Submerged floating tunnel (SFT) is a novel type traffic structure for crossing long strait and deep lakes. To investigate the dynamic pressure acting on an SFT under compression (P) wave incidence, a theoretical analy...Submerged floating tunnel (SFT) is a novel type traffic structure for crossing long strait and deep lakes. To investigate the dynamic pressure acting on an SFT under compression (P) wave incidence, a theoretical analysis model considering marine sediment effect has been proposed. Based on displacement potential functions, the reflection and refraction coefficients of P wave in different media are derived. Numerical examples are employed to illustrate the effects of the thickness of sediment layer, the incident P wave angle, the tether stiffness and spacing, and the permeability of the sediment on the dynamic pressure loading on the SFT. The results show that dynamic pressure is related to the saturation of sediment and affected by the thickness of sediment. The partially saturated sediment will amplify the dynamic pressure loading on the SFT, and the resonance frequency increases a little with the fully saturated sediment. Besides, increasing the tether stiffness and decreasing in the tether spacing will lead to a dynamic pressure falling. Deepening the SFT position and reducing the permeability of the sediment are effective measures to reduce dynamic pressure acting on the SFT.展开更多
Soil washing is a promising technology for the remediation of polycyclic aromatic hydrocarbons(PAH)-contaminated sites,but surfactant needs to be recovered to reduce remediation cost and avoid secondary pollution.In t...Soil washing is a promising technology for the remediation of polycyclic aromatic hydrocarbons(PAH)-contaminated sites,but surfactant needs to be recovered to reduce remediation cost and avoid secondary pollution.In this study,activated carbon(AC),prepared from waste walnut shells,was applied to the adsorptive removal of phenanthrene(PHE)from synthetic soil washing effluent with Tween 80 as a model surfactant.Box-Behnken statistical experiment design(BBD)and response surface methodology(RSM)were used to investigate the influence of AC dosage,Tween 80 concentration and adsorption time,and their potential interaction effect on PHE removal.A response surface model was established based on the BBD experimental results.The goodness of fit of the model was confirmed by determination coefficient,coefficient of variation(CV)and residuals analysis.The RSM model indicates that AC dosage or adsorption time had positive effect on PHE removal while Tween 80 concentration had negative effect.The interaction effect between AC dosage and Tween 80 concentration was significant but the other two interaction effects were not.The 3D response surface plots were developed based on the RSM equation.The RSM model was validated by an additional experiment and the obtained result of PHE removal was very close to the model prediction,indicating the RSM model can effectively predict the PHE removal from soil washing effluent with activated carbon adsorption.展开更多
The adsorption performances of individual adsorbent such as UiO-66-NH_(2)and MgAl-layered double hydroxides(MgAl-LDH)toward levofloxacin(LVX)is less satisfactory due to the disappointing uptake capacity and adsorption...The adsorption performances of individual adsorbent such as UiO-66-NH_(2)and MgAl-layered double hydroxides(MgAl-LDH)toward levofloxacin(LVX)is less satisfactory due to the disappointing uptake capacity and adsorption efficiency.Herein,a 3D flower-like composite adsorbent prepared via iterative hydrothermal synthesis method anchoring UiO-66-NH_(2)nanoparticles onto the MgAl-LDH surface.Attributed to the synergistic effects of UiO-66-NH_(2),and MgAl-LDH,the MgAl-LDH@UiO-66-NH_(2)exhibits an outstanding adsorption performance toward LVX.Typically,the maximum LVX uptake capacity over MgAl-LDH@UiO-66-NH_(2)reached 268 mg/g,which was higher than that of the individual adsorption materials UiO-66-NH_(2)(41 mg/g),MgAl-LDH(140 mg/g),and some adsorbents reported in previous literature.The rapid adsorption process can reach equilibrium within 20 min,which conformed well to the pseudo-second-order kinetics and the Langmuir isotherm model.Adsorption thermodynamic result also indicated that the adsorption was spontaneous and exothermic,simultaneous coexisting physical and chemical adsorption interactions.Importantly,the MgAl-LDH@UiO-66-NH_(2)still maintained excellent adsorption capacity with a slightly decrease after fifth cycle,exhibiting a remarkable reuse and stable performances.This work provides a highly novel strategy to prepare recyclable composite adsorbent for the LVX capture from aqueous solution.展开更多
Graph databases have gained widespread adoption in various industries and have been utilized in a range of applications,including financial risk assessment,commodity recommendation,and data lineage tracking.While the ...Graph databases have gained widespread adoption in various industries and have been utilized in a range of applications,including financial risk assessment,commodity recommendation,and data lineage tracking.While the principles and design of these databases have been the subject of some investigation,there remains a lack of comprehensive examination of aspects such as storage layout,query language,and deployment.The present study focuses on the design and implementation of graph storage layout,with a particular emphasis on tree-structured key-value stores.We also examine different design choices in the graph storage layer and present our findings through the development of TuGraph,a highly efficient single-machine graph database that significantly outperforms well-known Graph DataBase Management System(GDBMS).Additionally,TuGraph demonstrates superior performance in the Linked Data Benchmark Council(LDBC)Social Network Benchmark(SNB)interactive benchmark.展开更多
Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How ...Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling.MARCH3 is associated with IL-3Rα,mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation.MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells.In the cecal ligation and puncture(CLP)model of sepsis,MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines,organ damage and inflammatory death.Our findings suggest that regulation of IL-3Rαby MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.展开更多
Bitter is generally undesirable,although it is an important part of flavor.Bitter substances exhibit diverse health-promoting activities,which is in line with the famous Chinese saying‘a good medicine tastes bitter’...Bitter is generally undesirable,although it is an important part of flavor.Bitter substances exhibit diverse health-promoting activities,which is in line with the famous Chinese saying‘a good medicine tastes bitter’.Naringin(NAG)and neohesperidin(NHP),two important flavanones that give bitterness to citrus fruits,show various pharmacological activities.Interestingly,their hydrogenation products,i.e.naringin dihydrochalcone(NDC)and neohesperidin dihydrochalcone(NHDC),undergo a dramatic taste shift from bitter to intensely sweet,which can be 300 and 1000 times sweeter than sucrose,respectively.Such sweeteners not only provide a sweet taste without the burden of increased calorie intake and glycemia,but also may exert multiple bioactivities.This review summarizes common dietary bitter and sweet compounds with sensory scores.Taste conversions induced by structural changes from bitter NAG and NHP to sweet NDC and NHDC are particularly discussed.In addition,the taste-sensing mechanisms,pharmacological characteristics,dietary distribution,synthesis,and food industry applications of these bitter–sweet interchangeable compounds are outlined.In conclusion,the bitter NAG and NHP are promising therapeutic candidates for management of diverse etiologically complex diseases while their corresponding dihydrochalcones NDC and NHDC are promising sweeteners,which might be a blessing for those who need to control sugar intake.展开更多
The Panda X-4T experiment, a 4-ton scale dark matter direct detection experiment, is being planned at the China Jinping Underground Laboratory. In this paper we present a simulation study of the expected background in...The Panda X-4T experiment, a 4-ton scale dark matter direct detection experiment, is being planned at the China Jinping Underground Laboratory. In this paper we present a simulation study of the expected background in this experiment. In a 2.8-ton fiducial mass and the signal region between 1-10 keV electron equivalent energy, the total electron recoil background is found to be 4.9 × 10^(-5) kg^(-1) d^(-1) keV^(-1). The nuclear recoil background in the same region is 2.8 × 10^(-7) kg^(-1) d^(-1) keV^(-1). With an exposure of 5.6 ton-years, the sensitivity of Panda X-4 T could reach a minimum spin-independent dark matter-nucleon cross section of 6 × 10^(-48) cm^2 at a dark matter mass of 40 Ge V/c^2.展开更多
Monoclonal antibodies(m Abs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17 A can induce a rapid inflammatory response both alone and synergistic...Monoclonal antibodies(m Abs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17 A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17 A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-h IL-17 A antibody. From a large na?ve phage-displayed library, we isolated the anti-IL-17 A m Ab 7 H9 that can neutralize the effects of recombinant human IL-17 A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. In vitro affinity optimization was then used to generate 8 D3 by using yeast-displayed random mutagenesis libraries.This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions(CDRs) of 8 D3 were further grafted onto the stable framework of the hu Fv 4 D5 to improve thermostability. The resulting hybrid antibody9 NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma cellbased assays and in vivo analyses in mice indicated that the anti-IL-17 A antibody 9 NT/S efficiently inhibited the secretion of IL-17 A-induced proinflammatory cytokines. Therefore, this lead anti-IL-17 A m Ab might be used as a potential best-in-class candidate for treating IL-17 A related diseases.展开更多
MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified Z...MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.展开更多
The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase...The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.展开更多
Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we ide...Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.展开更多
