This paper focuses on the influence of glycidyl methacrylate functionalized polyolefin elastomer (SOG-03) on the properties of PC/PBT alloys, and also made a contrastive analysis with ethylene-methyl acrylate-glycidyl...This paper focuses on the influence of glycidyl methacrylate functionalized polyolefin elastomer (SOG-03) on the properties of PC/PBT alloys, and also made a contrastive analysis with ethylene-methyl acrylate-glycidyl methacrylate terpolymer (EMA-co-GMA) and methyl methacrylate-butadiene-styrene terpolymer (MBS), the common toughener in PC/PBT alloy. The impact performance test results of PC/PBT alloys with different addition of SOG-03 showed that the brittle-ductile transition began when SOG-03 content reached 3 wt%. The microstructure, differential scanning calorimeter (DSC) and multi-extrusion process results of PC/PBT alloys all showed that SOG-03 tends to be dispersed in PBT phase and the dispersed SOG-03 presents typical rubber-toughened polymer morphology. The toughening efficiency of MBS on PC/PBT alloy was much lower than EMA-co-GMA and SOG-03, and showed a worse processing stability after multi-extrusion process and long-term thermal ageing properties. The EMA-co-GMA and SOG-03 toughened PC/PBT alloys showed an equivalent toughness, while the PC/PBT alloy with SOG-03 showed a better processing stability during the multi-extrusion process and long-term thermal ageing property when the thermal aging time is more than 600 h.展开更多
The enzyme-mediated elevation of reactive oxygen species(ROS)at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment.Herein,we proposed a camouflaged bioni...The enzyme-mediated elevation of reactive oxygen species(ROS)at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment.Herein,we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on Ti_(3)C_(2)nanosheets for combined tumor enzyme dynamic therapy(EDT),phototherapy and deoxygenation-activated chemotherapy.Briefly,glucose oxidase(GOX)and chloroperoxidase(CPO)were chemically conjugated onto Ti_(3)C_(2)nanosheets,where the deoxygenation-activated drug tirapazamine(TPZ)was also loaded,and the Ti_(3)C_(2)-GOX-CPO/TPZ(TGCT)was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47(m_eTGCT).Due to biomimetic membrane camouflage and CD47 overexpression,m_eTGCT exhibited superior immune escape and homologous targeting capacities,which could effectively enhance the tumor preferential targeting and internalization.Once internalized into tumor cells,the cascade reaction of GOX and CPO could generate HClO for efficient EDT.Simultaneously,additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen(~1O_(2)).Furthermore,local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy.Consequently,m_eTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy,EDT and chemotherapy for efficient tumor inhibition.This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.展开更多
Background:Nitrogen(N)saturation theory proposes that an ecosystem might switch from N limitation to carbon(C),phosphorus(P),or other nutrient limitations if it receives continuous N input.Yet,after N limitation is re...Background:Nitrogen(N)saturation theory proposes that an ecosystem might switch from N limitation to carbon(C),phosphorus(P),or other nutrient limitations if it receives continuous N input.Yet,after N limitation is removed,which nutrient is the most limited and whether topography modulates such change is rarely tested at a microbial level.Here,we conducted a two-year N addition experiment under two different topography positions(i.e.a slope and a valley)in a N-saturated subtropical forest.Soil enzyme activity was measured,and ecoenzymatic stoichiometry indexes were calculated as indicators of microbial resource limitation.Results:In the valley,two-year N addition changed the activity of all studied enzymes to various degrees.As a result,microbial C limitation was aggravated in the valley,and consequently microbial decomposition of soil labile organic C increased,but microbial P limitation was alleviated due to the stoichiometry balance.On the slope,however,N addition did not significantly change the activity of the studied enzymes,and did not alter the status of microbial resource limitation.Conclusions:These results indicate that C is a more limited element for microbial growth than P after removing N limitation,but we also highlight that topography can regulate the effect of N deposition on soil microbial resource limitation in subtropical forests.These findings provide useful supplements to the N saturation theory.展开更多
