The significant variation in plant regeneration efficiency between indica and japonica rice poses a major challenge for crop improvement.However,the molecular basis for this divergence remains largely unclear.In this ...The significant variation in plant regeneration efficiency between indica and japonica rice poses a major challenge for crop improvement.However,the molecular basis for this divergence remains largely unclear.In this study,we investigated the role of Oryza sativa AUXIN RESPONSE FACTOR 13(OsARF13),a transcription factor involved in callus-related processes.We observed that OsARF13 expression is significantly higher in japonica rice callus than in indica rice callus.This differential expression might be associated with an allelic variation in the promoter region of OsARF13,where a deletion commonly found in indica rice corresponds to the loss of a conserved auxin-responsive element(AuxRE)motif.To functionally characterize OsARF13,we generated CRISPR/Cas9-mediated knockout mutants.These mutants exhibited a substantial reduction in callus fresh weight,demonstrating that OsARF13 is required for efficient callus induction.Transcriptome analysis of the osarf13 mutant further showed that OsARF13 influences the expression of genes involved in hormone signal transduction and stress responses.Our findings suggest that OsARF13 is a key component of the regulatory network governing callus induction and that natural variation in its promoter might provide a potential explanation for the differential regenerative capacity between japonica and indica rice subspecies.展开更多
The transcriptional cascade and regulatory loop play crucial roles in regulating plant-specialized metabolite biosynthesis.Capsaicinoids are unique to the genus Capsicum and confer a pungent flavor to its fruits.Howev...The transcriptional cascade and regulatory loop play crucial roles in regulating plant-specialized metabolite biosynthesis.Capsaicinoids are unique to the genus Capsicum and confer a pungent flavor to its fruits.However,the transcriptional regulation of capsaicinoid biosynthesis remains largely unknown.In this study,two AP2/ERF transcription factors(TFs),CaERF102 and CaERF111,were characterized for their role in the capsaicinoid biosynthesis process.Expression analysis of two ERFs and capsaicinoid biosynthetic genes(CBGs)suggested that they were associated with capsaicinoid biosynthesis.Both ERFs encode nuclear-localized proteins and function as transcriptional activators through their C-terminal activation motifs.The two ERF TFs participated in capsaicinoid biosynthesis by directly activating the promoters of key CBGs,and this activation was significantly enhanced when CaMYC2 was co-expressed.Moreover,CaERF102 and CaERF111 were found to interact with CaMYC2.This study helps elucidate the AP2/ERF TF regulatory network that governs capsaicinoid biosynthesis in Capsicum species.展开更多
BACKGROUND Gastric cancer is a malignant tumor with high morbidity and mortality worldwide.Neoadjuvant chemotherapy(NAC),defined as chemotherapy administered before the primary treatment(usually surgery)to reduce tumo...BACKGROUND Gastric cancer is a malignant tumor with high morbidity and mortality worldwide.Neoadjuvant chemotherapy(NAC),defined as chemotherapy administered before the primary treatment(usually surgery)to reduce tumor size and control micrometastases,has emerged as a crucial therapeutic strategy for locally advanced gastric cancer.Pathological complete response(pCR),characterized by the absence of viable tumor cells in the resected specimen after neoadjuvant treatment,is recognized as a strong predictor of favorable prognosis.However,the factors influencing the achievement of pCR remain incompletely understood.AIM To identify and analyze the predictive factors associated with achieving pCR after NAC in gastric cancer patients,thereby providing evidence-based guidance for clinical decision-making.METHODS A retrospective analysis was performed on 215 patients from Shandong Cancer Hospital and Tai’an Central Hospital with locally advanced gastric cancer who underwent NAC followed by radical surgery at our hospital between January 2015 and December 2023.Comprehensive clinical and pathological data were collected,including age,gender,tumor location,Lauren classification,clinical staging,chemotherapy regimens,number of chemotherapy cycles,and baseline hematological indicators.The baseline hematological indicators included neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio,albumin level,carcinoembryonic antigen(CEA),and carbohydrate antigen 19-9.Univariate and multivariate logistic regression analyses were employed to determine the independent predictive factors for pCR.RESULTS Among 215 gastric cancer patients,41(19.1%)achieved pCR after NAC.Multivariate analysis identified five independent predictive factors for pCR:Lauren intestinal type[odds ratio(OR)=3.28],lower clinical T stage(OR=2.75),CEA decrease≥70%after NAC(OR=3.42),pre-treatment NLR<2.5(OR=2.13),and≥4 chemotherapy cycles(OR=2.87).The fluorouracil,leucovorin,oxaliplatin,docetaxel regimen achieved the highest pCR rate(27.5%),and oxaliplatin-containing regimens were superior to cisplatin-containing regimens(22.3%vs 12.7%,P=0.034).Patients with both low NLR and platelet-to-lymphocyte ratio had the highest pCR rate(33.8%),while those with both high inflammatory markers had the lowest rate(10.7%).Earlier clinical stage disease(cT3N+vs cT4N+:28.6%vs 13.0%)and lower lymph node burden were associated with higher pCR rates.CONCLUSION The achievement of pCR after NAC in gastric cancer patients is closely associated with Lauren intestinal type,lower clinical T stage,a significant decrease in CEA after chemotherapy,low pre-treatment NLR,and an adequate number of chemotherapy cycles.展开更多
BACKGROUND Dental implants are widely used to replace missing teeth.Currently,clinicians assess osseointegration success by measuring the implant’s stability within the bone and monitoring the marginal tissue height....BACKGROUND Dental implants are widely used to replace missing teeth.Currently,clinicians assess osseointegration success by measuring the implant’s stability within the bone and monitoring the marginal tissue height.Diabetes,especially type 2 diabetes mellitus(T2DM),has been reported to impair implant healing,drastically reducing implant success rates.AIM To analyze the high-risk factors for inflammatory response and prognosis after dental implantation in patients with T2DM,and provide strong evidence for reducing the incidence of postimplant peri-implantitis(PI).METHODS We performed a retrospective review of 146 patients with T2DM who had dental implants placed at Tianjin Fifth Central Hospital,between September 2021 and September 2023,which was regarded as the observation group.Moreover,60 ageand gender-matched individuals with normal blood glucose levels served as the control group.The general information,postoperative periodontal indices,and levels of inflammatory factors were comprehensively analyzed and compared.Furthermore,the incidence of postimplant PI was counted,and multivariate logistic regression was used to identify the determinants of postimplant PI.RESULTS In terms of the periodontal indices,the probing depth,modified sulcus bleeding index,and marginal bone loss in the observation cohorts began to increase significantly at 6 months and 3 months,respectively,after the completion of dental implant restoration.The T2DM cases demonstrated significantly elevated counts of leukocytes,lymphocytes,and neutrophils compared to the controls at 24 hours postoperatively.Moreover,the TNF-α,IL-1β,and IL-6 concentrations started to increase significantly in the gingival crevicular fluid 3 months after the completion of dental implant restoration in both cohorts,with the observation group exhibiting higher levels than the controls at each time point.63 out of the 146 cases developed PI.Multivariate logistic regression analysis indicated that high glycosylated hemoglobin levels,smoking,daily tooth-brushing frequency of less than once,and the anterior tooth as the implant site independently contributed to postimplant PI in T2DM cases,while a tooth-brushing duration of≥3 minutes was a protective factor.CONCLUSION Patients with T2DM are at risk of developing PI following dental implantation.Clinically,it is necessary to enhance the identification of risk factors for postimplant PI,improve risk prediction,prevention,and control,and formulate targeted intervention countermeasures to reduce the occurrence of postimplant PI.展开更多
Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in s...Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.展开更多
Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant...Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.展开更多
Background The association of systemic inflammatory response index(SIRI)with prognosis of coronary artery disease(CAD)patients has never been investigated in a large sample with long-term follow-up.This study aimed to...Background The association of systemic inflammatory response index(SIRI)with prognosis of coronary artery disease(CAD)patients has never been investigated in a large sample with long-term follow-up.This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States.Methods A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey(NHANES)1999-2018 were included in this study.Cox proportional hazards model,restricted cubic spline(RCS),and receiver operating characteristic curve(ROC)were performed to investigate the association of SIRI with all-cause and cause-specific mortality.Piecewise linear regression and sensitivity analyses were also performed.Results During a median follow-up of 7.7 years,1454 all-cause mortality occurred.After adjusting for confounding factors,higher lnSIRI was significantly associated with higher risk of all-cause(HR=1.16,95%CI:1.09-1.23)and CVD mortality(HR=1.17,95%CI:1.05-1.30)but not cancer mortality(HR=1.17,95%CI:0.99-1.38).The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI,respectively.ROC curves showed that lnSIRI had robust predictive effect both in short and long terms.Conclusions SIRI was independently associated with all-cause and CVD mortality,and the dose-response relationship was Jshaped.SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.展开更多
Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.展开更多
Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family memb...Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.展开更多
Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin the...Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin therapy,substantial interindividual variability in treatment response persists,necessitating precision medicine approaches to optimize therapeutic outcomes.This comprehensive narrative review synthesizes current understanding of pharmacogenomic determinants influencing lipid-lowering therapy efficacy,examines mechanisms underlying residual cardiovascular risk,and evaluates emerging therapeutic modalities targeting previously unexploited pathways in lipid metabolism.Genetic variants in key genes including 3-hydroxy-3-methylglutaryl-CoA reductase,apolipoprotein E,low-density lipoprotein receptor,and proprotein convertase subtilisin/kexin type 9 demonstrate significant associations with differential treatment responses,with specific polymorphisms conferring enhanced efficacy or increased intolerance risk.Beyond traditional statin therapy,novel therapeutic approaches targeting proprotein convertase subtilisin/kexin type 9,angiopoietin-like protein 3,apolipoprotein C-Ⅲ,and ATP citrate lyase offer substantial low-density lipoprotein cholesterol reductions of 50-80%,while RNA-based therapies including antisense oligonucleotides and small interfering RNA provide precise molecular targeting capabilities.Despite intensive lipid-lowering interventions,residual cardiovascular risk persists through four principal mechanisms:triglyceride-rich lipoproteins,lipoprotein(a),inflammatory processes,and suboptimal treatment adherence.Integration of pharmacogenomic insights with emerging therapeutic modalities enables personalized risk stratification and treatment selection,representing a paradigm shift toward precision medicine in cardiovascular disease prevention and management.展开更多
Extensive transcriptomic reprogramming is triggered by biotic and abiotic stresses in plants,with coordinated regulation mediated through multiple transcription factor families,such as WRKY,MYB,NAC,and BBX proteins.Am...Extensive transcriptomic reprogramming is triggered by biotic and abiotic stresses in plants,with coordinated regulation mediated through multiple transcription factor families,such as WRKY,MYB,NAC,and BBX proteins.Among these,B-box(BBX)proteins represent a distinct class of zinc finger transcription factors characterized by the presence of conserved B-box domains.They serve as central regulators in plant photomorphogenesis and developmental processes.Accumulating genetic and biochemical evidence demonstrates that BBX family members orchestrate plant responses to biotic and abiotic stresses through multifaceted molecular mechanisms,including the regulation of reactive oxygen species(ROS)homeostasis,enhancement of anthocyanin biosynthesis,and modulation of hormonal signaling pathways.This review systematically summarizes recent advances in the identification of BBX family genes in different plant species.Furthermore,their emerging roles in mediating plant stress responses are elucidated,with molecularmechanisms being comprehensively analyzed at both transcriptional and post-translational levels.However,to fully harness the potential of BBX genes in crop improvement,a deeper understanding of their functional mechanisms including BBX-mediated hormonal crosstalk networks,growth-defense trade-offs,and more extensive field performance data remains essential.These insights provide a theoretical foundation for developing climate-resilient crop varieties through targeted genetic improvement strategies.展开更多
This paper proposes a robust control-oriented identification method for errors-in-variables(EIV)systems in output feedbacks using frequency-response(FR)experimental data.An important relation between such a closed-loo...This paper proposes a robust control-oriented identification method for errors-in-variables(EIV)systems in output feedbacks using frequency-response(FR)experimental data.An important relation between such a closed-loop EIV system and its coprime factor(CF)uncertainty description is first derived,based on which the FR measurements suitable for plant CF identification are able to be generated.Different factorizations of a given controller in the closed-loop system can be made best use to adjust right coprime factors(RCFs)of the plant so as to realize an improvement on the signal-to-noise ratio of identification experimental data.Subsequently,a nominal RCF model is estimated by linear matrix inequalities from the applicable FR measurements and its associated worst-case errors are quantified from a priori and a posteriori information on the underlying system.A resulting RCF perturbation model set can then be described by the nominal RCF model and its worst-case error bounds.Such a model set capable of being stabilized by the given controller is ready for its robust stabilizing controller redesign and robust performance analysis.Finally,a numerical simulation is given to show the efficacy of the proposed identification method.展开更多
Microorganisms actively participate in biogeochemical cycling processes and play a crucial role in maintaining the dynamic balance of hot spring ecosystems.However,the distribution of microbial functional genes and th...Microorganisms actively participate in biogeochemical cycling processes and play a crucial role in maintaining the dynamic balance of hot spring ecosystems.However,the distribution of microbial functional genes and their influencing factors in hot springs remain largely unclear.Therefore,this study investigated the microbial functional genes and their potential for controlling biogeochemical cycles(C,N,S,and P) in the hot Springs of Tengchong,China,using the Geochip method,a functional gene microarray technology.The examined hot springs have very different microbial functional genes.A total of 22 736 gene probe signals were identified,belonging to 567 functional genes and associated with 15 ecological functions,mainly involving stress response,carbon cycle,nitrogen cycle,sulfur cycle,phosphorus cycle and energy processes.The amyA,narG,dsrA and ppx genes were most abundant in carbon,nitrogen,sulfur and phosphorus cycles,respectively,and were significantly correlated with pH,temperature and SO_(4)^(2-).The diversity and abundance of detected gene probes were negatively correlated with temperature.The α-diversity(i.e.,Shannon index) was high at low temperature and low pH.Molecular functional interactions revealed by the gene connectivity levels were negatively correlated with temperature,pH and SO_(4)^(2-).These results suggested that the abundance,diversity and interactions of microbial functional genes were significantly influenced by geochemical parameters.-In addition,some genera possessed functional genes related to carbon,nitrogen,sulfur,and phosphorus cycles and can synergistically control the biogeochemical cycles of carbon,nitrogen,sulfur and phosphorus.These findings provide new insights into the functional potentials of microorganisms to participate in biogeochemical cycles and their responses to environmental factors in hot springs.展开更多
Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP)...Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.展开更多
BACKGROUND The pathogenesis of primary biliary cholangitis(PBC)remains unclear.Ursodeoxycholic acid(UDCA)is the only first-line clinical treatment,but approximately 40%of patients exhibit a poor response.AIM To identi...BACKGROUND The pathogenesis of primary biliary cholangitis(PBC)remains unclear.Ursodeoxycholic acid(UDCA)is the only first-line clinical treatment,but approximately 40%of patients exhibit a poor response.AIM To identify novel biomarkers for PBC to predict the efficacy of UDCA and enhance treatment.METHODS Microarray expression profiling datasets were downloaded from the Gene Expression Omnibus and analyzed to identify differentially expressed genes between PBC patients and healthy controls.Immunohistochemistry was performed to validate key genes in liver tissues of the participants.Logistic regression was employed to evaluate prognostic risk factors,receiver operating characteristic curves were used to assess predictive performance,and correlations between key genes and clinicopathological characteristics were analyzed.RESULTS By bioinformatic analysis,13 genes primarily associated with the progression of PBC were identified,and tumor necrosis factor alpha-induced protein 3(TNFAIP3)was selected for further investigation.Then expression of TNFAIP3 in PBC patients was significantly elevated compared to healthy controls on immunohistochemistry(P<0.0001).Multivariate Cox regression analysis indicated that both TNFAIP3 and fatigue were independent risk factors for response to UDCA in PBC patients(P<0.05).The area under the curve for TNFAIP3 and fatigue were 0.691 and 0.704,respectively,while their combination showed a significantly higher area under the curve of 0.848.The expression of TNFAIP3 was also correlated with age,albumin,total bilirubin,alkaline phosphatase and splenomegaly(P<0.05).CONCLUSION TNFAIP3 and fatigue are independent risk factors for response to UDCA in Chinese patients with PBC.TNFAIP3 may be a potential biomarker or therapeutic target for PBC.These findings offer new insights into the pathogenesis of PBC.展开更多
This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;...This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;28 met inclusion criteria(excluding non-adolescents,generic internet addiction,non-empirical work,or non-English).Thematic synthesis organized findings into three external risk domains—family,school,and peers—considering cultural/contextual mechanisms.Family dynamics(parental phubbing,harsh parenting,dysfunction),school stressors,and adverse peer relationships were identified as accumulating,direct and indirect contributors to smartphone addiction.These operate within a techno-ecological framework,where digital technologies amplify vulnerabilities and create new pathways for maladaptive use.Evidence favors an ecological,multi-level perspective.Future research should use longitudinal designs,standardize measures across cultures,and examine understudied regions—especially Africa—to guide culturally sensitive interventions.展开更多
In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)pro...In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.展开更多
BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and dep...BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and depression(PSD)do not receive sufficient attention.AIM To systematically evaluate risk factors and early identification markers for PSD for more precise screening and intervention strategies in clinical practice.METHODS This retrospective study analyzed clinical data from 112 patients with ischemic stroke admitted between January 2022 and December 2024.Based on assessments using the Hamilton Rating Scale for Anxiety(HAMA)and Hamilton Rating Scale for Depression(HAMD)at 2 weeks(±3 days)post-stroke,patients were classified into the PSD group(HAMA≥7 and/or HAMD≥7)and the non-PSD group(HAMA<7 and HAMD<7).Observation indicators included psychological assessment,demographic and clinical characteristics,stroke-related clinical indicators,neuroimaging assessments,and laboratory biomarkers.Multivariate logistic regression analysis was used to identify independent risk factors for PSD,and receiver operating characteristic curve analysis was used to evaluate the diagnostic value of potential biomarkers.RESULTS Of the 112 patients,46(41.1%)were diagnosed with PSD.Multivariate analysis identified five independent risk factors:Female gender[Odds ratio(OR)=2.32,95%confidence interval(CI):1.56-3.45],history of mental disorders prior to stroke(OR=3.17,95%CI:1.89-5.32),infarct location in the frontal lobe or limbic system(OR=2.86,95%CI:1.73-4.71),stroke severity with National Institutes of Health Stroke Scale≥8 at admission(OR=2.54,95%CI:1.62-3.99),and low social support(Social Support Rating Scale<35,OR=2.18,95%CI:1.42-3.36).Subgroup analysis showed that depression patients more commonly had left hemisphere lesions(68.4%vs 45.2%),while anxiety patients more frequently presented with right hemisphere lesions(59.5%vs 39.5%).The PSD group exhibited larger infarct volumes(8.7 cm^(3) vs 5.3 cm^(3)),more severe white matter hyperintensities,and more pronounced frontal lobe atrophy.Analysis of inflammatory markers showed significantly elevated levels of interleukin-6(7.8 pg/mL vs 4.5 pg/mL)and tumor necrosis factor-alpha(15.6 pg/mL vs 9.8 pg/mL)in the PSD group,while hypothalamicpituitary-adrenal axis function assessment revealed higher cortisol levels(386.5±92.3 nmol/L vs 328.7±75.6 nmol/L)and flattened diurnal rhythm in the PSD group.CONCLUSION PSD is a complex neuropsychiatric consequence of stroke involving disruption of the frontal-limbic circuitry,neuroinflammatory responses,and dysfunction of the hypothalamic-pituitary-adrenal axis.展开更多
With the increasing penetration of variable renewable energy,flexible resources are highly needed to hedge the growing uncertainty,and variability in the power system.Demand response has served as a cost-effective typ...With the increasing penetration of variable renewable energy,flexible resources are highly needed to hedge the growing uncertainty,and variability in the power system.Demand response has served as a cost-effective type of flexible resource in recent years.In order to balance the uncertainty of the system,it is crucial to assess how much flexibility demand response programs can provide.Thus,forecasting demand response potential is important for the operation of the bulk system.This paper proposes a modeling approach that can characterize the multi-timescale flexibility of demand response so that not only the power potential but also temporal-coupling characteristics can be considered.Furthermore,a day-ahead demand response potential forecasting method is proposed using deep convolutional generative adversarial networks.The proposed forecasting method is tested using data from 170 users in Pecan Street Dataport.The results show that the proposed method can forecast the multi-timescale flexibility of demand response with high accuracy.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.32201834 and 32201814)the Hainan Provincial Natural Science Foundation of China(Grant No.324RC530)+1 种基金the Hainan Provincial‘Nanhai NewStar’Science and Technology Innovation Platform Project,China(Grant No.NHXXRCXM-202362)the Research Startup Funding from Hainan Institute of Zhejiang University,China(Grant No.0201-6602-A12202).
