resistance and imbalances in the body.Although ovalbumin(OVA)has such biological effect as promoting tissue development and immunomodulation,its impact on repairing skeletal muscle injuries has been rarely reported.In this study,a mouse model of muscle injury was constructed and found that OVA significantly increased muscle weight,muscle thickness,and exercise capacity in muscle-injured mice.Meanwhile,OVA improved the morphology of muscle tissues by reducing serum levels of urea nitrogen,creatine kinase,and lactate dehydrogenase,as well as decreasing the levels of inflammatory factors interleukin(IL)-1β,tumor necrosis factor α,and IL-6,respectively.In addition,transcriptomic and metabolomic analyses revealed that OVA could enhance muscle tissue morphology by upregulating the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and improving amino acid metabolism through the upregulation of Col11a2,Ccn2,Thbs1,Tnc,Klf2,Bcl2l1,Adh3a1,and Rsad1.The study provided a theoretical foundation for understanding the molecular mechanisms in OVA-aided muscle injury repair.展开更多
As a specific spoilage organism of seafood under refrigerated temperature conditions,Shewanella spp.tend to form biofilms that exacerbate the occurrence of seafood spoilage.Biofilm-promoting factor A(BpfA)has been rep...As a specific spoilage organism of seafood under refrigerated temperature conditions,Shewanella spp.tend to form biofilms that exacerbate the occurrence of seafood spoilage.Biofilm-promoting factor A(BpfA)has been reported to promote the adhesion and biofilm formation of Shewanella spp.,but its role in adhesion and biofilm formation of S.putrefaciens under cold stress needs to be further investigated.To better comprehend the effect of BpfA on adhesion and biofilm formation of S.putrefaciens under cold stress(4℃),bacterial adhesion and biofilm phenotype of S.putrefaciens CN32 WT andΔbpfA at 4℃were analyzed and performed transcriptomics.The results showed that the deletion of bpfA had almost no effect on the growth of S.putrefaciens CN32 at 4℃,but weakened the unicellular adhesion capacity of S.putrefaciens CN32 and destabilized the stability of the multicellular adhesion layer.In addition,the biomass of the mature biofilm formed byΔbpfA was merely around 50%of that observed in the mature biofilm of S.putrefaciens CN32 WT,the average thickness and volume of the biofilm decreased by 18%and 27%,respectively,and the composition of the biofilm changed.Transcriptome analysis demonstrated that the deletion of bpfA led to differential expression of genes involved in metabolic pathways such as bacterial chemotaxis,two-component system,tyrosine metabolism,drug metabolism-other enzymes and biofilm formation-Vibrio cholerae,which in turn influenced bacterial adhesion and biofilm formation.Those results advance our acknowledgment of the character of BpfA on adhesion and biofilm formation of S.putrefaciens CN32,which contributes to understanding bacterial adhesion and the control of biofilm formation.展开更多
1.Introduction The field of exercise science is experiencing a renaissance,with recent research illuminating the molecular,cellular,and systemic effects of physical activity.This is largely due to the now unequivocal ...1.Introduction The field of exercise science is experiencing a renaissance,with recent research illuminating the molecular,cellular,and systemic effects of physical activity.This is largely due to the now unequivocal evidence that a lack of physical activity,not only has direct effects on the prevalence of non-contagious diseases(NCDs)but has profound additive effects of other risk factors for NCD such as obesity and hypertension.1 The articles in this special topic of Journal of Sport and Health Science(JSHS)are dedicated to research on Exercise biochemistry&metabolism.展开更多
Malolactic fermentation,started by lactic acid bacteria,plays a crucial role in the production of high-quality wines.As global warming increases the ethanol content in wines,the success of malolactic fermentation depe...Malolactic fermentation,started by lactic acid bacteria,plays a crucial role in the production of high-quality wines.As global warming increases the ethanol content in wines,the success of malolactic fermentation depends on selecting ethanol-tolerant strains,especially for wines from increasingly warm climates.Lentilactobacillus hilgardii Q19 was isolated and characterized as an indigenous malolactic bacterium with higher ethanol tolerance properties.In this study,it was indicated that ethanol stress had significant effects on ATPase activity,antioxidant system,and cell membrane of L.hilgardii Q19 by measuring the physiological indicators under stress which include H^(+)-ATPase,Na^(+)/K^(+)-ATPase,Ca^(2+)/Mg^(2+)-ATPase activity,glutathione content,superoxide dismutase(SOD)activity and intracellular reactive oxygen species(ROS)content.The main metabolic pathways involved in ethanol stress such as ATP-binding cassette(ABC)transporters,pentose phosphate pathway,phosphotransferase system,glutathione metabolic pathway and two-component systems were screened by transcriptome sequencing analysis.The functions of the pentose phosphate pathway,pyruvate metabolic pathway and glycerolipid metabolism under ethanol stress were verified by constructing the L.hilgardii Q19 ethanol stress related key genes gnt K,pyk,and glp K overexpression vectors.The above findings may contribute to our understanding of the metabolic pathways and regulatory mechanisms of L.hilgardii Q19 in response to ethanol stress.展开更多
Blueberry(Vaccinium ashei)is highly characterized by its nutritional value,with an extremely high anthocyanin content,and rabbiteye blueberry is widely grown across China.However,molecular regulatory mechanisms underl...Blueberry(Vaccinium ashei)is highly characterized by its nutritional value,with an extremely high anthocyanin content,and rabbiteye blueberry is widely grown across China.However,molecular regulatory mechanisms underlying the high anthocyanin accumulation during the fruit development and colouration of rabbiteye blueberry fruit,have not yet been fully clarified so far.The fruit anthocyanin content of rabbiteye blueberry in the karstic area of Guizhou Province,China,is much higher compared to that in other regions,and the fruit colour is highly affected by anthocyanin accumulation.Currently,the untargeted metabolomics and HPLC assays have been carried out using rabbiteye blueberry fruit at various stages,and it was investigated that cyanidin(Cy)and pelargonidin(Pg)reached their peaks at the red fruit(RF)stage,whereas delphinidin(Dp),petudinin(Pt),malvidin(Mv),and peonidin(Pn)got their ceilings at the mature fruit(MF)stage.Transcriptome and co-expression network analyses showed that 27 differentially expressed genes(DEGs)were associated with anthocyanin content,among which VdMYB56,belonging to the R2R3-MYB family,was markedly up-regulated during the development and colouration of fruit,and was significantly higher in the skin than in the pulp.Furthermore,VdMYB56-overexpressing tomato fruits demonstrated a substantial elevation in anthocyanin content on the 35th day after flowering(DAF).It was worth noting that VdMYB56 could directly bind to the promoter of Vd3GT to enhance its expression,thereby further strengthening the anthocyanin accumulation.Meantime,multiple assays verified that VdMYB69,an R2R3-MYB member,might interact with VdMYB56,leading to the promotion of VdMYB56 expression.Conclusively,the VdMYB56-VdMYB69 module is a positive regulator of anthocyanin biosynthesis in rabbiteye blueberry,which may provide new insights into high-anthocyanin breeding,particularly for the southern karstic regions.展开更多
Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms o...Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.展开更多
