Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.Howeve...Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.展开更多
The tensile property of the spliced yarn splice under different splicing conditions has been investigated. The retained spliced strength of the splice spliced under different splicing conditions was obtained as the in...The tensile property of the spliced yarn splice under different splicing conditions has been investigated. The retained spliced strength of the splice spliced under different splicing conditions was obtained as the indicator for the performance of the splicer under that particular splicing condition. The results showed that, the length of the yarn tails and the yarn linear density are the parameters that has the most important effect to the tensile property of the spliced yarn.展开更多
Cyber losses in terms of number of records breached under cyber incidents commonly feature a significant portion of zeros, specific characteristics of mid-range losses and large losses, which make it hard to model the...Cyber losses in terms of number of records breached under cyber incidents commonly feature a significant portion of zeros, specific characteristics of mid-range losses and large losses, which make it hard to model the whole range of the losses using a standard loss distribution. We tackle this modeling problem by proposing a three-component spliced regression model that can simultaneously model zeros, moderate and large losses and consider heterogeneous effects in mixture components. To apply our proposed model to Privacy Right Clearinghouse (PRC) data breach chronology, we segment geographical groups using unsupervised cluster analysis, and utilize a covariate-dependent probability to model zero losses, finite mixture distributions for moderate body and an extreme value distribution for large losses capturing the heavy-tailed nature of the loss data. Parameters and coefficients are estimated using the Expectation-Maximization (EM) algorithm. Combining with our frequency model (generalized linear mixed model) for data breaches, aggregate loss distributions are investigated and applications on cyber insurance pricing and risk management are discussed.展开更多
OCT4 is one of the key transcription factors in maintaining the pluripotency and self-renewal of embryonic stem （ES） cells.Human OCT4 can generate two isoforms OCT4A and OCT4B by alternative splicing.OCT4B1 is a rec...OCT4 is one of the key transcription factors in maintaining the pluripotency and self-renewal of embryonic stem （ES） cells.Human OCT4 can generate two isoforms OCT4A and OCT4B by alternative splicing.OCT4B1 is a recently discovered novel OCT4 spliced variant,which has been considered as a putative marker of stemness.Compared with the OCT4B mRNA,OCT4B1 mRNA is generated by retaining intron 2 as a cryptic exon which contains a TGA stop codon in it.As a result,the protein product of OCT4B1 mRNA could be truncated.Interestingly,we present here that OCT4B1 can indirectly produce the same protein products as OCT4B.We have demonstrated that OCT4B1 mRNA can be spliced into OCT4B mRNA,and encode three protein isoforms.The splicing of OCT4B1 mRNA into OCT4B mRNA can be remarkably inhibited by the mutation of the classical splicing site.Our result suggests that OCT4B mRNA may originate from OCT4B1 mRNA by alternative splicing.展开更多
The analysis of spliced column has been carried out to detect optimum location of providing splices in the column.In the present work,static and dynamic(free vibration)analyses of spliced column have been done by rand...The analysis of spliced column has been carried out to detect optimum location of providing splices in the column.In the present work,static and dynamic(free vibration)analyses of spliced column have been done by randomising the location of splicing.A symmetrical four storey steel framed building has been modelled,analysed and designed for loads(dead,live and earthquake loads)recommended by Indian Codal provisions using Staad.Pro.The critical column at each floor level is identified based on axial force(AF),bending moment(BM)and shear force(SF).The total 16 models of spliced columns have been designed and then modelled in a 3D CAD Design tool(SOLIDWORKS)and then imported in the finite element tool(ANSYSWorkbench 14.0)for detailed analysis.The variation of stress,strain and deflection of the spliced column are shown in the form of contour.Further,the modal analysis is performed to determine the natural frequencies.The results of static and dynamic analyses are compared for each modelled spliced column to obtain the optimum location for providing splices in the column.The dynamic analysis of spliced column is of utmost importance in the region where dynamic loadings like earthquake,cyclones etc.are more frequent,and mere static analysis does not account for the safety of the structure.This study will help the engineers to select directly the optimum size and location of the splices in the column of a steel framed building.展开更多
In this study, 414 whole protein-coding sequences (238 004 codons) of alternatively spliced genes of human chromosome 1 have been employed to explore the patterns of codon usage bias among genes. Overall codon usage d...In this study, 414 whole protein-coding sequences (238 004 codons) of alternatively spliced genes of human chromosome 1 have been employed to explore the patterns of codon usage bias among genes. Overall codon usage data analysis indicates that G- and C-ending codons are predominant in the genes. The base usage in all three codon positions suggests a selection-mutation balance. Multivariate statistical analysis reveals that the codon usage variation has a strong positive correlation with the expressivities of the genes (r=0.5790, P<0.0001). All 27 codons identified as optimal are G- and C-ending codons. Correlation analysis shows a strong negative correlation between the gene length and codon adaptation index value (r=0.2252, P<0.0001), and a significantly positive correlation between the gene length and Nc values (r=0.1876, P<0.0001). These results suggest that the comparatively shorter genes in the genes have higher codon usage bias to maximize translational efficiency, and selection may also contribute to the reduction of highly expressed proteins.展开更多
Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful...Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.展开更多
Moving from the most recent results on Foxg1 biology,we first summarize the available information on some special pleiotropic effectors of neurodevelopmental interest,involved in controlling both transcription and pos...Moving from the most recent results on Foxg1 biology,we first summarize the available information on some special pleiotropic effectors of neurodevelopmental interest,involved in controlling both transcription and post-transcriptional steps of gene expression.Then,after further analysis of the literature,we report evidence that,not strictly limited to neurodevelopmental effectors,such pleiotropy also applies to other transcription factors,involved in physiology and homeostasis.Furthermore,through the systematic analysis of a major public protein-protein interaction database,we gather strong evidence that the involvement of“canonical”transcription factors in post-transcriptional control of gene expression could be a pervasive phenomenon,characterizing hundreds of effectors.Finally,we discuss the biological significance of these findings and propose three evolutionary mechanisms that may have contributed to such an unexpected scenario.展开更多