Searching for the neutrinoless double beta decay(NLDBD)is now regarded as the topmost promising technique to explore the nature of neutrinos after the discovery of neutrino masses in oscillation experiments.Panda X-II...Searching for the neutrinoless double beta decay(NLDBD)is now regarded as the topmost promising technique to explore the nature of neutrinos after the discovery of neutrino masses in oscillation experiments.Panda X-III(particle and astrophysical xenon experiment III)will search for the NLDBD of136Xe at the China Jin Ping Underground Laboratory(CJPL).In the first phase of the experiment,a high pressure gas Time Projection Chamber(TPC)will contain 200 kg,90%136Xe enriched gas operated at10 bar.Fine pitch micro-pattern gas detector(Microbulk Micromegas)will be used at both ends of the TPC for the charge readout with a cathode in the middle.Charge signals can be used to reconstruct the electron tracks of the NLDBD events and provide good energy and spatial resolution.The detector will be immersed in a large water tank to ensure～5 m of water shielding in all directions.The second phase,a ton-scale experiment,will consist of five TPCs in the same water tank,with improved energy resolution and better control over backgrounds.展开更多
Background Track reconstruction is necessary for time projection chamber(TPC),because TPCs usually face the measure-ment error that impedes gaining precise spacial and angular resolution.Purpose Kalman filter is a wel...Background Track reconstruction is necessary for time projection chamber(TPC),because TPCs usually face the measure-ment error that impedes gaining precise spacial and angular resolution.Purpose Kalman filter is a well-performed and applicable algorithm to denoise and reconstruct the event track.Methods In this paper,we develop a six-dimensional Kalman filter to reconstruct the particle track in high-energy physics experiments,while the most common form of Kalman filter used in many research fields is four-dimensional.The modelisation is based on a gaseous TPC,and the whole reconstruction process is first tested by a toy Monte Carlo simulation.Results The results show the Kalman filter can effectively reduce the noise and improve the detector resolution.Then,the performance of the Kalman filter is also verified with the data produced by the Geant4 toolkit.展开更多
基金This work was supported by the National Natural Science Foundation of China (Grants 51541810 and 51279178)the Fundamental Research Funds for the Central Universities (Grant 2018QNA4032).
文摘Submerged floating tunnel (SFT) is a novel type traffic structure for crossing long strait and deep lakes. To investigate the dynamic pressure acting on an SFT under compression (P) wave incidence, a theoretical analysis model considering marine sediment effect has been proposed. Based on displacement potential functions, the reflection and refraction coefficients of P wave in different media are derived. Numerical examples are employed to illustrate the effects of the thickness of sediment layer, the incident P wave angle, the tether stiffness and spacing, and the permeability of the sediment on the dynamic pressure loading on the SFT. The results show that dynamic pressure is related to the saturation of sediment and affected by the thickness of sediment. The partially saturated sediment will amplify the dynamic pressure loading on the SFT, and the resonance frequency increases a little with the fully saturated sediment. Besides, increasing the tether stiffness and decreasing in the tether spacing will lead to a dynamic pressure falling. Deepening the SFT position and reducing the permeability of the sediment are effective measures to reduce dynamic pressure acting on the SFT.
基金funded by Shenzhen Basic Research Plan Project (No. JCYJ20150508152951667)Wuhan Applied Basic Research Project (No. 2016060101010074)Natural Science Foundation of Anhui Province (No. 1808085MB49)
文摘Soil washing is a promising technology for the remediation of polycyclic aromatic hydrocarbons(PAH)-contaminated sites,but surfactant needs to be recovered to reduce remediation cost and avoid secondary pollution.In this study,activated carbon(AC),prepared from waste walnut shells,was applied to the adsorptive removal of phenanthrene(PHE)from synthetic soil washing effluent with Tween 80 as a model surfactant.Box-Behnken statistical experiment design(BBD)and response surface methodology(RSM)were used to investigate the influence of AC dosage,Tween 80 concentration and adsorption time,and their potential interaction effect on PHE removal.A response surface model was established based on the BBD experimental results.The goodness of fit of the model was confirmed by determination coefficient,coefficient of variation(CV)and residuals analysis.The RSM model indicates that AC dosage or adsorption time had positive effect on PHE removal while Tween 80 concentration had negative effect.The interaction effect between AC dosage and Tween 80 concentration was significant but the other two interaction effects were not.The 3D response surface plots were developed based on the RSM equation.The RSM model was validated by an additional experiment and the obtained result of PHE removal was very close to the model prediction,indicating the RSM model can effectively predict the PHE removal from soil washing effluent with activated carbon adsorption.
