BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge...BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.展开更多
Obesity,a chronic,complex disease characterized by excess fat deposits,has become a major public health issue worldwide.Epidemiological studies have demonstrated that obesity can result in a greater risk of several ha...Obesity,a chronic,complex disease characterized by excess fat deposits,has become a major public health issue worldwide.Epidemiological studies have demonstrated that obesity can result in a greater risk of several harmful outcomes,such as diabetes mellitus and cardiovascular diseases[1].展开更多
Coptis chinensis Franch.and Panax ginseng C.A.Mey.are traditional herbal medicines with millennia of documented use and broad therapeutic applications,including anti-diabetic properties.However,the synergistic effect ...Coptis chinensis Franch.and Panax ginseng C.A.Mey.are traditional herbal medicines with millennia of documented use and broad therapeutic applications,including anti-diabetic properties.However,the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng on type 2 diabetes mellitus(T2DM)and its underlying mechanism remain unclear.The research demonstrated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng was 4∶1,exhibiting maximal efficacy in improving insulin resistance and gluconeogenesis in primary mouse hepatocytes.This combination demonstrated significant synergistic effects in improving glucose tolerance,reducing fasting blood glucose(FBG),the weight ratio of epididymal white adipose tissue(eWAT),and the homeostasis model assessment of insulin resistance(HOMA-IR)in leptin receptor-deficient(db/db)mice.Subsequently,a T2DM liver-specific network was constructed based on RNA sequencing(RNA-seq)experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions(PPIs).The network recovery index(NRI)score of the combined treatment group with a 4∶1 ratio exceeded that of groups treated with individual components.The research identified that activated adenosine 5'-monophosphate-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)signaling in the liver played a crucial role in the synergistic treatment of T2DM,as verified by western blot experiment in db/db mice.These findings demonstrate that the 4∶1 combination of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng significantly improves insulin resistance and glucose and lipid metabolism disorders in db/db mice,surpassing the efficacy of individual treatments.The synergistic mechanism correlates with enhanced AMPK/ACC signaling pathway activity.展开更多
This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of tr...This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.展开更多
Objective Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health.Analysis of these mixture exposures presents several key challenges for environmental epidemio...Objective Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health.Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment,including high dimensionality,correlated exposure,and subtle individual effects.Methods We proposed a novel statistical approach,the generalized functional linear model(GFLM),to analyze the health effects of exposure mixtures.GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation.The robustness and efficiency was evaluated under various scenarios through extensive simulation studies.Results We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey(NHANES).In the first application,we examined the effects of 37 nutrients on BMI(2011–2016 cycles).The GFLM identified a significant mixture effect,with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI,respectively.For the second application,we investigated the association between four pre-and perfluoroalkyl substances(PFAS)and gout risk(2007–2018 cycles).Unlike traditional methods,the GFLM indicated no significant association,demonstrating its robustness to multicollinearity.Conclusion GFLM framework is a powerful tool for mixture exposure analysis,offering improved handling of correlated exposures and interpretable results.It demonstrates robust performance across various scenarios and real-world applications,advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.展开更多
Ship emissions contribute considerably to air pollution and are expected to decline under domestic policies and international cooperation such as green shipping corridors(GSCs).However,evaluation of the emission reduc...Ship emissions contribute considerably to air pollution and are expected to decline under domestic policies and international cooperation such as green shipping corridors(GSCs).However,evaluation of the emission reduction potential by the Domestic Emission Control Area(DECA)policy and GSC cooperation is still lacking.Here,a series of multi-year high spatiotemporal ship emission inventories around Hainan,a representative island province of China,were developed with the state-of-the-art Shipping Emission Inventory Model.The improved origin-destination identification algorithm allowed emission allocation to port level.The emission reduction potential of the DECA policy and Hainan's joining GSCwas analyzed.In 2022,ship emission intensity in waters 12 Nm from Hainan(Hainan-12Nm)were 6.4%-7.4% of that in waters 12 Nm from China.From 2019 to 2022,Hainan-12Nm emissions dropped by 66.7%-77.8% for SO_(2) and PM2.5.Ideally,with adequate ultra-low-sulfur fuel,DECA can reduce SO_(2) and PM2.5 emissions by 16.6% and 22.4% yearly compared with no-DECA scenario.However,emission reduction would drop markedly if ultra-low-sulfur fuel is short in supply.Emissions of voyages passing through 200 Nm from Hainan took up 1%-4%of international shipping emissions,implying great emission reduction potential for Hainan's establishing GSCs,especially considering the flourishing South-South trade.This study provides a thorough assessment of the current state of shipping emissions around Hainan as well as offers excellent data support for Hainan to further advance the future upgrade of ship emission management policies.展开更多
