Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we sh...Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we showed that lysophosphatidylserine(LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation.Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS.Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling.In vivo,reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke.Thus,our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation,and suggest it as a potential therapeutic target for demyelination-associated diseases.展开更多
Polyolefin-b-poly(ethylene oxide)(PEO)represents the most widely investigated amphiphilic block copolymers.So far,one-pot continuous synthesis of such hybrid block copolymers has only been fulfilled by anionic polymer...Polyolefin-b-poly(ethylene oxide)(PEO)represents the most widely investigated amphiphilic block copolymers.So far,one-pot continuous synthesis of such hybrid block copolymers has only been fulfilled by anionic polymerization through sequen-tial addition of vinyl monomers and ethylene oxide(EO).It still remains challenging to achieve altogether high block efficiency,high polymerization efficiency,and high molar mass for PEO.Here,we report a one-pot hybrid block copolymerization approach to polyisoprene/polystyrene(PI/PS)-b-PEO,in which PI/PS are formed by sBuLi-initiated anionic vinyl-addition polymerization,then in situ employed as macroinitiators for the anionic ring-opening polymerization(ROP)of EO aided by an organic Lewis pair.The cooperative(dual-ion-complexing)catalytic effect of organobase and triethylborane is proven,for thefirst time,effective for lithium alkoxide initiator system,allowing to achieve at room temperature high ROP activity(complete EO conversion and PEO of 3–64 kg/mol reached in 1–6 h),narrow molar mass distribution,controlled block lengths and composition.Density functional the-ory calculation shows that phosphazene bases are particularly effective,compared with N-heterocyclic bases,for complexing with Li+and enhancing the nucleophilicity of oxyanion.The rate of ROP is also affected by Li^(+)-induced aggregation of the chain-end ion pairs,which though can be offset by adequate catalyst loadings.The versatility of this approach is further demonstrated in the one-pot synthesis of tri-/tetrablock ter-/quaterpolymers constituted by PI,PS,PEO,and poly(propylene oxide).Of great interest,PS-b-PI-b-PEO triblock terpolymer with a specific com-position is found to form internally microphase-separated micellar aggregates when dispersed in water.展开更多
Signal reconstruction through software processing is a crucial component of the background and signal models in the PandaX-4T experiment,which is a multi-tonne dark matter direct search experiment.The accuracy of sign...Signal reconstruction through software processing is a crucial component of the background and signal models in the PandaX-4T experiment,which is a multi-tonne dark matter direct search experiment.The accuracy of signal reconstruction is influenced by various detector artifacts,including noise,dark count of photomultiplier,photoionization of impurities in the detector,and other relevant considerations.In this study,we presented a detailed description of a semi-data-driven approach designed to simulate a signal waveform.This work provides a reliable model for the efficiency and bias of the signal reconstruction in the data analysis of PandaX-4T.By comparing critical variables that relate to the temporal shape and hit pattern of the signals,we found good agreement between the simulation and data.展开更多
The proton-proton(pp)fusion chain dominates the neutrino production in the Sun.The uncertainty of the predicted pp neutrino flux is at the sub-percent level,whereas that of the best measurement is O(10%).In this study...The proton-proton(pp)fusion chain dominates the neutrino production in the Sun.The uncertainty of the predicted pp neutrino flux is at the sub-percent level,whereas that of the best measurement is O(10%).In this study,for the first time,we measure solar pp neutrinos in the electron recoil energy range from 24 to 144 keV using the PandaX-4T commissioning data with 0.63 tonne×year exposure.The pp neutrino flux is determined as(8.0±3.9(stat)±10.0(syst))×1010 s^(-1)cm^(-2),which is consistent with the Standard Solar Model and existing measurements,corresponding to an upper flux limit of 23.3×10^(10)s^(-1)cm^(-2)at 90%C.L..展开更多