To develop herbicides with a novel mechanism of action,a series of 1,3,4-oxadiazolpyridine derivatives were designed and synthesized based on active substructure splicing and structure optimization.These derivatives(5...To develop herbicides with a novel mechanism of action,a series of 1,3,4-oxadiazolpyridine derivatives were designed and synthesized based on active substructure splicing and structure optimization.These derivatives(5aa-5bd)were characterized by their melting points,^(1)H and^(13)C nuclear magnetic resonance spectroscopy,and high-resolution mass spectrometry.The configuration of 5 al was determined using single-crystal X-ray diffraction.Additionally,5 al exhibited excellent herbicidal activity at a dosage of 75 g/hm^(2),showing an EC 50 of 4.03 g/hm^(2)against both E.crus-galli and quinclorac-resistant E.crus-galli.At a dosage of 375 g/hm 2,5 al was safe for application on rice and sorghum and showed low toxicity(>200μg/g)towards Apis mellifera.After treatment with 5 al,the lamellae of the chloroplast grana of barnyard grass leaves were stacked disorderly and arranged loosely,and some thylakoids were broken,as observed by transmission electron microscopy.Transcriptomics analysis of E.crus-galli revealed that 5 al affects the defense response,membranes,plasma membranes,and chloroplasts of differentially expressed genes,which alter membrane permeability and energy metabolism,potentially leading to plant death.Thus,we successfully developed a novel molecular scaffold with a new mechanism of action that exhibits herbicidal activity against resistant E.crus-galli.Therefore,further development of lead herbicides based on this scaffold is required.展开更多
Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathologi...Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathological aggregation representing a hallmark of Alzheimer’s disease and related tauopathies.Despite extensive research into the role of TAU in neurodegeneration,its essentiality for human brain development has remained unclear.This perspective synthesizes recent genetic,molecular,and cellular evidence to demonstrate that the human brain-specific TAU isoform 0N3R is indispensable for proper neurodevelopment,pointing to loss-of-function of this isoform as a novel paradigm for TAU-associated disease.Alternative splicing of MAPT generates six brain-specific TAU isoforms,with 0N3R being exclusively expressed during fetal brain development.Analysis of large-scale human genetic datasets(gnomAD v4.0.0)reveals a high probability of loss-of-function intolerance(pLI=0.96)for the 0N3R isoform.This is in stark contrast to the canonical Matched Annotation from the NCBI and EMBL-EBI(MANE)transcript and peripheral“Big TAU,”both of which are tolerant to loss-of-function mutations.This intolerance is further supported by the scarcity of loss-of-function mutations in 0N3R-encoding exons and high missense constraint scores,suggesting strong evolutionary selection against disruption of this isoform.Functional studies using human induced pluripotent stem cell-derived cortical neurons with CRISPR-Cas9-mediated MAPT knockout reveal that,unlike in murine models where compensation by other microtubule-associated proteins occurs,loss of TAU in human neurons leads to deficits in neurite outgrowth,axon initial segment shortening,and a trend toward hyperexcitability,accompanied by broad transcriptomic changes affecting genes involved in microtubule organization and synaptic structure.Remarkably,re-expression of any of the six human brain-specific TAU isoforms rescues these phenotypes,underscoring their functional redundancy during development.These findings position the 0N3R isoform as essential for human brain development and suggest that loss-of-function mutations affecting this isoform likely result in neurodevelopmental impairment,potentially manifesting as intellectual disability without overt dysmorphic features.This contrasts with the apparent tolerance to MAPT loss-of-function in mice and peripheral tissues,highlighting a critical species-and isoform-specific requirement for TAU in human neurodevelopment.The hypothesis of 0N3R-TAU loss-of-function intolerance opens new avenues for understanding neurodevelopmental disorders and refines the conceptual framework of TAU-associated disease mechanisms beyond toxic gain-of-function.展开更多
Environmental stresses profoundly altered accumulation of nonsense mRNAs including intron-retaining （IR） transcripts in Arabidopsis. Temporal patterns of stress-induced IR mRNAs were dissected using both oscillating...Environmental stresses profoundly altered accumulation of nonsense mRNAs including intron-retaining （IR） transcripts in Arabidopsis. Temporal patterns of stress-induced IR mRNAs were dissected using both oscillating and non-oscillating transcripts. Broad-range thermal cycles triggered a sharp increase in the long IR CCA1 isoforms and altered their phasing to different times of day. Both abiotic and biotic stresses such as drought or Pseudomonas syringae infection induced a similar increase. Thermal stress induced a time delay in accumulation of CCA1 14Rb transcripts, whereas functional mRNA showed steady oscillations. Our data favor a hypothesis that stress-induced instabilities of the central oscillator can be in part compensated through fluctuations in abundance and out-of-phase oscillations of CCA1 IR transcripts. Taken together, our results support a concept that mRNA abundance can be modulated through altering ratios between functional and nonsense/IR transcripts. SR45 protein specifically bound to the retained CCA1 intron in vitro, suggesting that this sp!icing factor could be involved in regulation of intron retention. Transcriptomes of nonsense-mediated mRNA decay （NMD）-impaired and heat-stressed plants shared a set of retained introns associated with stress- and defense-inducible transcripts. Constitutive activation of certain stress response networks in an NMD mutant could be linked to disequilibrium between functional and nonsense mRNAs.展开更多