文摘The significant variation in plant regeneration efficiency between indica and japonica rice poses a major challenge for crop improvement.However,the molecular basis for this divergence remains largely unclear.In this study,we investigated the role of Oryza sativa AUXIN RESPONSE FACTOR 13(OsARF13),a transcription factor involved in callus-related processes.We observed that OsARF13 expression is significantly higher in japonica rice callus than in indica rice callus.This differential expression might be associated with an allelic variation in the promoter region of OsARF13,where a deletion commonly found in indica rice corresponds to the loss of a conserved auxin-responsive element(AuxRE)motif.To functionally characterize OsARF13,we generated CRISPR/Cas9-mediated knockout mutants.These mutants exhibited a substantial reduction in callus fresh weight,demonstrating that OsARF13 is required for efficient callus induction.Transcriptome analysis of the osarf13 mutant further showed that OsARF13 influences the expression of genes involved in hormone signal transduction and stress responses.Our findings suggest that OsARF13 is a key component of the regulatory network governing callus induction and that natural variation in its promoter might provide a potential explanation for the differential regenerative capacity between japonica and indica rice subspecies.
基金funded by the National Natural Science Foundation of China(Grant Nos.32202502,U21A20230,32070331,32102380 and 32072580)National Key Research and Development Program(Grant No.2018YFD1000800)+3 种基金the Key-Area Research and Development Program of Guangdong Province(Grant No.2022B0202080001)the Special Fund for Seed Industry of Guangdong Province Rural Revitalization Strategy(Grant No.2022-NPY00-024)Tibet Autonomous Region of Lhasa City Science and Technology Project(Grant No.LSKJ202310)the Science and Technology Project of Bijie City(Grant No.BKK2022-3)。
文摘The transcriptional cascade and regulatory loop play crucial roles in regulating plant-specialized metabolite biosynthesis.Capsaicinoids are unique to the genus Capsicum and confer a pungent flavor to its fruits.However,the transcriptional regulation of capsaicinoid biosynthesis remains largely unknown.In this study,two AP2/ERF transcription factors(TFs),CaERF102 and CaERF111,were characterized for their role in the capsaicinoid biosynthesis process.Expression analysis of two ERFs and capsaicinoid biosynthetic genes(CBGs)suggested that they were associated with capsaicinoid biosynthesis.Both ERFs encode nuclear-localized proteins and function as transcriptional activators through their C-terminal activation motifs.The two ERF TFs participated in capsaicinoid biosynthesis by directly activating the promoters of key CBGs,and this activation was significantly enhanced when CaMYC2 was co-expressed.Moreover,CaERF102 and CaERF111 were found to interact with CaMYC2.This study helps elucidate the AP2/ERF TF regulatory network that governs capsaicinoid biosynthesis in Capsicum species.
文摘BACKGROUND Gastric cancer is a malignant tumor with high morbidity and mortality worldwide.Neoadjuvant chemotherapy(NAC),defined as chemotherapy administered before the primary treatment(usually surgery)to reduce tumor size and control micrometastases,has emerged as a crucial therapeutic strategy for locally advanced gastric cancer.Pathological complete response(pCR),characterized by the absence of viable tumor cells in the resected specimen after neoadjuvant treatment,is recognized as a strong predictor of favorable prognosis.However,the factors influencing the achievement of pCR remain incompletely understood.AIM To identify and analyze the predictive factors associated with achieving pCR after NAC in gastric cancer patients,thereby providing evidence-based guidance for clinical decision-making.METHODS A retrospective analysis was performed on 215 patients from Shandong Cancer Hospital and Tai’an Central Hospital with locally advanced gastric cancer who underwent NAC followed by radical surgery at our hospital between January 2015 and December 2023.Comprehensive clinical and pathological data were collected,including age,gender,tumor location,Lauren classification,clinical staging,chemotherapy regimens,number of chemotherapy cycles,and baseline hematological indicators.The baseline hematological indicators included neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio,albumin level,carcinoembryonic antigen(CEA),and carbohydrate antigen 19-9.Univariate and multivariate logistic regression analyses were employed to determine the independent predictive factors for pCR.RESULTS Among 215 gastric cancer patients,41(19.1%)achieved pCR after NAC.Multivariate analysis identified five independent predictive factors for pCR:Lauren intestinal type[odds ratio(OR)=3.28],lower clinical T stage(OR=2.75),CEA decrease≥70%after NAC(OR=3.42),pre-treatment NLR<2.5(OR=2.13),and≥4 chemotherapy cycles(OR=2.87).The fluorouracil,leucovorin,oxaliplatin,docetaxel regimen achieved the highest pCR rate(27.5%),and oxaliplatin-containing regimens were superior to cisplatin-containing regimens(22.3%vs 12.7%,P=0.034).Patients with both low NLR and platelet-to-lymphocyte ratio had the highest pCR rate(33.8%),while those with both high inflammatory markers had the lowest rate(10.7%).Earlier clinical stage disease(cT3N+vs cT4N+:28.6%vs 13.0%)and lower lymph node burden were associated with higher pCR rates.CONCLUSION The achievement of pCR after NAC in gastric cancer patients is closely associated with Lauren intestinal type,lower clinical T stage,a significant decrease in CEA after chemotherapy,low pre-treatment NLR,and an adequate number of chemotherapy cycles.