Phenols,in stead of con venti onal alcoholic compounds,are used to in itiate ring-openi ng polymerizati on(ROP)of ethyle neoxide and propyle ne oxide in bulk at room temperature in cooperati on with the recently preva...Phenols,in stead of con venti onal alcoholic compounds,are used to in itiate ring-openi ng polymerizati on(ROP)of ethyle neoxide and propyle ne oxide in bulk at room temperature in cooperati on with the recently prevaili ng bicompone nt metal-free catalyst comprising an organobase and triethylborane.Experimental and DFT calculation results both point out that due to the lower nucleophilicity of the initiating(phe no late)species than the propagating(alcoholate)species,chai n initiat ion is distinctly slower tha n propagation and the difference becomes eve n larger as the acidity of the phe nolic in itiator increases.Nevertheless,we 11-defi ned polyethers with expected molar mass,low dispersity,and high end-group fidelity are afforded substa ntiating that the ROP is living/c on trolled in spite of the slow initiation.Evolution of product composition indicates that the reaction on alcoholates(i.e.,propagation)is effectively inhib-ited by the unreacted phenols during the initiation step because of the adequately large acidity differenee,which is key to the success of the slow-initiation living/controlled polymerization.The acidity difference betwee n phe nol and alcohol also facilitates the fulfill-ment of highly selective phenolysis of epoxides,a"1+1"type addition reaction between phenol and epoxide(in excess)rather than the"1+n"type ROP reaction,by use of a milder organobase and decreased Lewis acid/base ratio.展开更多
Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators agains...Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators against Src homology region 2 domain-containing phosphatase-1(SHP-1)to block STAT3 pathway represents a promising strategy for DLBCL therapy.Here we reported a new class of thieno[2,3-b]quinolineprocaine hybrid molecules as SHP-1 allosteric activators.The representative hybrid compound 3b displayed SHP-1 activating effect with EC50 of 5.48±0.28μmol/L.Further investigations confirmed that 3b allosterically interacted with SHP-1,switched it from close to open conformation,blocked SHP-1/p-STAT3 pathway,induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro,and delayed tumor growth in the xenograft model of SU-DHL-2.Overall,this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors,and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway.展开更多
Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and sti...Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and still not fully understood.Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin,leading to reduced ATP production and activation of AMP-activated protein kinase(AMPK).Meanwhile,many novel targets of metformin have been gradually discovered.In recent years,multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes.Herein,we summarized the benefits of metformin in four types of diseases,including metabolic associated diseases,cancer,aging and age-related diseases,neurological disorders.We comprehensively discussed the pharmacokinetic properties and the mechanisms of action,treatment strategies,the clinical application,the potential risk of metformin in various diseases.This review provides a brief summary of the benefits and concerns of metformin,aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research.Although there have been countless studies of metformin,longitudinal research in each field is still much warranted.展开更多
To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins...To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins1.Recently,several strategies have been investigated to address TPD,including targeting E2,E3 for POI degradation2,or employing DUBs to stabilize POI3.Among them,proteolysis targeting chimeras(PROTACs)have emerged as the predominant approach in both preclinical and clinical investigations by connecting an E3 recruiting ligand to a POI ligand4.Proteasome,the primary protease responsible for proteolysis in eukaryotes,is a more central and widely present component in the UPS,consisting mainly of the 19S and 20S subcomplexes5.展开更多
We propose a major upgrade to the existing PandaX-4T experiment at the China Jinping Underground Laboratory.The new experiment,PandaX-xT,will be a multi-ten-tonne liquid xenon,ultra-low background,and general-purpose ...We propose a major upgrade to the existing PandaX-4T experiment at the China Jinping Underground Laboratory.The new experiment,PandaX-xT,will be a multi-ten-tonne liquid xenon,ultra-low background,and general-purpose observatory.The full-scaled PandaX-xT contains a 43-t liquid xenon active target.Such an experiment will significantly advance our fundamental understanding of particle physics and astrophysics.The sensitivity of dark matter direct detection will be improved by nearly two orders of magnitude compared to the current best limits,approaching the so-called“neutrino floor”for a dark matter mass above 10 GeV/c^(2),providing a key test to the Weakly Interacting Massive Particle paradigm.By searching for the neutrinoless double beta decay of^(136)Xe isotope in the detector,the effective Majorana neutrino mass can be measured to a 10-41 meV/c^(2) sensitivity,providing a key test to the Dirac/Majorana nature of neutrinos.Astrophysical neutrinos and other ultra-rare interactions can also be measured and searched for with an unprecedented background level,opening up new windows of discovery.Depending on the findings,PandaX-xT will seek the next stage upgrade utilizing isotopic separation of natural xenon.展开更多
基金supported by the National Key Research and Development Program of China(grant number 2020YFA0509101)the National Natural Science Foundation of China(grant numbers 81821001,82130107,U20A20359)the CAS Project for Young Scientists in Basic Research(YSBR-074).