Alternative splicing is a tightly regulated process that contributes to cancer development.CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers.However,wheth...Alternative splicing is a tightly regulated process that contributes to cancer development.CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers.However,whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear.In this study,we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies.The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner.Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies,including 3 reported and 8 unreported,and also implicated that the overexpressed isoforms differed in various cancer types.Furthermore,anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples,and even had different impacts on the expression of CRNDE isoforms.Finally,experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types.Collectively,our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms,and may provide promising targets for cancer diagnosis and therapy.展开更多
Circular RNAs(circ RNAs),covalently closed continuous RNA loops,are generated from cognate linear RNAs through back splicing events,and alternative splicing events may generate different circ RNA isoforms at the same ...Circular RNAs(circ RNAs),covalently closed continuous RNA loops,are generated from cognate linear RNAs through back splicing events,and alternative splicing events may generate different circ RNA isoforms at the same locus.However,the challenges of reconstruction and quantification of alternatively spliced full-length circ RNAs remain unresolved.On the basis of the internal structural characteristics of circ RNAs,we developed Circ AST,a tool to assemble alternatively spliced circ RNA transcripts and estimate their expression by using multiple splice graphs.Simulation studies showed that Circ AST correctly assembled the full sequences of circ RNAs with a sensitivity of 85.63%–94.32%and a precision of 81.96%–87.55%.By assigning reads to specific isoforms,Circ AST quantified the expression of circ RNA isoforms with correlation coefficients of 0.85–0.99 between theoretical and estimated values.We evaluated Circ AST on an in-house mouse testis RNA-seq dataset with RNase R treatment for enriching circ RNAs and identified 380 circ RNAs with full-length sequences different from those of their corresponding cognate linear RNAs.RT-PCR and Sanger sequencing analyses validated 32 out of 37 randomly selected isoforms,thus further indicating the good performance of Circ AST,especially for isoforms with low abundance.We also applied Circ AST to published experimental data and observed substantial diversity in circular transcripts across samples,thus suggesting that circ RNA expression is highly regulated.Circ AST can be accessed freely at https://github--com.3pco.8686c.com/xiaofengsong/CircAST.展开更多
Genes encoding proteins with PHD (plant homeodomain) finger motif (C4HC3) are highly conserved from Arabidopsis to Homo sapiens. One of the major functions of these genes is regulating the expression of homeotic genes...Genes encoding proteins with PHD (plant homeodomain) finger motif (C4HC3) are highly conserved from Arabidopsis to Homo sapiens. One of the major functions of these genes is regulating the expression of homeotic genes during the stage of embryonic development. They play a role in cell-cycle and cell differentiation and seem to be related with some human malignant diseases, such as leukemia. A human placenta cDNA library has been screened with cDNA probe amplified by PCR. The PGR primers have been designed according to the M96 (a mouse gene encoding a protein with PHD domain) homologous data in dbEST.A 2. 1 kb insert fragment in a positive cDNA clone has been isolated and sequenced. This new full-length cDNA is named PHF2 (GenBank Acc: AF052205). The putative protein composed of 567 aa has two typical PHD fingers at its N-terminus. Meanwhile it is identified that there are several alternatively spliced transcripts of PHF2 in different human tissues through the PCR amplification, Northern blot展开更多
All lymphocytes depend on the cytokine IL-7 for their development and homeostasis,and cell surface expression of the IL-7 receptor is a prerequisite for responses to IL-7.1 Notably,the IL-7 receptorα-chain(IL-7Rα)do...All lymphocytes depend on the cytokine IL-7 for their development and homeostasis,and cell surface expression of the IL-7 receptor is a prerequisite for responses to IL-7.1 Notably,the IL-7 receptorα-chain(IL-7Rα)does not only exist as a membranebound form but is also found as a soluble protein in human serum.2,3 The exact role of soluble IL-7Rα(sIL-7Rα)proteins remains to be determined.However,increased amounts of sIL-7Rαhave been associated with an increased risk of inflammation and autoimmunity.3,4 Mechanistically,sIL-7Rαproteins can be generated by alternative splicing of Il7r gene transcripts that encode IL-7Rα.Curiously,however,such Il7r splice isoforms have only been described in humans and have never been described in mice.5 Consequently,the importance of Il7r alternative splice products that are not conserved across species has remained questionable.展开更多
The formation of root system architecture(RSA)plays a crucial role in plant growth.OsDRO1 is known to have a function in controlling RSA in rice,however,the role of potato StDRO2,a homolog of rice OsDRO1,in root growt...The formation of root system architecture(RSA)plays a crucial role in plant growth.OsDRO1 is known to have a function in controlling RSA in rice,however,the role of potato StDRO2,a homolog of rice OsDRO1,in root growth remains unclear.In this study,we obtained potato dro2 mutant lines by Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-Associated 9(CRISPR/Cas9)-mediated genome editing system.The mutant lines were generated from a splicing defect of the StDRO2 intron 1,which causes a nonsense mutation in StDRO2.Furthermore,the secondary structure of StDRO2 mRNA analyzed with RNAfold Web Server was altered in the dro2 mutant.Mutation of StDRO2 conveys potato adaptation through changing the RSA via alteration of auxin transport under drought stress.The potato dro2 lines showed higher plant height,longer root length,smaller root growth angle and increased tuber weight than the wild-type.The alteration of RSA was associated with a disturbance of IAA distribution in the dro2 mutant,and the levels of StPIN7 and StPIN10 detected by using real-time PCR were up-regulated in the roots of potato dro2 lines grown under drought stress.Moreover,the microRNAs(miRNAs)PmiREN024536 and PmiREN024486 targeted the StDRO2 gene,and auxin positively and negatively regulated the expression of StDRO2 and the miRNAs PmiREN024536 and PmiREN024486,respectively,in the potato roots.Our data shows that a regulatory network involving auxin,StDRO2,PmiREN024536 and PmiREN024486 can control RSA to convey potato fitness under drought stress.展开更多