As its tuberous alkaloids induce valuable pharmacological effects,Pinellia ternata has considerable clinical value.However,its production currently fails to meet its demand.In vitro microtuber culture,combined with sa...As its tuberous alkaloids induce valuable pharmacological effects,Pinellia ternata has considerable clinical value.However,its production currently fails to meet its demand.In vitro microtuber culture,combined with salicylic acid(SA)elicitation,may provide an effective alternative to traditional field production.In this study,an in vitro P.ternata microtuber induction system was developed and used to evaluate SA-induced elicitation of alkaloid accumulation.The quality of in vitro microtubers was assessed by total alkaloid measurement,a cytotoxicity assay,and transcriptomic analysis.With or without SA treatment,P.ternata microtuber induction was achieved within 60 d using petiole-derived explants,with a microtuber proliferation rate of approximately 17 microtubers per explant.The total alkaloid content of in vitro microtubers elicited with 100μM SA was equivalent to that of field-grown tubers,while those not treated with SA contained lower alkaloid content.The cytotoxicity assay showed preliminary cytotoxic effects of SA-treated microtubers against the breast cancer cell line SUM159,comparable to field-grown tubers.Transcriptomic analysis revealed many differentially expressed genes(DEGs)in SA-treated in vitro microtubers.Six and twelve DEGs were annotated to the tropane,piperidine,and pyridine alkaloid pathway and the isoquinoline alkaloid pathway,respectively.RT-qPCR confirmed that the genes encoding spermidine synthase(c64642_g1),hyoscyamine(6S)-dioxygenase(c62620_g1),catechol oxidase(c61704_g3),monoamine oxidase(c65996_g3),and aspartate transaminase(c71069_g1)were significantly induced by SA.This study advances the production of P.ternata microtubers without field cultivation and provides considerable genetic information regarding SA-promoted alkaloid accumulation in P.ternata.展开更多
Gibbons are small,arboreal apes that play a critical role in tropical biodiversity and ecosystem ecology.However,nearly all species of gibbons are threatened by habitat loss,illegal trade,hunting,and other human activ...Gibbons are small,arboreal apes that play a critical role in tropical biodiversity and ecosystem ecology.However,nearly all species of gibbons are threatened by habitat loss,illegal trade,hunting,and other human activities.Long-term poor understanding of their genetics and evolution undermines effective conservation efforts.In this study,we analyse comparative population genomic data of four Nomascus species.Our results reveal strong genetic differentiation and gene flow among Nomascus species.Additionally,we identify genomic features that are potentially related to natural selection linked to vocalization,fructose metabolism,motor balance,and body size,consistent with the unique phenotype and adaptability of gibbons.Inbreeding,coupled with population declines due to climate change and historical human activities,leads to reduced genetic diversity and the accumulation of deleterious variations that likely affect cardiovascular disease and the reproductive potential of gibbons and further reduce their fitness,highlighting the urgent need for effective conservation strategies.展开更多
Nitric oxide(NO)is a key vasodilator that regulates vascular pressure and blood flow.Tibetans have developed a"blunted"mechanism for regulating NO levels at high altitude,with GTP cyclohydrolase 1(GCH1)ident...Nitric oxide(NO)is a key vasodilator that regulates vascular pressure and blood flow.Tibetans have developed a"blunted"mechanism for regulating NO levels at high altitude,with GTP cyclohydrolase 1(GCH1)identified as a key candidate gene.Here,we present comprehensive genetic and functional analyses of GCH1,which exhibits strong Darwinian positive selection in Tibetans.We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans.Based on this observation,we generate the heterozygous Gch1 knockout(Gch1^(+/-))mouse model to simulate its downregulation in Tibetans.We find that under prolonged hypoxia,the Gch1^(+/-)mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type(WT)controls,providing better oxygen supplies to the cardiovascular and pulmonary systems.Markedly,hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1^(^(+/-))mice compared with the WT controls,likely due to the adaptive changes in molecular regulations related to metabolism,inflammation,circadian rhythm,extracellular matrix,and oxidative stress.This study sheds light on the role of GCH1 in regulating blood NO,contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.展开更多
Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations i...Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations in LDD could be used to identify or interpret the causes of heterogeneity in clinical features.This study aimed to identify the transcriptomic classification of degenerated discs in LDD patients and whether the molecular subtypes of LDD could be accurately predicted using clinical features.Methods:One hundred and twenty-two nucleus pulposus(NP)tissues from 108 patients were consecutively collected for bulk RNA sequencing(RNA-seq).An unsupervised clustering method was employed to analyze the bulk RNA matrix.Differential analysis was performed to characterize the transcriptional signatures and subtype-specific extracellular matrix(ECM)dysregulation.The cell subpopulation states of each subtype were inferred by integrating bulk and single-cell sequencing datasets.Transwell and dual-luciferase reporter gene assays were employed to investigate possible molecular mechanisms involved.Machine learning algorithm diagnostic prediction models were developed to correlate molecular classification with clinical features.Results:LDD was classified into 4 subtypes with distinct molecular signatures and ECM remodeling:C1 with collagenesis,C2 with ossification,C3 with low chondrogenesis,and C4 with fibrogenesis.Chond1-3 in C1 dominated disc collagenesis via the activation of the mechanosensors TRPV4 and PIEZO1;NP progenitor cells in C2 exhibited chondrogenic and osteogenic phenotypes;Chond1 in C3 was linked to a disrupted hypoxic microenvironment leading to reduced chondrogenesis;Macrophages in C4 played a crucial role in disc fibrogenesis via the secretion of tumor necrosis factor-α(TNF-α).Furthermore,the random forest diagnostic prediction model was proven to have a robust performance[area under the receiver operating characteristic(ROC)curve:0.9312;accuracy:0.84]in stratifying the molecular subtypes of LDD based on 12 clinical features.Conclusions:Our study delineates 4 distinct molecular subtypes of LDD that can be accurately stratified on the basis of clinical features.The identification of these subtypes would facilitate precise diagnostics and guide the development of personalized treatment strategies for LDD.展开更多
Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve thro...Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve throughout the disease course.This review examined 95 studies(2000-2025)from PubMed,Web of Science,and CNKI databases including longitudinal cohorts,randomized controlled trials,and mixed-methods research,to characterize the complex interplay between biological,psychological,and social factors affecting RA patients’mental health.Findings revealed three distinct vulnerability trajectories(45%persistently low,30%fluctuating improvement,25%persistently high)and four adaptation stages,with critical intervention periods occurring 3-6 months postdiagnosis and during disease flares.Multiple factors significantly influence psychological outcomes,including gender(females showing 1.8-fold increased risk),age(younger patients experiencing 42%higher vulnerability),pain intensity,inflammatory markers,and neuroendocrine dysregulation(48%showing cortisol rhythm disruption).Early psychological intervention(within 3 months of diagnosis)demonstrated robust benefits,reducing depression incidence by 42%with effects persisting 24-36 months,while different modalities showed complementary advantages:Cognitive behavioral therapy for depression(Cohen’s d=0.68),mindfulness for pain acceptance(38%improvement),and peer support for meaning reconstruction(25.6%increase).These findings underscore the importance of integrating routine psychological assessment into standard RA care,developing stage-appropriate interventions,and advancing research toward personalized biopsychosocial approaches that address the dynamic psychological dimensions of the disease.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
