Here we report a family with a clinical spectrum of Pachyonychia Congenita Tarda (PCT) encompassing two generations via a balanced chromosomal translocation between 4q26 and 12p12.3. We discuss the effects of chromoso...Here we report a family with a clinical spectrum of Pachyonychia Congenita Tarda (PCT) encompassing two generations via a balanced chromosomal translocation between 4q26 and 12p12.3. We discuss the effects of chromosomal translocations on gene expression through involved breakpoints and structural gene abnormalities detected by array CGH. We believe that the family we present gives further insight to the better understanding of molecular and structural basis of keratin disorders, and to the late onset and genetic basis of PCT through the possible role of C-type lectins and human epithelial membrane protein1 (EMP1). Better understanding of the molecular basis of keratin disorders is the foundation for improved diagnosis, genetic counseling and novel therapeutic approaches to overcome the current treatment limitations related to this disease.展开更多
Pod shattering is an agronomical trait that is a result of the coordinated action of cell differentiation and separation. In Arabidopsis, pod shattering is controlled by a complex genetic network in which ALCATRAZ （...Pod shattering is an agronomical trait that is a result of the coordinated action of cell differentiation and separation. In Arabidopsis, pod shattering is controlled by a complex genetic network in which ALCATRAZ （ALC）, a member of the basic helix-loop-helix family, is critical for cell separation during fruit dehiscence. Herein, we report the identification of ALC-INTERACTING PROTEIN1 （ACI1） via the yeast two-hybrid screen. ACll encodes a nuclear protein with a lysine-rich domain and a C-terminal serine-rich domain. ACI1 is mainly expressed in the vascular system throughout the plant and mesocarp of the valve in siliques. Our data showed that ACI1 interacts strongly with the N-terminal portion of ALC in yeast cells and in plant cells in the nucleus as demonstrated by bimolecular fluorescence complementaUon assay. Both ACI1 and ALC share an overlapping expression pattern, suggesting that they likely function together in planta. However, no detectable phenotype was found in plants with reduced ACll expression by RNA interference technology, suggesting that ACll may be redundant. Taken together, these data indicate that ALC may interact with ACI1 and its homologs to control cell separation during fruit dehiscence in Arabidopsis.展开更多
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively dete...α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.展开更多
Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CR...Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.展开更多
Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can signi...Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can significantly increase survival rates.Here,a novel blood-based cancer screening as a pre-test in combination with targeted MRI imaging enabled the early diagnosis of prostate cancer.Case Description:We present the case of a 64-year-old man who participated in a prospective,interventional,multicenter cancer screening study where an immunological biopsy-based technique served as a part of a novel screening technique.This immunology technique represents a blood test exploiting two biomarkers,which may allow for the identification of individuals at an early stage of tumor development.Due to the elevated biomarker levels of Transketolase-like protein 1(TKTL1)and Apoptoic-associated cell population 10(Apo10),magnetic resonance imaging(MRI)was indicated for further clarification.A multiparametric MRI of the pelvis/prostate revealed an enlarged prostate gland and several suspicious lesions classified as Prostate Imaging Reporting and Data System(PI-RADS)4 and PI-RADS 5.In further assessments,both lesions were categorized as an acinar adenocarcinoma of the prostate(Gleason Score 6,International Society of Urological Pathology(ISUP)1,no perineural infiltration).After surgical resection,the tumor was classified histopathologically as an adenocarcinoma,pT2c pN0(0/7),L0,V0,Pn1,R0,Gleason score 7a,ISUP 2.Conclusions:The combination of the TKTL1/Apo10 blood test and subsequent imaging made it possible to detect a developing prostate carcinoma in a localized stage.All in all,this case report proves not just the ability but also the potential of the TKTL1/Apo10 blood test for early detection of(pre-)malignant lesions,which still present with a promising prospect for a cure.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,wi...Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.展开更多
Background Goat milk is increasingly recognized for high digestibility and a distinctive compositional profile.Protein acetylation,an important post-translational modification,regulates biosynthetic and metabolic path...Background Goat milk is increasingly recognized for high digestibility and a distinctive compositional profile.Protein acetylation,an important post-translational modification,regulates biosynthetic and metabolic pathways.This study aimed to identify critical acetylated proteins and specific modification sites involved in milk production and component synthesis in dairy goats,thereby elucidating the molecular mechanisms of lactation.We performed a comparative TMT-based acetylomic and proteomic analysis of mammary tissues from Saanen dairy goats during peak lactation and the dry period using LC–MS/MS.A candidate acetylation site was further investigated in goat mammary epithelial cells(GMECs)through site-directed mutagenesis and lipid metabolic assays,establishing functional links between acetylation and mammary lipid metabolism and providing a foundation for molecular strategies to improve milk quality and yield.Results We established a comprehensive mammary acetylome,identifying 862 significantly acetylated proteins and 2,028 modification sites across the two physiological phases.Differentially acetylated proteins were predominantly localized to the cytoplasm(39.98%).From these,54 key acetylated proteins,including