Take Chinese yew cooperative organization for example,different game structures of forestry cooperation model were analyzed,the elative merit and applicable occasion was discussed combined with empirical investigation...Take Chinese yew cooperative organization for example,different game structures of forestry cooperation model were analyzed,the elative merit and applicable occasion was discussed combined with empirical investigation,and some suggestions were given also.The results showed that depending entirely on normal forest farmers cooperate spontaneously is difficult.Policies should be designed from the perspective of promoted village cadres and influential family salons to cooperation.When market factors become the main obstacle,it is necessary to introduce companies,relax constraints of forest management and build the right market atmosphere.According to unequal status of company and forest farmers,develop the cooperation model of " company + cooperation organization + farmers".In certain circumstances,especially there are several companies vicious competition,the intervention of association can play a coordinating role.展开更多
Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)...Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)is unsatisfactory.Moreover,fatal side effects greatly impede CAR T cell application.Extracellular vesicles(EVs)are excellent carriers of therapeutic agents.Nevertheless,EVs mainly accumulate in the liver when administered without modification.As an envelope glycoprotein of Epstein–Barr viruses,gp350 can efficiently bind CD21 on B cells.Here,gp350 was directly anchored onto red blood cell EVs(RBC-EVs)via its transmembrane region combined with low-voltage electroporation.The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs(RBC-EVs/gp350^(Etp))exhibited increased targeting to CD21+BL and B-CLL relative to RBC-EVs.After the loading of doxorubicin or fludarabine,RBC-EVs/gp350^(Etp) had powerful cytotoxicity and therapeutic efficacy on CD21+BL or B-CLL,respectively.Moreover,RBC-EVs/gp350^(Etp) loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal Bcells.Therefore,our findings indicate that drug-loaded RBC-EVs/gp350^(Etp) may be adopted in the treatment of CD21+B cell malignancies.展开更多
Inflammatory bowel disease(IBD)is caused by an uncontrolled immune response in the intestinal lumen,leading to inflammation in genetically predisposed individuals.Immunotherapy may be a promising approach to the treat...Inflammatory bowel disease(IBD)is caused by an uncontrolled immune response in the intestinal lumen,leading to inflammation in genetically predisposed individuals.Immunotherapy may be a promising approach to the treatment of IBD.Here,we show that transforming growth factor-β1(TGF-β1)gene-modified immature dendritic cells(imDCs)could enhance the inhibitory function of imDCs and delay the progress of IBD induced by dextran sodium sulfate in mice.The results of fluorescence-activated cell sorter(FACS)demonstrated that this protective effect is mediated partially by inducing CD4^(+)Foxp3^(+)regulatory T cells(Tregs)in mesentery lymph nodes to control inflammation.In vitro experiments also supported this hypothesis.In conclusion,we provide evidence that TGF-b1-modified bone marrow-derived imDCs may have a therapeutic effect to IBD.展开更多
Salmeterol is a long-acting β2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the imm...Salmeterol is a long-acting β2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the immunoregulatory effects of salmeterol. We found that salmeterol decreases the production of pro-inflammatory cytokines in a model of allergen-challenged mice that expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Dendritic cells (DCs) are antigen-presenting cells and act as sentinels in the airway. We found that salmeterol (10-s mol/I) reduced the inflammation caused by lipopolysaccharide (0.1 pg/ml) in activated murine bone marrow-derived DCs. Moreover, western blots demonstrated that this protective effect was mediated partially by inhibiting signaling through the nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathways and dramatically decreased levels of p-ERK. We suggest that salmeterol regulates the inflammation of allergen-induced asthma by modulating DCs. In conclusion, we provide evidence that DCs are the target immune cells responsible for the action of salmeterol against asthma.展开更多
The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signa...The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8^+ T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.展开更多
The Shen-Guang II Upgrade(SG-Ⅱ-U) laser facility consists of eight high-power nanosecond laser beams and one shortpulse picosecond petawatt laser. It is designed for the study of inertial confinement fusion(ICF), esp...The Shen-Guang II Upgrade(SG-Ⅱ-U) laser facility consists of eight high-power nanosecond laser beams and one shortpulse picosecond petawatt laser. It is designed for the study of inertial confinement fusion(ICF), especially for conducting fast ignition(FI) research in China and other basic science experiments. To perform FI successfully with hohlraum targets containing a golden cone, the long-pulse beam and cylindrical hohlraum as well as the short-pulse beam and cone target alignment must satisfy tight specifications(30 and 20 μm rms for each case). To explore new ICF ignition targets with six laser entrance holes(LEHs), a rotation sensor was adapted to meet the requirements of a three-dimensional target and correct beam alignment. In this paper, the strategy for aligning the nanosecond beam based on target alignment sensor(TAS) is introduced and improved to meet requirements of the picosecond lasers and the new six LEHs hohlraum targets in the SG-II-U facility. The expected performance of the alignment system is presented, and the alignment error is also discussed.展开更多