The mechanical, morphological and thermo-oxidative aging properties of the glass fiber reinforced polypropylene (RGF-PP) were studied based on four different maleic anhydride grafted polypropylene (PP-g-MAH) compatibi...The mechanical, morphological and thermo-oxidative aging properties of the glass fiber reinforced polypropylene (RGF-PP) were studied based on four different maleic anhydride grafted polypropylene (PP-g-MAH) compatibilizers with different content of residual maleic anhydride (MAH). It was shown that PP-g-MAH compatibilizer could significantly improve the mechanical properties of RGF-PP, while from thermal and morphological analysis results, the content of residual MAH had negative influence on long term thermo- oxidative aging properties of RGF-PP with adding PP-g-MAH compatibilizer;the lower the residual content of MAH is, the better the thermo stability of the PP-g-MAH is, and also the better the thermo-oxidative aging properties was obtained.展开更多
Image-guided thermal ablation(TA),which is less invasive,has been widely applied for treating various kinds of tumors.However,TA still poses the potential risk of thermal damage to sensitive tissue nearby.Therefore,an...Image-guided thermal ablation(TA),which is less invasive,has been widely applied for treating various kinds of tumors.However,TA still poses the potential risk of thermal damage to sensitive tissue nearby.Therefore,an adjunctive thermoprotective hydrodissection technique with constant injection of 5%glucose(5%Glu)has currently been adopted for clinical application,but this may be hazardous to humans.In this study,a multifunctional hyaluronic acid-based hydrogel(HA-Dc)was developed for hydrodissection.Compared with 5%Glu(the most clinically used solution)and the previously reported F127 hydrogel,the HA-Dc hydrogel was studied in vitro in a porcine liver model and in vivo in a rabbit model and showed good injectability and better tissue retention,stability,and thermoprotective properties throughout the TA procedure.Furthermore,in the preclinical evaluation in a Macaca fascicularis(M.fascicularis)model,HA-Dc showed excellent performance in terms of stricter neuroprotection compared with 5%Glu.In addition,the HA-Dc hydrogel with good biocompatibility and controllable degradation behavior in vivo could be a promising platform for thermal protection during clinical TA procedures.展开更多
With the large-scale integration of renewable energy,the traditional maintenance arrangement during the load valley period cannot satisfy the transmission demand of renewable energy generation.Simultaneously,in a mark...With the large-scale integration of renewable energy,the traditional maintenance arrangement during the load valley period cannot satisfy the transmission demand of renewable energy generation.Simultaneously,in a market-oriented operation mode,the power dispatching control center aims to reduce the overall power purchase cost while ensuring the security of the power system.Therefore,a security-constrained transmission maintenance optimization model considering generation and operational risk costs is proposed herein.This model is built on double-layer optimization framework,where the upper-layer model is used for maintenance and generation planning,and the lowerlayer model is primarily used to address the operational security risk arising from the random prediction error and N-1 transmission failure.Correspondingly,a generation-maintenance iterative algorithm based on a defined cost feedback is included to increase solution efficiency.Generation cost is determined using long-term security-constrained unit commitment,and the operational risk cost is obtained using a double-layer N-1 risk assessment model.An electrical correlation coupling coefficient is proposed for the solution process to avoid maintenance of associated equipment simultaneously,thereby improving model convergence efficiency.The IEEE 118-bus system is used as a test case for illustration,and test results suggest that the proposed model and algorithm can reduce the total cost of transmission maintenance and system operation while effectively improving the solution efficiency of the joint optimization model.展开更多