MTOR,BCAT2,QARS1,GOT1,GOT2,BDH1,ACSS1,STAT5B,FABP5,and GPAM were prioritized as candidates involved in milk protein synthesis,milk fat synthesis,lactose synthesis,and other lactation-related processes.Among them,β-hydroxybutyrate dehydrogenase 1(BDH1)acetylation was characterized in detail.Members of the HDAC family were identified as primary regulators mediating BDH1 deacetylation.BDH1 acetylation promoted lipid droplet formation and triglyceride synthesis in GMECs.At the transcriptional level,BDH1 acetylation upregulated LXRα,ACSL1 and SCD1,whereas deacetylation downregulated SCD1,FASN,and ACSL1.Notably,BDH1 acetylation/deacetylation significantly reduced SREBP1 expression,linking this modification to coordinated control of lipogenic gene networks.Conclusions This study established,for the first time,the comprehensive acetylome of mammary gland tissues in dairy goats,revealing a substantial number of differentially acetylated proteins and modification sites.We demonstrate that acetylation of BDH1 regulated by HDACs promotes lipid droplet biogenesis and triglyceride synthesis in GMECs through transcriptional modulation of key lipogenic genes and suppression of SREBP1.These findings provide mechanistic insights into the post-translational regulation of mammary lipid metabolism and offer molecular targets for future genetic and nutritional strategies aimed at enhancing milk quality and yield in dairy goats.展开更多
Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein bet...Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein beta-1 in cerebral ischemia/reperfusion injury remains unclear.Here,using both in vivo and in vitro models of ischemic injury-middle cerebral artery occlusion/reperfusion in C57BL/6J mice and oxygen-glucose deprivation/reoxygenation in BV-2 microglial cells-we observed that heat shock protein beta-1 overexpression significantly reduced infarct volume,mitigated neuronal loss,and improved neurological outcomes.Mechanistically,heat shock protein beta-1 attenuated lipid peroxidation,intracellular iron accumulation,and reactive oxygen species generation in microglia;this was accompanied by enhanced glutathione peroxidase 4 expression and suppressed nuclear factor-κB pathway activation.Notably,the pharmacological activation of nuclear factor-κB with phorbol 12-myristate 13-acetate reversed the protective effects of heat shock protein beta-1,confirming the functional relevance of this pathway.Together,our findings indicate that heat shock protein beta-1 exerts neuroprotective effects against cerebral ischemia/reperfusion injury by suppressing microglial ferroptosis and pro-inflammatory activation via modulation of the nuclear factor-κB/glutathione peroxidase 4 signaling axis.These findings establish heat shock protein beta-1 as a critical regulator of the nuclear factor-κB/glutathione peroxidase 4 axis in microglia,thereby offering a dual-targeted strategy to inhibit ferroptosis and inflammation in ischemic stroke.Importantly,our study highlights heat shock protein beta-1 as a promising therapeutic candidate for preserving neurological function following cerebral ischemic injury.展开更多
HPPD(4-hydroxyphenylpyruvate dioxygenase)inhibitor are widely used in agriculture due to their high efficacy and environmental friendliness.However,many important crops,such as rice,wheat,and soybean,are naturally sen...HPPD(4-hydroxyphenylpyruvate dioxygenase)inhibitor are widely used in agriculture due to their high efficacy and environmental friendliness.However,many important crops,such as rice,wheat,and soybean,are naturally sensitive to these herbicides.In this study,we employed a directed evolution strategy to enhance the metabolic capacity of OsHSL2,OsHSL4,OsHSL6,and SbHSL1 proteins toward HPPD inhibitors,providing a new technological approach as well as theoretical foundation for molecular breeding of herbicide-resistant crops.By combining AlphaFold 3 protein models with crystal structures,we systematically redesigned key residues to resemble the active residues found in HIS1.Catalytic activity assays demonstrated that specific mutations significantly improved the metabolic activity of HSLs proteins toward various HPPD inhibitors.Notably,the OsHSL2-M4 mutant exhibited enhanced metabolic activity for BBC-OH and methyl-benquitrione,while the OsHSL4-M5 mutant completely metabolized BBC-OH and topramezone.Additionally,the SbHSL1-M4 mutant showed significant improvement in the metabolism of BBC-OH and several other herbicides,providing strong evidence to support the use of structure-guided HSL mutations to enhance crop resistance to HPPD inhibitors.展开更多
Because the pathogenesis of Alzheimer’s disease is multifactorial and complex,integrated multi-level omics analysis is essential to comprehensively elucidate its molecular alterations.We therefore utilized the well-e...Because the pathogenesis of Alzheimer’s disease is multifactorial and complex,integrated multi-level omics analysis is essential to comprehensively elucidate its molecular alterations.We therefore utilized the well-established amyloid precursor protein/presenilin 1 mouse model to carry out an integrated multi-omics study using transcriptomic,proteomic,N^(6)-methyladenosine epitranscriptomic,and phosphoproteomic analyses.The results revealed substantial molecular alterations across multiple biological dimensions and the alteration in the expression of several key genes,such as GFAP,APP,and RTN4,in a mouse model of Alzheimer’s disease.The pronounced elevation of RTN4 in reactive astrocytes is indicative of its involvement in Alzheimer’s disease pathogenesis.Furthermore,we identified dysregulation of pathways related to endocytosis,highlighting the critical role of this process in disease progression.Our findings underscore the significant impact of post-transcriptional(N^(6)-methyladenosine methylation)and post-translational(phosphorylation)protein modifications,which have been underrepresented in Alzheimer’s disease research.The significant contribution made by this study is the integrated,multi-level omics analysis that we carried out to investigate the complex biological changes that occur in Alzheimer’s disease.Our findings provide novel insights into Alzheimer’s disease pathogenesis and suggest potential therapeutic targets,such as RTN4.展开更多
Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways ...Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.展开更多
Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exh...Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exhibit substantial regional heterogeneity and display variable responses to different neurological diseases.Such diversity in astrocyte morphology and function is essential for understanding both normal brain function and the underlying mechanisms of neurological disorders.To investigate this heterogeneity,we developed a novel method for the selective and sparse labeling of astrocytes in various brain regions.This technique utilizes a dual adeno-associated virus system that allows for the expression of Cre recombinase and enhanced green fluorescent protein under the control of the glial fibrillary acidic protein(GfaABC1D)promoter.The system was tested in C57BL/6J mice and successfully labeled astrocytes across multiple brain regions.The method enabled the detailed visualization of individual astrocytes-including their intricate peripheral processes-through three-dimensional reconstructions from confocal microscopy images.Furthermore,the labeling efficiency of this dual adeno-associated virus technology was validated by examining astrocyte function in a spared nerve injury model and through chemogenetic modulation.This innovative approach holds great promise for future research because it enables a more comprehensive understanding of astrocyte variation not only in spared nerve injury but also in a broad spectrum of neurological diseases.The ability to selectively label and study astrocytes in different brain regions provides a powerful tool for exploring the complexities of these essential cells and their roles in physiological and pathological conditions.展开更多
Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying m...Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.Methods:LoVo CRC cell line was exposed to oxaliplatin at an increased dose,and cells were cultured in the presence of oxaliplatin to develop LoVo^(OXR) cells.Microarray and Quantitative Reverse Transcription Polymerase Chain Reaction(qRT-PCR),western blot,and transwell assay were used to evaluate the chemoresistance in LoVo^(OXR) CRC cells.Results:Microarray and qRT-PCR analysis showed an increased expression of miR-100-5p in LoVo^(OXR) cells.MTT assay and flow cytometry analysis revealed less apoptosis and higher cell viability in LoVo^(OXR) cells.mRNA prediction target gene analysis showed C-terminal domain small phosphatase-like(CTDSPL),a phosphatase-like tumor suppressor,as a key target of miR-100-5p.CTDSPL expression was low in LoVo^(OXR) cells compared to LoVoWT cells.miR-100-5p regulates G1/S and S-phase transitions and inhibits differentiation by targeting the CTDSPL/pRB/E2F1 signaling pathway,which involves the modulation of cell cycle effectors in LoVo^(OXR) cells.Further,we found that forkhead box P3(FOXP3),as the upstream target of miR-100-5p,is highly expressed in LoVo^(OXR) cells.Inhibiting miR-100-5p and FOXP3 down-regulates miR-100-5p expression,while increased CTDSPL expression contributed to reduced cell proliferation and promoted cell apoptosis in LoVo^(OXR) CRC cells.Conclusions:miR-100-5p plays an oncogenic role in inducing chemoresistance through modulation of the CTDSPL/retinoblastoma protein(pRB)/E2F transcription factor 1(E2F1)axis in CRC cells.展开更多
Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed t...Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed to investigate the role of cardiac injury-related bclaf1-interacting lncRNA(lncCIRBIL)in JWS and to delineate the molecular mechanisms.Methods:Whole-cell patch-clamp techniques were used to record ionic currents and action potentials(APs).Protein and mRNA expression related to I_(to)current were assessed.RNA immunoprecipitation,RNA Pulldown,mRNA stability,and decapping assays were performed to dissect the underlying mechanisms.Results:Plasma lncCIRBIL levels were significantly reduced in JWS patients and cold-induced JWS mice.Knockout of lncCIRBIL increased the incidence of J-wave and the susceptibility to ventricular arrhythmia in mice.In lncCIRBIL-deficient mice,the transmural gradient of Kv4.2 expression and I_(to)current density was markedly enhanced in the right ventricle,but not the left ventricle.In contrast,cardiomyocyte-specific transgenic overexpression of lncCIRBIL produced the opposite effects.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),the conserved human homologous fragment of lncCIRBIL(hcf-CIRBIL)suppressed I_(to),attenuated the AP notch,and prolonged APD20.Mechanistically,lncCIRBIL directly binds to up-frameshift protein1(UPF1),promoting KCND2 mRNA decay by enhancing its decapping.Conclusions:LncCIRBIL modulates the transmural heterogeneity of KCND2 expression by regulating UPF1-mediated mRNA decay.Inhibition of lncCIRBIL exacerbates JWS by enhancing right ventricular I_(to)heterogeneity,whereas its overexpression exerts protective effects.These findings identify lncCIRBIL as a potential therapeutic target for J-wave syndrome.展开更多
文摘Here we report a family with a clinical spectrum of Pachyonychia Congenita Tarda (PCT) encompassing two generations via a balanced chromosomal translocation between 4q26 and 12p12.3. We discuss the effects of chromosomal translocations on gene expression through involved breakpoints and structural gene abnormalities detected by array CGH. We believe that the family we present gives further insight to the better understanding of molecular and structural basis of keratin disorders, and to the late onset and genetic basis of PCT through the possible role of C-type lectins and human epithelial membrane protein1 (EMP1). Better understanding of the molecular basis of keratin disorders is the foundation for improved diagnosis, genetic counseling and novel therapeutic approaches to overcome the current treatment limitations related to this disease.