文摘Sterile neuroinflammation is a major driver of multiple neurological diseases.Myelin debris can act as an inflammatory stimulus to promote inflammation and pathologies,but the mechanism is poorly understood.Here,we showed that lysophosphatidylserine(LysoPS)-GPR34 axis played a critical role in microglia-mediated myelin debris sensing and the subsequent neuroinflammation.Myelin debris-induced microglia activation and proinflammatory cytokine expression relied on its lipid component LysoPS.Both myelin debris and LysoPS promoted microglia activation and the production of proinflammatory cytokines via GPR34 and its downstream PI3K-AKT and ERK signaling.In vivo,reducing the content of LysoPS in myelin or inhibition of GPR34 with genetic or pharmacological approaches reduced neuroinflammation and pathologies in the mouse models of multiple sclerosis and stroke.Thus,our results identify GPR34 as a key receptor to sense demyelination and CNS damage and promote neuroinflammation,and suggest it as a potential therapeutic target for demyelination-associated diseases.
基金National Natural Science Foundation of China,Grant/Award Number:52022031Guangdong Provincial Key Laboratory of Luminescence from Molecular Aggregates,Grant/Award Number:2023B1212060003Hunan Provincial Natural Science Foundation of China,Grant/Award Number:2023JJ40620。
文摘Polyolefin-b-poly(ethylene oxide)(PEO)represents the most widely investigated amphiphilic block copolymers.So far,one-pot continuous synthesis of such hybrid block copolymers has only been fulfilled by anionic polymerization through sequen-tial addition of vinyl monomers and ethylene oxide(EO).It still remains challenging to achieve altogether high block efficiency,high polymerization efficiency,and high molar mass for PEO.Here,we report a one-pot hybrid block copolymerization approach to polyisoprene/polystyrene(PI/PS)-b-PEO,in which PI/PS are formed by sBuLi-initiated anionic vinyl-addition polymerization,then in situ employed as macroinitiators for the anionic ring-opening polymerization(ROP)of EO aided by an organic Lewis pair.The cooperative(dual-ion-complexing)catalytic effect of organobase and triethylborane is proven,for thefirst time,effective for lithium alkoxide initiator system,allowing to achieve at room temperature high ROP activity(complete EO conversion and PEO of 3–64 kg/mol reached in 1–6 h),narrow molar mass distribution,controlled block lengths and composition.Density functional the-ory calculation shows that phosphazene bases are particularly effective,compared with N-heterocyclic bases,for complexing with Li+and enhancing the nucleophilicity of oxyanion.The rate of ROP is also affected by Li^(+)-induced aggregation of the chain-end ion pairs,which though can be offset by adequate catalyst loadings.The versatility of this approach is further demonstrated in the one-pot synthesis of tri-/tetrablock ter-/quaterpolymers constituted by PI,PS,PEO,and poly(propylene oxide).Of great interest,PS-b-PI-b-PEO triblock terpolymer with a specific com-position is found to form internally microphase-separated micellar aggregates when dispersed in water.
基金supported in part by the National Science Foundation of China(12090060,12090061)Ministry of Science and Technology of China(2023YFA1606200)+1 种基金Office of Science and Technology,Shanghai Municipal Government(22JC1410100)the Double First Class Plan of the Shanghai Jiao Tong University and Guangzhou Municipal Science and Technology Project(202201010991)。
文摘Signal reconstruction through software processing is a crucial component of the background and signal models in the PandaX-4T experiment,which is a multi-tonne dark matter direct search experiment.The accuracy of signal reconstruction is influenced by various detector artifacts,including noise,dark count of photomultiplier,photoionization of impurities in the detector,and other relevant considerations.In this study,we presented a detailed description of a semi-data-driven approach designed to simulate a signal waveform.This work provides a reliable model for the efficiency and bias of the signal reconstruction in the data analysis of PandaX-4T.By comparing critical variables that relate to the temporal shape and hit pattern of the signals,we found good agreement between the simulation and data.