Medium-voltage distribution systems(MVDSs)mainly consist of a feeder head,lines,distribution transformers,and the equivalent load or power supply interfaced with the distribution transformers.The information of such l...Medium-voltage distribution systems(MVDSs)mainly consist of a feeder head,lines,distribution transformers,and the equivalent load or power supply interfaced with the distribution transformers.The information of such load or power supply can be measured via the three-wattmeter method(THM)and the two-wattmeter method(TWM).The measurements can be used to perform the control of the power supply and simulate the characteristics of the load,so the models of the load and the power supply need to consider the measurement characteristics.Existing research works on three-phase power flow(PF)just consider the measurement characteristics of THM.Hence,the PF equation of the bus measured via TWM is firstly built.Based on conventional measurements,an accurate and general model of the grounded and ungrounded slack bus is proposed.Furthermore,the influence arising from the connection type and angle shift of distribution transformers on the admittance matrix is considered,and thus a general three-phase transformer model is summarized,which is applicable for all the transformers mentioned herein.Finally,Newton's method is adopted to solve the PF calculation,and the performance of the proposed PF model is demonstrated through designed tests.展开更多
Gene regulatory network(GRN)refers to the complex network formed by regulatory interactions between genes in living cells.In this paper,we consider inferring GRNs in single cells based on single-cell RNA sequencing(sc...Gene regulatory network(GRN)refers to the complex network formed by regulatory interactions between genes in living cells.In this paper,we consider inferring GRNs in single cells based on single-cell RNA sequencing(scRNA-seq)data.In scRNA-seq,single cells are often profiled from mixed populations,and their cell identities are unknown.A common practice for single-cell GRN analysis is to first cluster the cells and infer GRNs for every cluster separately.However,this two-step procedure ignores uncertainty in the clustering step and thus could lead to inaccurate estimation of the networks.Here,we consider the mixture Poisson lognormal model(MPLN)for network inference of count data from mixed populations.The precision matrices of the MPLN are the GRNs of different cell types.To avoid the intractable optimization of the MPLN’s log-likelihood,we develop an algorithm called variational mixture Poisson log-normal(VMPLN)to jointly estimate the GRNs of different cell types based on the variational inference method.We compare VMPLN with state-of-the-art single-cell regulatory network inference methods.Comprehensive simulation shows that VMPLN achieves better performance,especially in scenarios where different cell types have a high mixing degree.Benchmarking on real scRNA-seq data also demonstrates that VMPLN can provide more accurate network estimation in most cases.Finally,we apply VMPLN to a large scRNA-seq dataset from patients infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and find that VMPLN identifies critical differences in regulatory networks in immune cells between patients with moderate and severe symptoms.The source codes are available on the GitHub website(github.com/XiDsLab/SCVMPLN).展开更多
Nanomaterial-mediated phototherapy in tumor treatment has been developed rapidly in the past few years due to its noninvasive character.However,the low energy conversion efficiency and high recombination rate of the p...Nanomaterial-mediated phototherapy in tumor treatment has been developed rapidly in the past few years due to its noninvasive character.However,the low energy conversion efficiency and high recombination rate of the photo-triggered electron–hole pairs of single nano-agent limit the phototherapy efficiency.Herein,we constructed a novel two-dimensional nanoheterojunction MoS_(2)-Ti_(3)C_(2)(MT),which allowed a high photothermal conversion efficiency(59.1%)as well as an effective separation of photo-triggered electron–hole pairs for reactive oxygen species(ROS)generation under single 808 nm laser irradiation.Upon the modification of the mitochondrial targeted molecule(3-proxycarboxylic)triphenyl phosphine bromide(TPP)and 4T1 cell membrane,m@MoS_(2)-Ti_(3)C_(2)/TPP(m@MTT)could effectively target to the tumor cell and further locate to the mitochondria to amplify tumor-specific oxidative stress,which not merely effectively inhibits the local tumor growth but also induces tumor immunogenic cell death(ICD)for activating antitumor immune response.Additionally,cytosine guanine dinucleotide(CPG),as a Toll-like receptor 9(TLR9)agonist,was further introduced to the system to boost adaptive immune responses,resulting in improved level of cytotoxic T cells as well as a decrease in the number of regulatory T cells.In vivo antitumor mechanism studies demonstrated that not only the primary and distant tumors in 4T1 bearing-tumor mice model were significantly inhibited,but also the lung metastasis of tumor was effectively suppressed.Therefore,this work revealed the ROS generation mechanism of MT nanoheterojunction and provided a novel strategy to fabricate a biomedically applicable MT nanoheterojunction for tumor treatment.展开更多
