Poor filling and low weight of inferior kernels limit the further improvement of wheat yield. Two cultivars, Shuangda 1 and Xinong 538, with different grain weights, were selected to investigate the physiological chan...Poor filling and low weight of inferior kernels limit the further improvement of wheat yield. Two cultivars, Shuangda 1 and Xinong 538, with different grain weights, were selected to investigate the physiological changes of inferior kernels by removal of superior kernels(RS) at the flowering stage. i TRAQ combined with physiological indexes was used to identify factors limiting the filling of inferior kernels.Removal of superior kernels significantly increased the mean filling rate of inferior kernels and thus increased their weight. A set of 6012 proteins in inferior wheat kernels were differentially expressed between the RS and control. These differentially expressed proteins were involved mainly in carbon metabolism and energy metabolism. The main reason for the promoting effect of RS on the filling of inferior kernels may be that RS downregulated proteins involved in glycolysis and pyruvate metabolism while upregulating proteins involved in carbon fixation and photosynthesis. Consequently, RS greatly increased the ATP content in inferior kernels, supplying energy for them to absorb photosynthetic assimilates. Removal of superior kernels increased the activities of sucrose synthase, soluble starch synthase,adenosine diphosphate glucose pyrophosphorylase, and starch branching enzyme in inferior kernels and promoted starch accumulation in them. Thus, RS promoted the filling of inferior kernels and increased their weight. The promoting effect of RS on starch synthesis in inferior kernels was associated with their endogenous IAA and ABA levels.展开更多
Ammonia plays an important role in cellular metabolism.However,ammonia is considered a toxic product.In bone marrow-derived mesenchymal stem cells,multipotent stem cells with high expression of glutamine synthetase(GS...Ammonia plays an important role in cellular metabolism.However,ammonia is considered a toxic product.In bone marrow-derived mesenchymal stem cells,multipotent stem cells with high expression of glutamine synthetase(GS)in bone marrow,ammonia and glutamate can be converted to glutamine via glutamine synthetase activity to support the proliferation of MSCs.As a major nutritional amino acid for biosynthesis,glutamine can activate the Akt/mTOR/S6k pathway to stimulate cell proliferation.The activation of mTOR can promote cell entry into S phase,thereby enhancing DNA synthesis and cell proliferation.Our studies demonstrated that mesenchymal stem cells can convert the toxic waste product ammonia into nutritional glutamine via GS activity.Then,the Akt/mTOR/S6k pathway is activated to promote bone marrow-derived mesenchymal stem cell proliferation.These results suggest a new therapeutic strategy and potential target for the treatment of diseases involving hyperammonemia.展开更多
Biochar amendment offers a chance for sustainable agriculture.However,the effectiveness of biochar relies on its physical and chemical properties,which are heavily affected by biochar production conditions and managem...Biochar amendment offers a chance for sustainable agriculture.However,the effectiveness of biochar relies on its physical and chemical properties,which are heavily affected by biochar production conditions and management practices.Therefore,substantial uncertainties regarding the use of biochar exist in agricultural systems globally.This study provides the first quantitative evaluation of the impacts of biochar characteristics and management practices on key ecosystem services by performing a second-order meta-analysis based on 34,628 paired observations in biochar-amended and unamended systems.Overall,biochar enhances phytotoxicity alleviation,physiology regulation,soil remediation and carbon sequestration,and microbial functional gene abundance.However,some prominent trade-offs exist between crop productivity and ecosystem service deliveries including for nutrient cycling,microbial function,climate change mitigation,and the soil microbial community.The adoption of low C:N biochar produced at high pyrolysis temperatures from sewage sludge-derived feedstock,in combination with a moderate application rate and inorganic fertilizer input,shows potential for achieving synergistic promotion of crop productivity and ecosystem services.These outcomes highlight the need for judicious implementation of biochar-based solutions to site-specific soil constraints.The quantified synergy and tradeoff relationships will aid the establishment of a sustainable biochar development framework that strengthens necessary ecosystem services commensurate with food security assurance.展开更多