The canonical CRISPR/Cas editors are constrained by the requirement for specific PAMs,which substantially limits their editable target range.Rice(particularly indica rice)is sensitive to low temperature,which impacts ...The canonical CRISPR/Cas editors are constrained by the requirement for specific PAMs,which substantially limits their editable target range.Rice(particularly indica rice)is sensitive to low temperature,which impacts the yield and restricts the geographic distribution of rice.In this study,we developed PAM-flexible multiplex genome editing tools based on Sp G(recognising NGN-PAMs)and Sp RY(recognising NNN-PAMs)variants.We then tested the feasibility of using a sweet potato leaf curl virus(SPLCV)replicon-based expression vector and single-stranded DNA-binding domain(DBD)to improve the editing efficiency of these PAM-flexible editors.Furthermore,we used Sp G-mediated multiplex genome editing to achieve comprehensive improvement in cold tolerance in indica rice by editing WRKY transcription factors Os WRKY53 and Os WRKY63,to generate high cold-resistant indica rice lines.We concluded that these PAM-flexible multiplex genome editors are powerful tools for multi-gene editing for crop genetic improvement.展开更多
Microcystis panniformis is a bloom forming species with flat panniform-like colonies. This species was recently found in Lake Taihu, China. To specifically characterize M. panniformis based on isolated strains, morpho...Microcystis panniformis is a bloom forming species with flat panniform-like colonies. This species was recently found in Lake Taihu, China. To specifically characterize M. panniformis based on isolated strains, morphological examination on colonial transition and genetic examination are needed. Three M. panniformis strains isolated from a water bloom sample in Lake Taihu were characterized by molecular analysis and toxin quantification. Phylogenetic analysis based on both 16S rRNA gene and internal transcribed spacer(ITS) between 16S and 23S rRNA genes were performed and compared to facilitate easy identification of the species.Relatively high similarities(98%–99%) were shown in 16S rDNA sequences between the strains of M. panniformis and those of other Microcystis species, whereas the similarities for ITS sequences were 88%–95%. In the phylogenetic tree based on the 16S rDNA sequences, the M. panniformis and M. aeruginosa strains were intermixed together with no clear division,whereas all of the M. panniformis strains were clustered together in a single clade based on the ITS sequences based phylogenyetic tree. The mcyE gene was detected in all three strains, and microcystin was determined by high-performance liquid chromatography. The molecular detection and toxin production of M. panniformis strains are of great significance for the environmental risk assessment of Microcystis blooms.展开更多
基金Supported by National Natural Science Foundation of China,No.82360231Yunnan Basic Research Program General Project,No.202401AT070075+1 种基金Dali Basic Research Program Key Project,No.202301A020021Youth Special Project for Basic Research of Local Universities in Yunnan Province,No.202301BA070001-127.
文摘BACKGROUND Fear-related disorders,such as post-traumatic stress disorder(PTSD),significantly impact patients and families.Exposure therapy is a common treatment,but imp-roving its effectiveness remains a key challenge.Fear conditioning and extinction in animal models offer insights into its mechanisms.Our previous research indi-cates that DNA methyltransferases play a role in fear memory renewal.AIM To investigate the role of DNA methylation in the extinction of fear memory,with the goal of identifying potential strategies to enhance the efficacy of exposure therapy for fear-related disorders.METHODS This study investigated the role of DNA methylation in fear memory extinction in mice.DNA methylation was manipulated using N-phthalyl-L-tryptophan(RG108)to reduce methylation and L-methionine injections to enhance it.Neuronal activity,and dendritic spine density was measured following extinction training.RESULTS RG108 suppressed extinction,reduced spine density,and inhibited neuronal activity.Methionine injections facilitated extinction.CONCLUSION DNA methylation is crucial for fear memory extinction.Enhancing methylation may improve the efficacy of exposure therapy,offering a potential strategy to treat fear-related disorders.
基金supported in part by the Young Scientists Fund of the National Natural Science Foundation of China(Grant No.82304253).
文摘Obesity,a chronic,complex disease characterized by excess fat deposits,has become a major public health issue worldwide.Epidemiological studies have demonstrated that obesity can result in a greater risk of several harmful outcomes,such as diabetes mellitus and cardiovascular diseases[1].
基金supported by the Pioneer and Leading Goose R&D Program of Zhejiang Province(No.2024C03106)the National Natural Science Foundation of China(No.U23A20513)+1 种基金Ningbo Top Medical and Health Research Program(No.2022030309)the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202002).