Domain adaptation aims to reduce the distribution gap between the training data(source domain)and the target data.This enables effective predictions even for domains not seen during training.However,most conventional ...Domain adaptation aims to reduce the distribution gap between the training data(source domain)and the target data.This enables effective predictions even for domains not seen during training.However,most conventional domain adaptation methods assume a single source domain,making them less suitable for modern deep learning settings that rely on diverse and large-scale datasets.To address this limitation,recent research has focused on Multi-Source Domain Adaptation(MSDA),which aims to learn effectively from multiple source domains.In this paper,we propose Efficient Domain Transition for Multi-source(EDTM),a novel and efficient framework designed to tackle two major challenges in existing MSDA approaches:(1)integrating knowledge across different source domains and(2)aligning label distributions between source and target domains.EDTM leverages an ensemble-based classifier expert mechanism to enhance the contribution of source domains that are more similar to the target domain.To further stabilize the learning process and improve performance,we incorporate imitation learning into the training of the target model.In addition,Maximum Classifier Discrepancy(MCD)is employed to align class-wise label distributions between the source and target domains.Experiments were conducted using Digits-Five,one of the most representative benchmark datasets for MSDA.The results show that EDTM consistently outperforms existing methods in terms of average classification accuracy.Notably,EDTM achieved significantly higher performance on target domains such as Modified National Institute of Standards and Technolog with blended background images(MNIST-M)and Street View House Numbers(SVHN)datasets,demonstrating enhanced generalization compared to baseline approaches.Furthermore,an ablation study analyzing the contribution of each loss component validated the effectiveness of the framework,highlighting the importance of each module in achieving optimal performance.展开更多
To address the issue of scarce labeled samples and operational condition variations that degrade the accuracy of fault diagnosis models in variable-condition gearbox fault diagnosis,this paper proposes a semi-supervis...To address the issue of scarce labeled samples and operational condition variations that degrade the accuracy of fault diagnosis models in variable-condition gearbox fault diagnosis,this paper proposes a semi-supervised masked contrastive learning and domain adaptation(SSMCL-DA)method for gearbox fault diagnosis under variable conditions.Initially,during the unsupervised pre-training phase,a dual signal augmentation strategy is devised,which simultaneously applies random masking in the time domain and random scaling in the frequency domain to unlabeled samples,thereby constructing more challenging positive sample pairs to guide the encoder in learning intrinsic features robust to condition variations.Subsequently,a ConvNeXt-Transformer hybrid architecture is employed,integrating the superior local detail modeling capacity of ConvNeXt with the robust global perception capability of Transformer to enhance feature extraction in complex scenarios.Thereafter,a contrastive learning model is constructed with the optimization objective of maximizing feature similarity across different masked instances of the same sample,enabling the extraction of consistent features from multiple masked perspectives and reducing reliance on labeled data.In the final supervised fine-tuning phase,a multi-scale attention mechanism is incorporated for feature rectification,and a domain adaptation module combining Local Maximum Mean Discrepancy(LMMD)with adversarial learning is proposed.This module embodies a dual mechanism:LMMD facilitates fine-grained class-conditional alignment,compelling features of identical fault classes to converge across varying conditions,while the domain discriminator utilizes adversarial training to guide the feature extractor toward learning domain-invariant features.Working in concert,they markedly diminish feature distribution discrepancies induced by changes in load,rotational speed,and other factors,thereby boosting the model’s adaptability to cross-condition scenarios.Experimental evaluations on the WT planetary gearbox dataset and the Case Western Reserve University(CWRU)bearing dataset demonstrate that the SSMCL-DA model effectively identifies multiple fault classes in gearboxes,with diagnostic performance substantially surpassing that of conventional methods.Under cross-condition scenarios,the model attains fault diagnosis accuracies of 99.21%for the WT planetary gearbox and 99.86%for the bearings,respectively.Furthermore,the model exhibits stable generalization capability in cross-device settings.展开更多
Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More r...Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.展开更多
Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the developmen...Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the development of targeted monocyte-based therapies for stroke.Here,we used a multi-omics approach combining single-cell and bulk transcriptomics.CellChat analysis revealed intercellular communication networks,while key genes were identified and predictive models built through Lasso regression.Immune cell infiltration dynamics were quantified using single-sample gene set enrichment analysis.Gene set enrichment analysis and gene set variation analysis identified disease-regulated pathways of core genes.MicroRNA networks and transcription factors were investigated using mircode and RcisTarget.Experimental validation was performed using oxygen-glucose deprivation and transient middle cerebral artery occlusion models,focusing on the influence of abhydrolase domain-containing protein 2 on monocyte function.We observed significantly elevated monocyte content in stroke brain tissue samples,and identified key monocyte genes associated with immune inflammation,chemokine signaling,and cell receptor function.A robust seven-gene predictive model for ischemic stroke was developed.CD274 strongly correlated with these seven genes,suggesting a potential immunomodulatory axis.In vivo transient middle cerebral artery occlusion experiments validated the predictive value of key genes.In vitro studies demonstrated that abhydrolase domain-containing protein 2 overexpression enhanced monocyte proliferation and phagocytic activity post-oxygen-glucose deprivation while reducing reactive oxygen species generation.In conclusion,this study maps post-stroke monocyte communication networks,identifies key signaling pathways,identifies regulatory mechanisms,and validates the functional importance of key genes,particularly abhydrolase domain-containing protein 2.These findings provide a foundation for developing targeted immunomodulatory therapies and precision diagnostics in ischemic stroke management.展开更多
Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer’s disease.However,whether this disruption occurs before the appearance of cognitive symptoms and whe...Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer’s disease.However,whether this disruption occurs before the appearance of cognitive symptoms and whether it drives disease development remain unclear.Understanding the temporal relationship between circadian rhythm dysregulation and early Alzheimer’s disease pathological changes may open up new avenues for disease prevention and intervention.To determine if circadian rhythm disruption precedes cognitive decline,we conducted high-resolution transcriptome analyses of the hippocampus in a 5-month-old mouse model of Alzheimer’s disease and age-matched wild-type control mice at multiple time points over a 24-hour period.While the mouse model of Alzheimer’s disease did not exhibit obvious cognitive symptoms at this stage,the expression of circadian-related genes in the hippocampus exhibited extensive abnormalities.In the control group,2109 genes exhibited rhythmic expression characteristics.In the mouse model of Alzheimer’s disease,a marked proportion of these genes lost their rhythmicity,some genes newly developed rhythmicity,and some maintained rhythmicity but with altered expression patterns.Genes related to neuronal function,including those involved in protein homeostasis regulation,neuroinflammation,and ion homeostasis,showed significant changes in circadian rhythm amplitude and phase,and some completely lost their rhythmicity.These findings point to the following critical early events in Alzheimer’s disease:hippocampal circadian gene disruption occurs before cognitive symptoms emerge,genes related to neuronal function are uniquely susceptible to this early dysregulation,and circadian dysfunction may even precede the pathological changes of Alzheimer’s disease and influence disease onset.This work advances Alzheimer’s disease research by clarifying that circadian disruption is an early pre-symptomatic event,reinforcing the potential of circadian rhythm regulation as a strategy for early intervention of Alzheimer’s disease,and identifying neuronal pathways that may serve as intervention targets.展开更多
Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,t...Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,there is still not enough knowledge on the active ingredients and possible ways that QSDs might work to treat RA.This study systematically investigated the active ingredients and mechanisms of action of QSD for treating wind-cold-dampness arthralgia type RA.Methods:UHPLC-QE-MS and network pharmacology techniques were employed to predict the potential active constituents,targets,and associated signalling pathways.Then,the therapeutic effect of QSD was examined using a wind-cold-dampness arthralgia paralytic RA rat model.Finally,the complex mechanism was comprehensively elucidated by integrating transcriptomics and network pharmacology.The above mechanisms were also verified by molecular docking,immunohistochemistry and Western blot.Results:UHPLC-QE-MS and network pharmacology analysis revealed that ferulic acid,imperatorin,magnolol,quercetin,and scopoletin could be the primary constituents in QSD responsible for its anti-RA effects.Animal experiments showed that QSD can significantly inhibit rat joint swelling degree,decrease the content of serum rheumatoid factor(RF),interleukin(IL)-1β,tumor necrosis factor-alpha(TNF-α),IL-6,and anti-citrullinated protein antibodies(ACPA),and increase the content of IL-4,IL-10 to relieve the clinical symptoms of wind-cold-dampness arthralgia type RA.The mechanistic study showed that QSD may effectively inhibit rat synovial hyperplasia via promoting autophagy and apoptosis of synovial cells by regulating the PI3K/Akt/mTOR signalling pathway.Conclusion:This study identifies key active ingredients in QSD and elucidates its potential mechanism for treating wind-cold-dampness arthralgia type RA,providing a basis for the clinical application of QSD.展开更多
Drought stress is the main limiting plant growth factor in arid and semiarid regions.The Lanzhou lily(Lilium davidii var.unicolor)is the only sweet-tasting lily grown in these regions of China that offers highly edibl...Drought stress is the main limiting plant growth factor in arid and semiarid regions.The Lanzhou lily(Lilium davidii var.unicolor)is the only sweet-tasting lily grown in these regions of China that offers highly edible,medicinal,health,and ornamental value.The Tresor lily is an ornamental flower known for its strong resistance.Plants were grown under three different drought intensity treatments,namely,being watered at intervals of 5,15,and 25 d(either throughout the study or during specific growth stages).We measured the biomass,leaf area,photosynthetic response,chlorophyll content(SPAD value),and osmoregulation of both the Lanzhou lily and the Tresor lily(Lilium‘Tresor’).Additionally,we employed RNA sequencing(RNA-Seq)and qRT-PCR to investigate transcriptomic changes of the Lanzhou lily in response to drought stress.Results showed that under drought stress,the decreasing rate in the Lanzhou lily bulb weight was lower than the corresponding Tresor lily bulb rate;the net photosynthetic rate,transpiration rate,and stomatal conductance of the Lanzhou lily were all higher compared to the Tresor lily;osmoregulation constituents,such as glucose,fructose,sucrose,trehalose,and soluble sugar,in the Lanzhou lily were comparatively higher;PYL,NCED,and ERS genes were significantly expressed in the Lanzhou lily.Under moderate drought,the biosynthesis of flavonoids,circadian rhythms,and the tryptophan metabolism pathway of the Lanzhou lily were all significant.Under severe drought stress,fatty acid elongation,photosynthetic antenna protein,plant hormone signal transduction,flavone and flavonol biosynthesis,and the carotenoid biosynthesis pathway were all significant.The Lanzhou lily adapted to drought stress by coordinating its organs and the unique role of its bulb,regulating photosynthesis,increasing osmolyte content,activating circadian rhythms,signal transduction,fatty acid elongation metabolism,and phenylalanine and flavonoid metabolic pathways,which may collectively be the main adaptation strategy and mechanisms used by the Lanzhou lily under drought stress.展开更多
基金supported by the Financial Special Fund,grant number XZ202401JD0027National Barley Industry Technology System(CARS-05-01A-08)+3 种基金the Xizang Agri-Tech Innovation Project(XZNKY-2025-CXGC-T01)the Joint Funds of the National Natural Science Foundation of China(No.U20A2026)the Financial Special Fund,grant number(32401784,2017CZZX001/2,XZNKY-2018-C-021 and NYSTC202401)the China Agriculture Research System of Barley(CARS-05).
文摘Qingke,a staple crop grown on the high-altitude Tibetan Plateau,has evolved a metabolomic profile providing both environmental stress resilience and human nutrition.We review the hypothesis that the metabolites that confer cold and UV resistance on the crop also facilitate human adaptation to high-altitude stresses.Specifically,β-glucans regulate blood glucose primarily via short-chain fatty acids(SCFAs)produced through gut microbiota fermentation,which directly mediate glucose homeostasis.Phenolamides accumulate via the phenylpropanoid pathway,with chalcone isomerase(CHI)serving as a key enzyme in flavonoid biosynthesis and enhancing UV-B resistance.Under low temperatures,β-glucans improve frost tolerance by modulating osmotic balance and inhibiting ice-nucleating proteins,while lipids maintain membrane fluidity to sustain cellular function during cold stress.Importantly,we explore the hypothesis that these same metabolites,upon consumption,may facilitate human adaptation to high-altitude stresses.This hypothesis is supported by preliminary epidemiological associations between Qingke consumption and favorable health outcomes in high-altitude populations,as well as established bioactivities of the implicated metabolites in vitro and in animal models.However,direct causal evidence in humans and a comprehensive understanding of the underlying molecular mechanisms remain key knowledge gaps that warrant future investigation.Qingke as a unique resource at the interface of agricultural resilience and human nutrition.Understanding its metabolic blueprint will inform the development of functional foods and climate-resilient crops.
基金funded by the Project of National Key Research and Development Program of China(2022YFD2101001)the Project of National Natural Science Foundation of China(32172226)+4 种基金China Agriculture Research System(CARS-40-K25CARS-40-S11)the Special Fund for Anhui Agriculture Research System(AHCYJSTX-NCPJG)-15the Project of Key Laboratory for Animal Food Green Manufacturing and Resource Ming of Anhui Province(PA2023GDSK0125)the Cooperative Project of Hefei University of Technology-Anhui Rongda Food Co.,Ltd.(W2020JSKF0489).
文摘Skeletal muscle injuries are prone to induce fatigue,decrease resistance and imbalances in the body.Although ovalbumin(OVA)has such biological effect as promoting tissue development and immunomodulation,its impact on repairing skeletal muscle injuries has been rarely reported.In this study,a mouse model of muscle injury was constructed and found that OVA significantly increased muscle weight,muscle thickness,and exercise capacity in muscle-injured mice.Meanwhile,OVA improved the morphology of muscle tissues by reducing serum levels of urea nitrogen,creatine kinase,and lactate dehydrogenase,as well as decreasing the levels of inflammatory factors interleukin(IL)-1β,tumor necrosis factor α,and IL-6,respectively.In addition,transcriptomic and metabolomic analyses revealed that OVA could enhance muscle tissue morphology by upregulating the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and improving amino acid metabolism through the upregulation of Col11a2,Ccn2,Thbs1,Tnc,Klf2,Bcl2l1,Adh3a1,and Rsad1.The study provided a theoretical foundation for understanding the molecular mechanisms in OVA-aided muscle injury repair.