基金the National Natural Science Foundation of China(No.22178325)Jinhua Science and Technology Plan Project.
文摘The adsorption performances of individual adsorbent such as UiO-66-NH_(2)and MgAl-layered double hydroxides(MgAl-LDH)toward levofloxacin(LVX)is less satisfactory due to the disappointing uptake capacity and adsorption efficiency.Herein,a 3D flower-like composite adsorbent prepared via iterative hydrothermal synthesis method anchoring UiO-66-NH_(2)nanoparticles onto the MgAl-LDH surface.Attributed to the synergistic effects of UiO-66-NH_(2),and MgAl-LDH,the MgAl-LDH@UiO-66-NH_(2)exhibits an outstanding adsorption performance toward LVX.Typically,the maximum LVX uptake capacity over MgAl-LDH@UiO-66-NH_(2)reached 268 mg/g,which was higher than that of the individual adsorption materials UiO-66-NH_(2)(41 mg/g),MgAl-LDH(140 mg/g),and some adsorbents reported in previous literature.The rapid adsorption process can reach equilibrium within 20 min,which conformed well to the pseudo-second-order kinetics and the Langmuir isotherm model.Adsorption thermodynamic result also indicated that the adsorption was spontaneous and exothermic,simultaneous coexisting physical and chemical adsorption interactions.Importantly,the MgAl-LDH@UiO-66-NH_(2)still maintained excellent adsorption capacity with a slightly decrease after fifth cycle,exhibiting a remarkable reuse and stable performances.This work provides a highly novel strategy to prepare recyclable composite adsorbent for the LVX capture from aqueous solution.
文摘Graph databases have gained widespread adoption in various industries and have been utilized in a range of applications,including financial risk assessment,commodity recommendation,and data lineage tracking.While the principles and design of these databases have been the subject of some investigation,there remains a lack of comprehensive examination of aspects such as storage layout,query language,and deployment.The present study focuses on the design and implementation of graph storage layout,with a particular emphasis on tree-structured key-value stores.We also examine different design choices in the graph storage layer and present our findings through the development of TuGraph,a highly efficient single-machine graph database that significantly outperforms well-known Graph DataBase Management System(GDBMS).Additionally,TuGraph demonstrates superior performance in the Linked Data Benchmark Council(LDBC)Social Network Benchmark(SNB)interactive benchmark.
基金This work was supported by grants from the State Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31830024 and 32070775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071).
文摘Interleukin-3(IL-3)is a hematopoietic growth factor and critical regulator of inflammatory response such as sepsis.IL-3 binds to IL-3 receptorα(IL-3Rα),which is then associated with IL-3Rβto initiate signaling.How IL-3-triggered physiological and pathological effects are regulated at the receptor level is unclear.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates IL-3-triggered signaling.MARCH3 is associated with IL-3Rα,mediates its K48-linked polyubiquitination at K377 and promotes its proteasomal degradation.MARCH3-deficiency promotes IL-3-triggered transcription of downstream effector genes and IL-3-induced expansion of myeloid cells.In the cecal ligation and puncture(CLP)model of sepsis,MARCH3-deficiency aggravates IL-3-ampified expression of inflammatory cytokines,organ damage and inflammatory death.Our findings suggest that regulation of IL-3Rαby MARCH3 plays an important role in IL-3-triggered physiological functions and inflammatory diseases.
基金supported by the SanNongJiuFang Project of Zhejiang Province(No.2022SNJF083)the National Agricultural Science and Technology Modernization Project between Zhejiang University and Changshan County(No.588970-Y12202)+1 种基金the Key Research and Development Program of Zhejiang Province(No.2021C02001)the Serving Local Economic Development Project of Shandong(Linyi)Institute of Modern Agriculture,Zhejiang University,China.