文摘Coptis chinensis Franch.and Panax ginseng C.A.Mey.are traditional herbal medicines with millennia of documented use and broad therapeutic applications,including anti-diabetic properties.However,the synergistic effect of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng on type 2 diabetes mellitus(T2DM)and its underlying mechanism remain unclear.The research demonstrated that the optimal ratio of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng was 4∶1,exhibiting maximal efficacy in improving insulin resistance and gluconeogenesis in primary mouse hepatocytes.This combination demonstrated significant synergistic effects in improving glucose tolerance,reducing fasting blood glucose(FBG),the weight ratio of epididymal white adipose tissue(eWAT),and the homeostasis model assessment of insulin resistance(HOMA-IR)in leptin receptor-deficient(db/db)mice.Subsequently,a T2DM liver-specific network was constructed based on RNA sequencing(RNA-seq)experiments and public databases by integrating transcriptional properties of disease-associated proteins and protein-protein interactions(PPIs).The network recovery index(NRI)score of the combined treatment group with a 4∶1 ratio exceeded that of groups treated with individual components.The research identified that activated adenosine 5'-monophosphate-activated protein kinase(AMPK)/acetyl-CoA carboxylase(ACC)signaling in the liver played a crucial role in the synergistic treatment of T2DM,as verified by western blot experiment in db/db mice.These findings demonstrate that the 4∶1 combination of total alkaloids from Coptis chinensis and total ginsenosides from Panax ginseng significantly improves insulin resistance and glucose and lipid metabolism disorders in db/db mice,surpassing the efficacy of individual treatments.The synergistic mechanism correlates with enhanced AMPK/ACC signaling pathway activity.
基金supported by the Natural Science Foundation of Guangdong Province(No.2023A1515030291)the Dongguan Science and Technology of Social Development Program(No.20211800905282)+8 种基金the National Key Research and Development Program of China(Nos.2022YFC2303600,2020YFA0908000)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDC-202002)the CACMS Innovation Fund(Nos.CI2023E002,CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Nos.CI2023D003,CI2021B014)the Science and Technology Foundation of Shenzhen(No.JCYJ20210324115800001)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the Shenzhen Medical Research Fund(No.B2302051)the Distinguished Expert Project of Sichuan Province Tianfu Scholar(No.CW202002)Shenzhen Science and Technology Program(No.RCBS20210609104424065).
文摘This study presents an approach to enhanced cancer immunotherapy through the in situ synthesis of potassium permanganate(KMnO_(4))derived manganese dioxide(MnO_(2))micro/nano-adjuvants.Addressing the limitations of traditional immunotherapy due to patient variability and the complexity of the tumor microenvironment,our research establishes KMnO_(4)as a potent immunomodulator that enhances the efficacy of anti-programmed death-ligand 1(αPD-L1)antibodies.The in situ synthesized MnO_(2)adjuvants in the tumor exhibit direct interactions with biological systems,leading to the reduction of MnO_(2)to Mn^(2+)within the tumor,and thereby improving the microenvironment for immune cell activity.Our in vitro and in vivo models demonstrate KMnO_(4)’s capability to induce concentration-dependent cytotoxicity in tumor cells,triggering DNA damage and apoptosis.It also potentiates immunogenic cell death by upregulating calreticulin and high mobility group box 1(HMGB1)on the cell surface.The combination of KMnO_(4)withαPD-L1 antibodies substantially inhibits tumor growth,promotes dendritic cell maturation,and enhances CD8^(+)T cell infiltration,resulting in a significant phenotypic shift in tumor-associated macrophages towards a pro-inflammatory M1 profile.Our findings advocate for further research into the long-term efficacy of KMnO_(4)and its application in diverse tumor models,emphasizing its potential to redefine immune checkpoint blockade therapy and offering a new vista in the fight against cancer.
基金supported in part by the Young Scientists Fund of the National Natural Science Foundation of China(Grant Nos.82304253)(and 82273709)the Foundation for Young Talents in Higher Education of Guangdong Province(Grant No.2022KQNCX021)the PhD Starting Project of Guangdong Medical University(Grant No.GDMUB2022054).
文摘Objective Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health.Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment,including high dimensionality,correlated exposure,and subtle individual effects.Methods We proposed a novel statistical approach,the generalized functional linear model(GFLM),to analyze the health effects of exposure mixtures.GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation.The robustness and efficiency was evaluated under various scenarios through extensive simulation studies.Results We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey(NHANES).In the first application,we examined the effects of 37 nutrients on BMI(2011–2016 cycles).The GFLM identified a significant mixture effect,with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI,respectively.For the second application,we investigated the association between four pre-and perfluoroalkyl substances(PFAS)and gout risk(2007–2018 cycles).Unlike traditional methods,the GFLM indicated no significant association,demonstrating its robustness to multicollinearity.Conclusion GFLM framework is a powerful tool for mixture exposure analysis,offering improved handling of correlated exposures and interpretable results.It demonstrates robust performance across various scenarios and real-world applications,advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
基金supported by the National Natural Science Foundation of China(No.42325505)the National Key R&D Program of China(No.2022YFC3704200)the Tsinghua University Initiative Scientific Research Program.