基金funded by the National Natural Science Foundation of China(32472401).
文摘As a specific spoilage organism of seafood under refrigerated temperature conditions,Shewanella spp.tend to form biofilms that exacerbate the occurrence of seafood spoilage.Biofilm-promoting factor A(BpfA)has been reported to promote the adhesion and biofilm formation of Shewanella spp.,but its role in adhesion and biofilm formation of S.putrefaciens under cold stress needs to be further investigated.To better comprehend the effect of BpfA on adhesion and biofilm formation of S.putrefaciens under cold stress(4℃),bacterial adhesion and biofilm phenotype of S.putrefaciens CN32 WT andΔbpfA at 4℃were analyzed and performed transcriptomics.The results showed that the deletion of bpfA had almost no effect on the growth of S.putrefaciens CN32 at 4℃,but weakened the unicellular adhesion capacity of S.putrefaciens CN32 and destabilized the stability of the multicellular adhesion layer.In addition,the biomass of the mature biofilm formed byΔbpfA was merely around 50%of that observed in the mature biofilm of S.putrefaciens CN32 WT,the average thickness and volume of the biofilm decreased by 18%and 27%,respectively,and the composition of the biofilm changed.Transcriptome analysis demonstrated that the deletion of bpfA led to differential expression of genes involved in metabolic pathways such as bacterial chemotaxis,two-component system,tyrosine metabolism,drug metabolism-other enzymes and biofilm formation-Vibrio cholerae,which in turn influenced bacterial adhesion and biofilm formation.Those results advance our acknowledgment of the character of BpfA on adhesion and biofilm formation of S.putrefaciens CN32,which contributes to understanding bacterial adhesion and the control of biofilm formation.
文摘1.Introduction The field of exercise science is experiencing a renaissance,with recent research illuminating the molecular,cellular,and systemic effects of physical activity.This is largely due to the now unequivocal evidence that a lack of physical activity,not only has direct effects on the prevalence of non-contagious diseases(NCDs)but has profound additive effects of other risk factors for NCD such as obesity and hypertension.1 The articles in this special topic of Journal of Sport and Health Science(JSHS)are dedicated to research on Exercise biochemistry&metabolism.
基金financially supported by the National Natural Science Foundation of China(32160578)Natural Science Foundation of Ningxia Hui Autonomous Region(2025AAC020032).
文摘Malolactic fermentation,started by lactic acid bacteria,plays a crucial role in the production of high-quality wines.As global warming increases the ethanol content in wines,the success of malolactic fermentation depends on selecting ethanol-tolerant strains,especially for wines from increasingly warm climates.Lentilactobacillus hilgardii Q19 was isolated and characterized as an indigenous malolactic bacterium with higher ethanol tolerance properties.In this study,it was indicated that ethanol stress had significant effects on ATPase activity,antioxidant system,and cell membrane of L.hilgardii Q19 by measuring the physiological indicators under stress which include H^(+)-ATPase,Na^(+)/K^(+)-ATPase,Ca^(2+)/Mg^(2+)-ATPase activity,glutathione content,superoxide dismutase(SOD)activity and intracellular reactive oxygen species(ROS)content.The main metabolic pathways involved in ethanol stress such as ATP-binding cassette(ABC)transporters,pentose phosphate pathway,phosphotransferase system,glutathione metabolic pathway and two-component systems were screened by transcriptome sequencing analysis.The functions of the pentose phosphate pathway,pyruvate metabolic pathway and glycerolipid metabolism under ethanol stress were verified by constructing the L.hilgardii Q19 ethanol stress related key genes gnt K,pyk,and glp K overexpression vectors.The above findings may contribute to our understanding of the metabolic pathways and regulatory mechanisms of L.hilgardii Q19 in response to ethanol stress.
基金supported by grants from the Core Program grants of Guizhou Province,China(Grant No.QKHZDZXZ[2024]28)the Guizhou Provincial Science and Technology Projects of China(Grant No.YQK[2023]008)the Guizhou Provincial Scientific and Technological Program(Grant No.QKHFQ[2024]004-1).
文摘Blueberry(Vaccinium ashei)is highly characterized by its nutritional value,with an extremely high anthocyanin content,and rabbiteye blueberry is widely grown across China.However,molecular regulatory mechanisms underlying the high anthocyanin accumulation during the fruit development and colouration of rabbiteye blueberry fruit,have not yet been fully clarified so far.The fruit anthocyanin content of rabbiteye blueberry in the karstic area of Guizhou Province,China,is much higher compared to that in other regions,and the fruit colour is highly affected by anthocyanin accumulation.Currently,the untargeted metabolomics and HPLC assays have been carried out using rabbiteye blueberry fruit at various stages,and it was investigated that cyanidin(Cy)and pelargonidin(Pg)reached their peaks at the red fruit(RF)stage,whereas delphinidin(Dp),petudinin(Pt),malvidin(Mv),and peonidin(Pn)got their ceilings at the mature fruit(MF)stage.Transcriptome and co-expression network analyses showed that 27 differentially expressed genes(DEGs)were associated with anthocyanin content,among which VdMYB56,belonging to the R2R3-MYB family,was markedly up-regulated during the development and colouration of fruit,and was significantly higher in the skin than in the pulp.Furthermore,VdMYB56-overexpressing tomato fruits demonstrated a substantial elevation in anthocyanin content on the 35th day after flowering(DAF).It was worth noting that VdMYB56 could directly bind to the promoter of Vd3GT to enhance its expression,thereby further strengthening the anthocyanin accumulation.Meantime,multiple assays verified that VdMYB69,an R2R3-MYB member,might interact with VdMYB56,leading to the promotion of VdMYB56 expression.Conclusively,the VdMYB56-VdMYB69 module is a positive regulator of anthocyanin biosynthesis in rabbiteye blueberry,which may provide new insights into high-anthocyanin breeding,particularly for the southern karstic regions.
基金supported by the National Key R&D Program of China,Nos.2021YFA1101703/2021YFA1101700(to YD).
文摘Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.
基金supported by the Key Project of Natural Science Research for Colleges and Universities in Anhui Province(2024AH051661,2023AH050345)Excellent Scientific Research and Innovation Team of University in Anhui Province(2022AH010029).
文摘As its tuberous alkaloids induce valuable pharmacological effects,Pinellia ternata has considerable clinical value.However,its production currently fails to meet its demand.In vitro microtuber culture,combined with salicylic acid(SA)elicitation,may provide an effective alternative to traditional field production.In this study,an in vitro P.ternata microtuber induction system was developed and used to evaluate SA-induced elicitation of alkaloid accumulation.The quality of in vitro microtubers was assessed by total alkaloid measurement,a cytotoxicity assay,and transcriptomic analysis.With or without SA treatment,P.ternata microtuber induction was achieved within 60 d using petiole-derived explants,with a microtuber proliferation rate of approximately 17 microtubers per explant.The total alkaloid content of in vitro microtubers elicited with 100μM SA was equivalent to that of field-grown tubers,while those not treated with SA contained lower alkaloid content.The cytotoxicity assay showed preliminary cytotoxic effects of SA-treated microtubers against the breast cancer cell line SUM159,comparable to field-grown tubers.Transcriptomic analysis revealed many differentially expressed genes(DEGs)in SA-treated in vitro microtubers.Six and twelve DEGs were annotated to the tropane,piperidine,and pyridine alkaloid pathway and the isoquinoline alkaloid pathway,respectively.RT-qPCR confirmed that the genes encoding spermidine synthase(c64642_g1),hyoscyamine(6S)-dioxygenase(c62620_g1),catechol oxidase(c61704_g3),monoamine oxidase(c65996_g3),and aspartate transaminase(c71069_g1)were significantly induced by SA.This study advances the production of P.ternata microtubers without field cultivation and provides considerable genetic information regarding SA-promoted alkaloid accumulation in P.ternata.