The steel tube arch rib in a large-span concrete-filled steel tube arch bridge has a large span and diameter,which also leads to a larger weld seam scale.Large-scale welding seams will inevitably cause more obvious we...The steel tube arch rib in a large-span concrete-filled steel tube arch bridge has a large span and diameter,which also leads to a larger weld seam scale.Large-scale welding seams will inevitably cause more obvious welding residual stress(WRS).For the purpose of studying the influence of WRS from large-scale welding seam on the mechanical properties of steel tube arch rib during arch rib splicing,test research and numerical simulation analysis on the WRS in arch rib splicing based on the Guangxi Pingnan Third Bridge,which is the world’s largest span concrete-filled steel tube arch bridge,were conducted in this paper,and the distribution pattern of WRS at the arch rib splicing joint was obtained.Subsequently,the WRS was introduced into the mechanical performance analysis of joints and structures to analyze its effects.The findings reveal that the distribution of WRS in the arch rib is greatly influenced by the rib plate,and the axial WRS in the heat-affected zone are primarily tensile,while the circumferential WRS are distributed in an alternating pattern of tensile and compressive stresses along the circumferential direction of the main tube.Under the influence of WRS,the ultimate bearing capacity of the joint is reduced by 29.4%,the initial axial stiffness is reduced by 4.32%,and the vertical deformation of the arch rib structure is increased by 4.7%.展开更多
Objectives:KH-type splicing regulatory protein(KHSRP)is an RNA-binding protein involved in several cellular processes,including nuclear splicing,mRNA localization,and cytoplasmic degradation.While KHSRP’s role has be...Objectives:KH-type splicing regulatory protein(KHSRP)is an RNA-binding protein involved in several cellular processes,including nuclear splicing,mRNA localization,and cytoplasmic degradation.While KHSRP’s role has been studied in other cancers,its specific involvement in gastric cancer remains poorly understood.This study aims to explore KHSRP expression in gastric cancer and its potential effects on tumor progression and immune response.Methods:KHSRP expression in gastric cancer tissues and normal tissues was analyzed using data from The Cancer Genome Atlas(TCGA)database.The correlation between KHSRP expression,patient survival,and immune response was also assessed.Immunohistochemistry was performed to evaluate KHSRP expression in gastric cancer tissues.Gain-and loss-of-function experiments were conducted to assess KHSRP’s effects on gastric cancer cell proliferation,stemness,and migration.Furthermore,the impact of KHSRP silencing on tumor volume and immune cell infiltration was evaluated in a C3H/He mouse xenograft model.Results:KHSRP was found to be overexpressed in gastric cancer tissues compared to normal tissues,with a positive correlation to tumor stage and a negative correlation with patient prognosis.Functional assays revealed that KHSRP promotes gastric cancer cell proliferation,enhances cancer stem cell properties,and increases migratory capabilities in vitro.In vivo,KHSRP silencing led to a significant reduction in tumor volume and increased immune cell infiltration in the mouse xenograft model.Conclusions:KHSRP acts as an oncogene in gastric cancer by promoting tumorigenesis and suppressing anti-tumor immune responses.Its overexpression is associated with poor prognosis,making KHSRP a potential prognostic marker and therapeutic target in gastric cancer.展开更多
Pentatricopeptide repeat(PPR)proteins are a large group of eukaryote-specific RNA-binding proteins that play pivotal roles in plant organelle gene expression.Here,we report the function of PPR21 in mitochondrial intro...Pentatricopeptide repeat(PPR)proteins are a large group of eukaryote-specific RNA-binding proteins that play pivotal roles in plant organelle gene expression.Here,we report the function of PPR21 in mitochondrial intron splicing and its role in maize kernel development.PPR21 is a typical P-type PPR protein targeted to mitochondria.The ppr21 mutants are arrested in embryogenesis and endosperm development,leading to embryo lethality.Null mutations of PPR21 reduce the splicing efficiency of nad2 intron 1,2,and 4 and impair the assembly and activity of mitochondrial complex I.Previous studies show that the P-type PPR protein EMP12 is required for the splicing of identical introns.However,our protein interaction analyses reveal that PPR21 does not interact with EMP12.Instead,both PPR21 and EMP12 interact with the small MutS-related(SMR)domain-containing PPR protein 1(PPR-SMR1)and the short P-type PPR protein 2(SPR2).PPR-SMR1 interacts with SPR2,and both proteins are required for the splicing of many introns in mitochondria,including nad2 intron 1,2,and 4.These results suggest that a PPR21-(PPR-SMR1/SPR2)-EMP12 complex is involved in the splicing of nad2 introns in maize mitochondria.展开更多
基金funded by Guizhou Province Science and Technology Plan Project Qiankehe Foundation-ZK[2023]General 360,362Science and Technology Fund project of Guizhou Provincial Health Commission(gzwkj-2022-09,gzwkj-2023-035)+1 种基金National Natural Science Foundation Cultivation Project of Guizhou Medical University(21NSFCP14,gyfynsfc-2022-25)The PhD Scientific Research Launch Fund Project of the Affiliated Hospital of Guizhou Medical University(gyfybsky-2022-02).
文摘Background:Glioblastoma(GBM)is one of the most malignant types of central nervous system tumors.Oxygen deprivation in the tumor microenvironment is thought to be an important factor in promoting GBM progression.However,the mechanisms of hypoxia-promoted tumor progression remain elusive.Methods:Alternative splicing of diacylglycerol kinase gamma(DGKG)-Δexon13 was amplified and verified by PCR-Sanger sequencing.The functions of DGKG and DGKG-Δexon13 were analyzed by Cell counting kit-8(CCK-8),Transwell,Matrigeltranswell experiments,and in vivo orthotropic GBM animal models.Transcriptome analyses were done to find out the regulated genes.Results:In this study,we found that a new transcript DGKG-Δexon13 was generated in GBM under hypoxia via alternative splicing.Moreover,the results of CCK-8,Transwell,and Matrigel-transwell experiments showed that the proliferation,migration,and invasion abilities of U87-MG and T98G were decreased after DGKG knockdown.Compared to wild-type DGKG,DGKG-Δexon13 overexpression significantly promoted cellular proliferation,migration,and invasion abilities in GBM.Furthermore,in vivo,orthotropic GBM animal models analysis showed that the tumor volumes were much smaller in the DGKG knockdown group.However,the tumor sizes in the DGKG and DGKG-Δexon13 rescue groups were restored,especially in the DGKG-Δexon13 group.Transcriptome analysis revealed that MORC1,KLHDC7B,ATP1A2,INHBE,TMEM119,and FGD3 were altered significantly when DGKG was knocked down.IL-16,CCN2,and EFNB3 were specifically regulated by DGKG-Δexon13.Conclusions:Our study found that hypoxia-induced alternative splicing transcript DGKG-Δexon13 promotes GBM proliferation and infiltration,which might provide a new potential target for the clinical treatment and diagnosis of GBM.
文摘The tensile property of the spliced yarn splice under different splicing conditions has been investigated. The retained spliced strength of the splice spliced under different splicing conditions was obtained as the indicator for the performance of the splicer under that particular splicing condition. The results showed that, the length of the yarn tails and the yarn linear density are the parameters that has the most important effect to the tensile property of the spliced yarn.