基金a Grant from the Ministry of Science and Technology of Chinato W.C. Yang (JY03-A-24)
文摘Pod shattering is an agronomical trait that is a result of the coordinated action of cell differentiation and separation. In Arabidopsis, pod shattering is controlled by a complex genetic network in which ALCATRAZ （ALC）, a member of the basic helix-loop-helix family, is critical for cell separation during fruit dehiscence. Herein, we report the identification of ALC-INTERACTING PROTEIN1 （ACI1） via the yeast two-hybrid screen. ACll encodes a nuclear protein with a lysine-rich domain and a C-terminal serine-rich domain. ACI1 is mainly expressed in the vascular system throughout the plant and mesocarp of the valve in siliques. Our data showed that ACI1 interacts strongly with the N-terminal portion of ALC in yeast cells and in plant cells in the nucleus as demonstrated by bimolecular fluorescence complementaUon assay. Both ACI1 and ALC share an overlapping expression pattern, suggesting that they likely function together in planta. However, no detectable phenotype was found in plants with reduced ACll expression by RNA interference technology, suggesting that ACll may be redundant. Taken together, these data indicate that ALC may interact with ACI1 and its homologs to control cell separation during fruit dehiscence in Arabidopsis.
基金supported by the Natural Science Foundation of Guangxi Zhuang Automomous Region,Nos.2019GXNSFDA245015(to MC),2022GXNSFBA035654(to HL)the National Natural Science Foundation of China,Nos.82360241(to MC),82304876(to HL)+1 种基金Scientific Research and Technology Development Project of Guilin City,Nos.20220139-3(to MC),20210218-5(to HL)Guangxi Medical and Health Key Discipline Construction Project(to QL)。
文摘α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease,although the mechanisms underlying misfoldedα-synuclein accumulation and propagation have not been conclusively determined.The expression of low-density lipoprotein receptor–related protein 1,which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor,is elevated in the neurons of patients with Parkinson's disease.However,whether there is a direct link between low-density lipoprotein receptor–related protein 1 andα-synuclein aggregation and propagation in Parkinson's disease remains unclear.Here,we established animal models of Parkinson's disease by inoculating monkeys and mice withα-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor–related protein 1 levels in the striatum and substantia nigra,accompanied by dopaminergic neuron loss and increasedα-synuclein levels.However,low-density lipoprotein receptor–related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase inα-synuclein levels in the nigrostriatal system.In HEK293A cells overexpressingα-synuclein fragments,low-density lipoprotein receptor–related protein 1 levels were upregulated only when the N-terminus ofα-synuclein was present,whereas anα-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor–related protein 1 upregulation.Furthermore,the N-terminus ofα-synuclein was found to be rich in lysine residues,and blocking lysine residues in PC12 cells treated withα-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor–related protein 1 andα-synuclein levels.These findings indicate that low-density lipoprotein receptor–related protein 1 regulates pathological transmission ofα-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in theα-synuclein N-terminus.
基金supported by the National Natural Science Foundation of China(82441036)Ganzhou Municipal Science and Technology Project(2022-RC1342)+3 种基金Guangdong Basic and Applied Basic Research Foundation(2022B1515130004)Key-Area Research and Development Program of Guangdong Province(2019B020234003)Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Cancer(2020B121201004)Open Project Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202210).