Photo-immunotherapy is a novel therapeutic approach against malignant tumors with minimal invasiveness.Herein,a targeting multifunctional black phosphorus(BP)nanoparticle,modified by PEGylated hyaluronic acid(HA),was ...Photo-immunotherapy is a novel therapeutic approach against malignant tumors with minimal invasiveness.Herein,a targeting multifunctional black phosphorus(BP)nanoparticle,modified by PEGylated hyaluronic acid(HA),was designed for photothermal/photodynamic/photo-immunotherapy.In vitro and in vivo assays indicated that HA-BP nanoparticles possess excellent biocompatibility,stability,and sufficient therapeutic efficacy in the combined therapy of photothermal therapy(PTT)and photodynamic therapy(PDT)for cancer therapy.Moreover,the results of in vitro showed that HA-BP down-regulated the expression of CD206(M2 macrophage marker)by 42.3%and up-regulated the ratio of CD86(M1 macrophage marker)by 59.6%,indicating that HABP nanoparticles have functions in remodeling tumor associated macrophages(TAMs)phenotype(from protumor M2 TAMs to anti-tumor M1 macrophages).Fluorescence(FL)and photoacoustic(PA)multimodal imaging confirmed the selective accumulation of HA-BP in tumor site via both CD44^+mediated active targeting and passive EPR effect.In vitro and in vivo studies suggested that the combined therapy of PDT,PTT and immunotherapy using HA-BP could not only significantly inhibit original tumor but also induce immunogenic cell death(ICD)and release Damage-associated molecular patterns(DAMPs),which could induce maturation of dendritic cells(DCs)and activate effector cells that robustly evoke the antitumor immune responses for cancer treatment.This study expands the biomedical application of BP nanoparticles and displays the potential of modified BP as a multifunctional therapeutic platform for the future cancer therapy.展开更多
Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we...Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we have designed and developed an oxygen-independent,ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles.The formulated artemether(ART)/Fe_(3)O_(4)-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth.Besides,the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe^(2+)ions formed in situ at acidic pH and external ultrasound irradiation,which is not affected by hypoxia tumor microenvironment.Consequently,the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs,achieving an incredible antitumor potency.Specifically,upon the chemo-sonodynamic therapy by ART/Fe_(3)O_(4)-loaded PEG-PPMDT NPs,all xenotransplants of human hepatocellular carcinoma(HepG2)in nude mice shrank significantly,and 40% of the tumors were completely eliminated.Importantly,the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures.Further,biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs.Thus,our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.展开更多
文摘This paper focuses on the influence of glycidyl methacrylate functionalized polyolefin elastomer (SOG-03) on the properties of PC/PBT alloys, and also made a contrastive analysis with ethylene-methyl acrylate-glycidyl methacrylate terpolymer (EMA-co-GMA) and methyl methacrylate-butadiene-styrene terpolymer (MBS), the common toughener in PC/PBT alloy. The impact performance test results of PC/PBT alloys with different addition of SOG-03 showed that the brittle-ductile transition began when SOG-03 content reached 3 wt%. The microstructure, differential scanning calorimeter (DSC) and multi-extrusion process results of PC/PBT alloys all showed that SOG-03 tends to be dispersed in PBT phase and the dispersed SOG-03 presents typical rubber-toughened polymer morphology. The toughening efficiency of MBS on PC/PBT alloy was much lower than EMA-co-GMA and SOG-03, and showed a worse processing stability after multi-extrusion process and long-term thermal ageing properties. The EMA-co-GMA and SOG-03 toughened PC/PBT alloys showed an equivalent toughness, while the PC/PBT alloy with SOG-03 showed a better processing stability during the multi-extrusion process and long-term thermal ageing property when the thermal aging time is more than 600 h.