基金supported by Science and Technology Program from the Forestry Administration of Guangdong Province(2024KJQT0012)the Guangdong Provincial Key R&D Program(2022B1111040001)+2 种基金the National Forestry Administration rare and endangered species field rescue and breeding project(Gui lin hu yu O10)the National Natural Science Foundation of China(32200337)a fellowship from the China Postdoctoral Science Foundation(2022M712003).
文摘Gibbons are small,arboreal apes that play a critical role in tropical biodiversity and ecosystem ecology.However,nearly all species of gibbons are threatened by habitat loss,illegal trade,hunting,and other human activities.Long-term poor understanding of their genetics and evolution undermines effective conservation efforts.In this study,we analyse comparative population genomic data of four Nomascus species.Our results reveal strong genetic differentiation and gene flow among Nomascus species.Additionally,we identify genomic features that are potentially related to natural selection linked to vocalization,fructose metabolism,motor balance,and body size,consistent with the unique phenotype and adaptability of gibbons.Inbreeding,coupled with population declines due to climate change and historical human activities,leads to reduced genetic diversity and the accumulation of deleterious variations that likely affect cardiovascular disease and the reproductive potential of gibbons and further reduce their fitness,highlighting the urgent need for effective conservation strategies.
基金funded by grants from the National Natural Science Foundation of China(32288101 and 91631306 to B.S32170632 and 32000390 to Y.H.32400503 to Y.G.)Major Scientific Project of Yunnan Province(202305AH340007 to B.S.)+4 种基金Yunnan Revitalization Talent Support Program Science&Technology Champion Project(202005AB160004 to B.S.)Yunnan Revitalization Talent Support Program Innovation Team(202405AS350008)Yunnan Scientist Workshops(to B.S.)the Youth Innovation Promotion Association of CAS(to Y.H.),the Science and Technology General Program of Yunnan Province(202301AW070010 and 202001AT070110 to Y.H.)and the Provincial Key Research,Development,and Translational Program(XZ202101ZY0009G to Baima.).
文摘Nitric oxide(NO)is a key vasodilator that regulates vascular pressure and blood flow.Tibetans have developed a"blunted"mechanism for regulating NO levels at high altitude,with GTP cyclohydrolase 1(GCH1)identified as a key candidate gene.Here,we present comprehensive genetic and functional analyses of GCH1,which exhibits strong Darwinian positive selection in Tibetans.We show that Tibetan-enriched GCH1 variants down-regulate its expression in the blood of Tibetans.Based on this observation,we generate the heterozygous Gch1 knockout(Gch1^(+/-))mouse model to simulate its downregulation in Tibetans.We find that under prolonged hypoxia,the Gch1^(+/-)mice have relatively higher blood NO and blood oxygen saturation levels compared with the wild-type(WT)controls,providing better oxygen supplies to the cardiovascular and pulmonary systems.Markedly,hypoxia-induced cardiac hypertrophy and pulmonary remodeling are significantly attenuated in the Gch1^(^(+/-))mice compared with the WT controls,likely due to the adaptive changes in molecular regulations related to metabolism,inflammation,circadian rhythm,extracellular matrix,and oxidative stress.This study sheds light on the role of GCH1 in regulating blood NO,contributing to the physiological adaptation of the cardiovascular and pulmonary systems in Tibetans at high altitude.
基金supported by the National Natural Science Foundation of China(32270887,82272507,32200654,82430079,and 82472519)the National Key Research and Development Program of China(2022YFA1103202)+7 种基金the Chongqing High-End Medical Talents for Middle-aged and Young(YXGD202408)the Army Scientific and Technological Innovation Talents Prioritized Suppor t Program(2023-124)the Natural Science Foundation of Chongqing(CSTB2023NSCQ-ZDJO008)the Postdoctoral Innovative Talent Support Program(BX20220397)the Open Project of State Key Laboratory of TraumaBurns and Combined Injury(SFLKF202201)the Project for Enhancing Innovation of Army Medical University(2023XJS39)the Talent Innovation Training Program at the Army Medical Center(ZXZYTSYS09)。
文摘Background:Lumbar disc degeneration(LDD)displays considerable heterogeneity in terms of clinical features and pathological changes.However,researchers have not clearly determined whether the transcriptome variations in LDD could be used to identify or interpret the causes of heterogeneity in clinical features.This study aimed to identify the transcriptomic classification of degenerated discs in LDD patients and whether the molecular subtypes of LDD could be accurately predicted using clinical features.Methods:One hundred and twenty-two nucleus pulposus(NP)tissues from 108 patients were consecutively collected for bulk RNA sequencing(RNA-seq).An unsupervised clustering method was employed to analyze the bulk RNA matrix.Differential analysis was performed to characterize the transcriptional signatures and subtype-specific extracellular matrix(ECM)dysregulation.The cell subpopulation states of each subtype were inferred by integrating bulk and single-cell sequencing datasets.Transwell and dual-luciferase reporter gene assays were employed to investigate possible molecular mechanisms involved.Machine learning algorithm diagnostic prediction models were developed to correlate molecular classification with clinical features.Results:LDD was classified into 4 subtypes with distinct molecular signatures and ECM remodeling:C1 with collagenesis,C2 with ossification,C3 with low chondrogenesis,and C4 with fibrogenesis.Chond1-3 in C1 dominated disc collagenesis via the activation of the mechanosensors TRPV4 and PIEZO1;NP progenitor cells in C2 exhibited chondrogenic and osteogenic phenotypes;Chond1 in C3 was linked to a disrupted hypoxic microenvironment leading to reduced chondrogenesis;Macrophages in C4 played a crucial role in disc fibrogenesis via the secretion of tumor necrosis factor-α(TNF-α).Furthermore,the random forest diagnostic prediction model was proven to have a robust performance[area under the receiver operating characteristic(ROC)curve:0.9312;accuracy:0.84]in stratifying the molecular subtypes of LDD based on 12 clinical features.Conclusions:Our study delineates 4 distinct molecular subtypes of LDD that can be accurately stratified on the basis of clinical features.The identification of these subtypes would facilitate precise diagnostics and guide the development of personalized treatment strategies for LDD.