文摘Ship emissions contribute considerably to air pollution and are expected to decline under domestic policies and international cooperation such as green shipping corridors(GSCs).However,evaluation of the emission reduction potential by the Domestic Emission Control Area(DECA)policy and GSC cooperation is still lacking.Here,a series of multi-year high spatiotemporal ship emission inventories around Hainan,a representative island province of China,were developed with the state-of-the-art Shipping Emission Inventory Model.The improved origin-destination identification algorithm allowed emission allocation to port level.The emission reduction potential of the DECA policy and Hainan's joining GSCwas analyzed.In 2022,ship emission intensity in waters 12 Nm from Hainan(Hainan-12Nm)were 6.4%-7.4% of that in waters 12 Nm from China.From 2019 to 2022,Hainan-12Nm emissions dropped by 66.7%-77.8% for SO_(2) and PM2.5.Ideally,with adequate ultra-low-sulfur fuel,DECA can reduce SO_(2) and PM2.5 emissions by 16.6% and 22.4% yearly compared with no-DECA scenario.However,emission reduction would drop markedly if ultra-low-sulfur fuel is short in supply.Emissions of voyages passing through 200 Nm from Hainan took up 1%-4%of international shipping emissions,implying great emission reduction potential for Hainan's establishing GSCs,especially considering the flourishing South-South trade.This study provides a thorough assessment of the current state of shipping emissions around Hainan as well as offers excellent data support for Hainan to further advance the future upgrade of ship emission management policies.
基金supported by grants from the National Natural Science Foundation of China(32272120)the Guangdong Basic and Applied Basic Research Foundation(2024A1515012120)+3 种基金the Guangzhou Basic and Applied Basic Research Foundation(2023A04J00359)Special Foundation for Introduction of Scientific Talents of GDAAS(R2022YJ-YB1003,R2021YJ-XD001)the Seed Industry Revitalization Project of Special Fund for Rural Revitalization Strategy in Guangdong Province(2024-NPY-00-001)Guangdong Key Laboratory of Rice Science and Technology(2023B1212060042)。
文摘The canonical CRISPR/Cas editors are constrained by the requirement for specific PAMs,which substantially limits their editable target range.Rice(particularly indica rice)is sensitive to low temperature,which impacts the yield and restricts the geographic distribution of rice.In this study,we developed PAM-flexible multiplex genome editing tools based on Sp G(recognising NGN-PAMs)and Sp RY(recognising NNN-PAMs)variants.We then tested the feasibility of using a sweet potato leaf curl virus(SPLCV)replicon-based expression vector and single-stranded DNA-binding domain(DBD)to improve the editing efficiency of these PAM-flexible editors.Furthermore,we used Sp G-mediated multiplex genome editing to achieve comprehensive improvement in cold tolerance in indica rice by editing WRKY transcription factors Os WRKY53 and Os WRKY63,to generate high cold-resistant indica rice lines.We concluded that these PAM-flexible multiplex genome editors are powerful tools for multi-gene editing for crop genetic improvement.
基金supported by the National Water Science and Technology Project (No.2017ZX07203-003)the National Basic Research Program of China (No.2017YFA0605201)the support from the National Natural Science Foundation of China (No.412111020)
文摘Microcystis panniformis is a bloom forming species with flat panniform-like colonies. This species was recently found in Lake Taihu, China. To specifically characterize M. panniformis based on isolated strains, morphological examination on colonial transition and genetic examination are needed. Three M. panniformis strains isolated from a water bloom sample in Lake Taihu were characterized by molecular analysis and toxin quantification. Phylogenetic analysis based on both 16S rRNA gene and internal transcribed spacer(ITS) between 16S and 23S rRNA genes were performed and compared to facilitate easy identification of the species.Relatively high similarities(98%–99%) were shown in 16S rDNA sequences between the strains of M. panniformis and those of other Microcystis species, whereas the similarities for ITS sequences were 88%–95%. In the phylogenetic tree based on the 16S rDNA sequences, the M. panniformis and M. aeruginosa strains were intermixed together with no clear division,whereas all of the M. panniformis strains were clustered together in a single clade based on the ITS sequences based phylogenyetic tree. The mcyE gene was detected in all three strains, and microcystin was determined by high-performance liquid chromatography. The molecular detection and toxin production of M. panniformis strains are of great significance for the environmental risk assessment of Microcystis blooms.
