This paper investigates the influence of the spanwise-distributed trailing-edge camber morphing on the dynamic stall characteristics of a finite-span wing at Re=2×10^(5).The mathematical model of the spanwise-dis...This paper investigates the influence of the spanwise-distributed trailing-edge camber morphing on the dynamic stall characteristics of a finite-span wing at Re=2×10^(5).The mathematical model of the spanwise-distributed trailing-edge camber morphing is established based on Chebyshev polynomials,and the deformed wing surface is modeled by a spline surface according to the rib's morphing in the chordwise direction.The Computational Fluid Dynamics(CFD)method is adopted to obtain flow-field results and aerodynamic forces.The SST-γmodel is introduced and the overset mesh technique is adopted.The numerical results show that the spanwisedistributed trailing-edge morphing obviously changes the aerodynamic and energy transfer characteristics of the dynamic stall.Especially when the phase difference between the trailing-edge motion and the wing pitch is-π/2,the interaction between the three-dimensional(3-D)Leading-Edge Vortex(LEV)and Trailing-Edge Vortex(TEV)is strengthened,and the work done by the aerodynamic force turns negative.This indicates that the trailing-edge deformation has the potential to suppress the oscillation amplitude of stall flutter.We also found that as the trailing-edge camber morphing varies more complexly along the spanwise direction,the suppression effect decreases accordingly.展开更多
Nanofiltration(NF)membranes with exceptional ion selectivity and permeability are needed for the recovery of lithium from waste lithium-ion batteries.Herein,inspired by the homogeneous microchannels in the skeletal st...Nanofiltration(NF)membranes with exceptional ion selectivity and permeability are needed for the recovery of lithium from waste lithium-ion batteries.Herein,inspired by the homogeneous microchannels in the skeletal structure of glass sponges,an innovative biomimetic sponge-like sub-nanostructured NF membrane was designed using an alkali-induced MXene(AMXene)-ethyl formate(EF)-induced bulk/interfacial diffusion decoupling strategy to simultaneously improve Li^(+)/Co^(2+)selectivity and membrane permeability.The Li^(+)/Co^(2+)separation factor(SLi,co=24)of the engineered membrane was improved by an order of magnitude compared to that of an NF270 membrane(SLi,Co=2).The selectivity of Mg^(2+)/Na+(B_(NaCl)/B_(MgCl_(2))=286)and SO_(4)^(2-)/Cl^(-)(BNaCl/BNaSO_(4)=941)increased by 3~12 times,and the permeability(25.8 L m-2 h-1 bar-1)remained at a desirable level,beyond the current upper bound of the other cutting-edge membranes.The superior performance was attributed to the limited release of amine in bulk phase and the boosted interfacial diffusion by reducing interfacial energy barrier during the interfacial polymerization reaction,which were realized via the synergetic effects of AMXene and EF.This approach yielded a biomimetic sponge-like sub-nanostructured NF membrane with controlled homogeneous pore radii(0.202 nm)and a thickness as small as 16.08 nm,which led to high ion selectivity and permeability.The engineered membrane was capable of efficient separation and recovery of Li^(+)/metal ions.展开更多
This paper proposes a formation of multiple unmanned aerial vehicles(UAVs)based on the R5DOS(RCC-5 and orientation direction)intersection model.After improving the R5DOS-intersection model,we evenly arranged 16 UAVs i...This paper proposes a formation of multiple unmanned aerial vehicles(UAVs)based on the R5DOS(RCC-5 and orientation direction)intersection model.After improving the R5DOS-intersection model,we evenly arranged 16 UAVs in 16 spatial regions.Compared with those of the rectangular formation model and the grid formation model,the communication costs,time costs,and energy costs of the R5DOS model formation were effectively reduced.At the same time,the operation time of UAV formation was significantly enhanced.The leader-follower method can enhance the robustness of the UAV formation and ensure the integrity of communication during UAV formation operation.Finally,we conducted a simulation experiment on the model and found that the R5DOS model formation was stable and could maintain the desired formation.The randomly generated UAVs could quickly fly to the formation path in a short time,establish formation,and carry out operations.When the leader fails,the follower could travel to the original trajectory of the failed leader in a short time,replace the leader,and continue to communicate and improve the robustness of the formation.To sum up,the UAV formation based on the R5DOS model has the advantages of long operation time,strong endurance,low communication cost,and stable formation,which is of great significance for research on UAV formation.展开更多