Regulatory B cells(Bregs)are a functionally defined B cell subset,and IL-10 is crucial for the suppressive functions of Bregs.However,little is known regarding how IL-10 production is regulated in B cells.To explore t...Regulatory B cells(Bregs)are a functionally defined B cell subset,and IL-10 is crucial for the suppressive functions of Bregs.However,little is known regarding how IL-10 production is regulated in B cells.To explore the mechanisms by which IL-10 is regulated in B cells,we used mRNA microarrays to screen for molecules that are upregulated in IL-10-producing B cells and identified RNA-binding motif protein 47(Rbm47)as a post-transcriptional regulator.Rbm47 was found to promote IL-10 production in B cells.We found that Rbm47 promotes the stability of IL-10 mRNA by binding to AU-rich elements in the 3′untranslated region of Il10 mRNA.In addition,we demonstrated that the overexpression of Rbm47 enabled B cells to facilitate Foxp3+regulator T-cell induction and reduce the severity of DSS-induced ulcerative colitis.Taken together,these results suggest that Rbm47 plays an important role in regulating IL-10 at the post-transcriptional level,thus promoting the regulatory functions of B cells.The findings presented in this study not only increase our understanding of the post-translational regulation of IL-10 in B cells but also identify a novel strategy for the potential application of Bregs.展开更多
PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is ...PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.展开更多
In high power laser facility for inertial confinement fusion research, final optics assembly(FOA) plays a critical role in the frequency conversion, beam focusing, color separation, beam sampling and debris shielding....In high power laser facility for inertial confinement fusion research, final optics assembly(FOA) plays a critical role in the frequency conversion, beam focusing, color separation, beam sampling and debris shielding. The design and performance of FOA in SG-II Upgrade laser facility are mainly introduced here. Due to the limited space and short focal length, a coaxial aspheric wedged focus lens is designed and applied in the FOA configuration. Then the ghost image analysis,the focus characteristic analysis, the B integral control design and the optomechanical design are carried out in the FOA design phase. In order to ensure the FOA performance, two key technologies are developed including measurement and adjustment technique of the wedged focus lens and the stray light management technique based on ground glass.Experimental results show that the design specifications including laser fluence, frequency conversion efficiency and perforation efficiency of the focus spot have been achieved, which meet the requirements of physical experiments well.展开更多
Angiotensin-converting enzyme 2(ACE2)is the receptor for severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 and is upregulated after infection with these viruses,which assists the entry of these vir...Angiotensin-converting enzyme 2(ACE2)is the receptor for severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 and is upregulated after infection with these viruses,which assists the entry of these viruses into the target cells.1,2,3 In addition,ACE2 is a human interferon-stimulated gene.4 In response to viral infection,host cells produce vast amounts of type I interferon(IFN)to defend against viral infection.5 Type I IFNs,such as IFN-α,can upregulate the phosphorylation of signal transducer and activator of transcription 1(STAT1)and 2(STAT2).6,7 Thus,whether and how IFN-αcould promote and whether blockade of the IFN-α-STAT pathway could inhibit the expression of ACE2 are largely unknown.Given the importance of ACE2 for SARS-CoV-2 invasion and the clinical practice of IFN treatment to combat viral infection,herein,we addressed these issues via a series of in vitro experiments.展开更多
基金Supported by the Youth Program of Humanities of Education Department(12YJCZH273,11YJCZH199)Humanity Planning Program of Education Department(12YJA790003)
文摘Take Chinese yew cooperative organization for example,different game structures of forestry cooperation model were analyzed,the elative merit and applicable occasion was discussed combined with empirical investigation,and some suggestions were given also.The results showed that depending entirely on normal forest farmers cooperate spontaneously is difficult.Policies should be designed from the perspective of promoted village cadres and influential family salons to cooperation.When market factors become the main obstacle,it is necessary to introduce companies,relax constraints of forest management and build the right market atmosphere.According to unequal status of company and forest farmers,develop the cooperation model of " company + cooperation organization + farmers".In certain circumstances,especially there are several companies vicious competition,the intervention of association can play a coordinating role.