基金Supported by Tianjin Municipality Health Science and Technology Project,No.TJWJ2023MS052.
文摘BACKGROUND Dental implants are widely used to replace missing teeth.Currently,clinicians assess osseointegration success by measuring the implant’s stability within the bone and monitoring the marginal tissue height.Diabetes,especially type 2 diabetes mellitus(T2DM),has been reported to impair implant healing,drastically reducing implant success rates.AIM To analyze the high-risk factors for inflammatory response and prognosis after dental implantation in patients with T2DM,and provide strong evidence for reducing the incidence of postimplant peri-implantitis(PI).METHODS We performed a retrospective review of 146 patients with T2DM who had dental implants placed at Tianjin Fifth Central Hospital,between September 2021 and September 2023,which was regarded as the observation group.Moreover,60 ageand gender-matched individuals with normal blood glucose levels served as the control group.The general information,postoperative periodontal indices,and levels of inflammatory factors were comprehensively analyzed and compared.Furthermore,the incidence of postimplant PI was counted,and multivariate logistic regression was used to identify the determinants of postimplant PI.RESULTS In terms of the periodontal indices,the probing depth,modified sulcus bleeding index,and marginal bone loss in the observation cohorts began to increase significantly at 6 months and 3 months,respectively,after the completion of dental implant restoration.The T2DM cases demonstrated significantly elevated counts of leukocytes,lymphocytes,and neutrophils compared to the controls at 24 hours postoperatively.Moreover,the TNF-α,IL-1β,and IL-6 concentrations started to increase significantly in the gingival crevicular fluid 3 months after the completion of dental implant restoration in both cohorts,with the observation group exhibiting higher levels than the controls at each time point.63 out of the 146 cases developed PI.Multivariate logistic regression analysis indicated that high glycosylated hemoglobin levels,smoking,daily tooth-brushing frequency of less than once,and the anterior tooth as the implant site independently contributed to postimplant PI in T2DM cases,while a tooth-brushing duration of≥3 minutes was a protective factor.CONCLUSION Patients with T2DM are at risk of developing PI following dental implantation.Clinically,it is necessary to enhance the identification of risk factors for postimplant PI,improve risk prediction,prevention,and control,and formulate targeted intervention countermeasures to reduce the occurrence of postimplant PI.
基金supported by the National Natural Science Foundation of China,Nos.82072165 and 82272256(both to XM)the Key Project of Xiangyang Central Hospital,No.2023YZ03(to RM)。
文摘Spinal cord injury represents a severe form of central nervous system trauma for which effective treatments remain limited.Microglia is the resident immune cells of the central nervous system,play a critical role in spinal cord injury.Previous studies have shown that microglia can promote neuronal survival by phagocytosing dead cells and debris and by releasing neuroprotective and anti-inflammatory factors.However,excessive activation of microglia can lead to persistent inflammation and contribute to the formation of glial scars,which hinder axonal regeneration.Despite this,the precise role and mechanisms of microglia during the acute phase of spinal cord injury remain controversial and poorly understood.To elucidate the role of microglia in spinal cord injury,we employed the colony-stimulating factor 1 receptor inhibitor PLX5622 to deplete microglia.We observed that sustained depletion of microglia resulted in an expansion of the lesion area,downregulation of brain-derived neurotrophic factor,and impaired functional recovery after spinal cord injury.Next,we generated a transgenic mouse line with conditional overexpression of brain-derived neurotrophic factor specifically in microglia.We found that brain-derived neurotrophic factor overexpression in microglia increased angiogenesis and blood flow following spinal cord injury and facilitated the recovery of hindlimb motor function.Additionally,brain-derived neurotrophic factor overexpression in microglia reduced inflammation and neuronal apoptosis during the acute phase of spinal cord injury.Furthermore,through using specific transgenic mouse lines,TMEM119,and the colony-stimulating factor 1 receptor inhibitor PLX73086,we demonstrated that the neuroprotective effects were predominantly due to brain-derived neurotrophic factor overexpression in microglia rather than macrophages.In conclusion,our findings suggest the critical role of microglia in the formation of protective glial scars.Depleting microglia is detrimental to recovery of spinal cord injury,whereas targeting brain-derived neurotrophic factor overexpression in microglia represents a promising and novel therapeutic strategy to enhance motor function recovery in patients with spinal cord injury.
基金supported by the National Natural Science Foundation of China(Nos.82171552 and 82170479)the Natural Science Foundation of Shanghai Ctiy(No.21ZR1457500)the Science and Technology Bureau of Shanghai Putuo District(No.ptkwws202102).
文摘Magnolol,a compound extracted from Magnolia officinalis,demonstrates potential efficacy in addressing metabolic dysfunction and cardiovascular diseases.Its biological activities encompass anti-inflammatory,antioxidant,anticoagulant,and anti-diabetic effects.Growth/differentiation factor-15(GDF-15),a member of the transforming growth factorβsuperfamily,is considered a potential therapeutic target for metabolic disorders.This study investigated the impact of magnolol on GDF-15 production and its underlying mechanism.The research examined the pharmacological effect of magnolol on GDF-15 expression in vitro and in vivo,and determined the involvement of endoplasmic reticulum(ER)stress signaling in this process.Luciferase reporter assays,chromatin immunoprecipitation,and in vitro DNA binding assays were employed to examine the regulation of GDF-15 by activating transcription factor 4(ATF4),CCAAT enhancer binding proteinγ(CEBPG),and CCCTC-binding factor(CTCF).The study also investigated the effect of magnolol and ATF4 on the activity of a putative enhancer located in the intron of the GDF-15 gene,as well as the influence of single nucleotide polymorphisms(SNPs)on magnolol and ATF4-induced transcription activity.Results demonstrated that magnolol triggers GDF-15 production in endothelial cells(ECs),hepatoma cell line G2(HepG2)and hepatoma cell line 3B(Hep3B)cell lines,and primary mouse hepatocytes.The cooperative binding of ATF4 and CEBPG upstream of the GDF-15 gene or the E1944285 enhancer located in the intron led to full-power transcription of the GDF-15 gene.SNP alleles were found to impact the magnolol and ATF4-induced transcription activity of GDF-15.In high-fat diet ApoE^(-/-)mice,administration of magnolol induced GDF-15 production and partially suppressed appetite through GDF-15.These findings suggest that magnolol regulates GDF-15 expression through priming of promoter and enhancer activity,indicating its potential as a drug for the treatment of metabolic disorders.