文摘Background:Thimerosal is a mercury-containing preservative widely used in vaccines.This study aimed to investigate its potential antitumor effects and mechanisms in solid malignancies,particularly colorectal cancer(CRC)and melanoma.Methods:A combination of in vitro and in vivo approaches was employed.Cell proliferation,apoptosis,migration,and invasion were assessed using Cell Counting Kit-8(CCK-8),colony formation,ATP viability,Western blotting,flow cytometry,wound-healing and Transwell assays.Subcutaneous,lung metastases,and Azoxymethane/Dextran Sulfate Sodium Salt(AOM/DSS)-induced colitis-associated CRC models were established to examine antitumor efficacy and safety.The functional role of mercury ions was validated using structural analogues.Mechanistic studies included RNA sequencing,Western blot,and immunohistochemical analysis of CD8^(+)T cell infiltration.The synergistic effect with programmed cell death protein 1(PD-1)antibody therapy was also evaluated.Results:Thimerosal potently inhibited tumor growth(with IC_(50) values ranging from 0.1 to 1μM in vitro)and significantly prolonged survival without overt toxicity in vivo.Mechanistically,mercury ions were identified as critical functional sites mediating Thimerosal’s antitumor effects.Specifically,Thimerosal inhibited the phosphorylation of Janus kinase 1(JAK1)and signal transducer and activator of transcription 3(STAT3).Furthermore,it enhanced the infiltration of CD8^(+)T cells into the tumor microenvironment and synergistically augmented the efficacy of anti-PD-1 therapy.Conclusion:Thimerosal exerts dual antitumor roles by direct JAK1/STAT3 inhibition and immune modulation via CD8^(+)T cell recruitment.It represents a promising repurposed drug and immunotherapeutic adjuvant for CRC and melanoma.
基金This study was conducted and financed by the sponsor Zyagnum AG,https://www.zyagnum.com/Zyagnum AG has not received any grants,rather,this study was fully financed by Zyagnum AG.The authors S.B.and A.L.C.G.participated in the study as investigators.The University Hospital Hamburg-Eppendorf received reimbursement for the study from Zyagnum AG.
文摘Background:With a total of 1.46 million new cases and 396,792 deaths in 2022,prostate cancer is a major medical challenge around the world.Detecting and treating cancer at earlier,preferably localized stages can significantly increase survival rates.Here,a novel blood-based cancer screening as a pre-test in combination with targeted MRI imaging enabled the early diagnosis of prostate cancer.Case Description:We present the case of a 64-year-old man who participated in a prospective,interventional,multicenter cancer screening study where an immunological biopsy-based technique served as a part of a novel screening technique.This immunology technique represents a blood test exploiting two biomarkers,which may allow for the identification of individuals at an early stage of tumor development.Due to the elevated biomarker levels of Transketolase-like protein 1(TKTL1)and Apoptoic-associated cell population 10(Apo10),magnetic resonance imaging(MRI)was indicated for further clarification.A multiparametric MRI of the pelvis/prostate revealed an enlarged prostate gland and several suspicious lesions classified as Prostate Imaging Reporting and Data System(PI-RADS)4 and PI-RADS 5.In further assessments,both lesions were categorized as an acinar adenocarcinoma of the prostate(Gleason Score 6,International Society of Urological Pathology(ISUP)1,no perineural infiltration).After surgical resection,the tumor was classified histopathologically as an adenocarcinoma,pT2c pN0(0/7),L0,V0,Pn1,R0,Gleason score 7a,ISUP 2.Conclusions:The combination of the TKTL1/Apo10 blood test and subsequent imaging made it possible to detect a developing prostate carcinoma in a localized stage.All in all,this case report proves not just the ability but also the potential of the TKTL1/Apo10 blood test for early detection of(pre-)malignant lesions,which still present with a promising prospect for a cure.
基金funded by Shanghai Yangpu District Science and Technology Commission(Grant No.YPQ202303(Xuejing Lin))Shanghai Yangpu Hospital Foundation(Grant No.Se1202420(Wenchao Wang)and Ye1202423(Juan Huang)).
文摘Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.