基金This work was supported by the National Natural Science Foundation of China(51773231)Shenzhen Science and Technology Project(JCYJ20190807160801664)the Project of Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province(2011A060901013).
文摘The enzyme-mediated elevation of reactive oxygen species(ROS)at the tumor sites has become an emerging strategy for regulating intracellular redox status for anticancer treatment.Herein,we proposed a camouflaged bionic cascaded-enzyme nanoreactor based on Ti_(3)C_(2)nanosheets for combined tumor enzyme dynamic therapy(EDT),phototherapy and deoxygenation-activated chemotherapy.Briefly,glucose oxidase(GOX)and chloroperoxidase(CPO)were chemically conjugated onto Ti_(3)C_(2)nanosheets,where the deoxygenation-activated drug tirapazamine(TPZ)was also loaded,and the Ti_(3)C_(2)-GOX-CPO/TPZ(TGCT)was embedded into nanosized cancer cell-derived membrane vesicles with high-expressed CD47(m_eTGCT).Due to biomimetic membrane camouflage and CD47 overexpression,m_eTGCT exhibited superior immune escape and homologous targeting capacities,which could effectively enhance the tumor preferential targeting and internalization.Once internalized into tumor cells,the cascade reaction of GOX and CPO could generate HClO for efficient EDT.Simultaneously,additional laser irradiation could accelerate the enzymic-catalytic reaction rate and increase the generation of singlet oxygen(~1O_(2)).Furthermore,local hypoxia environment with the oxygen depletion by EDT would activate deoxygenation-sensitive prodrug for additional chemotherapy.Consequently,m_eTGCT exhibits amplified synergistic therapeutic effects of tumor phototherapy,EDT and chemotherapy for efficient tumor inhibition.This intelligent cascaded-enzyme nanoreactor provides a promising approach to achieve concurrent and significant antitumor therapy.
基金funded by the Strategic Priority Research Program of Chinese Academy of Sciences(XDA13010302)the National Natural Science Foundation of China(Nos.31872691,41877094,and 31760153)+1 种基金Guangxi Bagui Scholarship Program to Dejun LiNational High-Level Talents Special Support Program to Dejun Li.
文摘Background:Nitrogen(N)saturation theory proposes that an ecosystem might switch from N limitation to carbon(C),phosphorus(P),or other nutrient limitations if it receives continuous N input.Yet,after N limitation is removed,which nutrient is the most limited and whether topography modulates such change is rarely tested at a microbial level.Here,we conducted a two-year N addition experiment under two different topography positions(i.e.a slope and a valley)in a N-saturated subtropical forest.Soil enzyme activity was measured,and ecoenzymatic stoichiometry indexes were calculated as indicators of microbial resource limitation.Results:In the valley,two-year N addition changed the activity of all studied enzymes to various degrees.As a result,microbial C limitation was aggravated in the valley,and consequently microbial decomposition of soil labile organic C increased,but microbial P limitation was alleviated due to the stoichiometry balance.On the slope,however,N addition did not significantly change the activity of the studied enzymes,and did not alter the status of microbial resource limitation.Conclusions:These results indicate that C is a more limited element for microbial growth than P after removing N limitation,but we also highlight that topography can regulate the effect of N deposition on soil microbial resource limitation in subtropical forests.These findings provide useful supplements to the N saturation theory.