文摘Bitter is generally undesirable,although it is an important part of flavor.Bitter substances exhibit diverse health-promoting activities,which is in line with the famous Chinese saying‘a good medicine tastes bitter’.Naringin(NAG)and neohesperidin(NHP),two important flavanones that give bitterness to citrus fruits,show various pharmacological activities.Interestingly,their hydrogenation products,i.e.naringin dihydrochalcone(NDC)and neohesperidin dihydrochalcone(NHDC),undergo a dramatic taste shift from bitter to intensely sweet,which can be 300 and 1000 times sweeter than sucrose,respectively.Such sweeteners not only provide a sweet taste without the burden of increased calorie intake and glycemia,but also may exert multiple bioactivities.This review summarizes common dietary bitter and sweet compounds with sensory scores.Taste conversions induced by structural changes from bitter NAG and NHP to sweet NDC and NHDC are particularly discussed.In addition,the taste-sensing mechanisms,pharmacological characteristics,dietary distribution,synthesis,and food industry applications of these bitter–sweet interchangeable compounds are outlined.In conclusion,the bitter NAG and NHP are promising therapeutic candidates for management of diverse etiologically complex diseases while their corresponding dihydrochalcones NDC and NHDC are promising sweeteners,which might be a blessing for those who need to control sugar intake.
基金supported by a 985-Ⅲ grant from Shanghai Jiao Tong University,the National Natural Science Foundation of China(Grant Nos.11435008,11455001,11505112,11525522,11775141,and 11755001)the Ministry of Science and Technology of China(Grant No.2016YFA0400301)+2 种基金the Office of Science and Technology,Shanghai Municipal Government(Grant Nos.11DZ2260700,and 16DZ2260200)the Key Laboratory for Particle Physics,Astrophysics and Cosmology,Ministry of Educationsupported in part by the Chinese Academy of Sciences Center for Excellence in Particle Physics(CCEPP)and Hongwen Foundation in Hong Kong
文摘The Panda X-4T experiment, a 4-ton scale dark matter direct detection experiment, is being planned at the China Jinping Underground Laboratory. In this paper we present a simulation study of the expected background in this experiment. In a 2.8-ton fiducial mass and the signal region between 1-10 keV electron equivalent energy, the total electron recoil background is found to be 4.9 × 10^(-5) kg^(-1) d^(-1) keV^(-1). The nuclear recoil background in the same region is 2.8 × 10^(-7) kg^(-1) d^(-1) keV^(-1). With an exposure of 5.6 ton-years, the sensitivity of Panda X-4 T could reach a minimum spin-independent dark matter-nucleon cross section of 6 × 10^(-48) cm^2 at a dark matter mass of 40 Ge V/c^2.
基金supported by National Key R&D Program of China under Grant 2017YFA0205400National Natural Science Foundation of China under Grant 81874316,81773781 and81530093+2 种基金National Drug Innovation Major Project of China under Grant 2018ZX09711001-003-001Chinese Academy of Medical Sciences(CAMS,Beijing,China)Central Publicinterest Scientific Institution Basal Research Fund under 2017PT31046 and 2018RC350004CAMS Innovation Found for Medical Sciences(2016-I2M-3-008 and 2016-I2M-1-007)
文摘Monoclonal antibodies(m Abs) are widely used in many fields due to their high specificity and ability to recognize a broad range of antigens. IL-17 A can induce a rapid inflammatory response both alone and synergistically with other proinflammatory cytokines. Accumulating evidence suggests that therapeutic intervention of IL-17 A signaling offers an attractive treatment option for autoimmune diseases and cancer. Here, we present a combinatorial approach for optimizing the affinity and thermostability of a novel anti-h IL-17 A antibody. From a large na?ve phage-displayed library, we isolated the anti-IL-17 A m Ab 7 H9 that can neutralize the effects of recombinant human IL-17 A. However, the modest neutralization potency and poor thermostability limit its therapeutic applications. In vitro affinity optimization was then used to generate 8 D3 by using yeast-displayed random mutagenesis libraries.This resulted in four key amino acid changes and provided an approximately 15-fold potency increase in a cell-based neutralization assay. Complementarity-determining regions(CDRs) of 8 D3 were further grafted onto the stable framework of the hu Fv 4 D5 to improve thermostability. The resulting hybrid antibody9 NT/S has superior stabilization and affinities beyond its original antibody. Human fibrosarcoma cellbased assays and in vivo analyses in mice indicated that the anti-IL-17 A antibody 9 NT/S efficiently inhibited the secretion of IL-17 A-induced proinflammatory cytokines. Therefore, this lead anti-IL-17 A m Ab might be used as a potential best-in-class candidate for treating IL-17 A related diseases.