基金supported by the National Key Research and Development Program of China(2022YFF1000102)Xi’an Agricultural Technology Research General Project(24NYGG0025)the National Natural Science Foundation of China(31702098)。
文摘Background Goat milk is increasingly recognized for high digestibility and a distinctive compositional profile.Protein acetylation,an important post-translational modification,regulates biosynthetic and metabolic pathways.This study aimed to identify critical acetylated proteins and specific modification sites involved in milk production and component synthesis in dairy goats,thereby elucidating the molecular mechanisms of lactation.We performed a comparative TMT-based acetylomic and proteomic analysis of mammary tissues from Saanen dairy goats during peak lactation and the dry period using LC–MS/MS.A candidate acetylation site was further investigated in goat mammary epithelial cells(GMECs)through site-directed mutagenesis and lipid metabolic assays,establishing functional links between acetylation and mammary lipid metabolism and providing a foundation for molecular strategies to improve milk quality and yield.Results We established a comprehensive mammary acetylome,identifying 862 significantly acetylated proteins and 2,028 modification sites across the two physiological phases.Differentially acetylated proteins were predominantly localized to the cytoplasm(39.98%).From these,54 key acetylated proteins,including MTOR,BCAT2,QARS1,GOT1,GOT2,BDH1,ACSS1,STAT5B,FABP5,and GPAM were prioritized as candidates involved in milk protein synthesis,milk fat synthesis,lactose synthesis,and other lactation-related processes.Among them,β-hydroxybutyrate dehydrogenase 1(BDH1)acetylation was characterized in detail.Members of the HDAC family were identified as primary regulators mediating BDH1 deacetylation.BDH1 acetylation promoted lipid droplet formation and triglyceride synthesis in GMECs.At the transcriptional level,BDH1 acetylation upregulated LXRα,ACSL1 and SCD1,whereas deacetylation downregulated SCD1,FASN,and ACSL1.Notably,BDH1 acetylation/deacetylation significantly reduced SREBP1 expression,linking this modification to coordinated control of lipogenic gene networks.Conclusions This study established,for the first time,the comprehensive acetylome of mammary gland tissues in dairy goats,revealing a substantial number of differentially acetylated proteins and modification sites.We demonstrate that acetylation of BDH1 regulated by HDACs promotes lipid droplet biogenesis and triglyceride synthesis in GMECs through transcriptional modulation of key lipogenic genes and suppression of SREBP1.These findings provide mechanistic insights into the post-translational regulation of mammary lipid metabolism and offer molecular targets for future genetic and nutritional strategies aimed at enhancing milk quality and yield in dairy goats.
基金“Dawn”Program of Shanghai Education Commission,No.22SG37(to PY)the National Natural Science Foundation of China,Nos.82371313(to PY),82401536(to YongxinZ).
文摘Heat shock protein beta-1 may be involved in regulating ferroptosis in cells.The expression of heat shock protein beta-1 is upregulated after stroke;however,the underlying mechanism of action of heat shock protein beta-1 in cerebral ischemia/reperfusion injury remains unclear.Here,using both in vivo and in vitro models of ischemic injury-middle cerebral artery occlusion/reperfusion in C57BL/6J mice and oxygen-glucose deprivation/reoxygenation in BV-2 microglial cells-we observed that heat shock protein beta-1 overexpression significantly reduced infarct volume,mitigated neuronal loss,and improved neurological outcomes.Mechanistically,heat shock protein beta-1 attenuated lipid peroxidation,intracellular iron accumulation,and reactive oxygen species generation in microglia;this was accompanied by enhanced glutathione peroxidase 4 expression and suppressed nuclear factor-κB pathway activation.Notably,the pharmacological activation of nuclear factor-κB with phorbol 12-myristate 13-acetate reversed the protective effects of heat shock protein beta-1,confirming the functional relevance of this pathway.Together,our findings indicate that heat shock protein beta-1 exerts neuroprotective effects against cerebral ischemia/reperfusion injury by suppressing microglial ferroptosis and pro-inflammatory activation via modulation of the nuclear factor-κB/glutathione peroxidase 4 signaling axis.These findings establish heat shock protein beta-1 as a critical regulator of the nuclear factor-κB/glutathione peroxidase 4 axis in microglia,thereby offering a dual-targeted strategy to inhibit ferroptosis and inflammation in ischemic stroke.Importantly,our study highlights heat shock protein beta-1 as a promising therapeutic candidate for preserving neurological function following cerebral ischemic injury.
基金supported by the National Key Research and Development Program of China(No.2024YFE0214300)Hubei Provincial Science and Technology Plan Project(2022BEC051)selfdetermined research funds of CCNU from the colleges'basic research and operation of MOE(No.CCNU24JCPT023).
文摘HPPD(4-hydroxyphenylpyruvate dioxygenase)inhibitor are widely used in agriculture due to their high efficacy and environmental friendliness.However,many important crops,such as rice,wheat,and soybean,are naturally sensitive to these herbicides.In this study,we employed a directed evolution strategy to enhance the metabolic capacity of OsHSL2,OsHSL4,OsHSL6,and SbHSL1 proteins toward HPPD inhibitors,providing a new technological approach as well as theoretical foundation for molecular breeding of herbicide-resistant crops.By combining AlphaFold 3 protein models with crystal structures,we systematically redesigned key residues to resemble the active residues found in HIS1.Catalytic activity assays demonstrated that specific mutations significantly improved the metabolic activity of HSLs proteins toward various HPPD inhibitors.Notably,the OsHSL2-M4 mutant exhibited enhanced metabolic activity for BBC-OH and methyl-benquitrione,while the OsHSL4-M5 mutant completely metabolized BBC-OH and topramezone.Additionally,the SbHSL1-M4 mutant showed significant improvement in the metabolism of BBC-OH and several other herbicides,providing strong evidence to support the use of structure-guided HSL mutations to enhance crop resistance to HPPD inhibitors.