文摘Cyber losses in terms of number of records breached under cyber incidents commonly feature a significant portion of zeros, specific characteristics of mid-range losses and large losses, which make it hard to model the whole range of the losses using a standard loss distribution. We tackle this modeling problem by proposing a three-component spliced regression model that can simultaneously model zeros, moderate and large losses and consider heterogeneous effects in mixture components. To apply our proposed model to Privacy Right Clearinghouse (PRC) data breach chronology, we segment geographical groups using unsupervised cluster analysis, and utilize a covariate-dependent probability to model zero losses, finite mixture distributions for moderate body and an extreme value distribution for large losses capturing the heavy-tailed nature of the loss data. Parameters and coefficients are estimated using the Expectation-Maximization (EM) algorithm. Combining with our frequency model (generalized linear mixed model) for data breaches, aggregate loss distributions are investigated and applications on cyber insurance pricing and risk management are discussed.
基金supported by the National Basic Research Program of China (973 Program) (No 2006CB943601)the National Natural Science Foundation of China (NSFC) (No 90919042)
文摘OCT4 is one of the key transcription factors in maintaining the pluripotency and self-renewal of embryonic stem （ES） cells.Human OCT4 can generate two isoforms OCT4A and OCT4B by alternative splicing.OCT4B1 is a recently discovered novel OCT4 spliced variant,which has been considered as a putative marker of stemness.Compared with the OCT4B mRNA,OCT4B1 mRNA is generated by retaining intron 2 as a cryptic exon which contains a TGA stop codon in it.As a result,the protein product of OCT4B1 mRNA could be truncated.Interestingly,we present here that OCT4B1 can indirectly produce the same protein products as OCT4B.We have demonstrated that OCT4B1 mRNA can be spliced into OCT4B mRNA,and encode three protein isoforms.The splicing of OCT4B1 mRNA into OCT4B mRNA can be remarkably inhibited by the mutation of the classical splicing site.Our result suggests that OCT4B mRNA may originate from OCT4B1 mRNA by alternative splicing.
文摘The analysis of spliced column has been carried out to detect optimum location of providing splices in the column.In the present work,static and dynamic(free vibration)analyses of spliced column have been done by randomising the location of splicing.A symmetrical four storey steel framed building has been modelled,analysed and designed for loads(dead,live and earthquake loads)recommended by Indian Codal provisions using Staad.Pro.The critical column at each floor level is identified based on axial force(AF),bending moment(BM)and shear force(SF).The total 16 models of spliced columns have been designed and then modelled in a 3D CAD Design tool(SOLIDWORKS)and then imported in the finite element tool(ANSYSWorkbench 14.0)for detailed analysis.The variation of stress,strain and deflection of the spliced column are shown in the form of contour.Further,the modal analysis is performed to determine the natural frequencies.The results of static and dynamic analyses are compared for each modelled spliced column to obtain the optimum location for providing splices in the column.The dynamic analysis of spliced column is of utmost importance in the region where dynamic loadings like earthquake,cyclones etc.are more frequent,and mere static analysis does not account for the safety of the structure.This study will help the engineers to select directly the optimum size and location of the splices in the column of a steel framed building.
基金the National Natural Science Foundation of China (No. 60171038) and the Science and Technology Ministry of China (No. 2001CCA01400)
文摘In this study, 414 whole protein-coding sequences (238 004 codons) of alternatively spliced genes of human chromosome 1 have been employed to explore the patterns of codon usage bias among genes. Overall codon usage data analysis indicates that G- and C-ending codons are predominant in the genes. The base usage in all three codon positions suggests a selection-mutation balance. Multivariate statistical analysis reveals that the codon usage variation has a strong positive correlation with the expressivities of the genes (r=0.5790, P<0.0001). All 27 codons identified as optimal are G- and C-ending codons. Correlation analysis shows a strong negative correlation between the gene length and codon adaptation index value (r=0.2252, P<0.0001), and a significantly positive correlation between the gene length and Nc values (r=0.1876, P<0.0001). These results suggest that the comparatively shorter genes in the genes have higher codon usage bias to maximize translational efficiency, and selection may also contribute to the reduction of highly expressed proteins.
基金supported by the Botha-Chan Research Fund,the Office of the Assistant Secretary of Defense for Health Affairs through award no.HT9425-24-1-0623(I.R.)the Brain Tumor Funders'Collaborative,the Ellie Kavalieros DIPG Research Fund+6 种基金the UPMC Children’s Hospital of Pittsburgh Foundation(G.K.,I.R.)the Children’s Brain Tumor Network(I.F.P.),a stipend from the Central South University Xiangya School of Medicine and University of Pittsburgh(Z.X.)by grant NS117742 from the National Institute of Health(T.G.F.)support from the Jesse H.&Mary Jones Gibbs Endowed Chair(T.G.F)supported in part by the University of Pittsburgh Center for Research Computing,RRID:SCR_022735through NIH award number S10OD028483Work performed in the UPMC Hillman Cancer Center Tissue and Research Pathology Services Shared Resource Facility and the services and instruments used in this project were supported,in part,by the University of Pittsburgh and the NCI of the NIH under Award Number P30CA047904.
文摘Glioblastoma(GBM)is an aggressive brain tumor with limited treatment options and a dismal prognosis.While immunotherapy has shown promise in treating some solid tumors,the treatment of GBM has been mostly unsuccessful because of a lack of targetable tumor antigens and high tumor heterogeneity.Here,we report RCAN1-4 as a novel tumor antigen derived from alternative splicing induced by the transcription factor C/EBPβ.Both C/EBPβand RCAN1-4 are highly expressed in GBM and glioma stem cells as mesenchymal subtype hallmarks.We report an immunogenic HLA-A24-specific splicing junction epitope within exon 4 and exon 5 that is unique to RCAN1-4.This epitope was validated for its ability to stimulate T cell responses in HLA-A24^(+)donors and GBM patients,leading us to identify RCAN1-4-reactive T cell receptors(TCRs)for the construction of TCR-engineered T cells(TCR-T cells).Functional studies of TCR-Ts demonstrated the in vitro and in vivo killing of RCAN1-4pos GBM tumor cells,highlighting its potential as an immunotherapeutic target in mesenchymal GBM.