基金National Key Research and Development Program of China(2022YFC2503500 and 2022YFC2503504)。
文摘Background The association of systemic inflammatory response index(SIRI)with prognosis of coronary artery disease(CAD)patients has never been investigated in a large sample with long-term follow-up.This study aimed to explore the association of SIRI with all-cause and cause-specific mortality in a nationally representative sample of CAD patients from United States.Methods A total of 3386 participants with CAD from the National Health and Nutrition Examination Survey(NHANES)1999-2018 were included in this study.Cox proportional hazards model,restricted cubic spline(RCS),and receiver operating characteristic curve(ROC)were performed to investigate the association of SIRI with all-cause and cause-specific mortality.Piecewise linear regression and sensitivity analyses were also performed.Results During a median follow-up of 7.7 years,1454 all-cause mortality occurred.After adjusting for confounding factors,higher lnSIRI was significantly associated with higher risk of all-cause(HR=1.16,95%CI:1.09-1.23)and CVD mortality(HR=1.17,95%CI:1.05-1.30)but not cancer mortality(HR=1.17,95%CI:0.99-1.38).The associations of SIRI with all-cause and CVD mortality were detected as J-shaped with threshold values of 1.05935 and 1.122946 for SIRI,respectively.ROC curves showed that lnSIRI had robust predictive effect both in short and long terms.Conclusions SIRI was independently associated with all-cause and CVD mortality,and the dose-response relationship was Jshaped.SIRI might serve as a valid predictor for all-cause and CVD mortality both in the short and long terms.
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
文摘Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
基金supported by grants from the National Natural Science Foundation of China (82071104)Science and Technology Commission of Shanghai Municipality (23XD1434200/22Y21901000)+9 种基金Shanghai Hospital Development Center(SHDC12022120)National Clinical Research Center for Oral Diseases (NCRCO2021-omics-07)Shanghai Clinical Research Center for Oral Diseases (19MC1910600)Major and Key Cultivation Projects of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (JYZP006)Shanghai’s Top Priority Research Center (2022ZZ01017)CAMS Innovation Fund for Medical Sciences (2019-I2M-5-037)Fundamental research program funding of Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine(JYZZ237)Eastern Talent Plan Leading Project (BJZH2024001)partly supported by the Shanghai Ninth People’s Hospital affiliated with Shanghai Jiao Tong University,School of Medicine(JYJC202223)Shanghai Key Laboratory of Translational Medicine on Ear and Nose diseases (14DZ2260300)
文摘Pulpitis is a common infective oral disease in clinical situations.The regulatory mechanisms of immune defense in pulpitis are still being investigated.Osteomodulin(OMD)is a small leucine-rich proteoglycan family member distributed in bones and teeth.It is a bioactive protein that promotes osteogenesis and suppresses the apoptosis of human dental pulp stem cells(hDPSCs).In this study,the role of OMD in pulpitis and the OMD-induced regulatory mechanism were investigated.The OMD expression in normal and inflamed human pulp tissues was detected via immunofluorescence staining.Intriguingly,the OMD expression decreased in the inflammatory infiltration area of pulpitis specimens.The cellular experiments demonstrated that recombined human OMD could resist the detrimental effects of lipopolysaccharide(LPS)-induced inflammation.A conditional Omd knockout mouse model with pulpal inflammation was established.LPS-induced inflammatory impairment significantly increased in conditional Omd knockout mice,whereas OMD administration exhibited a protective effect against pulpitis.Mechanistically,the transcriptome alterations of OMD overexpression showed significant enrichment in the nuclear factor-κB(NF-κB)signaling pathway.Interleukin-1 receptor 1(IL1R1),a vital membrane receptor activating the NF-κB pathway,was significantly downregulated in OMD-overexpressing hDPSCs.Additionally,the interaction between OMD and IL1R1 was verified using co-immunoprecipitation and molecular docking.In vivo,excessive pulpal inflammation in Omd-deficient mice was rescued using an IL1R antagonist.Overall,OMD played a protective role in the inflammatory response via the IL1R1/NF-κB signaling pathway.OMD may optimize the immunomodulatory functions of hDPSCs and can be used for regenerative endodontics.
文摘Atherosclerotic cardiovascular disease remains the leading cause of global mortality,with low-density lipoprotein cholesterol established as a primary causal risk factor.Despite widespread implementation of statin therapy,substantial interindividual variability in treatment response persists,necessitating precision medicine approaches to optimize therapeutic outcomes.This comprehensive narrative review synthesizes current understanding of pharmacogenomic determinants influencing lipid-lowering therapy efficacy,examines mechanisms underlying residual cardiovascular risk,and evaluates emerging therapeutic modalities targeting previously unexploited pathways in lipid metabolism.Genetic variants in key genes including 3-hydroxy-3-methylglutaryl-CoA reductase,apolipoprotein E,low-density lipoprotein receptor,and proprotein convertase subtilisin/kexin type 9 demonstrate significant associations with differential treatment responses,with specific polymorphisms conferring enhanced efficacy or increased intolerance risk.Beyond traditional statin therapy,novel therapeutic approaches targeting proprotein convertase subtilisin/kexin type 9,angiopoietin-like protein 3,apolipoprotein C-Ⅲ,and ATP citrate lyase offer substantial low-density lipoprotein cholesterol reductions of 50-80%,while RNA-based therapies including antisense oligonucleotides and small interfering RNA provide precise molecular targeting capabilities.Despite intensive lipid-lowering interventions,residual cardiovascular risk persists through four principal mechanisms:triglyceride-rich lipoproteins,lipoprotein(a),inflammatory processes,and suboptimal treatment adherence.Integration of pharmacogenomic insights with emerging therapeutic modalities enables personalized risk stratification and treatment selection,representing a paradigm shift toward precision medicine in cardiovascular disease prevention and management.
基金National Natural Science Foundation of China(grant No.32301870 and 32572302 to Chen Lin)Natural Science Foundation of Jiangsu Province(grant No.BK20230568 to Chen Lin)+3 种基金the Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund(grant No.CX(24)3124 to Chen Lin)Outstanding Ph.D.Program in Yangzhou(grant No.YZLYJFJH2022YXBS147 to Chen Lin)the General Project of Basic Scientific Research to colleges and universities in Jiangsu Province(grant No.22KJB210019 to Chen Lin)the Priority Academic Program Development of Jiangsu Higher Education Institutions is greatly acknowledged.