基金supported in part by the grants from the National Science Foundation of China(12090060,12090063,12105052,12005131,11905128,11925502)the Office of Science and Technology,Shanghai Municipal Government(22JC1410100)+6 种基金the National Science Foundation of Sichuan ProvinceChina(2024NSFSC1371)the support from the Double First Class Plan of Shanghai Jiao Tong Universitythe sponsorship from the Chinese Academy of Sciences Center for Excellence in Particle Physics(CCEPP)Hongwen Foundation in Hong KongTencentNew Cornerstone Science Foundation in China。
文摘The proton-proton(pp)fusion chain dominates the neutrino production in the Sun.The uncertainty of the predicted pp neutrino flux is at the sub-percent level,whereas that of the best measurement is O(10%).In this study,for the first time,we measure solar pp neutrinos in the electron recoil energy range from 24 to 144 keV using the PandaX-4T commissioning data with 0.63 tonne×year exposure.The pp neutrino flux is determined as(8.0±3.9(stat)±10.0(syst))×1010 s^(-1)cm^(-2),which is consistent with the Standard Solar Model and existing measurements,corresponding to an upper flux limit of 23.3×10^(10)s^(-1)cm^(-2)at 90%C.L..
基金support of the National Natural Science Founda-tion of China(Nos.52022031,21734004,21971075)the Fund of Guangdong Provincial Key Laboratory of Luminescenee from Molecular Aggregates(No.2019B030301003)is acknowledged.
文摘Phenols,in stead of con venti onal alcoholic compounds,are used to in itiate ring-openi ng polymerizati on(ROP)of ethyle neoxide and propyle ne oxide in bulk at room temperature in cooperati on with the recently prevaili ng bicompone nt metal-free catalyst comprising an organobase and triethylborane.Experimental and DFT calculation results both point out that due to the lower nucleophilicity of the initiating(phe no late)species than the propagating(alcoholate)species,chai n initiat ion is distinctly slower tha n propagation and the difference becomes eve n larger as the acidity of the phe nolic in itiator increases.Nevertheless,we 11-defi ned polyethers with expected molar mass,low dispersity,and high end-group fidelity are afforded substa ntiating that the ROP is living/c on trolled in spite of the slow initiation.Evolution of product composition indicates that the reaction on alcoholates(i.e.,propagation)is effectively inhib-ited by the unreacted phenols during the initiation step because of the adequately large acidity differenee,which is key to the success of the slow-initiation living/controlled polymerization.The acidity difference betwee n phe nol and alcohol also facilitates the fulfill-ment of highly selective phenolysis of epoxides,a"1+1"type addition reaction between phenol and epoxide(in excess)rather than the"1+n"type ROP reaction,by use of a milder organobase and decreased Lewis acid/base ratio.
基金supported by National Natural Science Foundation of China(Nos.81773779,21772068 and 22277043)National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(No.2018ZX09711002-007-1)+1 种基金Natural Science Foundation of Jiangsu Province(No.BK20190608)Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX22_2330).
文摘Small molecule activators could equally provide powerful tools as inhibitors do for interrogating cellular signal transduction.However,targeted protein activation is chemically challenging.Developing activators against Src homology region 2 domain-containing phosphatase-1(SHP-1)to block STAT3 pathway represents a promising strategy for DLBCL therapy.Here we reported a new class of thieno[2,3-b]quinolineprocaine hybrid molecules as SHP-1 allosteric activators.The representative hybrid compound 3b displayed SHP-1 activating effect with EC50 of 5.48±0.28μmol/L.Further investigations confirmed that 3b allosterically interacted with SHP-1,switched it from close to open conformation,blocked SHP-1/p-STAT3 pathway,induced apoptosis and inhibited ABC-DLBCL cell proliferation in vitro,and delayed tumor growth in the xenograft model of SU-DHL-2.Overall,this work offered a novel paradigm to develop SHP-1 allosteric activators through chemical space evolution of PTPs inhibitors,and firstly validated the therapeutic strategy that directly activating SHP-1 alone could be a potential therapy against ABC-DLBCL via blocking STAT3 pathway.
