Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remai...Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.展开更多
In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tum...In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.展开更多
Two supramolecular organic frameworks(SOFs)have been constructed from the co-assembly of biimidazolium-derived octacationic components and cucurbit[8]uril in water.Dynamic light scattering and ^(1)H NMR experiments re...Two supramolecular organic frameworks(SOFs)have been constructed from the co-assembly of biimidazolium-derived octacationic components and cucurbit[8]uril in water.Dynamic light scattering and ^(1)H NMR experiments reveal that both SOFs can undergo reversible assembly and disassembly at room temperature.One of the SOFs displays unprecedently high maximum tolerated dose of 120 mg/kg with mice,which improves by 40%compared with the highest value of the reported SOFs.In vitro and in vivo tests show that the SOF can adsorb doxorubicin and overcome the resistance of multidrugresistant MDR A549/ADR tumor cells to realize intracellular delivery,leading to enhanced antitumor efficacy.Moreover,it can also completely inhibit the posttreatment phototoxicity of photofrin and fully neutralize the anticoagulation of both unfractionated heparin and low molecular weight heparins through efficient inclusion and elimination or sequestration mechanism.As the first examples that undergo roomtemperature reversible assembly and disassembly,the new SOFs in principle allow for quantitative analysis of the molecular components in the body that is prerequisite for preclinical evaluation in the future.展开更多
Background:Neonatal-onset multisystem inflammatory disease is characterized by fever,urticarial rash,aseptic meningitis,deforming arthropathy,hearing loss,and mental retardation.Many patients have mutations in the col...Background:Neonatal-onset multisystem inflammatory disease is characterized by fever,urticarial rash,aseptic meningitis,deforming arthropathy,hearing loss,and mental retardation.Many patients have mutations in the cold-induced autoinflammatory syndrome 1(CIAS1)gene,encoding cryopyrin,a protein that regulates inflammation.展开更多
Correction to:Neurosci.Bull.December,2016,32(6):577–584.https://doi.org/10.1007/s12264-016-0068-z In this article,in Fig 5A,the picture of the Vector+Nogo-66 group was incorrect and should have appeared as shown below.
The efficient recovery of fluorite is paid more and more attention with the increasing application especially in strategic emerging industries.In this study,acrylic acid-2-acrylamido-2-methylpropane sulfonic acid copo...The efficient recovery of fluorite is paid more and more attention with the increasing application especially in strategic emerging industries.In this study,acrylic acid-2-acrylamido-2-methylpropane sulfonic acid copolymer(AAAMPS)was first used as the depressant in fluorite flotation,and its effect on the flotation separation of fluorite and dolomite in sodium oleate(NaOL)system was investigated.The depression mechanism was analyzed by contact angle measurement,zeta potential test,FTIR and XPS analyses.The micro-flotation test results showed that dolomite can be inhibited in fluorite flotation system in the addition of 2 mg/L AA-AMPS and 20 mg/L NaOL at pH 10.The CaF_(2) grade increased from 49.85%in the artificial mixed mineral to 89.60%in the fluorite concentrate.The depression mechanism indicated that AA-AMPS could adsorb strongly on dolomite surface by the chelation with Ca and Mg active sites.Moreover,the further adsorption of NaOL on dolomite surface was prevented by the AA-AMPS adsorption,but that on fluorite surface was little affected,thereby increasing the difference in the hydrophobicity and floatability of the two minerals.展开更多
The influence of NaF on the microstructure,composition and corrosion performance of WE43 Mg alloy in 3.5 wt.%NaCl solution was systematically investigated by means of SEM,TEM,EPMA,XRD,XPS and electrochemical measureme...The influence of NaF on the microstructure,composition and corrosion performance of WE43 Mg alloy in 3.5 wt.%NaCl solution was systematically investigated by means of SEM,TEM,EPMA,XRD,XPS and electrochemical measurements.It was proved that NaF is an effective inhibitor for WE43 Mg alloy and the highest inhibition efficiency is 92.6%at its concentration of 40 mmol/L in neutral NaCl solution.The dissolution of WE43 alloy is inhibited by formation and deposition of a dense and protective double-layered corrosion film by chemical reaction between corrosion inhibitor and dissolved Mg^(2+).The microstructure and composition of this double-layered corrosion film were investigated by FIB and TEM.The outer layer of the corrosion film is found to be composed of NaMgF_(3),MgF_(2)and MgO,while the inner layer mainly consists of MgO and MgF_(2).展开更多