基金supported by grants from the National Key R&D Program of China(2017YFA0505800,2016YFA0502102)the National Natural Science Foundation of China(31630045,31521091,91429304 and 31671465)+1 种基金the Fundamental Research Funds for the Central Universities(2042017kf0205,2042017kf0242)Wuhan University Experiment Technology Project Funding.
文摘MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.
基金This work was supported by grants from the National Key R&D Program of China(2017YFA0505800)the National Natural Science Foundation of China(31630045,31830024,31900556,and 32070775)+2 种基金the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the National Postdoctoral Program for Innovative Talents(BX20190255)the China Postdoctoral Science Foundation(2019M662706).
文摘The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.
基金This work was supported by grants from the National Natural Science Foundation of China(32188101,31830024 and 32070775)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071)the Fundamental Research Funds for the Central Universities.
文摘Interleukin 5(IL-5)plays crucial roles in type 2-high asthma by mediating eosinophil maturation,activation,chemotaxis and survival.Inhibition of IL-5 signaling is considered a strategy for asthma treatment.Here,we identified MARCH2 and MARCH3 as critical negative regulators of IL-5-triggered signaling.MARCH2 and MARCH3 associate with the IL-5 receptorαchain(IL-5Rα)and mediate its K27-linked polyubiquitination at K379 and K383,respectively,and its subsequent lysosomal degradation.Deficiency of MARCH2 or MARCH3 modestly increases the level of IL-5Rαand enhances IL-5-induced signaling,whereas double knockout of MARCH2/3 has a more dramatic effect.March2/3 double knockout markedly increases the proportions of eosinophils in the bone marrow and peripheral blood in mice.Double knockout of March2/3 aggravates ovalbumin(OVA)-induced eosinophilia and causes increased inflammatory cell infiltration,peribronchial mucus secretion and production of Th2 cytokines.Neutralization of Il-5 attenuates OVA-induced airway inflammation and the enhanced effects of March2/3 double deficiency.These findings suggest that MARCH2 and MARCH3 play redundant roles in targeting IL-5Rαfor degradation and negatively regulating allergic airway inflammation.
基金supported by the National Key Programme for Research and Development (NKPRD) (Grant No. 2016YFA0400300)Shanghai Jiao Tong University (SJTU) for their financial and technical support+1 种基金technical and administrative assistance from China Jin Ping Underground Laboratory (CJPL)the European Research Council (Grant No. ERC-2009-St G-240054)
文摘Searching for the neutrinoless double beta decay(NLDBD)is now regarded as the topmost promising technique to explore the nature of neutrinos after the discovery of neutrino masses in oscillation experiments.Panda X-III(particle and astrophysical xenon experiment III)will search for the NLDBD of136Xe at the China Jin Ping Underground Laboratory(CJPL).In the first phase of the experiment,a high pressure gas Time Projection Chamber(TPC)will contain 200 kg,90%136Xe enriched gas operated at10 bar.Fine pitch micro-pattern gas detector(Microbulk Micromegas)will be used at both ends of the TPC for the charge readout with a cathode in the middle.Charge signals can be used to reconstruct the electron tracks of the NLDBD events and provide good energy and spatial resolution.The detector will be immersed in a large water tank to ensure～5 m of water shielding in all directions.The second phase,a ton-scale experiment,will consist of five TPCs in the same water tank,with improved energy resolution and better control over backgrounds.
文摘Background Track reconstruction is necessary for time projection chamber(TPC),because TPCs usually face the measure-ment error that impedes gaining precise spacial and angular resolution.Purpose Kalman filter is a well-performed and applicable algorithm to denoise and reconstruct the event track.Methods In this paper,we develop a six-dimensional Kalman filter to reconstruct the particle track in high-energy physics experiments,while the most common form of Kalman filter used in many research fields is four-dimensional.The modelisation is based on a gaseous TPC,and the whole reconstruction process is first tested by a toy Monte Carlo simulation.Results The results show the Kalman filter can effectively reduce the noise and improve the detector resolution.Then,the performance of the Kalman filter is also verified with the data produced by the Geant4 toolkit.