基金Supported by Chongqing Health Commission and Chongqing Science and Technology Bureau,No.2023MSXM182。
文摘Rheumatoid arthritis(RA)patients face significant psychological challenges alongside physical symptoms,necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve throughout the disease course.This review examined 95 studies(2000-2025)from PubMed,Web of Science,and CNKI databases including longitudinal cohorts,randomized controlled trials,and mixed-methods research,to characterize the complex interplay between biological,psychological,and social factors affecting RA patients’mental health.Findings revealed three distinct vulnerability trajectories(45%persistently low,30%fluctuating improvement,25%persistently high)and four adaptation stages,with critical intervention periods occurring 3-6 months postdiagnosis and during disease flares.Multiple factors significantly influence psychological outcomes,including gender(females showing 1.8-fold increased risk),age(younger patients experiencing 42%higher vulnerability),pain intensity,inflammatory markers,and neuroendocrine dysregulation(48%showing cortisol rhythm disruption).Early psychological intervention(within 3 months of diagnosis)demonstrated robust benefits,reducing depression incidence by 42%with effects persisting 24-36 months,while different modalities showed complementary advantages:Cognitive behavioral therapy for depression(Cohen’s d=0.68),mindfulness for pain acceptance(38%improvement),and peer support for meaning reconstruction(25.6%increase).These findings underscore the importance of integrating routine psychological assessment into standard RA care,developing stage-appropriate interventions,and advancing research toward personalized biopsychosocial approaches that address the dynamic psychological dimensions of the disease.
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 Research Foundation of Korea(NRF)grant funded by the Korea government(MSIT)(No.RS-2024-00406320)the Institute of Information&Communica-tions Technology Planning&Evaluation(IITP)-Innovative Human Resource Development for Local Intellectualization Program Grant funded by the Korea government(MSIT)(IITP-2026-RS-2023-00259678).
文摘Domain adaptation aims to reduce the distribution gap between the training data(source domain)and the target data.This enables effective predictions even for domains not seen during training.However,most conventional domain adaptation methods assume a single source domain,making them less suitable for modern deep learning settings that rely on diverse and large-scale datasets.To address this limitation,recent research has focused on Multi-Source Domain Adaptation(MSDA),which aims to learn effectively from multiple source domains.In this paper,we propose Efficient Domain Transition for Multi-source(EDTM),a novel and efficient framework designed to tackle two major challenges in existing MSDA approaches:(1)integrating knowledge across different source domains and(2)aligning label distributions between source and target domains.EDTM leverages an ensemble-based classifier expert mechanism to enhance the contribution of source domains that are more similar to the target domain.To further stabilize the learning process and improve performance,we incorporate imitation learning into the training of the target model.In addition,Maximum Classifier Discrepancy(MCD)is employed to align class-wise label distributions between the source and target domains.Experiments were conducted using Digits-Five,one of the most representative benchmark datasets for MSDA.The results show that EDTM consistently outperforms existing methods in terms of average classification accuracy.Notably,EDTM achieved significantly higher performance on target domains such as Modified National Institute of Standards and Technolog with blended background images(MNIST-M)and Street View House Numbers(SVHN)datasets,demonstrating enhanced generalization compared to baseline approaches.Furthermore,an ablation study analyzing the contribution of each loss component validated the effectiveness of the framework,highlighting the importance of each module in achieving optimal performance.
基金supported by the National Natural Science Foundation of China Funded Project(Project Name:Research on Robust Adaptive Allocation Mechanism of Human Machine Co-Driving System Based on NMS Features,Project Approval Number:52172381).
文摘To address the issue of scarce labeled samples and operational condition variations that degrade the accuracy of fault diagnosis models in variable-condition gearbox fault diagnosis,this paper proposes a semi-supervised masked contrastive learning and domain adaptation(SSMCL-DA)method for gearbox fault diagnosis under variable conditions.Initially,during the unsupervised pre-training phase,a dual signal augmentation strategy is devised,which simultaneously applies random masking in the time domain and random scaling in the frequency domain to unlabeled samples,thereby constructing more challenging positive sample pairs to guide the encoder in learning intrinsic features robust to condition variations.Subsequently,a ConvNeXt-Transformer hybrid architecture is employed,integrating the superior local detail modeling capacity of ConvNeXt with the robust global perception capability of Transformer to enhance feature extraction in complex scenarios.Thereafter,a contrastive learning model is constructed with the optimization objective of maximizing feature similarity across different masked instances of the same sample,enabling the extraction of consistent features from multiple masked perspectives and reducing reliance on labeled data.In the final supervised fine-tuning phase,a multi-scale attention mechanism is incorporated for feature rectification,and a domain adaptation module combining Local Maximum Mean Discrepancy(LMMD)with adversarial learning is proposed.This module embodies a dual mechanism:LMMD facilitates fine-grained class-conditional alignment,compelling features of identical fault classes to converge across varying conditions,while the domain discriminator utilizes adversarial training to guide the feature extractor toward learning domain-invariant features.Working in concert,they markedly diminish feature distribution discrepancies induced by changes in load,rotational speed,and other factors,thereby boosting the model’s adaptability to cross-condition scenarios.Experimental evaluations on the WT planetary gearbox dataset and the Case Western Reserve University(CWRU)bearing dataset demonstrate that the SSMCL-DA model effectively identifies multiple fault classes in gearboxes,with diagnostic performance substantially surpassing that of conventional methods.Under cross-condition scenarios,the model attains fault diagnosis accuracies of 99.21%for the WT planetary gearbox and 99.86%for the bearings,respectively.Furthermore,the model exhibits stable generalization capability in cross-device settings.
基金supported by the National Natural Science Foundation of China,Nos.82404892(to QY),82061160374(to ZZ)the Science and Technology Development Fund,Macao Special Administrative Region,China,Nos.0023/2020/AFJ,0035/2020/AGJ+2 种基金the University of Macao Research Grant,Nos.MYRG2022-00248-ICMS,MYRG-CRG2022-00010-ICMS(to MPMH)the Natural Science Foundation of Guangdong Province,No.2024A1515012818(to ZZ)the Fundamental Research Funds for the Central Universities,No.21623114(to ZZ).
文摘Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.
基金National Natural Science Foundation of China,No.82471361(to MZ)the Natural Science Foundation for Excellent Young Scholars of Hunan Province,No.2021JJ20095(to MZ)+3 种基金the Key Research and Development Program of Hunan Province,No.2020SK2063(to MZ)the Research Project on Education and Teaching Innovation of Central South University,No.2021jy145(to MZ)the Natural Science Foundations of Hunan Province,No.2020JJ4134(to MZ)the Fundamental Research Funds for the Central Universities of Central South University,No.2023ZZTS0595(to YP).
文摘Monocytes play a crucial role in post-stroke immune infiltration,yet the intricate immune regulatory networks they orchestrate in ischemic stroke remain poorly understood.This knowledge gap has hindered the development of targeted monocyte-based therapies for stroke.Here,we used a multi-omics approach combining single-cell and bulk transcriptomics.CellChat analysis revealed intercellular communication networks,while key genes were identified and predictive models built through Lasso regression.Immune cell infiltration dynamics were quantified using single-sample gene set enrichment analysis.Gene set enrichment analysis and gene set variation analysis identified disease-regulated pathways of core genes.MicroRNA networks and transcription factors were investigated using mircode and RcisTarget.Experimental validation was performed using oxygen-glucose deprivation and transient middle cerebral artery occlusion models,focusing on the influence of abhydrolase domain-containing protein 2 on monocyte function.We observed significantly elevated monocyte content in stroke brain tissue samples,and identified key monocyte genes associated with immune inflammation,chemokine signaling,and cell receptor function.A robust seven-gene predictive model for ischemic stroke was developed.CD274 strongly correlated with these seven genes,suggesting a potential immunomodulatory axis.In vivo transient middle cerebral artery occlusion experiments validated the predictive value of key genes.In vitro studies demonstrated that abhydrolase domain-containing protein 2 overexpression enhanced monocyte proliferation and phagocytic activity post-oxygen-glucose deprivation while reducing reactive oxygen species generation.In conclusion,this study maps post-stroke monocyte communication networks,identifies key signaling pathways,identifies regulatory mechanisms,and validates the functional importance of key genes,particularly abhydrolase domain-containing protein 2.These findings provide a foundation for developing targeted immunomodulatory therapies and precision diagnostics in ischemic stroke management.
