Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance...Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。展开更多
This paper proposes a co-optimal strategy using line hardening,mobile devices(mobile ice-melting device,mobile emergency generator,mobile energy storage system),and repair crew dispatching to improve distribution syst...This paper proposes a co-optimal strategy using line hardening,mobile devices(mobile ice-melting device,mobile emergency generator,mobile energy storage system),and repair crew dispatching to improve distribution system resilience during ice storms.A multi-stage defender-attacker-defender model is established to take into account interactions and coupling relationships between different measures.In our proposed model,ice storms will attack the distribution and transportation system in a worst-case scenario,affecting system performance from various perspectives.Corresponding to the different operating states in the distribution system affected by ice storms,aiming at minimizing the weighted load shedding value,this paper applies various measures to different stages to improve the response and defense capabilities to ice storms and realize restoration of the distribution system ultimately.The nested column-and-constraint generation algorithm is used to solve the model efficiently.The effectiveness of the proposed model and solution method for enhancing the distribution system resilience is verified on the modified IEEE 33-bus distribution system and modified realworld zone of Caracas 141-bus distribution system.展开更多
Lift-to-drag ratio (L/D) is nearly the most important index in determining the aerodynamic performance of a hypersonic flight vehicle,because the flight distance is linearly proportional to the L/D according to Bregue...Lift-to-drag ratio (L/D) is nearly the most important index in determining the aerodynamic performance of a hypersonic flight vehicle,because the flight distance is linearly proportional to the L/D according to Breguet's equation.In general,the higher the L/D of a vehicle,the greater the flight range if the specific impulse,structural mass ratio,and flight velocity are given.Naturally,the pursuit of a high L/D for hypersonic vehicles has never ceased [1,2].展开更多
Hybrid manufacturing(HM)uses additive manufacturing(AM)techniques to prepare complex or fine structures on traditional processing parts,which can fully utilize the advantages of AM to form complex parts,and the high e...Hybrid manufacturing(HM)uses additive manufacturing(AM)techniques to prepare complex or fine structures on traditional processing parts,which can fully utilize the advantages of AM to form complex parts,and the high efficiency and low cost of conventional processing methods in manufacturing regular components.A bimetal material was produced by selective laser melting(SLM)of AlSi10Mg on the deformed Al6061 alloy substrate in this study.Firstly,the interface characteristics of the two alloys were studied.The results show that a metallurgical interface with a thickness of 100–200μm was formed as the result of the Marangoni convection during SLM preparation.In detail,the circular flow in the melt pool at the interface led to the dilution of alloying elements and the change of microstructure.Moreover,a suitable first-layer thickness can eff ectively suppress the hot cracks at the interfacial region.Based on the optimized results,the hybrid manufactured samples with diff erent SLM processed volume ratios(SLM-part)to the substrate were prepared to study the mechanical properties and the deformation behavior of hybrid parts.The results show that the volume ratio of the SLM-part to the substrate had an influence on the strength and the elasto-plastic behavior by aff ecting the distribution of plastic deformation.展开更多
A full account of semisyntheses of polychlorinated marine steroids clionastatins A and B is described.We have developed a unique two-stage chlorination-oxidation strategy that enabled concise and divergent semisynthes...A full account of semisyntheses of polychlorinated marine steroids clionastatins A and B is described.We have developed a unique two-stage chlorination-oxidation strategy that enabled concise and divergent semisyntheses of clionastatins A and B in 16 steps from inexpensive testosterone.Key transformations in chlorination stage include(a)conformationally controlled,stereospecific dichlorination through an unusualβ-chloronium intermediate to install the diequatorial C1,C2-dichloride;(b)C4-OH directed C19–H oxygenation followed by challenging neopentyl chlorination to install the C19–Cl.The high oxidation level was constructed through(a)the desaturation at C6–C7 through one-pot photochemical dibromination–reductive debromination;(b)regioselective anti-Markovnikov oxidation of the C6–C7 double bond by photoredox-metal dual catalysis to forge the B ring enone;(c)late-stage desaturation with SeO_(2)to introduce C8–C9 double bond.Wharton transposition was used to forge the D-ring enone,and thermodynamically driven epimerization secured the cis-fused C/D ring system.Furthermore,we also provided a 14-step approach to clionastatin A by optimizing the construction of the D-ring enone with a dehydration-oxidation sequence.展开更多
基金the National Natural Science Foundation of China(22377093)the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR23C100001,China)the Zhejiang Qianjiang Talent Plan(QJD20020224,China).