Increasing carbon(C)sequestration and stability in agricultural soils is a key strategy to mitigate climate change towards C neutrality.Crop diversification is an initiative to increase C sequestration in fields,but i...Increasing carbon(C)sequestration and stability in agricultural soils is a key strategy to mitigate climate change towards C neutrality.Crop diversification is an initiative to increase C sequestration in fields,but it is unclear how legume-based crop diversification impacts the functional components of soil organic carbon(SOC)in dryland,including the formation and transformation of particulate organic carbon(POC)and mineral-associated organic carbon(MAOC).We investigated the decomposition of straw residues,the fate of photosynthesized C,as well as the formation of MAOC and POC fractions using an in situ 13C labeling technique in the soybean-wheat intercropping,soybeanmaize intercropping and their respective monocropping systems,with and without cover crops.After 4-year treatments,the total SOC content in bulk soil remained unchanged,while MAOC content increased significantly by 5.6%with intercropping.Moreover,the in situ 13C labeling results confirmed that more photosynthesized C was transferred to MAOC,and less was retained in the POC fraction.Intercropping significantly increased total soil N and mineral N content by 15.3%and 13.4%,respectively,and decreased soil and microbial C/N ratio by 11.3%and 17.4%,respectively.This outcome,therefore,relieved microbial N limitation and accelerated straw residue decomposition.Accordingly,the potential of MAOC formation was strengthened for better SOC persistence.Our study suggests that legume-based crop diversification can effectively enrich N and support POC transformation to MAOC,accordingly contributing to the persistent SOC pool and thus potentially achieving C neutrality under climate change in dryland agroecosystems.展开更多
A 2-year-old girl was diagnosed as Weill-Marchesani syndrome with typical systemic features of short stature,short and stubby hands and feet,language disorders and mental retardation.He developed bilateral angle closu...A 2-year-old girl was diagnosed as Weill-Marchesani syndrome with typical systemic features of short stature,short and stubby hands and feet,language disorders and mental retardation.He developed bilateral angle closure glaucoma,ectopia lentis and suffered visual loss from the ocular features of Weill-Marchesani syndrome.The child was successfully treated by combined CO_(2) laser-assisted sclerectomy surgery and trabeculectomy.展开更多
DNA methylation plays a significant role in various biological events, and its precise determination is vital for the prognosis and treatment of cancer. Here, we proposed an ultrasensitive electrochemical biosensor fo...DNA methylation plays a significant role in various biological events, and its precise determination is vital for the prognosis and treatment of cancer. Here, we proposed an ultrasensitive electrochemical biosensor for the quantitative analysis of multiple methylation-locus in DNA sequence via DNA anchoring the gold nanoparticles (DNA-AuNPs) and bienzyme dual signal amplifications. After the target DNA captured by the DNA-AuNPs of the biosensor, the methyl-CpG binding protein MeCP2 could specifically conjugate to the methylation-loci in the double-stranded DNA. Successively, the glucose oxidase (GOD) and horseradish (HRP) co-labeled antibody captured the His tagged MeCP2, which leads to a cascade enzymatic catalysis of the substrates to yield a detectable electrochemical signal. Both the two strategies, including the high content of DNA-AuNPs and the associated catalysis of bienzyme, dramatically enhanced the sensitivity of the biosensor. The response current elevated with the increasing numbers of methylation-locus, thus the multiple methylated DNA was identified by detecting the corresponding current signals. This method could detect the methylated target as low as 0.1 fM, and showed a wide linear range from 10 - 15 M to 10 - 7 M. Besides, the long-term stability and repeatability of the biosensor were also validated. The prepared electrochemical immunosensor exhibits ultrasensitivity through the bienzyme labeling process, which can be applied for the detection of DNA methylation with low concentration.展开更多
The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAM...The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAMPs),are easily taken up by phagocytes and simultaneously activate innate immunity.In the current study,we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine.Ovalbumin(OVA)and tyrosinase-related protein 2(TRP2)were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides.The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2.Engineered OVA-and TRP2-containing mitochondria(OVA-MITO and TRP2-MITO)were extracted and evaluated as potential cancer vaccines.Impressively,the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models.Mechanistically,OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells(DCs)and induced a tumor-specific cell-mediated immunity.Moreover,DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist,namely,cardiolipin derived from the mitochondrial membrane.The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery,which could preferably target local dendritic cells and exert strong adaptive cellular immunity.This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.展开更多
Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Ou...Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Our earlier study showed that centromeric Localization of HP1α depends on the epigenetic mark H3K9me3 in interphase,while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.Here,we identified a PXVXL-containing protein,Ligand-dependent nuclear receptorinteracting factor 1 (LRIF1),which recruits HPla to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis.LRIF1 interacts directly with HPla chromoshadow domain via an evolutionariLy conserved PXVXL motif within its C-terminus.Importantly,the LRIF1-HPla interaction is critical for Aurora B activity in the inner centromere.Mutation of PXVXL motif of LRIF1 Leads to defects in HPla centromere targeting and aberrant chromosome segregation.These findings reveal a previously unrecognized direct Link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.展开更多
Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human c...Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.展开更多
Reducing nitrogen application rates can mitigate issues such as environmental degradation and resource wastage.However,it can also exacerbate problems such as wheat floret degeneration,leading to reduced yields.Theref...Reducing nitrogen application rates can mitigate issues such as environmental degradation and resource wastage.However,it can also exacerbate problems such as wheat floret degeneration,leading to reduced yields.Therefore,investigating wheat floret degeneration mechanisms under low-nitrogen stress and identifying mitigation measures are conducive to achieving high yields and sustainable development.To investigate the physiological mechanism of how low-nitrogen stress affects wheat floret degradation and whether exogenous brassinosteroids(BRs)can alleviate this stress,experiments were designed with treatments of three nitrogen application rates(N0,no nitrogen application;N1,120 kg ha–1 pure nitrogen;N2,240 kg ha–1 pure nitrogen)and exogenous spraying(N0CK,no nitrogen with water spraying;N0BR,no nitrogen with 24-epibrassinolide(an active brassinosteroid)spraying;N1,120 kg ha–1 pure nitrogen with water spraying).The results indicated that low-nitrogen stress generated a large amount of reactive oxygen species.Although wheat spikes synthesized flavonoids to combat oxidative stress,their energy metabolism(glycolysis and tricarboxylic acid cycle)and ascorbate-glutathione cycle were inhibited,which kept the reactive oxygen levels elevated within the spike,induced cell death and exacerbated floret degeneration.Furthermore,brassinosteroids played a role in regulating wheat floret degeneration under low-nitrogen stress.Exogenous foliar spraying of 24-epibrassinolide promoted energy metabolism and the ascorbate-glutathione cycle within the spike,which enhanced the energy charge and effectively mitigated a portion of the reactive oxygen induced by low-nitrogen stress,thereby alleviating the floret degeneration caused by low-nitrogen stress.In summary,low-nitrogen stress disrupts the redox homeostasis of wheat spikes,leading to floret degeneration,while brassinosteroids alleviate floret degeneration by improving the redox state of wheat spikes.This study provides theoretical support for balancing the contradiction between high yields and sustainable development and will be beneficial for the application of low nitrogen in production.展开更多
Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,not...Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,notably cancer.With the development of various drugs targeting epigenetic regulators,epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials.In this review,we summarize the aberrant functions of enzymes in DNA methylation,histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.展开更多
Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms under...Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore–microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore–microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore–microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore–microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore–microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.展开更多
基金supported by the National Natural Science Foundation of China (31871567)the National Key Research and Development Program of China (2017YFD0300202-2)Tang Young Scholar (2017)。
文摘Poor filling and low weight of inferior kernels limit the further improvement of wheat yield. Two cultivars, Shuangda 1 and Xinong 538, with different grain weights, were selected to investigate the physiological changes of inferior kernels by removal of superior kernels(RS) at the flowering stage. i TRAQ combined with physiological indexes was used to identify factors limiting the filling of inferior kernels.Removal of superior kernels significantly increased the mean filling rate of inferior kernels and thus increased their weight. A set of 6012 proteins in inferior wheat kernels were differentially expressed between the RS and control. These differentially expressed proteins were involved mainly in carbon metabolism and energy metabolism. The main reason for the promoting effect of RS on the filling of inferior kernels may be that RS downregulated proteins involved in glycolysis and pyruvate metabolism while upregulating proteins involved in carbon fixation and photosynthesis. Consequently, RS greatly increased the ATP content in inferior kernels, supplying energy for them to absorb photosynthetic assimilates. Removal of superior kernels increased the activities of sucrose synthase, soluble starch synthase,adenosine diphosphate glucose pyrophosphorylase, and starch branching enzyme in inferior kernels and promoted starch accumulation in them. Thus, RS promoted the filling of inferior kernels and increased their weight. The promoting effect of RS on starch synthesis in inferior kernels was associated with their endogenous IAA and ABA levels.
基金supported by the National Natural Science Foundation of China(No.81602492)the National Science Fund for Excellent Young Scholars National Science Fund for Excellent Young Scholars(No.32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003).