基金supported by the Natural Science Foundation of Zhejiang Province(LY19H160009 and LY20H120007)the National Natural Science Foundation of China(82130053,81971871,31970845 and 81901571)+1 种基金the Joint Preresearch Fund for Clinical Scientific Research of Hangzhou First People’s Hospital Affiliated to Zhejiang University(YYJJ2019Z07)the Major Project of Hangzhou Health Science and Technology Plan(Z20200134).
文摘Although chimeric antigen receptor-modified(CAR)T cell therapy has been successfully applied in the treatment of acute B lymphocytic leukemia,its effect on Burkitt lymphoma(BL)and chronic B lymphocytic leukemia(B-CLL)is unsatisfactory.Moreover,fatal side effects greatly impede CAR T cell application.Extracellular vesicles(EVs)are excellent carriers of therapeutic agents.Nevertheless,EVs mainly accumulate in the liver when administered without modification.As an envelope glycoprotein of Epstein–Barr viruses,gp350 can efficiently bind CD21 on B cells.Here,gp350 was directly anchored onto red blood cell EVs(RBC-EVs)via its transmembrane region combined with low-voltage electroporation.The results showed that gp350 could anchor to RBC-EVs with high efficiency and that the resulting gp350-anchored RBC-EVs(RBC-EVs/gp350^(Etp))exhibited increased targeting to CD21+BL and B-CLL relative to RBC-EVs.After the loading of doxorubicin or fludarabine,RBC-EVs/gp350^(Etp) had powerful cytotoxicity and therapeutic efficacy on CD21+BL or B-CLL,respectively.Moreover,RBC-EVs/gp350^(Etp) loaded with a drug did not exhibit any apparent systemic toxicity and specifically induced the apoptosis of tumor B cells but not normal Bcells.Therefore,our findings indicate that drug-loaded RBC-EVs/gp350^(Etp) may be adopted in the treatment of CD21+B cell malignancies.
基金We thank Professor Lin-Rong Lu for his critical review of the manuscript.This work was supported by the National Key Basic Research Program of China(Grant 2007CB512400)the National High Technology Research and Development Program of China(Grants2006AA02A239 and 2007AA021102)+1 种基金the National Natural Science Foundation of China(Grant 30671909 and 30972725)Natural Science Foundation of Zhejiang Province(Z2090042).
文摘Inflammatory bowel disease(IBD)is caused by an uncontrolled immune response in the intestinal lumen,leading to inflammation in genetically predisposed individuals.Immunotherapy may be a promising approach to the treatment of IBD.Here,we show that transforming growth factor-β1(TGF-β1)gene-modified immature dendritic cells(imDCs)could enhance the inhibitory function of imDCs and delay the progress of IBD induced by dextran sodium sulfate in mice.The results of fluorescence-activated cell sorter(FACS)demonstrated that this protective effect is mediated partially by inducing CD4^(+)Foxp3^(+)regulatory T cells(Tregs)in mesentery lymph nodes to control inflammation.In vitro experiments also supported this hypothesis.In conclusion,we provide evidence that TGF-b1-modified bone marrow-derived imDCs may have a therapeutic effect to IBD.
文摘Salmeterol is a long-acting β2-agonist that activates adenylate cyclase, causing long-lasting bronchodilation and has been used for many years to control asthma. However, little information is available about the immunoregulatory effects of salmeterol. We found that salmeterol decreases the production of pro-inflammatory cytokines in a model of allergen-challenged mice that expressed tumor-necrosis factor-alpha, interleukin-1 and interleukin-6. Dendritic cells (DCs) are antigen-presenting cells and act as sentinels in the airway. We found that salmeterol (10-s mol/I) reduced the inflammation caused by lipopolysaccharide (0.1 pg/ml) in activated murine bone marrow-derived DCs. Moreover, western blots demonstrated that this protective effect was mediated partially by inhibiting signaling through the nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathways and dramatically decreased levels of p-ERK. We suggest that salmeterol regulates the inflammation of allergen-induced asthma by modulating DCs. In conclusion, we provide evidence that DCs are the target immune cells responsible for the action of salmeterol against asthma.
基金The work was supported by the Specialized Research Fund for the Chinese National 973 Project (2013CB530502), the Doctoral Program of Higher Education of China (20110101110105), the Project of the Chinese National Nature Science Foundation (31370902, 31070795, 31270944), the Projects in Science and Technology Plan of Zhejiang Province (013C33G2010434) of China, the National Key Science and Technology Specific Proiect of China (2012ZX10002006), the National High Technology Research and Development Program (2012AA020900), and the Project of the Chinese National Natural Science Fund Committee for Talent Cultivation (J1103603).