The Coordinate Descent Method for K-means(CDKM)is an improved algorithm of K-means.It identifies better locally optimal solutions than the original K-means algorithm.That is,it achieves solutions that yield smaller ob...The Coordinate Descent Method for K-means(CDKM)is an improved algorithm of K-means.It identifies better locally optimal solutions than the original K-means algorithm.That is,it achieves solutions that yield smaller objective function values than the K-means algorithm.However,CDKM is sensitive to initialization,which makes the K-means objective function values not small enough.Since selecting suitable initial centers is not always possible,this paper proposes a novel algorithm by modifying the process of CDKM.The proposed algorithm first obtains the partition matrix by CDKM and then optimizes the partition matrix by designing the split-merge criterion to reduce the objective function value further.The split-merge criterion can minimize the objective function value as much as possible while ensuring that the number of clusters remains unchanged.The algorithm avoids the distance calculation in the traditional K-means algorithm because all the operations are completed only using the partition matrix.Experiments on ten UCI datasets show that the solution accuracy of the proposed algorithm,measured by the E value,is improved by 11.29%compared with CDKM and retains its efficiency advantage for the high dimensional datasets.The proposed algorithm can find a better locally optimal solution in comparison to other tested K-means improved algorithms in less run time.展开更多
As the first magnetic kagome material to exhibit the charge density wave(CDW)order,FeGe has attracted much attention in recent research.Similar to AV_(3)Sb_(5)(A=K,Cs,Rb),FeGe exhibits the CDW pattern with an in-plane...As the first magnetic kagome material to exhibit the charge density wave(CDW)order,FeGe has attracted much attention in recent research.Similar to AV_(3)Sb_(5)(A=K,Cs,Rb),FeGe exhibits the CDW pattern with an in-plane 2×2 structure and the existence of van Hove singularities near the Fermi level.However,sharply different from AV_(3)Sb_(5)which has phonon instability at M point,all the theoretically calculated phonon frequencies in FeGe remain positive.Based on first-principles calculations,we surprisingly find that the maximum of nesting function is at K point instead of M point.Two Fermi pockets with Fe-d_(xz)and Fe-d_(x^(2)-y^(2))/d_(xy)orbital characters have large contribution to the Fermi nesting,which evolve significantly with k_(z),indicating the highly three-dimensional(3D)feature of FeGe in contrast to AV_(3)Sb_(5).Considering the effect of local Coulomb interaction,we reveal that the instability at K point is significantly suppressed due to the sublattice interference mechanism.Meanwhile,the wave functions nested by vector M have many ingredients located at the same Fe site,thus the instability at M point is enhanced.This indicates that the electron correlation,rather than electron-phonon interaction,plays a key role in the CDW transition at M point.展开更多
The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy.Although many cancers originate in mucosal tissues,current RNA cancer vaccines are mainly administe...The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy.Although many cancers originate in mucosal tissues,current RNA cancer vaccines are mainly administered non-mucosally.Here,we developed a non-invasive intranasal cancer vaccine utilizing circular RNA encapsulated in lipid nanoparticles to induce localized mucosal immune responses.This strategy elicited potent anti-tumor T cell responses in preclinical lung cancer models while mitigating the systemic adverse effects commonly associated with intravenous RNA vaccination.Specifically,type 1 conventional dendritic cells were indispensable for T cell priming post-vaccination,with both alveolar macrophages and type 1 conventional dendritic cells boosting antigen-specific T cell responses in lung tissues.Moreover,the vaccination facilitated the expansion of both endogenous and adoptive transferred antigen-specific T cells,resulting in robust anti-tumor efficacy.Single-cell RNA sequencing revealed that the vaccination reprograms endogenous T cells,enhancing their cytotoxicity and inducing a memory-like phenotype.Additionally,the intranasal vaccine can modulate the response of CAR-T cells to augment therapeutic efficacy against tumor cells expressing specific tumor-associated antigens.Collectively,the intranasal RNA vaccine strategy represents a novel and promising approach for developing RNA vaccines targeting mucosal malignancies.展开更多