文摘Ammonia plays an important role in cellular metabolism.However,ammonia is considered a toxic product.In bone marrow-derived mesenchymal stem cells,multipotent stem cells with high expression of glutamine synthetase(GS)in bone marrow,ammonia and glutamate can be converted to glutamine via glutamine synthetase activity to support the proliferation of MSCs.As a major nutritional amino acid for biosynthesis,glutamine can activate the Akt/mTOR/S6k pathway to stimulate cell proliferation.The activation of mTOR can promote cell entry into S phase,thereby enhancing DNA synthesis and cell proliferation.Our studies demonstrated that mesenchymal stem cells can convert the toxic waste product ammonia into nutritional glutamine via GS activity.Then,the Akt/mTOR/S6k pathway is activated to promote bone marrow-derived mesenchymal stem cell proliferation.These results suggest a new therapeutic strategy and potential target for the treatment of diseases involving hyperammonemia.
基金funded by the National Natural Science Foundation of China(32272233)the National Key Research and Development Program of China(2023YFD2302300)+1 种基金the Shaanxi Innovative Talents Promotion Plan,China(2023KJXX-012)the Science and Technology Plan Project of Inner Mongolia,China(2022YFDZ0018)。
文摘Biochar amendment offers a chance for sustainable agriculture.However,the effectiveness of biochar relies on its physical and chemical properties,which are heavily affected by biochar production conditions and management practices.Therefore,substantial uncertainties regarding the use of biochar exist in agricultural systems globally.This study provides the first quantitative evaluation of the impacts of biochar characteristics and management practices on key ecosystem services by performing a second-order meta-analysis based on 34,628 paired observations in biochar-amended and unamended systems.Overall,biochar enhances phytotoxicity alleviation,physiology regulation,soil remediation and carbon sequestration,and microbial functional gene abundance.However,some prominent trade-offs exist between crop productivity and ecosystem service deliveries including for nutrient cycling,microbial function,climate change mitigation,and the soil microbial community.The adoption of low C:N biochar produced at high pyrolysis temperatures from sewage sludge-derived feedstock,in combination with a moderate application rate and inorganic fertilizer input,shows potential for achieving synergistic promotion of crop productivity and ecosystem services.These outcomes highlight the need for judicious implementation of biochar-based solutions to site-specific soil constraints.The quantified synergy and tradeoff relationships will aid the establishment of a sustainable biochar development framework that strengthens necessary ecosystem services commensurate with food security assurance.
基金supported by the National Natural Science Foundation of China(32161143012,32401359)China Postdoctoral Science Foundation(2024M751261)+1 种基金Foreign Youth Talent Program of the Ministry of Science and Technology(QN202217500345L)“111”Program(BP0719040).
文摘Increasing carbon(C)sequestration and stability in agricultural soils is a key strategy to mitigate climate change towards C neutrality.Crop diversification is an initiative to increase C sequestration in fields,but it is unclear how legume-based crop diversification impacts the functional components of soil organic carbon(SOC)in dryland,including the formation and transformation of particulate organic carbon(POC)and mineral-associated organic carbon(MAOC).We investigated the decomposition of straw residues,the fate of photosynthesized C,as well as the formation of MAOC and POC fractions using an in situ 13C labeling technique in the soybean-wheat intercropping,soybeanmaize intercropping and their respective monocropping systems,with and without cover crops.After 4-year treatments,the total SOC content in bulk soil remained unchanged,while MAOC content increased significantly by 5.6%with intercropping.Moreover,the in situ 13C labeling results confirmed that more photosynthesized C was transferred to MAOC,and less was retained in the POC fraction.Intercropping significantly increased total soil N and mineral N content by 15.3%and 13.4%,respectively,and decreased soil and microbial C/N ratio by 11.3%and 17.4%,respectively.This outcome,therefore,relieved microbial N limitation and accelerated straw residue decomposition.Accordingly,the potential of MAOC formation was strengthened for better SOC persistence.Our study suggests that legume-based crop diversification can effectively enrich N and support POC transformation to MAOC,accordingly contributing to the persistent SOC pool and thus potentially achieving C neutrality under climate change in dryland agroecosystems.
文摘A 2-year-old girl was diagnosed as Weill-Marchesani syndrome with typical systemic features of short stature,short and stubby hands and feet,language disorders and mental retardation.He developed bilateral angle closure glaucoma,ectopia lentis and suffered visual loss from the ocular features of Weill-Marchesani syndrome.The child was successfully treated by combined CO_(2) laser-assisted sclerectomy surgery and trabeculectomy.