文摘Extensive transcriptomic reprogramming is triggered by biotic and abiotic stresses in plants,with coordinated regulation mediated through multiple transcription factor families,such as WRKY,MYB,NAC,and BBX proteins.Among these,B-box(BBX)proteins represent a distinct class of zinc finger transcription factors characterized by the presence of conserved B-box domains.They serve as central regulators in plant photomorphogenesis and developmental processes.Accumulating genetic and biochemical evidence demonstrates that BBX family members orchestrate plant responses to biotic and abiotic stresses through multifaceted molecular mechanisms,including the regulation of reactive oxygen species(ROS)homeostasis,enhancement of anthocyanin biosynthesis,and modulation of hormonal signaling pathways.This review systematically summarizes recent advances in the identification of BBX family genes in different plant species.Furthermore,their emerging roles in mediating plant stress responses are elucidated,with molecularmechanisms being comprehensively analyzed at both transcriptional and post-translational levels.However,to fully harness the potential of BBX genes in crop improvement,a deeper understanding of their functional mechanisms including BBX-mediated hormonal crosstalk networks,growth-defense trade-offs,and more extensive field performance data remains essential.These insights provide a theoretical foundation for developing climate-resilient crop varieties through targeted genetic improvement strategies.
文摘This paper proposes a robust control-oriented identification method for errors-in-variables(EIV)systems in output feedbacks using frequency-response(FR)experimental data.An important relation between such a closed-loop EIV system and its coprime factor(CF)uncertainty description is first derived,based on which the FR measurements suitable for plant CF identification are able to be generated.Different factorizations of a given controller in the closed-loop system can be made best use to adjust right coprime factors(RCFs)of the plant so as to realize an improvement on the signal-to-noise ratio of identification experimental data.Subsequently,a nominal RCF model is estimated by linear matrix inequalities from the applicable FR measurements and its associated worst-case errors are quantified from a priori and a posteriori information on the underlying system.A resulting RCF perturbation model set can then be described by the nominal RCF model and its worst-case error bounds.Such a model set capable of being stabilized by the given controller is ready for its robust stabilizing controller redesign and robust performance analysis.Finally,a numerical simulation is given to show the efficacy of the proposed identification method.
基金supported by grants from the National Natural Science Foundation of China(Nos.42172339,91951205)。
文摘Microorganisms actively participate in biogeochemical cycling processes and play a crucial role in maintaining the dynamic balance of hot spring ecosystems.However,the distribution of microbial functional genes and their influencing factors in hot springs remain largely unclear.Therefore,this study investigated the microbial functional genes and their potential for controlling biogeochemical cycles(C,N,S,and P) in the hot Springs of Tengchong,China,using the Geochip method,a functional gene microarray technology.The examined hot springs have very different microbial functional genes.A total of 22 736 gene probe signals were identified,belonging to 567 functional genes and associated with 15 ecological functions,mainly involving stress response,carbon cycle,nitrogen cycle,sulfur cycle,phosphorus cycle and energy processes.The amyA,narG,dsrA and ppx genes were most abundant in carbon,nitrogen,sulfur and phosphorus cycles,respectively,and were significantly correlated with pH,temperature and SO_(4)^(2-).The diversity and abundance of detected gene probes were negatively correlated with temperature.The α-diversity(i.e.,Shannon index) was high at low temperature and low pH.Molecular functional interactions revealed by the gene connectivity levels were negatively correlated with temperature,pH and SO_(4)^(2-).These results suggested that the abundance,diversity and interactions of microbial functional genes were significantly influenced by geochemical parameters.-In addition,some genera possessed functional genes related to carbon,nitrogen,sulfur,and phosphorus cycles and can synergistically control the biogeochemical cycles of carbon,nitrogen,sulfur and phosphorus.These findings provide new insights into the functional potentials of microorganisms to participate in biogeochemical cycles and their responses to environmental factors in hot springs.
基金funded by the National Institutes of Health,grant numbers UG3OD023285,P42ES030991,and P30ES036084.
文摘Stem cell fate decisions are increasingly understood through the dynamic interplay of two fundamental stress-adaptive programs:the integrated stress response(ISR)and the senescence-associated secretory phenotype(SASP).These pathways act as a Yin-Yang system,balancing beneficial and detrimental outcomes across development,tissue homeostasis,and disease.On the yin(protective)side,transient ISR activation and acute SASP signaling foster adaptation,embryonic patterning,wound healing,and regeneration.On the yang(maladaptive)side,chronic ISR signaling and unresolved SASP output drive stem cell exhaustion,fibrosis,inflammation,and tumorigenesis.This duality highlights their roles as both guardians and disruptors of stem cell integrity.Mechanistically,ISR regulates translational control via eukaryotic initiation factor 2 alpha(eIF2α)phosphorylation and activating transcription factor 4(ATF4)-dependent transcription,while SASP reprograms the extracellular milieu through cytokines,growth factors,and proteases.Their crosstalk creates feedback loops that shape tissue niches and long-termstemcell potential.Framing ISR-SASP interactions through a Yin-Yang lens underscores the balance between resilience and decline,to offer new insights into regenerative medicine,anti-aging interventions,and cancer therapeutics.
基金Supported by the National Natural Science Foundation of China,No.81671600 and No.81241094Natural Science Foundation of Shandong Province,China,No.ZR2016HM13 and No.ZR2023MH066Qingdao Medical and Health Scientific Research Project,China,No.2024-WJKY160.
文摘BACKGROUND The pathogenesis of primary biliary cholangitis(PBC)remains unclear.Ursodeoxycholic acid(UDCA)is the only first-line clinical treatment,but approximately 40%of patients exhibit a poor response.AIM To identify novel biomarkers for PBC to predict the efficacy of UDCA and enhance treatment.METHODS Microarray expression profiling datasets were downloaded from the Gene Expression Omnibus and analyzed to identify differentially expressed genes between PBC patients and healthy controls.Immunohistochemistry was performed to validate key genes in liver tissues of the participants.Logistic regression was employed to evaluate prognostic risk factors,receiver operating characteristic curves were used to assess predictive performance,and correlations between key genes and clinicopathological characteristics were analyzed.RESULTS By bioinformatic analysis,13 genes primarily associated with the progression of PBC were identified,and tumor necrosis factor alpha-induced protein 3(TNFAIP3)was selected for further investigation.Then expression of TNFAIP3 in PBC patients was significantly elevated compared to healthy controls on immunohistochemistry(P<0.0001).Multivariate Cox regression analysis indicated that both TNFAIP3 and fatigue were independent risk factors for response to UDCA in PBC patients(P<0.05).The area under the curve for TNFAIP3 and fatigue were 0.691 and 0.704,respectively,while their combination showed a significantly higher area under the curve of 0.848.The expression of TNFAIP3 was also correlated with age,albumin,total bilirubin,alkaline phosphatase and splenomegaly(P<0.05).CONCLUSION TNFAIP3 and fatigue are independent risk factors for response to UDCA in Chinese patients with PBC.TNFAIP3 may be a potential biomarker or therapeutic target for PBC.These findings offer new insights into the pathogenesis of PBC.