文摘The mechanical, morphological and thermo-oxidative aging properties of the glass fiber reinforced polypropylene (RGF-PP) were studied based on four different maleic anhydride grafted polypropylene (PP-g-MAH) compatibilizers with different content of residual maleic anhydride (MAH). It was shown that PP-g-MAH compatibilizer could significantly improve the mechanical properties of RGF-PP, while from thermal and morphological analysis results, the content of residual MAH had negative influence on long term thermo- oxidative aging properties of RGF-PP with adding PP-g-MAH compatibilizer;the lower the residual content of MAH is, the better the thermo stability of the PP-g-MAH is, and also the better the thermo-oxidative aging properties was obtained.
基金financially supported by the National Natural Science Foundation of China(81971632,51773231)the Natural Science Foundation of Guangdong Province(2020A1515010425,2022A1515010024)+1 种基金Key Scientific and Technological Program of Guangzhou City(201802020023)Shenzhen Science and Technology Project(JCYJ20190807160801664,JCYJ20220818103207016).
文摘Image-guided thermal ablation(TA),which is less invasive,has been widely applied for treating various kinds of tumors.However,TA still poses the potential risk of thermal damage to sensitive tissue nearby.Therefore,an adjunctive thermoprotective hydrodissection technique with constant injection of 5%glucose(5%Glu)has currently been adopted for clinical application,but this may be hazardous to humans.In this study,a multifunctional hyaluronic acid-based hydrogel(HA-Dc)was developed for hydrodissection.Compared with 5%Glu(the most clinically used solution)and the previously reported F127 hydrogel,the HA-Dc hydrogel was studied in vitro in a porcine liver model and in vivo in a rabbit model and showed good injectability and better tissue retention,stability,and thermoprotective properties throughout the TA procedure.Furthermore,in the preclinical evaluation in a Macaca fascicularis(M.fascicularis)model,HA-Dc showed excellent performance in terms of stricter neuroprotection compared with 5%Glu.In addition,the HA-Dc hydrogel with good biocompatibility and controllable degradation behavior in vivo could be a promising platform for thermal protection during clinical TA procedures.
基金supported by the Scientific and Technological Project of State Grid Corporation of China“Multilevel maintenance scheduling and its coordination with medium-term and long-term dispatching decision”(No.5442DZ210012)。
文摘With the large-scale integration of renewable energy,the traditional maintenance arrangement during the load valley period cannot satisfy the transmission demand of renewable energy generation.Simultaneously,in a market-oriented operation mode,the power dispatching control center aims to reduce the overall power purchase cost while ensuring the security of the power system.Therefore,a security-constrained transmission maintenance optimization model considering generation and operational risk costs is proposed herein.This model is built on double-layer optimization framework,where the upper-layer model is used for maintenance and generation planning,and the lowerlayer model is primarily used to address the operational security risk arising from the random prediction error and N-1 transmission failure.Correspondingly,a generation-maintenance iterative algorithm based on a defined cost feedback is included to increase solution efficiency.Generation cost is determined using long-term security-constrained unit commitment,and the operational risk cost is obtained using a double-layer N-1 risk assessment model.An electrical correlation coupling coefficient is proposed for the solution process to avoid maintenance of associated equipment simultaneously,thereby improving model convergence efficiency.The IEEE 118-bus system is used as a test case for illustration,and test results suggest that the proposed model and algorithm can reduce the total cost of transmission maintenance and system operation while effectively improving the solution efficiency of the joint optimization model.
基金supported in part by the National Natural Science Foundation of China(No.52177071).
文摘Medium-voltage distribution systems(MVDSs)mainly consist of a feeder head,lines,distribution transformers,and the equivalent load or power supply interfaced with the distribution transformers.The information of such load or power supply can be measured via the three-wattmeter method(THM)and the two-wattmeter method(TWM).The measurements can be used to perform the control of the power supply and simulate the characteristics of the load,so the models of the load and the power supply need to consider the measurement characteristics.Existing research works on three-phase power flow(PF)just consider the measurement characteristics of THM.Hence,the PF equation of the bus measured via TWM is firstly built.Based on conventional measurements,an accurate and general model of the grounded and ungrounded slack bus is proposed.Furthermore,the influence arising from the connection type and angle shift of distribution transformers on the admittance matrix is considered,and thus a general three-phase transformer model is summarized,which is applicable for all the transformers mentioned herein.Finally,Newton's method is adopted to solve the PF calculation,and the performance of the proposed PF model is demonstrated through designed tests.