Sclerosteosis,an ultra-rare disorder characterised by high bone mass(HBM)and skeletal overgrowth,leads to facial paralysis,hearing loss and raised intracranial pressure,which is currently managed only through high-ris...Sclerosteosis,an ultra-rare disorder characterised by high bone mass(HBM)and skeletal overgrowth,leads to facial paralysis,hearing loss and raised intracranial pressure,which is currently managed only through high-risk surgery.Sclerosteosis is caused by SOST mutations and loss of functional sclerostin,a protein that suppresses osteogenesis by antagonising Wnt/β-catenin signalling.Herein,using in vitro and in vivo approaches,we explore whether LGK974,another potent Wnt inhibitor that targets porcupine(PORCN,Wnt-specific acyltransferase),is a promising sclerosteosis therapeutic.In vitro assays showed that 100 nmol/L LGK974 significantly reduced osteoblast alkaline phosphatase(ALP)activity/mineralisation,decreased Wnt/osteoblast marker(Axin2,Runx2 and Ocn)expression,and downregulated ossification and the Wnt signalling pathway,without affecting osteoclast numbers/resorption.To assess in vivo effects,6-week-old male and female Sost deficient(Sost-/-)mice received LGK974 for 4 weeks and right hindlimbs were subjected to 20 N peak loading to assess mechanoadaptive interactions.µCT revealed significant reductions in vertebral trabecular number and lower cortical bone volume in loaded and non-loaded tibiae in male and female LGK974-treated Sost-/-mice.Interestingly,the target engagement biomarker Axin2 was only significantly reduced in male vertebrae,which may indicate differences in male and female response to LGK974.This study also shows that PORCN inhibition may effectively limit characteristic HBM and skeletal overgrowth in sclerosteosis patients at sites with severe pathology.展开更多
Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,...Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,and bone abnormalities,including tibial pseudarthrosis and spine deformity.Here,we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity.We explored the Prss56-Nf1 knockout(KO)mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells,a neural crest subset,and their derivatives.Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age,associated with vertebral anomalies reminiscent of patients with NF1.Fate mapping revealed a significant increase in OSX^(+)osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice.Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature.Finally,we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity.Overall,the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.展开更多
In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor...In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor tissues for nanomedicine applications by using mesoporous organic silica(PMO)anisotropic ally grown on the surface of the platinum(Pt)nanoparticles(PMO@Pt).The prepared PMO@Pt had unique Janus structure with an average size of approximately 236 nm.The loading capacity of V9302 was evaluated to be 44.37%when the mass ratio of V9302 to PMO@Pt was maintained at 2.0 and in vitro release studies demonstrated that acidic environments significantly enhanced the drug release.Then this nanomotor was loaded with perfluorohexane(PFH),a phase-change material,and the glutamine inhibitor V9302(denoted as Janus PMO@Pt@PFH@V9302,JPV).Janus PMO@Pt@PFH(JPP)nanomotors demonstrated enhanced fluorescence intensity and distribution within 3D tumor spheroids compared to Janus PMO@Pt nanomotors,attributed to the photothermal-induced phase change of PFH.The nanomotors exhibited high biocompatibility,with cell viability exceeding 98%at high concentrations.However,the incorporation of V9302 into the nanomotors(JPV)significantly reduced 4T1 cell viability under laser irradiation,indicating a cytotoxic effect resulting from the synergy between photothermal therapy and glutamine metabolism inhibition.In vivo,JPV nanomotors effectively inhibited tumor growth and induced apoptosis without causing significant systemic toxicity,showcasing their potential as a therapeutic agent for breast cancer.This integrated nanomotor offers a promising approach for enhanced ultrasound imaging and photothermal therapy in cancer treatment.展开更多