Background:Colorectal cancer liver metastasis(CRLM)is characterized by an immunosuppressive microenvironment and a blunted response to immunotherapy.Notably,tumor-associated macrophages(TAMs)play a critical role in mo...Background:Colorectal cancer liver metastasis(CRLM)is characterized by an immunosuppressive microenvironment and a blunted response to immunotherapy.Notably,tumor-associated macrophages(TAMs)play a critical role in modulating immune responses and exhibit significant heterogeneity in CRLM.Sphingosine kinase 1(SPHK1)serves as a pivotal kinase in maintaining the balance between ceramide and sphingosine-1-phosphate(S1P)levels.However,the effects of SPHK1 within TAMs on tumor immune evasion during CRLM remain elusive.This study aimed at investigating the role of TAM-intrinsic SPHK1 in tumor immunosuppressive microenvironment in CRLM.Methods:SPHK1 expression levels in TAMs were estimated by immunofluorescence and bioinformatics analysis.Several animal models were established to elucidate the role of SPHK1 in tumor immunity reprogramming in vivo.Flow cytometry,cytokine assay,and transwell assay were conducted to investigate the effects of SPHK1 in TAMs in cell-cell communication in vitro.RNA-sequencing,Western blotting,and quantitative real-time polymerase chain reaction were used to explore the molecularmechanism by which SPHK1 activatedNLR family pyrin domain containing 3(NLRP3)inflammasome in TAMs.Results:We found that SPHK1 was mainly expressed in TAMs and identified SPHK1+TAMs as associated with CRLM and diminished efficacy of immunotherapy in human patients.These SPHK1+TAMs exhibited strong immunosuppressive activities by inducing CD8^(+)T cell exhaustionwith high programmed cell death 1(PD-1)expression via the interaction between TAMs and CRC cells.Mechanistically,SPHK1-produced S1P exerted an autocrine effect to activate NLRP3 inflammasome and interleukin 1 beta(IL-1β)release via nuclear factor-kappa B(NF-κB)and hypoxia inducible factor 1 subunit alpha(HIF-1α)signaling in TAMs.Paracrine IL-1β then upregulated the expression of monocyte chemoattractants and ADAM metallopeptidase domain 17(ADAM17)sheddase in CRC cells,resulting in TAM infiltration and CD8^(+)T cell dysfunction in the liver microenvironment.Furthermore,combining SPHK1-targeting treatments with anti-PD-1 therapy or radioimmunotherapy largely stalled liver metastasis and caused a significant extension of lifespan in preclinical mouse models.Conclusions:Our findings highlighted the role of SPHK1 of TAMs in facilitating CRLM by promoting CD8^(+)T cell dysfunction and immunosuppressive microenvironment.Combining SPHK1 blockade with anti-PD-1 therapy may be a promising treatment regimen for patients with CRLM.展开更多
Cytochrome P450(CYP450)enzymes,as versatile biocatalysts with the broadest range of catalytic reactions in nature,play critical roles in the metabolism of medicinal plants.They are involved in various oxidative modifi...Cytochrome P450(CYP450)enzymes,as versatile biocatalysts with the broadest range of catalytic reactions in nature,play critical roles in the metabolism of medicinal plants.They are involved in various oxidative modification processes of active ingredients,facilitating both the synthesis and degradation of bioactive substances.This review delves into the classification,structure,and catalytic mechanisms of CYP450 enzymes,emphasizing their indispensable roles in plant biosynthesis.Using representative cases,including the biosynthetic pathways of tanshinones,artemisinin,celastrol,paclitaxel,and berberine,this review highlights the functional importance of specific CYP450s.For instance,CYP71AV1 catalyzes the production of artemisinin and artemisinic aldehyde,with its activity directly affecting artemisinin yield.Similarly,CYP76AH1 and CYP76AK1 play pivotal roles in the backbone construction and postmodification of tanshinones,acting as key players in their metabolic network.In the case of celastrol,CYP712K1,CYP712K2,and CYP712K3 initiate the first oxidative reaction,providing a solid foundation for subsequent biosynthetic processes.These examples highlight the pivotal role of CYP450 enzymes in the biosynthesis of medicinal plants,showcasing both their complexity and significance in plant metabolic pathways.Furthermore,this review examines the oxidative metabolism of CYP450 enzymes under aerobic conditions and their reductive metabolism in specific environments,offering deeper insights into their catalytic mechanisms.A comprehensive understanding of these processes lays the groundwork for the effective application of CYP450 enzymes in biotechnology and plant metabolic engineering.展开更多
Nonconvex Activated Fuzzy Zeroing Neural Network-based(NAFZNN)and Nonconvex Activated Fuzzy Noise-Tolerant Zeroing Neural Network-based(NAFNTZNN)models are devised and analyzed,drawing inspiration from the classical Z...Nonconvex Activated Fuzzy Zeroing Neural Network-based(NAFZNN)and Nonconvex Activated Fuzzy Noise-Tolerant Zeroing Neural Network-based(NAFNTZNN)models are devised and analyzed,drawing inspiration from the classical ZNN/NTZNN-based model for online addressing Time-Varying Quadratic Programming Problems(TVQPPs)with Equality and Inequality Constraints(EICs)in noisy circumstances,respectively.Furthermore,the proposed NAFZNN model and NAFNTZNN model are considered as general proportion-differentiation controller,along with general proportion-integration-differentiation controller.Besides,theoretical results demonstrate the global convergence of both the NAFZNN and NAFNTZNN models for TVQPPs with EIC under noisy conditions.Moreover,numerical results illustrate the efficiency,robustness,and ascendancy of the NAFZNN and NAFZNN models in addressing TVQPPs online,exhibiting inherent noise tolerance.Ultimately,an application example to plant leaf disease identification is conducted to support the feasibility and efficacy of the designed NAFNTZNN model,which shows its potential practical value in the field of image recognition.展开更多
Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products(PNPs).Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient pro...Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products(PNPs).Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient production of PNPs through synthetic biology.In this study,we engineered Saccharomyces cerevisiae to optimize the microenvironment for boosting the activities of P450s,including coexpression with the redox partner genes,enhancing NADPH supply,expanding the endoplasmic reticulum(ER),strengthening heme biosynthesis,and regulating iron uptake.This created a platform for the efficient production 11,20-dihydroxyferruginol,a key intermediate of the bioactive compound tanshinones.The yield was enhanced by 42.1-fold through 24 effective genetic edits.The optimized strain produced up to 67.69±1.33 mg/L 11,20-dihydroxyferruginol in shake flasks.Our work represents a promising advancement toward constructing yeast cell factories containing P450s and paves the way for microbial biosynthesis of tanshinones in the future.展开更多
Precise control of circulating lipid levels is vital in both health and disease.We recently uncovered that bulk lipids,transported by lipoproteins,enter the circulation initially via the coat protein complex II(COPII)...Precise control of circulating lipid levels is vital in both health and disease.We recently uncovered that bulk lipids,transported by lipoproteins,enter the circulation initially via the coat protein complex II(COPII)in a condensation-dependent manner.Divalent manganese,acting as a signaling messenger,selectively controls COPII condensation to regulate lipid homeostasis in vivo.Here,we present evidence for a manganese-based therapy in murine models of hypolipidemia and hyperlipidemia.展开更多
Bacterial cellulose is a versatile material with applications in many industries. However, the widespread uptake of bacterial cellulose faces challenges including high production costs and lack of scalability. One app...Bacterial cellulose is a versatile material with applications in many industries. However, the widespread uptake of bacterial cellulose faces challenges including high production costs and lack of scalability. One approach to address these obstacles is the use of alternative substrates and media, compared to the Hestrin-Schramm (HS) media. By evaluating and selecting appro- priate media and substrates, the production of bacterial cellulose can be more efficient: enabling sustainable systems and supply chains where less energy and materials are lost, and the output production is increased. The purpose of this paper is to analyze the current landscape of bac- terial cellulose alternative media and substrates (ingredients). Through a systematic review of 198 papers, this review identifies 299 alternative substrates from 12 industries and 101 bacte- rial cellulose-producing strains, which were systematically compared. This review also finds that there are methodological gaps in this field such as data variability, papers mislabelling the HS media or not using a comparison media, and a lack of strain names. This alternative substrate analysis for bacterial cellulose production demonstrates that overall, for some applications al- ternative substrates can be taken into consideration that are not only cheaper, but also produce higher yields than HS media.展开更多
基金co-supported by the National Natural Science Foundation of China(No.12472332)。
文摘This paper investigates the influence of the spanwise-distributed trailing-edge camber morphing on the dynamic stall characteristics of a finite-span wing at Re=2×10^(5).The mathematical model of the spanwise-distributed trailing-edge camber morphing is established based on Chebyshev polynomials,and the deformed wing surface is modeled by a spline surface according to the rib's morphing in the chordwise direction.The Computational Fluid Dynamics(CFD)method is adopted to obtain flow-field results and aerodynamic forces.The SST-γmodel is introduced and the overset mesh technique is adopted.The numerical results show that the spanwisedistributed trailing-edge morphing obviously changes the aerodynamic and energy transfer characteristics of the dynamic stall.Especially when the phase difference between the trailing-edge motion and the wing pitch is-π/2,the interaction between the three-dimensional(3-D)Leading-Edge Vortex(LEV)and Trailing-Edge Vortex(TEV)is strengthened,and the work done by the aerodynamic force turns negative.This indicates that the trailing-edge deformation has the potential to suppress the oscillation amplitude of stall flutter.We also found that as the trailing-edge camber morphing varies more complexly along the spanwise direction,the suppression effect decreases accordingly.