文摘Currently, the efficacy of albumin-bound paclitaxel (PTX@Alb) is still limited due to theimpaired PTX@Alb accumulation in tumors partly mediated by the dense collagen distribution. Meanwhile,acquired immune resistance always occurs due to the enhanced programmed cell death-ligand 1(PD-L1) expression after PTX@Alb treatment, which then leads to immune tolerance. To fill these gaps,we newly revealed that tamoxifen (TAM), a clinically widely used adjuvant therapy for breast cancer withmitochondrial metabolism blockade capacity, could also be used as a novel effective PD-L1 and TGF-bdual-inhibitor via inducing the phosphorylation of adenosine 5ʹ-monophosphate-activated protein kinase(AMPK) protein. Following this, to obtain a more significant effect, TPP-TAM was prepared by conjugatingmitochondria-targeted triphenylphosphine (TPP) with TAM, which then further self-assembledwith albumin (Alb) to form TPP-TAM@Alb nanoparticles. By doing this, TPP-TAM@Alb nanoparticleseffectively decreased the expression of collagen in vitro, which then led to the enhanced accumulation ofPTX@Alb in 4T1 tumors. Besides, TPP-TAM@Alb also effectively decreased the expression of PD-L1 and TGF-b in tumors to better sensitize PTX@Alb-mediated chemo-immunotherapy by enhancing T cellinfiltration. All in all, we newly put forward a novel mitochondrial metabolism blockade strategy toinhibit PTX@Alb-resistant tumors, further supporting its better clinical application。
文摘This paper proposes a co-optimal strategy using line hardening,mobile devices(mobile ice-melting device,mobile emergency generator,mobile energy storage system),and repair crew dispatching to improve distribution system resilience during ice storms.A multi-stage defender-attacker-defender model is established to take into account interactions and coupling relationships between different measures.In our proposed model,ice storms will attack the distribution and transportation system in a worst-case scenario,affecting system performance from various perspectives.Corresponding to the different operating states in the distribution system affected by ice storms,aiming at minimizing the weighted load shedding value,this paper applies various measures to different stages to improve the response and defense capabilities to ice storms and realize restoration of the distribution system ultimately.The nested column-and-constraint generation algorithm is used to solve the model efficiently.The effectiveness of the proposed model and solution method for enhancing the distribution system resilience is verified on the modified IEEE 33-bus distribution system and modified realworld zone of Caracas 141-bus distribution system.
基金supported by the National Natural Science Foundation of China(Grant No.11572333)the State Key Laboratory of High Temperature Gas Dynamics,Institute of Mechanics,Chinese Academy of Sciences(Grant No.LHD2017TC01)the Chinese Academy of Sciences Foundation Frontier Scientific Research Program(Grant No.ZDBS-LY-JSC005)。
文摘Lift-to-drag ratio (L/D) is nearly the most important index in determining the aerodynamic performance of a hypersonic flight vehicle,because the flight distance is linearly proportional to the L/D according to Breguet's equation.In general,the higher the L/D of a vehicle,the greater the flight range if the specific impulse,structural mass ratio,and flight velocity are given.Naturally,the pursuit of a high L/D for hypersonic vehicles has never ceased [1,2].
文摘Hybrid manufacturing(HM)uses additive manufacturing(AM)techniques to prepare complex or fine structures on traditional processing parts,which can fully utilize the advantages of AM to form complex parts,and the high efficiency and low cost of conventional processing methods in manufacturing regular components.A bimetal material was produced by selective laser melting(SLM)of AlSi10Mg on the deformed Al6061 alloy substrate in this study.Firstly,the interface characteristics of the two alloys were studied.The results show that a metallurgical interface with a thickness of 100–200μm was formed as the result of the Marangoni convection during SLM preparation.In detail,the circular flow in the melt pool at the interface led to the dilution of alloying elements and the change of microstructure.Moreover,a suitable first-layer thickness can eff ectively suppress the hot cracks at the interfacial region.Based on the optimized results,the hybrid manufactured samples with diff erent SLM processed volume ratios(SLM-part)to the substrate were prepared to study the mechanical properties and the deformation behavior of hybrid parts.The results show that the volume ratio of the SLM-part to the substrate had an influence on the strength and the elasto-plastic behavior by aff ecting the distribution of plastic deformation.
基金Financial support from the National Natural Science Foundation of China(Nos.22071205 and 21772164)NFFTBS(J1310024)+1 种基金NCETFJ,and PCSIRT is acknowledged.The authors are also grateful for the financial support(LMDBKF-2019-03)the Laboratory for Marine Drugs and Bioproducts,Pilot National Laboratory for Marine Science and Technology.
文摘A full account of semisyntheses of polychlorinated marine steroids clionastatins A and B is described.We have developed a unique two-stage chlorination-oxidation strategy that enabled concise and divergent semisyntheses of clionastatins A and B in 16 steps from inexpensive testosterone.Key transformations in chlorination stage include(a)conformationally controlled,stereospecific dichlorination through an unusualβ-chloronium intermediate to install the diequatorial C1,C2-dichloride;(b)C4-OH directed C19–H oxygenation followed by challenging neopentyl chlorination to install the C19–Cl.The high oxidation level was constructed through(a)the desaturation at C6–C7 through one-pot photochemical dibromination–reductive debromination;(b)regioselective anti-Markovnikov oxidation of the C6–C7 double bond by photoredox-metal dual catalysis to forge the B ring enone;(c)late-stage desaturation with SeO_(2)to introduce C8–C9 double bond.Wharton transposition was used to forge the D-ring enone,and thermodynamically driven epimerization secured the cis-fused C/D ring system.Furthermore,we also provided a 14-step approach to clionastatin A by optimizing the construction of the D-ring enone with a dehydration-oxidation sequence.