基金supported by SISSA(intramural funding to AM)International FOXG1 Research Foundation(Grant to AM)+1 种基金Italian Ministery of University and Research(Grant PRIN222022M95RC7 to AM)Fondazione Telethon(Grant GMR22T2018 to AM).
文摘Moving from the most recent results on Foxg1 biology,we first summarize the available information on some special pleiotropic effectors of neurodevelopmental interest,involved in controlling both transcription and post-transcriptional steps of gene expression.Then,after further analysis of the literature,we report evidence that,not strictly limited to neurodevelopmental effectors,such pleiotropy also applies to other transcription factors,involved in physiology and homeostasis.Furthermore,through the systematic analysis of a major public protein-protein interaction database,we gather strong evidence that the involvement of“canonical”transcription factors in post-transcriptional control of gene expression could be a pervasive phenomenon,characterizing hundreds of effectors.Finally,we discuss the biological significance of these findings and propose three evolutionary mechanisms that may have contributed to such an unexpected scenario.
基金supported by the National Key Research and Development Program of China(2023YFD1400504)Natural Science Foundation of Hunan Province(2024JJ2036)+3 种基金Natural Science Foundation of China(32172433)Foundation for Tobacco Science of China National Tobacco Corporation(110202401015,(LS-05))Scientific-Innovative of Hunan Agricultural Sciences and Technology(2024CX69)China Agriculture Research System of MOF and MARA(CARS-16-E19)。
文摘To develop herbicides with a novel mechanism of action,a series of 1,3,4-oxadiazolpyridine derivatives were designed and synthesized based on active substructure splicing and structure optimization.These derivatives(5aa-5bd)were characterized by their melting points,^(1)H and^(13)C nuclear magnetic resonance spectroscopy,and high-resolution mass spectrometry.The configuration of 5 al was determined using single-crystal X-ray diffraction.Additionally,5 al exhibited excellent herbicidal activity at a dosage of 75 g/hm^(2),showing an EC 50 of 4.03 g/hm^(2)against both E.crus-galli and quinclorac-resistant E.crus-galli.At a dosage of 375 g/hm 2,5 al was safe for application on rice and sorghum and showed low toxicity(>200μg/g)towards Apis mellifera.After treatment with 5 al,the lamellae of the chloroplast grana of barnyard grass leaves were stacked disorderly and arranged loosely,and some thylakoids were broken,as observed by transmission electron microscopy.Transcriptomics analysis of E.crus-galli revealed that 5 al affects the defense response,membranes,plasma membranes,and chloroplasts of differentially expressed genes,which alter membrane permeability and energy metabolism,potentially leading to plant death.Thus,we successfully developed a novel molecular scaffold with a new mechanism of action that exhibits herbicidal activity against resistant E.crus-galli.Therefore,further development of lead herbicides based on this scaffold is required.
文摘Hans Zempel1,2 TAU,a microtubule-associated protein,encoded by the microtubule-associated protein tau(MAPT)gene,is a central regulator of microtubule stability and axonal function in the human brain,with its pathological aggregation representing a hallmark of Alzheimer’s disease and related tauopathies.Despite extensive research into the role of TAU in neurodegeneration,its essentiality for human brain development has remained unclear.This perspective synthesizes recent genetic,molecular,and cellular evidence to demonstrate that the human brain-specific TAU isoform 0N3R is indispensable for proper neurodevelopment,pointing to loss-of-function of this isoform as a novel paradigm for TAU-associated disease.Alternative splicing of MAPT generates six brain-specific TAU isoforms,with 0N3R being exclusively expressed during fetal brain development.Analysis of large-scale human genetic datasets(gnomAD v4.0.0)reveals a high probability of loss-of-function intolerance(pLI=0.96)for the 0N3R isoform.This is in stark contrast to the canonical Matched Annotation from the NCBI and EMBL-EBI(MANE)transcript and peripheral“Big TAU,”both of which are tolerant to loss-of-function mutations.This intolerance is further supported by the scarcity of loss-of-function mutations in 0N3R-encoding exons and high missense constraint scores,suggesting strong evolutionary selection against disruption of this isoform.Functional studies using human induced pluripotent stem cell-derived cortical neurons with CRISPR-Cas9-mediated MAPT knockout reveal that,unlike in murine models where compensation by other microtubule-associated proteins occurs,loss of TAU in human neurons leads to deficits in neurite outgrowth,axon initial segment shortening,and a trend toward hyperexcitability,accompanied by broad transcriptomic changes affecting genes involved in microtubule organization and synaptic structure.Remarkably,re-expression of any of the six human brain-specific TAU isoforms rescues these phenotypes,underscoring their functional redundancy during development.These findings position the 0N3R isoform as essential for human brain development and suggest that loss-of-function mutations affecting this isoform likely result in neurodevelopmental impairment,potentially manifesting as intellectual disability without overt dysmorphic features.This contrasts with the apparent tolerance to MAPT loss-of-function in mice and peripheral tissues,highlighting a critical species-and isoform-specific requirement for TAU in human neurodevelopment.The hypothesis of 0N3R-TAU loss-of-function intolerance opens new avenues for understanding neurodevelopmental disorders and refines the conceptual framework of TAU-associated disease mechanisms beyond toxic gain-of-function.
文摘Environmental stresses profoundly altered accumulation of nonsense mRNAs including intron-retaining （IR） transcripts in Arabidopsis. Temporal patterns of stress-induced IR mRNAs were dissected using both oscillating and non-oscillating transcripts. Broad-range thermal cycles triggered a sharp increase in the long IR CCA1 isoforms and altered their phasing to different times of day. Both abiotic and biotic stresses such as drought or Pseudomonas syringae infection induced a similar increase. Thermal stress induced a time delay in accumulation of CCA1 14Rb transcripts, whereas functional mRNA showed steady oscillations. Our data favor a hypothesis that stress-induced instabilities of the central oscillator can be in part compensated through fluctuations in abundance and out-of-phase oscillations of CCA1 IR transcripts. Taken together, our results support a concept that mRNA abundance can be modulated through altering ratios between functional and nonsense/IR transcripts. SR45 protein specifically bound to the retained CCA1 intron in vitro, suggesting that this sp!icing factor could be involved in regulation of intron retention. Transcriptomes of nonsense-mediated mRNA decay （NMD）-impaired and heat-stressed plants shared a set of retained introns associated with stress- and defense-inducible transcripts. Constitutive activation of certain stress response networks in an NMD mutant could be linked to disequilibrium between functional and nonsense mRNAs.