基金founded by China Postdoctoral Science Foundation(No.2021M703345)the National Natural Science Foundation of China(Nos.82130099,81971265,and 81821005)+3 种基金Shanghai Science and Technology Development Funds(Nos.22YF1457100 and 22ZR1415200)National Key R&D Program of China(No.2022YFA1303802)the National Natural Science Foundation of China for Innovation Research Group(No.81821005)the Lingang Laboratory(Nos.LG202103-03-04,LG202103-03-01,and LG202103-03-05).
文摘Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety,low cost,and outstanding hypoglycemic effect clinically.The mechanisms underlying these benefits are complex and still not fully understood.Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin,leading to reduced ATP production and activation of AMP-activated protein kinase(AMPK).Meanwhile,many novel targets of metformin have been gradually discovered.In recent years,multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes.Herein,we summarized the benefits of metformin in four types of diseases,including metabolic associated diseases,cancer,aging and age-related diseases,neurological disorders.We comprehensively discussed the pharmacokinetic properties and the mechanisms of action,treatment strategies,the clinical application,the potential risk of metformin in various diseases.This review provides a brief summary of the benefits and concerns of metformin,aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research.Although there have been countless studies of metformin,longitudinal research in each field is still much warranted.
基金supported by Guangdong High-Level New R&D Institute(2023000003 and 2019B090904008,China)Guangdong High-level Innovative Research Institute(2021B0909050003,China)+2 种基金National Natural Science Foundation of China(82121005,81803432,and 82273951,China)Zhejiang Provincial Natural Science Foundation of China(LY24H300003,China)Scientific Research Foundation of Zhejiang University City College(No.X-202202,China).
文摘To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins1.Recently,several strategies have been investigated to address TPD,including targeting E2,E3 for POI degradation2,or employing DUBs to stabilize POI3.Among them,proteolysis targeting chimeras(PROTACs)have emerged as the predominant approach in both preclinical and clinical investigations by connecting an E3 recruiting ligand to a POI ligand4.Proteasome,the primary protease responsible for proteolysis in eukaryotes,is a more central and widely present component in the UPS,consisting mainly of the 19S and 20S subcomplexes5.
基金supported by the Office of Science and Technology,Shanghai Municipal Government(Grant Nos.23JC1410200,and 22JCJC1410200)the Ministry of Science and Technology of China(Grant No.2023YFA1606200)+6 种基金the National Natural Science Foundation of China(Grant Nos.1209060,12005131,11905128,11925502,12222505,and 12175139)support from Double First Class Plan of the Shanghai Jiao Tong Universitythe Tsung-Dao Lee Institute Experimental Platform Development Fundthe sponsorship from the Hongwen Foundation in Hong KongTencentNew Cornerstone Science Foundation in ChinaYangyang Development Fund。
文摘We propose a major upgrade to the existing PandaX-4T experiment at the China Jinping Underground Laboratory.The new experiment,PandaX-xT,will be a multi-ten-tonne liquid xenon,ultra-low background,and general-purpose observatory.The full-scaled PandaX-xT contains a 43-t liquid xenon active target.Such an experiment will significantly advance our fundamental understanding of particle physics and astrophysics.The sensitivity of dark matter direct detection will be improved by nearly two orders of magnitude compared to the current best limits,approaching the so-called“neutrino floor”for a dark matter mass above 10 GeV/c^(2),providing a key test to the Weakly Interacting Massive Particle paradigm.By searching for the neutrinoless double beta decay of^(136)Xe isotope in the detector,the effective Majorana neutrino mass can be measured to a 10-41 meV/c^(2) sensitivity,providing a key test to the Dirac/Majorana nature of neutrinos.Astrophysical neutrinos and other ultra-rare interactions can also be measured and searched for with an unprecedented background level,opening up new windows of discovery.Depending on the findings,PandaX-xT will seek the next stage upgrade utilizing isotopic separation of natural xenon.