基金financial support from the National Key Research and Development Program of China(2023YFC3208002)National Natural Science Foundation of China(NSFC)(52370007)+2 种基金the Natural Science Foundation of Heilongjiang Province(YQ2022E034)Project funded by China Postdoctoral Science Foundation(2019 M651290,2019 M651290)State Key Laboratory of Urban Water Resource and Environment(Harbin Institute of Technology)(No.2021TS27)。
文摘Nanofiltration(NF)membranes with exceptional ion selectivity and permeability are needed for the recovery of lithium from waste lithium-ion batteries.Herein,inspired by the homogeneous microchannels in the skeletal structure of glass sponges,an innovative biomimetic sponge-like sub-nanostructured NF membrane was designed using an alkali-induced MXene(AMXene)-ethyl formate(EF)-induced bulk/interfacial diffusion decoupling strategy to simultaneously improve Li^(+)/Co^(2+)selectivity and membrane permeability.The Li^(+)/Co^(2+)separation factor(SLi,co=24)of the engineered membrane was improved by an order of magnitude compared to that of an NF270 membrane(SLi,Co=2).The selectivity of Mg^(2+)/Na+(B_(NaCl)/B_(MgCl_(2))=286)and SO_(4)^(2-)/Cl^(-)(BNaCl/BNaSO_(4)=941)increased by 3~12 times,and the permeability(25.8 L m-2 h-1 bar-1)remained at a desirable level,beyond the current upper bound of the other cutting-edge membranes.The superior performance was attributed to the limited release of amine in bulk phase and the boosted interfacial diffusion by reducing interfacial energy barrier during the interfacial polymerization reaction,which were realized via the synergetic effects of AMXene and EF.This approach yielded a biomimetic sponge-like sub-nanostructured NF membrane with controlled homogeneous pore radii(0.202 nm)and a thickness as small as 16.08 nm,which led to high ion selectivity and permeability.The engineered membrane was capable of efficient separation and recovery of Li^(+)/metal ions.
基金This study was supported by the National Natural Science Foundation of China(Grant Nos.41601454 and 41671397,URL:http://www.nsfc.gov.cn/)Science and Technology Development Project of Jilin Province,China(Grant No.20191001008XH,URL:http://www.jlkjxm.com/)+2 种基金Science Foundation of Jilin Provincial Education Department,China(Grant No.:JJKH20200329KJ,URL:http://jyt.jl.gov.cn/)Development and Reform Commission Project of Jilin Province,China(Grant No.2020C037-7,URL:http://jldrc.jl.gov.cn/)Ecology and Environment Department Project of Jilin Province,China(Grant Nos.2019-02 and 2020-18,URL:http://sthjt.jl.gov.cn/).
文摘This paper proposes a formation of multiple unmanned aerial vehicles(UAVs)based on the R5DOS(RCC-5 and orientation direction)intersection model.After improving the R5DOS-intersection model,we evenly arranged 16 UAVs in 16 spatial regions.Compared with those of the rectangular formation model and the grid formation model,the communication costs,time costs,and energy costs of the R5DOS model formation were effectively reduced.At the same time,the operation time of UAV formation was significantly enhanced.The leader-follower method can enhance the robustness of the UAV formation and ensure the integrity of communication during UAV formation operation.Finally,we conducted a simulation experiment on the model and found that the R5DOS model formation was stable and could maintain the desired formation.The randomly generated UAVs could quickly fly to the formation path in a short time,establish formation,and carry out operations.When the leader fails,the follower could travel to the original trajectory of the failed leader in a short time,replace the leader,and continue to communicate and improve the robustness of the formation.To sum up,the UAV formation based on the R5DOS model has the advantages of long operation time,strong endurance,low communication cost,and stable formation,which is of great significance for research on UAV formation.
基金funded by National Defense Basic Research Program,grant number JCKY2019411B001funded by National Key Research and Development Program,grant number 2022YFC3601305funded by Key R&D Projects of Jilin Provincial Science and Technology Department,grant number 20210203218SF.