基金National Natural Science Foundation of China (Nos.81530003,81300403,81770153 and 91440114)The National Key Research and Development Program (No.2016YFC0902800)+1 种基金Shanghai Leading Talent Projects (No.2015008)the Academic Leader Program of Shanghai Science and Technology Committee (No.2015137).
文摘Alternative splicing is a tightly regulated process that contributes to cancer development.CRNDE is a long noncoding RNA with alternative splicing and is implicated in the pathogenesis of several cancers.However,whether deregulated expression of CRNDE is common and which isoforms are mainly involved in cancers remain unclear.In this study,we report that CRNDE is aberrantly expressed in the majority of solid and hematopoietic malignancies.The investigation of CRNDE expression in normal samples revealed that CRNDE was expressed in a tissue- and cell-specific manner.Further comparison of CRNDE expression in 2938 patient samples from 15 solid and hematopoietic tumors showed that CRNDE was significantly overexpressed in 11 malignancies,including 3 reported and 8 unreported,and also implicated that the overexpressed isoforms differed in various cancer types.Furthermore,anti-cancer drugs could efficiently repress CRNDE overexpression in cancer cell lines and primary samples,and even had different impacts on the expression of CRNDE isoforms.Finally,experimental profiles of 12 alternatively spliced isoforms demonstrated that the spliced variant CRNDE-g was the most highly expressed isoform in multiple cancer types.Collectively,our results emphasize the cancer-associated feature of CRNDE and its spliced isoforms,and may provide promising targets for cancer diagnosis and therapy.
基金the National Natural Science Foundation of China(Grant No.61571223)the National Key R&D Program of China(Grant No.2016YFA0503300)+4 种基金supported by the National Natural Science Foundation of China(Grant Nos.61171191,31471403,and 81771641)the 333 Project of Jiangsu Province(Grant No.BRA2016386)the Program for Distinguished Talents of Six Domains in Jiangsu Province(Grant No.YY-019)the Fundamental Research Funds for the Central Universities(Grant No.NP2018109)the Fok Ying Tung Education Foundation(Grant No.161037),China.
文摘Circular RNAs(circ RNAs),covalently closed continuous RNA loops,are generated from cognate linear RNAs through back splicing events,and alternative splicing events may generate different circ RNA isoforms at the same locus.However,the challenges of reconstruction and quantification of alternatively spliced full-length circ RNAs remain unresolved.On the basis of the internal structural characteristics of circ RNAs,we developed Circ AST,a tool to assemble alternatively spliced circ RNA transcripts and estimate their expression by using multiple splice graphs.Simulation studies showed that Circ AST correctly assembled the full sequences of circ RNAs with a sensitivity of 85.63%–94.32%and a precision of 81.96%–87.55%.By assigning reads to specific isoforms,Circ AST quantified the expression of circ RNA isoforms with correlation coefficients of 0.85–0.99 between theoretical and estimated values.We evaluated Circ AST on an in-house mouse testis RNA-seq dataset with RNase R treatment for enriching circ RNAs and identified 380 circ RNAs with full-length sequences different from those of their corresponding cognate linear RNAs.RT-PCR and Sanger sequencing analyses validated 32 out of 37 randomly selected isoforms,thus further indicating the good performance of Circ AST,especially for isoforms with low abundance.We also applied Circ AST to published experimental data and observed substantial diversity in circular transcripts across samples,thus suggesting that circ RNA expression is highly regulated.Circ AST can be accessed freely at https://github--com.3pco.8686c.com/xiaofengsong/CircAST.
文摘Genes encoding proteins with PHD (plant homeodomain) finger motif (C4HC3) are highly conserved from Arabidopsis to Homo sapiens. One of the major functions of these genes is regulating the expression of homeotic genes during the stage of embryonic development. They play a role in cell-cycle and cell differentiation and seem to be related with some human malignant diseases, such as leukemia. A human placenta cDNA library has been screened with cDNA probe amplified by PCR. The PGR primers have been designed according to the M96 (a mouse gene encoding a protein with PHD domain) homologous data in dbEST.A 2. 1 kb insert fragment in a positive cDNA clone has been isolated and sequenced. This new full-length cDNA is named PHF2 (GenBank Acc: AF052205). The putative protein composed of 567 aa has two typical PHD fingers at its N-terminus. Meanwhile it is identified that there are several alternatively spliced transcripts of PHF2 in different human tissues through the PCR amplification, Northern blot
基金supported by the Intramural Research Program of the US National Institutes of Health,the National Cancer Institute,the Center for Cancer Researchthe Financial Support Project,Long-Term Overseas Dispatch,Tenure-Track Faculty,Pusan National University.