The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against va...The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against various classes of antibiotics,highlighting the urgent need to discover novel antimicrobial agents for combating bacterial infections.Anti-virulence therapy has emerged as a promising therapeutic strategy that neutralizes pathogens by targeting their virulence determinants.The strategies for screening virulence arresting drugs(VADs)in bacteria represent a multifaceted approach that involves elucidating molecular pathogenesis mechanisms of bacterial pathogenicity,identifying evolutionarily conserved virulence factors across different pathogens,and employing integrated approaches combining in silico prediction with experimental validation.Recent technological advancements have established standardized protocols for effective identification and validation of anti-virulence compounds.This review systematically examines contemporary screening methodologies,primarily focusing on quorum-sensing disruption and biofilm suppression strategies,including in silico screening,activity-based screening with bioassays,in vitro and in vivo models.Additionally,we emphasize the imperative for standardized preclinical validation through physiologically relevant animal models,while proposing framework recommendations for developing next-generation VAD screening platforms.This synthesis not only outlines current best practices but also proposes innovative avenues for future antimicrobial discovery research.展开更多
The limited chemical and dispersive stabilities of transition metal carbides and nitrides(MXenes)significantly hinder their practical applications despite the demonstrated excellent performances.In this study,colloida...The limited chemical and dispersive stabilities of transition metal carbides and nitrides(MXenes)significantly hinder their practical applications despite the demonstrated excellent performances.In this study,colloidally stable Ti_(2)CT_(x)-and Ti_(3)C_(2)T_(x)-MXene aqueous dispersions(0.1 mg.m L^(-1))were achieved through a corrosion inhibition strategy by incorporating sodium tartrate(ST).The addition of ST(0.3 mg.m L^(-1))effectively increased the activation energy and enthalpy for the degradation of Ti_(2)CT_(x)and Ti_(3)C_(2)T_(x)in aqueous solutions,largely extending their time constants to 565.5 h and 239.3 days,respectively.This strong oxidation inhibition effect of ST preserved the structural integrity and colloidal properties of both MXenes without compromising their electrical and electrochemical performances.The vacuum-filteredTi_(2)CT_(x)and Ti_(3)C_(2)T_(x)film electrodes demonstrated capacitance retentions of 96.7%and 88.5%after 96 h and 24 days of aging at 25°C,respectively.Multiscale simulations revealed that single-deprotonated ST-preferentially adsorbed onto edges and defect sites of MXene nanosheets via oxygen heteroatoms on the carbonyl moiety bonding to Ti vacancies.This work offers a promising and straightforward approach to stabilize the diluted MXene aqueous dispersions,fundamentally address their oxidation issues,and meet the requirements for temporary storage.展开更多
The study investigated the effects of monetary rewards and punishments on the behavioral inhibition in children with attention deficit hyperactivity disorder(ADHD)tendencies.The present study adopted the signal stoppi...The study investigated the effects of monetary rewards and punishments on the behavioral inhibition in children with attention deficit hyperactivity disorder(ADHD)tendencies.The present study adopted the signal stopping task paradigm,with 66 children with ADHD tendencies as the research subjects.A mixed design of 2(reward and punishment type:reward,punishment)×2(stimulus type:monetary stimulus,social stimulus)was used.The analysis applied a between intervention group(with reward and punishment type variables)and within type of reward approach(by stimulus type as intra subject variables).The results showed that monetary punishment better promotes behavioral inhibition in children with an ADHD tendency than does reward.In addition,this study showed that monetary punishment and social rewards affected the speed–accuracy trade-off of inhibited behavior in children with an ADHD tendency.Thesefindings suggest that withdrawal of a material token resulted in more behavioural compliance in children with an ADHD tendency.展开更多