基金National Key Research and Development Program of China,Grant/Award Numbers:2020YFE0204200,2020YFE0204000National Natural Science Foundation of China,Grant/Award Numbers:11971039,12371286Foundation of Shuanghu Laboratory,Grant/Award Number:SH‐2024JK01。
文摘Gene regulatory network(GRN)refers to the complex network formed by regulatory interactions between genes in living cells.In this paper,we consider inferring GRNs in single cells based on single-cell RNA sequencing(scRNA-seq)data.In scRNA-seq,single cells are often profiled from mixed populations,and their cell identities are unknown.A common practice for single-cell GRN analysis is to first cluster the cells and infer GRNs for every cluster separately.However,this two-step procedure ignores uncertainty in the clustering step and thus could lead to inaccurate estimation of the networks.Here,we consider the mixture Poisson lognormal model(MPLN)for network inference of count data from mixed populations.The precision matrices of the MPLN are the GRNs of different cell types.To avoid the intractable optimization of the MPLN’s log-likelihood,we develop an algorithm called variational mixture Poisson log-normal(VMPLN)to jointly estimate the GRNs of different cell types based on the variational inference method.We compare VMPLN with state-of-the-art single-cell regulatory network inference methods.Comprehensive simulation shows that VMPLN achieves better performance,especially in scenarios where different cell types have a high mixing degree.Benchmarking on real scRNA-seq data also demonstrates that VMPLN can provide more accurate network estimation in most cases.Finally,we apply VMPLN to a large scRNA-seq dataset from patients infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and find that VMPLN identifies critical differences in regulatory networks in immune cells between patients with moderate and severe symptoms.The source codes are available on the GitHub website(github.com/XiDsLab/SCVMPLN).
基金the National Natural Science Foundation of China(No.51773231)Shenzhen Science and Technology Project(No.JCYJ20190807160801664)the Foundation of Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument(No.2020B1212060077).
文摘Nanomaterial-mediated phototherapy in tumor treatment has been developed rapidly in the past few years due to its noninvasive character.However,the low energy conversion efficiency and high recombination rate of the photo-triggered electron–hole pairs of single nano-agent limit the phototherapy efficiency.Herein,we constructed a novel two-dimensional nanoheterojunction MoS_(2)-Ti_(3)C_(2)(MT),which allowed a high photothermal conversion efficiency(59.1%)as well as an effective separation of photo-triggered electron–hole pairs for reactive oxygen species(ROS)generation under single 808 nm laser irradiation.Upon the modification of the mitochondrial targeted molecule(3-proxycarboxylic)triphenyl phosphine bromide(TPP)and 4T1 cell membrane,m@MoS_(2)-Ti_(3)C_(2)/TPP(m@MTT)could effectively target to the tumor cell and further locate to the mitochondria to amplify tumor-specific oxidative stress,which not merely effectively inhibits the local tumor growth but also induces tumor immunogenic cell death(ICD)for activating antitumor immune response.Additionally,cytosine guanine dinucleotide(CPG),as a Toll-like receptor 9(TLR9)agonist,was further introduced to the system to boost adaptive immune responses,resulting in improved level of cytotoxic T cells as well as a decrease in the number of regulatory T cells.In vivo antitumor mechanism studies demonstrated that not only the primary and distant tumors in 4T1 bearing-tumor mice model were significantly inhibited,but also the lung metastasis of tumor was effectively suppressed.Therefore,this work revealed the ROS generation mechanism of MT nanoheterojunction and provided a novel strategy to fabricate a biomedically applicable MT nanoheterojunction for tumor treatment.