基金supported by the National Natural Science Foundation of China,No.82374552(to WP)the Natural Science Foundation of Hunan Province,Nos.2024JJ2086,2024JJ6597(to JK)+1 种基金the Science and Technology Innovation Program of Hunan Province,No.2022RC1220(to WP)Support Plan for High-Level Health and Medical Talents in Hunan Province,No.20240304076(to WP).
文摘Because the pathogenesis of Alzheimer’s disease is multifactorial and complex,integrated multi-level omics analysis is essential to comprehensively elucidate its molecular alterations.We therefore utilized the well-established amyloid precursor protein/presenilin 1 mouse model to carry out an integrated multi-omics study using transcriptomic,proteomic,N^(6)-methyladenosine epitranscriptomic,and phosphoproteomic analyses.The results revealed substantial molecular alterations across multiple biological dimensions and the alteration in the expression of several key genes,such as GFAP,APP,and RTN4,in a mouse model of Alzheimer’s disease.The pronounced elevation of RTN4 in reactive astrocytes is indicative of its involvement in Alzheimer’s disease pathogenesis.Furthermore,we identified dysregulation of pathways related to endocytosis,highlighting the critical role of this process in disease progression.Our findings underscore the significant impact of post-transcriptional(N^(6)-methyladenosine methylation)and post-translational(phosphorylation)protein modifications,which have been underrepresented in Alzheimer’s disease research.The significant contribution made by this study is the integrated,multi-level omics analysis that we carried out to investigate the complex biological changes that occur in Alzheimer’s disease.Our findings provide novel insights into Alzheimer’s disease pathogenesis and suggest potential therapeutic targets,such as RTN4.
基金supported by the Foundation Project:National Natural Science.Foundation of China(Nos.:82460249,82100417,81760094)The Foundation of Jiangxi Provincial Department of Science and Technology Outstanding Youth Fund Project(20212BAB206022,20242BAB23080).
文摘Objective:Leucine-rich alpha-2 glycoprotein 1(Lrg1)could regulate diverse cells in cerebral ischemiareperfusion.Our study seeks to uncover Lrg1’s impact on endothelial cell heterogeneity via differentiation pathways and transcription factors.Method:The CSOmap model measured cell-to-brain-center distances using single-cell RNA sequencing(scRNA-seq)data in middle cerebral artery occlusion reperfusion(MCAO/R).Monocle2 mapped endothelial differentiation paths.Gene set enrichment analysis(GSEA)analyzed endothelial subcluster variations.Database searches revealed a zinc finger MIZ-type containing 1 protein-frizzled 3(Zmiz1-Fzd3)promoter interaction.Endothelial cells were transfected with a Fzd3 promoter-luciferase plasmid.Polymerase chain reaction(PCR)and western blotting assessed MCAO/R or Zmiz1 overexpression effects on Fzd3-related mRNA and proteins.A retroviral vector carrying Zmiz1 was injected into the brains of mice to study its effect on Fzd3.Result:Lrg1−/−mice exhibited elevated cell adhesion proteins and decreased microvascular leakage after MCAO/R.CSOmap showed widened astrocyte spacing in thesemice.RSS revealed Zmiz1 overexpression inMCAO/R+Lrg1−/−mice.MCAO/R and pcDNA3-Zmiz1 transfection both enhanced luciferase activity with Fzd3,indicating Zmiz1 binding to Fzd3.Retroviral Zmiz1 injection or knockdown disrupted ischemic brain tight junctions,highlighting Zmiz1’s key role in blood-brain barrier protection,likely through Fzd3 pathway modulation.Conclusion:The findings indicate Lrg1 knockout induces endothelial differentiation by activating Zmiz1,which is crucial for maintaining blood-brain barrier function,possibly via modulating the Fzd3 pathway.
基金National Natural Science Foundation of China,No.32271148(to JW)the National Key Research and the Development Program of China,No.2023M740625(to ML)+1 种基金the Natural Science Foundation of Guangdong Province,Nos.2021B1515120050(to HW)and 2023A1515110782(to ML)and Key R&D Program of Ningxia Hui Autonomous Region,No.2024BEG02027(to JW).
文摘Astrocytes are the most abundant glial cells in the central nervous system.They perform a diverse array of functions,with a critical role in structural integrity,synapse formation,and neurotransmission.These cells exhibit substantial regional heterogeneity and display variable responses to different neurological diseases.Such diversity in astrocyte morphology and function is essential for understanding both normal brain function and the underlying mechanisms of neurological disorders.To investigate this heterogeneity,we developed a novel method for the selective and sparse labeling of astrocytes in various brain regions.This technique utilizes a dual adeno-associated virus system that allows for the expression of Cre recombinase and enhanced green fluorescent protein under the control of the glial fibrillary acidic protein(GfaABC1D)promoter.The system was tested in C57BL/6J mice and successfully labeled astrocytes across multiple brain regions.The method enabled the detailed visualization of individual astrocytes-including their intricate peripheral processes-through three-dimensional reconstructions from confocal microscopy images.Furthermore,the labeling efficiency of this dual adeno-associated virus technology was validated by examining astrocyte function in a spared nerve injury model and through chemogenetic modulation.This innovative approach holds great promise for future research because it enables a more comprehensive understanding of astrocyte variation not only in spared nerve injury but also in a broad spectrum of neurological diseases.The ability to selectively label and study astrocytes in different brain regions provides a powerful tool for exploring the complexities of these essential cells and their roles in physiological and pathological conditions.