To address the critical need for safer and cleaner explosion suppression technologies in industrial settings,the suppression differences and mechanisms of the flame acceleration characteristics of CH_(4),LPG and H_(2)...To address the critical need for safer and cleaner explosion suppression technologies in industrial settings,the suppression differences and mechanisms of the flame acceleration characteristics of CH_(4),LPG and H_(2) explosions by N_(2)-water mist two-phase medium were investigated.The flame acceleration characteristics and suppression mechanism of methane,LPG and H_(2) explosions in N_(2)-water mist twophase medium were studied qualitatively and quantitatively from both experimental and simulation aspects.The experimental results show that compared with single N_(2) or water mist,the N_(2)-water mist two-phase medium is more effective in reducing the flame propagation speed and delaying the formation of flame hydrodynamic structure,thus slowing down the flame acceleration characteristics.The simulation results show that this two-phase medium exhibits a strong inhibitory effect on the thermal diffusion instability of CH_(4) and LPG,and significantly weakens the hydrodynamic instability of CH_(4),LPG,and H_(2) simultaneously.Mechanistic analysis confirms that the N_(2)-water mist two-phase medium has both chemical and physical inhibitory effects,among which the physical inhibition plays a dominant role.In addition,the study reveals a linear correlation between the concentration of H radicals in the three combustible gases and the laminar burning velocity.Moreover,this two-phase medium can significantly reduce the reaction rate of the H radical chain reaction,thereby effectively suppressing the laminar burning velocity.展开更多
A new type of corrosion-resistant alloyed-steel rebar,Cr10MoV,was researched using techniques such as corrosion electrochemistry,X-ray computed tomography,and zero resistance ammeter to systematically study the macro-...A new type of corrosion-resistant alloyed-steel rebar,Cr10MoV,was researched using techniques such as corrosion electrochemistry,X-ray computed tomography,and zero resistance ammeter to systematically study the macro-cell corrosion behavior and corrosion resistance of alloyed-steel rebar in mortar and concrete samples induced by chloride ion concentration in the marine environment.The macro-cell corrosion characteristics and development patterns induced by chloride ion concentration in alloyed-steel rebar were preliminarily revealed.In the macro-cell corrosion system of rebar mortar samples induced by 29 times chloride ion concentration,the corrosion current density of the alloyed-steel rebar combination stabilizes at 1.6–2.4μA/cm^(2),which is only one-third of that of the carbon-steel rebar combination,while the dissimilar steel rebar combination stabilizes at 0–0.4μA/cm^(2).Alloyed-steel rebar and carbon-steel rebar are configured in high concentration and low concentration chlorine salt areas,respectively.With the help of high corrosion resistance,the long-term stable corrosion resistance of alloyed-steel rebar is ensured.The potential difference between carbon-steel rebar and alloyed-steel rebar is reduced to weaken the driving force of macro-cell corrosion.It is a useful way to inhibit the macro-cell corrosion of dissimilar steel rebar and ensure the high corrosion resistance and durability of marine reinforced concrete structures.展开更多
Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases invo...Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases involved in angiogenesis[2].However,their involvement in regulating endothelial regeneration remains largely unknown.展开更多