文摘All lymphocytes depend on the cytokine IL-7 for their development and homeostasis,and cell surface expression of the IL-7 receptor is a prerequisite for responses to IL-7.1 Notably,the IL-7 receptorα-chain(IL-7Rα)does not only exist as a membranebound form but is also found as a soluble protein in human serum.2,3 The exact role of soluble IL-7Rα(sIL-7Rα)proteins remains to be determined.However,increased amounts of sIL-7Rαhave been associated with an increased risk of inflammation and autoimmunity.3,4 Mechanistically,sIL-7Rαproteins can be generated by alternative splicing of Il7r gene transcripts that encode IL-7Rα.Curiously,however,such Il7r splice isoforms have only been described in humans and have never been described in mice.5 Consequently,the importance of Il7r alternative splice products that are not conserved across species has remained questionable.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.32260085,31860064,31660501,31970609,32260718 and 31901870)the Key Projects of the Applied Basic Research Plan of Yunnan Province(Grant No.202301AS070082)+3 种基金the Start-up fund from Xishuangbanna Tropical Botanical Garden,the‘Top Talents Program in Science and Technology’from Yunnan Province,the Major Science and Technology Project in Yunnan Province(Grant Nos.202102AE090042 and 202202AE090036)the Young and Middle-Aged Academic and Technical Leaders Reserve Talent Program in Yunnan Province(Grant No.202205AC160076)China Postdoctoral Science Foundation(Grant No.2019M653849XB)the High-level Talents Introduction Plan of Yunnan Province-Young Talents Special Project。
文摘The formation of root system architecture(RSA)plays a crucial role in plant growth.OsDRO1 is known to have a function in controlling RSA in rice,however,the role of potato StDRO2,a homolog of rice OsDRO1,in root growth remains unclear.In this study,we obtained potato dro2 mutant lines by Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR-Associated 9(CRISPR/Cas9)-mediated genome editing system.The mutant lines were generated from a splicing defect of the StDRO2 intron 1,which causes a nonsense mutation in StDRO2.Furthermore,the secondary structure of StDRO2 mRNA analyzed with RNAfold Web Server was altered in the dro2 mutant.Mutation of StDRO2 conveys potato adaptation through changing the RSA via alteration of auxin transport under drought stress.The potato dro2 lines showed higher plant height,longer root length,smaller root growth angle and increased tuber weight than the wild-type.The alteration of RSA was associated with a disturbance of IAA distribution in the dro2 mutant,and the levels of StPIN7 and StPIN10 detected by using real-time PCR were up-regulated in the roots of potato dro2 lines grown under drought stress.Moreover,the microRNAs(miRNAs)PmiREN024536 and PmiREN024486 targeted the StDRO2 gene,and auxin positively and negatively regulated the expression of StDRO2 and the miRNAs PmiREN024536 and PmiREN024486,respectively,in the potato roots.Our data shows that a regulatory network involving auxin,StDRO2,PmiREN024536 and PmiREN024486 can control RSA to convey potato fitness under drought stress.
基金funded by the Science and Technology Research Program of the Chongqing Municipal Education Commission(grant number KJQN202403002).
文摘The steel tube arch rib in a large-span concrete-filled steel tube arch bridge has a large span and diameter,which also leads to a larger weld seam scale.Large-scale welding seams will inevitably cause more obvious welding residual stress(WRS).For the purpose of studying the influence of WRS from large-scale welding seam on the mechanical properties of steel tube arch rib during arch rib splicing,test research and numerical simulation analysis on the WRS in arch rib splicing based on the Guangxi Pingnan Third Bridge,which is the world’s largest span concrete-filled steel tube arch bridge,were conducted in this paper,and the distribution pattern of WRS at the arch rib splicing joint was obtained.Subsequently,the WRS was introduced into the mechanical performance analysis of joints and structures to analyze its effects.The findings reveal that the distribution of WRS in the arch rib is greatly influenced by the rib plate,and the axial WRS in the heat-affected zone are primarily tensile,while the circumferential WRS are distributed in an alternating pattern of tensile and compressive stresses along the circumferential direction of the main tube.Under the influence of WRS,the ultimate bearing capacity of the joint is reduced by 29.4%,the initial axial stiffness is reduced by 4.32%,and the vertical deformation of the arch rib structure is increased by 4.7%.
基金Supported by the Jiangxi Provincial Health Technology Project(No.202130037 to CWL)was also sponsored by the Jiangxi Provincial Health Technology Project(No.202410009 to SHL)。
文摘Objectives:KH-type splicing regulatory protein(KHSRP)is an RNA-binding protein involved in several cellular processes,including nuclear splicing,mRNA localization,and cytoplasmic degradation.While KHSRP’s role has been studied in other cancers,its specific involvement in gastric cancer remains poorly understood.This study aims to explore KHSRP expression in gastric cancer and its potential effects on tumor progression and immune response.Methods:KHSRP expression in gastric cancer tissues and normal tissues was analyzed using data from The Cancer Genome Atlas(TCGA)database.The correlation between KHSRP expression,patient survival,and immune response was also assessed.Immunohistochemistry was performed to evaluate KHSRP expression in gastric cancer tissues.Gain-and loss-of-function experiments were conducted to assess KHSRP’s effects on gastric cancer cell proliferation,stemness,and migration.Furthermore,the impact of KHSRP silencing on tumor volume and immune cell infiltration was evaluated in a C3H/He mouse xenograft model.Results:KHSRP was found to be overexpressed in gastric cancer tissues compared to normal tissues,with a positive correlation to tumor stage and a negative correlation with patient prognosis.Functional assays revealed that KHSRP promotes gastric cancer cell proliferation,enhances cancer stem cell properties,and increases migratory capabilities in vitro.In vivo,KHSRP silencing led to a significant reduction in tumor volume and increased immune cell infiltration in the mouse xenograft model.Conclusions:KHSRP acts as an oncogene in gastric cancer by promoting tumorigenesis and suppressing anti-tumor immune responses.Its overexpression is associated with poor prognosis,making KHSRP a potential prognostic marker and therapeutic target in gastric cancer.
基金supported by the National Natural Science Foundation of China(32072126 and 32230075)the Shandong Provincial Natural Science Foundation(ZR2019MC005).
文摘Pentatricopeptide repeat(PPR)proteins are a large group of eukaryote-specific RNA-binding proteins that play pivotal roles in plant organelle gene expression.Here,we report the function of PPR21 in mitochondrial intron splicing and its role in maize kernel development.PPR21 is a typical P-type PPR protein targeted to mitochondria.The ppr21 mutants are arrested in embryogenesis and endosperm development,leading to embryo lethality.Null mutations of PPR21 reduce the splicing efficiency of nad2 intron 1,2,and 4 and impair the assembly and activity of mitochondrial complex I.Previous studies show that the P-type PPR protein EMP12 is required for the splicing of identical introns.However,our protein interaction analyses reveal that PPR21 does not interact with EMP12.Instead,both PPR21 and EMP12 interact with the small MutS-related(SMR)domain-containing PPR protein 1(PPR-SMR1)and the short P-type PPR protein 2(SPR2).PPR-SMR1 interacts with SPR2,and both proteins are required for the splicing of many introns in mitochondria,including nad2 intron 1,2,and 4.These results suggest that a PPR21-(PPR-SMR1/SPR2)-EMP12 complex is involved in the splicing of nad2 introns in maize mitochondria.