文摘DNA methylation plays a significant role in various biological events, and its precise determination is vital for the prognosis and treatment of cancer. Here, we proposed an ultrasensitive electrochemical biosensor for the quantitative analysis of multiple methylation-locus in DNA sequence via DNA anchoring the gold nanoparticles (DNA-AuNPs) and bienzyme dual signal amplifications. After the target DNA captured by the DNA-AuNPs of the biosensor, the methyl-CpG binding protein MeCP2 could specifically conjugate to the methylation-loci in the double-stranded DNA. Successively, the glucose oxidase (GOD) and horseradish (HRP) co-labeled antibody captured the His tagged MeCP2, which leads to a cascade enzymatic catalysis of the substrates to yield a detectable electrochemical signal. Both the two strategies, including the high content of DNA-AuNPs and the associated catalysis of bienzyme, dramatically enhanced the sensitivity of the biosensor. The response current elevated with the increasing numbers of methylation-locus, thus the multiple methylated DNA was identified by detecting the corresponding current signals. This method could detect the methylated target as low as 0.1 fM, and showed a wide linear range from 10 - 15 M to 10 - 7 M. Besides, the long-term stability and repeatability of the biosensor were also validated. The prepared electrochemical immunosensor exhibits ultrasensitivity through the bienzyme labeling process, which can be applied for the detection of DNA methylation with low concentration.
基金supported by the National Science Foundation for Excellent Young Scholars(32122052)National Natural Science Foundation Regional Innovation and Development(No.U19A2003)+1 种基金West China Hospital Postdoctoral Research and Development Fund(2023HXBH068)Guizhou Provincial Science and Technology Projects-ZK[2021]General 455.
文摘The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency.Mitochondria,which feature prokaryotic characteristics and contain various damage-associated molecular patterns(DAMPs),are easily taken up by phagocytes and simultaneously activate innate immunity.In the current study,we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine.Ovalbumin(OVA)and tyrosinase-related protein 2(TRP2)were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides.The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2.Engineered OVA-and TRP2-containing mitochondria(OVA-MITO and TRP2-MITO)were extracted and evaluated as potential cancer vaccines.Impressively,the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models.Mechanistically,OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells(DCs)and induced a tumor-specific cell-mediated immunity.Moreover,DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist,namely,cardiolipin derived from the mitochondrial membrane.The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery,which could preferably target local dendritic cells and exert strong adaptive cellular immunity.This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases.
基金grants from the Ministry of Science and Technology of the People's Republic of China (2017YFA0503600 and 2016YFA0100500)the National Natural Science Foundation of China (31430054,31320103904, 91313303,31621002,31501095,and 31671405)+1 种基金the Ministry of Education of the People's Republic of China (IRT_17R102)the US National Institutes of Health (CA164133,DK56292, and DKl15812).
文摘Heterochromatin protein 1α (HP1α)regulates chromatin specification and plasticity during cell fate decision.Different structural determinants account for HP1α Localization and function during cell division cycle.Our earlier study showed that centromeric Localization of HP1α depends on the epigenetic mark H3K9me3 in interphase,while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors.Here,we identified a PXVXL-containing protein,Ligand-dependent nuclear receptorinteracting factor 1 (LRIF1),which recruits HPla to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis.LRIF1 interacts directly with HPla chromoshadow domain via an evolutionariLy conserved PXVXL motif within its C-terminus.Importantly,the LRIF1-HPla interaction is critical for Aurora B activity in the inner centromere.Mutation of PXVXL motif of LRIF1 Leads to defects in HPla centromere targeting and aberrant chromosome segregation.These findings reveal a previously unrecognized direct Link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.
基金This work was supported by the National Natural Science Foundation Regional Innovation and Development(No.U19A2003)National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001)+1 种基金Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(No.2019JDJQ008)Development Program of China(No.2016YFA0201402).
文摘Exposure to ionizing radiation,a physical treatment that inactivates live tumor cells,has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials.However,the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored.Here,we demonstrate that oxidized mitochondrial DNA(mtDNA)and stimulator of interferon genes(STING)signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine.Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells.Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells(DCs).Oxidized mtDNA,as a DAMP or adjuvant,activated the STING-TBK1-IRF3-IFN-β pathway in DCs,which subsequently cross-presented irradiated tumor cell-derived antigens to CD8^(+)T cells and elicited antitumor immunity.The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity,which may have implications for new strategies to improve the efficacy of irradiated vaccines.