Weathered crust elution-deposited rare earth ores(WREOs)are rich in medium and heavy rare earth.In order to improve the in-situ leaching process,which is prone to landslides and poor permeability,cationic hydroxyethyl...Weathered crust elution-deposited rare earth ores(WREOs)are rich in medium and heavy rare earth.In order to improve the in-situ leaching process,which is prone to landslides and poor permeability,cationic hydroxyethyl cellulose(PQ-10)was used as a novel green swelling inhibitor and percolation promoter and was mixed with conventional leaching agent ammonium sulfate((NH_(4))_(2)SO_(4))to form a composite leaching agent to study the performance and mechanism of swelling inhibition and percolation promotion.Adding PQ-10 can inhibit the hydration swelling of WREOs,promote the percolation effect of the leaching agent,improve the rare earth(RE)leaching efficiency,and reduce the im purity aluminum(Al)leaching efficiency.Compared with the conventional leaching agent 2 wt%(NH_(4))_(2)SO_(4),the percolation time is reduced by 50%by using the composite leaching agent(0.02 wt%PQ-10+2 wt%(NH_(4))_(2)SO_(4)).PQ-10 has positively charged quaternary ammonium groups and hydrophilic group hydroxyl groups,which makes it easy to adsorb on WREOs multiple sites through electrostatic interaction and hydrogen bonding,weakening the electrostatic repulsion between mineral particles,reducing the WREOs interlayer spacing,compressing the double electric layer thickness at the solid-liquid interface,weakening the mineral hydration swelling and increasing the percolation rate.The long carbon chains of the polymer entangle and link the fine mineral particles to agglomerate them,increasing their particle size and reduc ing their hydration dispersion,and preventing blockage of the pe rcolation pores caused by migration of the fine particles through the ore body with the solution.PQ-10 molecules also insert the mine ral interlayer and expulsion of the internal water,further inhibiting the swelling of WREOs.Adding PQ-10 reduces the surface tension of(NH_(4))_(2)SO_(4)solution,improving the spreading and spreading ability of the solution,reducing the adhesion work between molecules in the solid-liquid phase and the adhesion work reduction factor.It proves that PQ-10 promotes the percolation effect of the leaching process of WREOs.In addition,PQ-10 expands the leaching pore size and seepage channels,further improving the percolation rate.展开更多
Pinless friction stir spot welding(P-FSSW)was performed to manufacture Mg/steel lap joints.Orthogonal tests for P-FSSW of Mg/steel were investigated,and the main factors affecting the properties of Mg/steel lap joints...Pinless friction stir spot welding(P-FSSW)was performed to manufacture Mg/steel lap joints.Orthogonal tests for P-FSSW of Mg/steel were investigated,and the main factors affecting the properties of Mg/steel lap joints were derived.The shear force of the Mg/steel lap joints gradually increased and then decreased as the welding time increased.Maximum shear force was 5.3 kN.Fe-Al intermetallic compound(IMC)was formed at the Mg/steel interface near the steel side,and Mg-Al IMCs were formed at the Mg/steel interface near the Mg alloy side.Mg/steel lap joint was transformed from an initial solid-state welding to fusion-brazing welding as the welding time increased.No hole defects were formed in Mg/steel solid-state welding joints,whereas hole defects appeared in Mg/steel fusion-brazing welding joints.The temperature field of Mg/steel lap joints was simulated to analyze hole defects generated during the welding process.Hole defects can be eliminated by changing the spindle deflection angle,and the shear force decreased.Excessive spindle deflection can also lead to failure to form a stable joint.Hole defects were removed because the spindle deflection angle reduced the interfacial reaction temperature,and a solid-state welding joint was formed,which resulted in an absence of fusion-brazing welding hole formation.展开更多
Solidification cracking(SC)of 2024 high-strength aluminium alloy during fusion welding or additive manufacturing has been a long-term issue.In this work,crack-free weld could be obtained using a Zr-core-Alshell wire(Z...Solidification cracking(SC)of 2024 high-strength aluminium alloy during fusion welding or additive manufacturing has been a long-term issue.In this work,crack-free weld could be obtained using a Zr-core-Alshell wire(ZCASW filler material,a novel filler)coupled with an oscillating laser-arc hybrid welding process,and we investigated the solidification cracking susceptibility(SCS)and cracking behavior of AA2024 weld fabricated with different filler materials.The cracking inhibition mechanism of the weld fabricated with ZCASW filler material was elucidated by combined experiments and phase-field simulation.The results show that