文摘The Coordinate Descent Method for K-means(CDKM)is an improved algorithm of K-means.It identifies better locally optimal solutions than the original K-means algorithm.That is,it achieves solutions that yield smaller objective function values than the K-means algorithm.However,CDKM is sensitive to initialization,which makes the K-means objective function values not small enough.Since selecting suitable initial centers is not always possible,this paper proposes a novel algorithm by modifying the process of CDKM.The proposed algorithm first obtains the partition matrix by CDKM and then optimizes the partition matrix by designing the split-merge criterion to reduce the objective function value further.The split-merge criterion can minimize the objective function value as much as possible while ensuring that the number of clusters remains unchanged.The algorithm avoids the distance calculation in the traditional K-means algorithm because all the operations are completed only using the partition matrix.Experiments on ten UCI datasets show that the solution accuracy of the proposed algorithm,measured by the E value,is improved by 11.29%compared with CDKM and retains its efficiency advantage for the high dimensional datasets.The proposed algorithm can find a better locally optimal solution in comparison to other tested K-means improved algorithms in less run time.
基金supported by the National Natural Science Foundation of China(Grant Nos.12188101,11834006,12004170,and 12334007)the National Key R&D Program of China(Grant No.2022YFA1403601)+2 种基金the Natural Science Foundation of Jiangsu Province(Grant No.BK20200326)the excellent programme in Nanjing Universitysupported by the New Cornerstone Science Foundation through the XPLORER PRIZE。
文摘As the first magnetic kagome material to exhibit the charge density wave(CDW)order,FeGe has attracted much attention in recent research.Similar to AV_(3)Sb_(5)(A=K,Cs,Rb),FeGe exhibits the CDW pattern with an in-plane 2×2 structure and the existence of van Hove singularities near the Fermi level.However,sharply different from AV_(3)Sb_(5)which has phonon instability at M point,all the theoretically calculated phonon frequencies in FeGe remain positive.Based on first-principles calculations,we surprisingly find that the maximum of nesting function is at K point instead of M point.Two Fermi pockets with Fe-d_(xz)and Fe-d_(x^(2)-y^(2))/d_(xy)orbital characters have large contribution to the Fermi nesting,which evolve significantly with k_(z),indicating the highly three-dimensional(3D)feature of FeGe in contrast to AV_(3)Sb_(5).Considering the effect of local Coulomb interaction,we reveal that the instability at K point is significantly suppressed due to the sublattice interference mechanism.Meanwhile,the wave functions nested by vector M have many ingredients located at the same Fe site,thus the instability at M point is enhanced.This indicates that the electron correlation,rather than electron-phonon interaction,plays a key role in the CDW transition at M point.
基金supported by the National Natural Science Foundation of China(82294366062 to X.L.)Beijing Municipal Science and Technology Commission(Z231100007223007 to G.C.Y.and X.L.)Shandong Provincial Natural Science Foundation(ZR2023LSW006toX.L.).
文摘The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy.Although many cancers originate in mucosal tissues,current RNA cancer vaccines are mainly administered non-mucosally.Here,we developed a non-invasive intranasal cancer vaccine utilizing circular RNA encapsulated in lipid nanoparticles to induce localized mucosal immune responses.This strategy elicited potent anti-tumor T cell responses in preclinical lung cancer models while mitigating the systemic adverse effects commonly associated with intravenous RNA vaccination.Specifically,type 1 conventional dendritic cells were indispensable for T cell priming post-vaccination,with both alveolar macrophages and type 1 conventional dendritic cells boosting antigen-specific T cell responses in lung tissues.Moreover,the vaccination facilitated the expansion of both endogenous and adoptive transferred antigen-specific T cells,resulting in robust anti-tumor efficacy.Single-cell RNA sequencing revealed that the vaccination reprograms endogenous T cells,enhancing their cytotoxicity and inducing a memory-like phenotype.Additionally,the intranasal vaccine can modulate the response of CAR-T cells to augment therapeutic efficacy against tumor cells expressing specific tumor-associated antigens.Collectively,the intranasal RNA vaccine strategy represents a novel and promising approach for developing RNA vaccines targeting mucosal malignancies.