基金supported by the Key Research and Development Program of Shaanxi,China(2021NY-083)the National Natural Science Foundation of China(31871567)。
文摘Reducing nitrogen application rates can mitigate issues such as environmental degradation and resource wastage.However,it can also exacerbate problems such as wheat floret degeneration,leading to reduced yields.Therefore,investigating wheat floret degeneration mechanisms under low-nitrogen stress and identifying mitigation measures are conducive to achieving high yields and sustainable development.To investigate the physiological mechanism of how low-nitrogen stress affects wheat floret degradation and whether exogenous brassinosteroids(BRs)can alleviate this stress,experiments were designed with treatments of three nitrogen application rates(N0,no nitrogen application;N1,120 kg ha–1 pure nitrogen;N2,240 kg ha–1 pure nitrogen)and exogenous spraying(N0CK,no nitrogen with water spraying;N0BR,no nitrogen with 24-epibrassinolide(an active brassinosteroid)spraying;N1,120 kg ha–1 pure nitrogen with water spraying).The results indicated that low-nitrogen stress generated a large amount of reactive oxygen species.Although wheat spikes synthesized flavonoids to combat oxidative stress,their energy metabolism(glycolysis and tricarboxylic acid cycle)and ascorbate-glutathione cycle were inhibited,which kept the reactive oxygen levels elevated within the spike,induced cell death and exacerbated floret degeneration.Furthermore,brassinosteroids played a role in regulating wheat floret degeneration under low-nitrogen stress.Exogenous foliar spraying of 24-epibrassinolide promoted energy metabolism and the ascorbate-glutathione cycle within the spike,which enhanced the energy charge and effectively mitigated a portion of the reactive oxygen induced by low-nitrogen stress,thereby alleviating the floret degeneration caused by low-nitrogen stress.In summary,low-nitrogen stress disrupts the redox homeostasis of wheat spikes,leading to floret degeneration,while brassinosteroids alleviate floret degeneration by improving the redox state of wheat spikes.This study provides theoretical support for balancing the contradiction between high yields and sustainable development and will be beneficial for the application of low nitrogen in production.
基金This work is supported by the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China(No.2019JDJQ0008)the National Major Scientific and Technological Special Project for“Significant New Drugs Development”of China(No.2018ZX09733001)the National Key Research and Development Program of China(No.2016YFA0201402).
文摘Epigenetic alternations concern heritable yet reversible changes in histone or DNA modifications that regulate gene activity beyond the underlying sequence.Epigenetic dysregulation is often linked to human disease,notably cancer.With the development of various drugs targeting epigenetic regulators,epigenetic-targeted therapy has been applied in the treatment of hematological malignancies and has exhibited viable therapeutic potential for solid tumors in preclinical and clinical trials.In this review,we summarize the aberrant functions of enzymes in DNA methylation,histone acetylation and histone methylation during tumor progression and highlight the development of inhibitors of or drugs targeted at epigenetic enzymes.
基金This work was supported in part by the National Natural Science Foundation of China(31430054,31320103904,31621002,31671405,91854203,91853115,21922706,31671407,31871359,31601097,and 21672201)the National Key Research and Development Program of China(2017YFA0503600 and 2016YFA0100500)+2 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDB19000000)Chinese Academy of Sciences Center for Excellence in Molecular Cell Science(2015HSC-UE010)MOE Innovative Team(IRT_17R102),and the US National Institutes of Health(CA164133and DK26929).
文摘Faithful segregation of mitotic chromosomes requires bi-orientation of sister chromatids, which relies on the sensing of correct attachments between spindle microtubules and kinetochores. Although the mechanisms underlying PLK1 activation have been extensively studied, the regulatory mechanisms that couple PLK1 activity to accurate chromosome segregation are not well understood. In particular, PLK1 is implicated in stabilizing kinetochore–microtubule attachments, but how kinetochore PLK1 activity is regulated to avoid hyperstabilized kinetochore–microtubules in mitosis remains elusive. Here, we show that kinetochore PLK1 kinase activity is modulated by SET7/9 via lysine methylation during early mitosis. The SET7/9-elicited dimethylation occurs at the Lys191 of PLK1, which tunes down its activity by limiting ATP utilization. Overexpression of the non-methylatable PLK1 mutant or chemical inhibition of SET7/9 methyltransferase activity resulted in mitotic arrest due to destabilized kinetochore–microtubule attachments. These data suggest that kinetochore PLK1 is essential for stable kinetochore–microtubule attachments and methylation by SET7/9 promotes dynamic kinetochore–microtubule attachments for accurate error correction. Our findings define a novel homeostatic regulation at the kinetochore that integrates protein phosphorylation and methylation with accurate chromosome segregation for maintenance of genomic stability.