基金supported by the China Medical University Hospital,Department of Medical Research(DMR-110-209)the Ministry of Science and Technology,Taiwan(MOST:109-2320-B-303-001-MY2),CMU107-ASIA-08,CMU109-MF-76 and CMU105-ASIA-01Taichung Armed Forces General Hospital:TCAFGH_D_115034.
文摘Objective:MicroRNAs(miRNAs)are small,non-coding RNAs that play a key role in the development of chemoresistance in various cancer types,including colorectal cancer(CRC).In this study,we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC.Methods:LoVo CRC cell line was exposed to oxaliplatin at an increased dose,and cells were cultured in the presence of oxaliplatin to develop LoVo^(OXR) cells.Microarray and Quantitative Reverse Transcription Polymerase Chain Reaction(qRT-PCR),western blot,and transwell assay were used to evaluate the chemoresistance in LoVo^(OXR) CRC cells.Results:Microarray and qRT-PCR analysis showed an increased expression of miR-100-5p in LoVo^(OXR) cells.MTT assay and flow cytometry analysis revealed less apoptosis and higher cell viability in LoVo^(OXR) cells.mRNA prediction target gene analysis showed C-terminal domain small phosphatase-like(CTDSPL),a phosphatase-like tumor suppressor,as a key target of miR-100-5p.CTDSPL expression was low in LoVo^(OXR) cells compared to LoVoWT cells.miR-100-5p regulates G1/S and S-phase transitions and inhibits differentiation by targeting the CTDSPL/pRB/E2F1 signaling pathway,which involves the modulation of cell cycle effectors in LoVo^(OXR) cells.Further,we found that forkhead box P3(FOXP3),as the upstream target of miR-100-5p,is highly expressed in LoVo^(OXR) cells.Inhibiting miR-100-5p and FOXP3 down-regulates miR-100-5p expression,while increased CTDSPL expression contributed to reduced cell proliferation and promoted cell apoptosis in LoVo^(OXR) CRC cells.Conclusions:miR-100-5p plays an oncogenic role in inducing chemoresistance through modulation of the CTDSPL/retinoblastoma protein(pRB)/E2F transcription factor 1(E2F1)axis in CRC cells.
基金supported by National Natural Science Foundation of China(82270320 to Yin D C,82300280 to Jin X X,82070344,81870295 to Pan Z W)HMU Marshal Initiative Funding(HMUMIF-21017 to Pan Z W)Excellent Young Medical Talents Training Fund of the First Affiliated Hospital of Harbin Medical University(No.2024YQ03 to Jin X X).
文摘Background:Transmural heterogeneity of the transient outward potassium current(I_(to))is a major contributor to J-wave syndrome(JWS).However,the underlying molecular mechanisms remain elusive.The present study aimed to investigate the role of cardiac injury-related bclaf1-interacting lncRNA(lncCIRBIL)in JWS and to delineate the molecular mechanisms.Methods:Whole-cell patch-clamp techniques were used to record ionic currents and action potentials(APs).Protein and mRNA expression related to I_(to)current were assessed.RNA immunoprecipitation,RNA Pulldown,mRNA stability,and decapping assays were performed to dissect the underlying mechanisms.Results:Plasma lncCIRBIL levels were significantly reduced in JWS patients and cold-induced JWS mice.Knockout of lncCIRBIL increased the incidence of J-wave and the susceptibility to ventricular arrhythmia in mice.In lncCIRBIL-deficient mice,the transmural gradient of Kv4.2 expression and I_(to)current density was markedly enhanced in the right ventricle,but not the left ventricle.In contrast,cardiomyocyte-specific transgenic overexpression of lncCIRBIL produced the opposite effects.In human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),the conserved human homologous fragment of lncCIRBIL(hcf-CIRBIL)suppressed I_(to),attenuated the AP notch,and prolonged APD20.Mechanistically,lncCIRBIL directly binds to up-frameshift protein1(UPF1),promoting KCND2 mRNA decay by enhancing its decapping.Conclusions:LncCIRBIL modulates the transmural heterogeneity of KCND2 expression by regulating UPF1-mediated mRNA decay.Inhibition of lncCIRBIL exacerbates JWS by enhancing right ventricular I_(to)heterogeneity,whereas its overexpression exerts protective effects.These findings identify lncCIRBIL as a potential therapeutic target for J-wave syndrome.