基金supported by the 2025 Fujian Provincial Social Science Foundation Project(FJ2025C074).
文摘This systematic review synthesizes empirical research on external risk factors for adolescent smartphone addiction.Scopus and Web of Science were searched for English peer-reviewed empirical articles from 2008 onward;28 met inclusion criteria(excluding non-adolescents,generic internet addiction,non-empirical work,or non-English).Thematic synthesis organized findings into three external risk domains—family,school,and peers—considering cultural/contextual mechanisms.Family dynamics(parental phubbing,harsh parenting,dysfunction),school stressors,and adverse peer relationships were identified as accumulating,direct and indirect contributors to smartphone addiction.These operate within a techno-ecological framework,where digital technologies amplify vulnerabilities and create new pathways for maladaptive use.Evidence favors an ecological,multi-level perspective.Future research should use longitudinal designs,standardize measures across cultures,and examine understudied regions—especially Africa—to guide culturally sensitive interventions.
基金Supported by Italian Association for Cancer Research(AIRC),No.21956Italian Ministry of Health-5×1000 funds 2023.
文摘In this editorial,we comment on the article by Zhang et al recently published in the World Journal of Gastroenterology.The manuscript elucidates significant novel mechanisms underlying hepatocellular carcinoma(HCC)progression.HCC is currently considered one of the major causes of global cancer-associated deaths,underscoring the critical need for novel therapeutic targets.Growing evidence underlines the role of the lipid raft protein flotillin-1(FLOT1)in cancer,whose dysregulation drives tumor cell growth and survival.However,the regulatory role of FLOT1 on Golgi apparatus function in HCC is unknown.In this study,Zhang et al elucidated a pivotal mechanism by which FLOT1 promotes HCC progression through activation of transcription factor E3-mediated Golgi stress response.The study reveals that FLOT1 inhibits the mechanistic target of rapamycin complexes 1 and 2 by ubiquitination,facilitating transcription factor E3 dephosphorylation,nuclear translocation,and subsequent upregulation of Golgi stress-associated genes,thereby leading to enhanced HCC cell growth and invasive capacity.These findings obtained in vitro/in vivo highlight the interplay between FLOT1 and Golgi homeostasis in HCC.Targeting FLOT1 may offer a new strategy for the treatment of HCC.
文摘BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and depression(PSD)do not receive sufficient attention.AIM To systematically evaluate risk factors and early identification markers for PSD for more precise screening and intervention strategies in clinical practice.METHODS This retrospective study analyzed clinical data from 112 patients with ischemic stroke admitted between January 2022 and December 2024.Based on assessments using the Hamilton Rating Scale for Anxiety(HAMA)and Hamilton Rating Scale for Depression(HAMD)at 2 weeks(±3 days)post-stroke,patients were classified into the PSD group(HAMA≥7 and/or HAMD≥7)and the non-PSD group(HAMA<7 and HAMD<7).Observation indicators included psychological assessment,demographic and clinical characteristics,stroke-related clinical indicators,neuroimaging assessments,and laboratory biomarkers.Multivariate logistic regression analysis was used to identify independent risk factors for PSD,and receiver operating characteristic curve analysis was used to evaluate the diagnostic value of potential biomarkers.RESULTS Of the 112 patients,46(41.1%)were diagnosed with PSD.Multivariate analysis identified five independent risk factors:Female gender[Odds ratio(OR)=2.32,95%confidence interval(CI):1.56-3.45],history of mental disorders prior to stroke(OR=3.17,95%CI:1.89-5.32),infarct location in the frontal lobe or limbic system(OR=2.86,95%CI:1.73-4.71),stroke severity with National Institutes of Health Stroke Scale≥8 at admission(OR=2.54,95%CI:1.62-3.99),and low social support(Social Support Rating Scale<35,OR=2.18,95%CI:1.42-3.36).Subgroup analysis showed that depression patients more commonly had left hemisphere lesions(68.4%vs 45.2%),while anxiety patients more frequently presented with right hemisphere lesions(59.5%vs 39.5%).The PSD group exhibited larger infarct volumes(8.7 cm^(3) vs 5.3 cm^(3)),more severe white matter hyperintensities,and more pronounced frontal lobe atrophy.Analysis of inflammatory markers showed significantly elevated levels of interleukin-6(7.8 pg/mL vs 4.5 pg/mL)and tumor necrosis factor-alpha(15.6 pg/mL vs 9.8 pg/mL)in the PSD group,while hypothalamicpituitary-adrenal axis function assessment revealed higher cortisol levels(386.5±92.3 nmol/L vs 328.7±75.6 nmol/L)and flattened diurnal rhythm in the PSD group.CONCLUSION PSD is a complex neuropsychiatric consequence of stroke involving disruption of the frontal-limbic circuitry,neuroinflammatory responses,and dysfunction of the hypothalamic-pituitary-adrenal axis.
基金supported by the National Key R&D Program of China(No.2021YFB2401200)National Natural Science Foundation of China(72242105)Organized Research Support Program,Department of Electrical Engineering,Tsinghua University.
文摘With the increasing penetration of variable renewable energy,flexible resources are highly needed to hedge the growing uncertainty,and variability in the power system.Demand response has served as a cost-effective type of flexible resource in recent years.In order to balance the uncertainty of the system,it is crucial to assess how much flexibility demand response programs can provide.Thus,forecasting demand response potential is important for the operation of the bulk system.This paper proposes a modeling approach that can characterize the multi-timescale flexibility of demand response so that not only the power potential but also temporal-coupling characteristics can be considered.Furthermore,a day-ahead demand response potential forecasting method is proposed using deep convolutional generative adversarial networks.The proposed forecasting method is tested using data from 170 users in Pecan Street Dataport.The results show that the proposed method can forecast the multi-timescale flexibility of demand response with high accuracy.