基金Shenzhen Science Technology and Innovation Commission,No.JCYJ20220531100811026Shenzhen Clinical Research Center for Trauma Treatment,No.LCYSSQ20220823091405012(both to YZ)Shenzhen Science and Technology Program,No.KQTD20240729102249044.
文摘Mounting evidence suggests that circadian rhythm disruption may be linked to the onset and progression of Alzheimer’s disease.However,whether this disruption occurs before the appearance of cognitive symptoms and whether it drives disease development remain unclear.Understanding the temporal relationship between circadian rhythm dysregulation and early Alzheimer’s disease pathological changes may open up new avenues for disease prevention and intervention.To determine if circadian rhythm disruption precedes cognitive decline,we conducted high-resolution transcriptome analyses of the hippocampus in a 5-month-old mouse model of Alzheimer’s disease and age-matched wild-type control mice at multiple time points over a 24-hour period.While the mouse model of Alzheimer’s disease did not exhibit obvious cognitive symptoms at this stage,the expression of circadian-related genes in the hippocampus exhibited extensive abnormalities.In the control group,2109 genes exhibited rhythmic expression characteristics.In the mouse model of Alzheimer’s disease,a marked proportion of these genes lost their rhythmicity,some genes newly developed rhythmicity,and some maintained rhythmicity but with altered expression patterns.Genes related to neuronal function,including those involved in protein homeostasis regulation,neuroinflammation,and ion homeostasis,showed significant changes in circadian rhythm amplitude and phase,and some completely lost their rhythmicity.These findings point to the following critical early events in Alzheimer’s disease:hippocampal circadian gene disruption occurs before cognitive symptoms emerge,genes related to neuronal function are uniquely susceptible to this early dysregulation,and circadian dysfunction may even precede the pathological changes of Alzheimer’s disease and influence disease onset.This work advances Alzheimer’s disease research by clarifying that circadian disruption is an early pre-symptomatic event,reinforcing the potential of circadian rhythm regulation as a strategy for early intervention of Alzheimer’s disease,and identifying neuronal pathways that may serve as intervention targets.
基金the National Natural Science Foundation of China(82204935)the construction project of Zhao Feng National Old Pharmacist Inheritance Studio of State Administration of Traditional Chinese Medicine(National Traditional Chinese Medicine Education Letter[2024]255)+1 种基金the open project of the Key Laboratory of Basic and New Drug Research of Traditional Chinese Medicine in Shaanxi Province(KF202302)the project of Xi’an Municipal Bureau of Science and Technology(23YXYJ0042)for financial support.
文摘Background:One of the first hundred traditional Chinese medicines(TCM)formulas administered in China,Qianghuo Shengshi Decoction(QSD)has a positive clinical and therapeutic impact on rheumatoid arthritis(RA).Even so,there is still not enough knowledge on the active ingredients and possible ways that QSDs might work to treat RA.This study systematically investigated the active ingredients and mechanisms of action of QSD for treating wind-cold-dampness arthralgia type RA.Methods:UHPLC-QE-MS and network pharmacology techniques were employed to predict the potential active constituents,targets,and associated signalling pathways.Then,the therapeutic effect of QSD was examined using a wind-cold-dampness arthralgia paralytic RA rat model.Finally,the complex mechanism was comprehensively elucidated by integrating transcriptomics and network pharmacology.The above mechanisms were also verified by molecular docking,immunohistochemistry and Western blot.Results:UHPLC-QE-MS and network pharmacology analysis revealed that ferulic acid,imperatorin,magnolol,quercetin,and scopoletin could be the primary constituents in QSD responsible for its anti-RA effects.Animal experiments showed that QSD can significantly inhibit rat joint swelling degree,decrease the content of serum rheumatoid factor(RF),interleukin(IL)-1β,tumor necrosis factor-alpha(TNF-α),IL-6,and anti-citrullinated protein antibodies(ACPA),and increase the content of IL-4,IL-10 to relieve the clinical symptoms of wind-cold-dampness arthralgia type RA.The mechanistic study showed that QSD may effectively inhibit rat synovial hyperplasia via promoting autophagy and apoptosis of synovial cells by regulating the PI3K/Akt/mTOR signalling pathway.Conclusion:This study identifies key active ingredients in QSD and elucidates its potential mechanism for treating wind-cold-dampness arthralgia type RA,providing a basis for the clinical application of QSD.
基金the Gansu Science and Technology Major Project(Grant No.182D2NA010)the Science and Technology Service Network Initiative of the Chinese Academy of Sciences(Grant No.KFJ-STS-QYZD-120)the Key R&D plan of the Ningxia Hui Autonomous Region(Grant No.2019BBF02018)for the funding they provided。
文摘Drought stress is the main limiting plant growth factor in arid and semiarid regions.The Lanzhou lily(Lilium davidii var.unicolor)is the only sweet-tasting lily grown in these regions of China that offers highly edible,medicinal,health,and ornamental value.The Tresor lily is an ornamental flower known for its strong resistance.Plants were grown under three different drought intensity treatments,namely,being watered at intervals of 5,15,and 25 d(either throughout the study or during specific growth stages).We measured the biomass,leaf area,photosynthetic response,chlorophyll content(SPAD value),and osmoregulation of both the Lanzhou lily and the Tresor lily(Lilium‘Tresor’).Additionally,we employed RNA sequencing(RNA-Seq)and qRT-PCR to investigate transcriptomic changes of the Lanzhou lily in response to drought stress.Results showed that under drought stress,the decreasing rate in the Lanzhou lily bulb weight was lower than the corresponding Tresor lily bulb rate;the net photosynthetic rate,transpiration rate,and stomatal conductance of the Lanzhou lily were all higher compared to the Tresor lily;osmoregulation constituents,such as glucose,fructose,sucrose,trehalose,and soluble sugar,in the Lanzhou lily were comparatively higher;PYL,NCED,and ERS genes were significantly expressed in the Lanzhou lily.Under moderate drought,the biosynthesis of flavonoids,circadian rhythms,and the tryptophan metabolism pathway of the Lanzhou lily were all significant.Under severe drought stress,fatty acid elongation,photosynthetic antenna protein,plant hormone signal transduction,flavone and flavonol biosynthesis,and the carotenoid biosynthesis pathway were all significant.The Lanzhou lily adapted to drought stress by coordinating its organs and the unique role of its bulb,regulating photosynthesis,increasing osmolyte content,activating circadian rhythms,signal transduction,fatty acid elongation metabolism,and phenylalanine and flavonoid metabolic pathways,which may collectively be the main adaptation strategy and mechanisms used by the Lanzhou lily under drought stress.