基金This work was supported by the National Natural Science Foundation of China(51773231)the Natural Science Foundation of Guangdong Province(2014A030312018,2016A030313315)the Project of Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province(2011A060901013).
文摘Photo-immunotherapy is a novel therapeutic approach against malignant tumors with minimal invasiveness.Herein,a targeting multifunctional black phosphorus(BP)nanoparticle,modified by PEGylated hyaluronic acid(HA),was designed for photothermal/photodynamic/photo-immunotherapy.In vitro and in vivo assays indicated that HA-BP nanoparticles possess excellent biocompatibility,stability,and sufficient therapeutic efficacy in the combined therapy of photothermal therapy(PTT)and photodynamic therapy(PDT)for cancer therapy.Moreover,the results of in vitro showed that HA-BP down-regulated the expression of CD206(M2 macrophage marker)by 42.3%and up-regulated the ratio of CD86(M1 macrophage marker)by 59.6%,indicating that HABP nanoparticles have functions in remodeling tumor associated macrophages(TAMs)phenotype(from protumor M2 TAMs to anti-tumor M1 macrophages).Fluorescence(FL)and photoacoustic(PA)multimodal imaging confirmed the selective accumulation of HA-BP in tumor site via both CD44^+mediated active targeting and passive EPR effect.In vitro and in vivo studies suggested that the combined therapy of PDT,PTT and immunotherapy using HA-BP could not only significantly inhibit original tumor but also induce immunogenic cell death(ICD)and release Damage-associated molecular patterns(DAMPs),which could induce maturation of dendritic cells(DCs)and activate effector cells that robustly evoke the antitumor immune responses for cancer treatment.This study expands the biomedical application of BP nanoparticles and displays the potential of modified BP as a multifunctional therapeutic platform for the future cancer therapy.
基金supported by the National Natural Science Foundation of China(51773231)the Natural Science Foundation of Guangdong Province(2016A030313315)+1 种基金Shenzhen Science and Technology Project(JCYJ20190807160801664)the Project of Key Laboratory of Sensing Technology and Biomedical Instruments of Guangdong Province(2011A060901013)。
文摘Although sonodynamic therapy(SDT)is a promising non-invasive tumor treatment strategy due to its safety,tissue penetration depth and low cost,the hypoxic tumor microenvironment limits its therapeutic effects.Herein,we have designed and developed an oxygen-independent,ROS-amplifying chemo-sonodynamic antitumor therapy based on novel pH/GSH/ROS triple-responsive PEG-PPMDT nanoparticles.The formulated artemether(ART)/Fe_(3)O_(4)-loaded PEG-PPMDT NPs can rapidly release drug under the synergistic effect of acidic endoplasmic pH and high intracellular GSH/ROS levels to inhibit cancer cell growth.Besides,the ROS level in the NPs-treated tumor cells is magnified by ART via interactions with both Fe^(2+)ions formed in situ at acidic pH and external ultrasound irradiation,which is not affected by hypoxia tumor microenvironment.Consequently,the enriched intracellular ROS level can cause direct necrosis of ROS-stressed tumor cells and further accelerate the drug release from the ROS-responsive PEG-PPMDT NPs,achieving an incredible antitumor potency.Specifically,upon the chemo-sonodynamic therapy by ART/Fe_(3)O_(4)-loaded PEG-PPMDT NPs,all xenotransplants of human hepatocellular carcinoma(HepG2)in nude mice shrank significantly,and 40% of the tumors were completely eliminated.Importantly,the Fe3O4 encapsulated in the NPs is an efficient MRI contrast agent and can be used to guide the therapeutic procedures.Further,biosafety analyses show that the PEG-PPMDT NPs possess minimal toxicity to main organs.Thus,our combined chemo-sonodynamic therapeutic method is promising for potent antitumor treatment by controlled release of drug and facile exogenous generation of abundant ROS at target tumor sites.