文摘The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8^+ T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.
文摘The Shen-Guang II Upgrade(SG-Ⅱ-U) laser facility consists of eight high-power nanosecond laser beams and one shortpulse picosecond petawatt laser. It is designed for the study of inertial confinement fusion(ICF), especially for conducting fast ignition(FI) research in China and other basic science experiments. To perform FI successfully with hohlraum targets containing a golden cone, the long-pulse beam and cylindrical hohlraum as well as the short-pulse beam and cone target alignment must satisfy tight specifications(30 and 20 μm rms for each case). To explore new ICF ignition targets with six laser entrance holes(LEHs), a rotation sensor was adapted to meet the requirements of a three-dimensional target and correct beam alignment. In this paper, the strategy for aligning the nanosecond beam based on target alignment sensor(TAS) is introduced and improved to meet requirements of the picosecond lasers and the new six LEHs hohlraum targets in the SG-II-U facility. The expected performance of the alignment system is presented, and the alignment error is also discussed.
基金supported by National Basic Research Program 973 Grants(2015CB943301)the Key Program of the Beijing Natural Science Foundation(7141007)the National Nature and Science Funds(31770951,31770956 and 81471529).
文摘Regulatory B cells(Bregs)are a functionally defined B cell subset,and IL-10 is crucial for the suppressive functions of Bregs.However,little is known regarding how IL-10 production is regulated in B cells.To explore the mechanisms by which IL-10 is regulated in B cells,we used mRNA microarrays to screen for molecules that are upregulated in IL-10-producing B cells and identified RNA-binding motif protein 47(Rbm47)as a post-transcriptional regulator.Rbm47 was found to promote IL-10 production in B cells.We found that Rbm47 promotes the stability of IL-10 mRNA by binding to AU-rich elements in the 3′untranslated region of Il10 mRNA.In addition,we demonstrated that the overexpression of Rbm47 enabled B cells to facilitate Foxp3+regulator T-cell induction and reduce the severity of DSS-induced ulcerative colitis.Taken together,these results suggest that Rbm47 plays an important role in regulating IL-10 at the post-transcriptional level,thus promoting the regulatory functions of B cells.The findings presented in this study not only increase our understanding of the post-translational regulation of IL-10 in B cells but also identify a novel strategy for the potential application of Bregs.
基金This work was supported by the National Natural Science Foundation of China(82130053,31970845,31870876,81971871 and 81901571).
文摘PD-L1+tumor-derived extracellular vesicles(TEVs)cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody(αPD-L1)blockade.However,whether and how PD-L1+TEVs mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.
文摘In high power laser facility for inertial confinement fusion research, final optics assembly(FOA) plays a critical role in the frequency conversion, beam focusing, color separation, beam sampling and debris shielding. The design and performance of FOA in SG-II Upgrade laser facility are mainly introduced here. Due to the limited space and short focal length, a coaxial aspheric wedged focus lens is designed and applied in the FOA configuration. Then the ghost image analysis,the focus characteristic analysis, the B integral control design and the optomechanical design are carried out in the FOA design phase. In order to ensure the FOA performance, two key technologies are developed including measurement and adjustment technique of the wedged focus lens and the stray light management technique based on ground glass.Experimental results show that the design specifications including laser fluence, frequency conversion efficiency and perforation efficiency of the focus spot have been achieved, which meet the requirements of physical experiments well.
基金supported by grants from the Natural Science Foundation of Zhejiang Province(No.LY19H150007,G.SZ)National Natural Science Foundations of China(No.81971871,G.SZ+1 种基金No.81901941,S.F.Z.)National Key R&D Program of China(2017YFC1310604,H.Q.H.).
文摘Angiotensin-converting enzyme 2(ACE2)is the receptor for severe acute respiratory syndrome coronavirus(SARS-CoV)and SARS-CoV-2 and is upregulated after infection with these viruses,which assists the entry of these viruses into the target cells.1,2,3 In addition,ACE2 is a human interferon-stimulated gene.4 In response to viral infection,host cells produce vast amounts of type I interferon(IFN)to defend against viral infection.5 Type I IFNs,such as IFN-α,can upregulate the phosphorylation of signal transducer and activator of transcription 1(STAT1)and 2(STAT2).6,7 Thus,whether and how IFN-αcould promote and whether blockade of the IFN-α-STAT pathway could inhibit the expression of ACE2 are largely unknown.Given the importance of ACE2 for SARS-CoV-2 invasion and the clinical practice of IFN treatment to combat viral infection,herein,we addressed these issues via a series of in vitro experiments.