基金National Natural Science Foundation of China,Grant/Award Numbers:82403009,82103595the Guangdong Basic and Applied Basic Research Foundation,Grant/Award Numbers:2022A1515111142,2023A1515011789,2023A1515010980,2025A1515011911+2 种基金Science and Technology Program of Guangzhou,Grant/Award Number:2025A04J4189Outstanding Youth Cultivation Program of Nanfang Hospital of Southern Medical University,Grant/Award Number:2020J010China Postdoctoral Science Foundation,Grant/Award Number:2023M731542。
文摘Background:Colorectal cancer liver metastasis(CRLM)is characterized by an immunosuppressive microenvironment and a blunted response to immunotherapy.Notably,tumor-associated macrophages(TAMs)play a critical role in modulating immune responses and exhibit significant heterogeneity in CRLM.Sphingosine kinase 1(SPHK1)serves as a pivotal kinase in maintaining the balance between ceramide and sphingosine-1-phosphate(S1P)levels.However,the effects of SPHK1 within TAMs on tumor immune evasion during CRLM remain elusive.This study aimed at investigating the role of TAM-intrinsic SPHK1 in tumor immunosuppressive microenvironment in CRLM.Methods:SPHK1 expression levels in TAMs were estimated by immunofluorescence and bioinformatics analysis.Several animal models were established to elucidate the role of SPHK1 in tumor immunity reprogramming in vivo.Flow cytometry,cytokine assay,and transwell assay were conducted to investigate the effects of SPHK1 in TAMs in cell-cell communication in vitro.RNA-sequencing,Western blotting,and quantitative real-time polymerase chain reaction were used to explore the molecularmechanism by which SPHK1 activatedNLR family pyrin domain containing 3(NLRP3)inflammasome in TAMs.Results:We found that SPHK1 was mainly expressed in TAMs and identified SPHK1+TAMs as associated with CRLM and diminished efficacy of immunotherapy in human patients.These SPHK1+TAMs exhibited strong immunosuppressive activities by inducing CD8^(+)T cell exhaustionwith high programmed cell death 1(PD-1)expression via the interaction between TAMs and CRC cells.Mechanistically,SPHK1-produced S1P exerted an autocrine effect to activate NLRP3 inflammasome and interleukin 1 beta(IL-1β)release via nuclear factor-kappa B(NF-κB)and hypoxia inducible factor 1 subunit alpha(HIF-1α)signaling in TAMs.Paracrine IL-1β then upregulated the expression of monocyte chemoattractants and ADAM metallopeptidase domain 17(ADAM17)sheddase in CRC cells,resulting in TAM infiltration and CD8^(+)T cell dysfunction in the liver microenvironment.Furthermore,combining SPHK1-targeting treatments with anti-PD-1 therapy or radioimmunotherapy largely stalled liver metastasis and caused a significant extension of lifespan in preclinical mouse models.Conclusions:Our findings highlighted the role of SPHK1 of TAMs in facilitating CRLM by promoting CD8^(+)T cell dysfunction and immunosuppressive microenvironment.Combining SPHK1 blockade with anti-PD-1 therapy may be a promising treatment regimen for patients with CRLM.
基金supported by the National Key R&D Program of China(2023YFC3404900,2020YFA0908000)the Key Project at the Central Government Level,“The Ability Establishment of Sustainable Use for Valuable Chinese Medicine Resources”(2060302)+2 种基金the National Natural Science Foundation of China(82003902,82003894)the Fundamental Research Funds for Central Public Welfare Research Institutes(ZZXT202008,ZZ14-YQ-046)the Scientific and Technological Innovation Project of the China Academy of Chinese Medical Sciences(CI2021B014).
文摘Cytochrome P450(CYP450)enzymes,as versatile biocatalysts with the broadest range of catalytic reactions in nature,play critical roles in the metabolism of medicinal plants.They are involved in various oxidative modification processes of active ingredients,facilitating both the synthesis and degradation of bioactive substances.This review delves into the classification,structure,and catalytic mechanisms of CYP450 enzymes,emphasizing their indispensable roles in plant biosynthesis.Using representative cases,including the biosynthetic pathways of tanshinones,artemisinin,celastrol,paclitaxel,and berberine,this review highlights the functional importance of specific CYP450s.For instance,CYP71AV1 catalyzes the production of artemisinin and artemisinic aldehyde,with its activity directly affecting artemisinin yield.Similarly,CYP76AH1 and CYP76AK1 play pivotal roles in the backbone construction and postmodification of tanshinones,acting as key players in their metabolic network.In the case of celastrol,CYP712K1,CYP712K2,and CYP712K3 initiate the first oxidative reaction,providing a solid foundation for subsequent biosynthetic processes.These examples highlight the pivotal role of CYP450 enzymes in the biosynthesis of medicinal plants,showcasing both their complexity and significance in plant metabolic pathways.Furthermore,this review examines the oxidative metabolism of CYP450 enzymes under aerobic conditions and their reductive metabolism in specific environments,offering deeper insights into their catalytic mechanisms.A comprehensive understanding of these processes lays the groundwork for the effective application of CYP450 enzymes in biotechnology and plant metabolic engineering.
基金supported in part by the Key Science and Technology Project of Jilin Province,China(No.20240304028SF)the Funding of Jilin Province Science and Technology(No.JJKH20240422KJ).
文摘Nonconvex Activated Fuzzy Zeroing Neural Network-based(NAFZNN)and Nonconvex Activated Fuzzy Noise-Tolerant Zeroing Neural Network-based(NAFNTZNN)models are devised and analyzed,drawing inspiration from the classical ZNN/NTZNN-based model for online addressing Time-Varying Quadratic Programming Problems(TVQPPs)with Equality and Inequality Constraints(EICs)in noisy circumstances,respectively.Furthermore,the proposed NAFZNN model and NAFNTZNN model are considered as general proportion-differentiation controller,along with general proportion-integration-differentiation controller.Besides,theoretical results demonstrate the global convergence of both the NAFZNN and NAFNTZNN models for TVQPPs with EIC under noisy conditions.Moreover,numerical results illustrate the efficiency,robustness,and ascendancy of the NAFZNN and NAFZNN models in addressing TVQPPs online,exhibiting inherent noise tolerance.Ultimately,an application example to plant leaf disease identification is conducted to support the feasibility and efficacy of the designed NAFNTZNN model,which shows its potential practical value in the field of image recognition.
基金supported by the National Key R&D Program of China(2020YFA0908000)Scientific and technological innovation project of China Academy of Chinese Medical Sciences(CI2023D002,CI2023E002,CI2021A04110,CI2021B014)+1 种基金the National Natural Science Foundation of China(81822046)Key project at central government level:The ability to establish sustainable use of valuable Chinese medicine resources(2060302).
文摘Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products(PNPs).Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient production of PNPs through synthetic biology.In this study,we engineered Saccharomyces cerevisiae to optimize the microenvironment for boosting the activities of P450s,including coexpression with the redox partner genes,enhancing NADPH supply,expanding the endoplasmic reticulum(ER),strengthening heme biosynthesis,and regulating iron uptake.This created a platform for the efficient production 11,20-dihydroxyferruginol,a key intermediate of the bioactive compound tanshinones.The yield was enhanced by 42.1-fold through 24 effective genetic edits.The optimized strain produced up to 67.69±1.33 mg/L 11,20-dihydroxyferruginol in shake flasks.Our work represents a promising advancement toward constructing yeast cell factories containing P450s and paves the way for microbial biosynthesis of tanshinones in the future.
基金The work is supported by the National Natural Science Foundation of China(NSFC:32125021,92254308,91957119,91954001,31571213 to X.W.C,32100947 to X.W.,and 62027901 to J.T.)the National Key R&D Program(2021YFA0804802).
文摘Precise control of circulating lipid levels is vital in both health and disease.We recently uncovered that bulk lipids,transported by lipoproteins,enter the circulation initially via the coat protein complex II(COPII)in a condensation-dependent manner.Divalent manganese,acting as a signaling messenger,selectively controls COPII condensation to regulate lipid homeostasis in vivo.Here,we present evidence for a manganese-based therapy in murine models of hypolipidemia and hyperlipidemia.
文摘Bacterial cellulose is a versatile material with applications in many industries. However, the widespread uptake of bacterial cellulose faces challenges including high production costs and lack of scalability. One approach to address these obstacles is the use of alternative substrates and media, compared to the Hestrin-Schramm (HS) media. By evaluating and selecting appro- priate media and substrates, the production of bacterial cellulose can be more efficient: enabling sustainable systems and supply chains where less energy and materials are lost, and the output production is increased. The purpose of this paper is to analyze the current landscape of bac- terial cellulose alternative media and substrates (ingredients). Through a systematic review of 198 papers, this review identifies 299 alternative substrates from 12 industries and 101 bacte- rial cellulose-producing strains, which were systematically compared. This review also finds that there are methodological gaps in this field such as data variability, papers mislabelling the HS media or not using a comparison media, and a lack of strain names. This alternative substrate analysis for bacterial cellulose production demonstrates that overall, for some applications al- ternative substrates can be taken into consideration that are not only cheaper, but also produce higher yields than HS media.