the effectiveness of filler materials in reducing the SC gradually improves in the order of ER2319 filler material<ER4043 filler material<ZCASW filler material.The main cracking(when using the ER2319 filler material)branches and the micro cracking branches interact with each other to produce cracking coalescence,which aggravates the cracking propagation.The formation of the Al_(3) Zr phase(when using the ZCASW filler material)promotes heterogeneous nucleation of α-Al,thereby resulting in finer and equiaxed non-dendrite structures,which shortens the liquid phase channels and decreases cracking susceptibility index|d T/d(f_(s))^(1/2)|(T is temperature and f_(s) is solidification fraction)at final solidification.A higher proportion(7.65%area fraction)of inter-dendrite phase with spherical distribution state,a shorter(8.6 mm liquid channel length)inter-dendrite phase coupled with round non-dendrite structure(6μm dendrite size)effectively inhibit the SC.The present study can be a useful database for welding and additive manufacturing of AA2024.展开更多
The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the th...The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.展开更多
基金supported by grants from the Open Research Fund of the Zhejiang Key Laboratory of Precision Psychiatry(2025A2)the Natural Science Foundation of Zhejiang Province(LY23C090002)。
文摘Machado-Joseph disease,or spinocerebellar ataxia type 3(SCA3),represents the most common autosomal dominant cerebellar ataxia worldwide.Despite its progressive and debilitating nature,disease-modifying therapies remain elusive.Repetitive transcranial magnetic stimulation(rTMS)has emerged as a promising non-invasive intervention;however,its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding.A recent landmark study published in Brain Stimulation by Chen et al.addressed these challenges by combining a high-dose intermittent theta-burst stimulation(iTBS)protocol with concurrent transcranial magnetic stimulation-electroencephalography(TMS-EEG).This commentary provides an in-depth analysis of their findings,highlighting the restoration of cerebello-cortical inhibition(CBI)as a key therapeutic mechanism.Furthermore,we discuss the broader implications of this work,proposing that future translational research should integrate accelerated iTBS(aiTBS)paradigms,cortical response measurements(CRM),and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.
文摘In the words of the late Sir Colin Blakemore,neurologists have historically sought to infer brain functions in a manner akin to to king a hammer to a computeranalyzing localized anatomical lesions caused by trauma,tumors,or strokes,noting deficits,and inferring what functions certain brain regions may be responsible for.This approach exemplifies a deletion heuristic,where the absence of a specific function reveals insights about the underlying structures or mechanisms responsible for it.By observing what is lost when a particular brain region is damaged,throughout the history of the field,neurologists have pieced together the intricate relationship between anatomy and function.
基金the National Natural Science Foundation of China(No.21921003 for Z.T.L.and 22201293 for S.B.Y.)Shanghai Sailing Program(No.22YF1458300 for S.B.Y.)for financial support。
文摘Two supramolecular organic frameworks(SOFs)have been constructed from the co-assembly of biimidazolium-derived octacationic components and cucurbit[8]uril in water.Dynamic light scattering and ^(1)H NMR experiments reveal that both SOFs can undergo reversible assembly and disassembly at room temperature.One of the SOFs displays unprecedently high maximum tolerated dose of 120 mg/kg with mice,which improves by 40%compared with the highest value of the reported SOFs.In vitro and in vivo tests show that the SOF can adsorb doxorubicin and overcome the resistance of multidrugresistant MDR A549/ADR tumor cells to realize intracellular delivery,leading to enhanced antitumor efficacy.Moreover,it can also completely inhibit the posttreatment phototoxicity of photofrin and fully neutralize the anticoagulation of both unfractionated heparin and low molecular weight heparins through efficient inclusion and elimination or sequestration mechanism.As the first examples that undergo roomtemperature reversible assembly and disassembly,the new SOFs in principle allow for quantitative analysis of the molecular components in the body that is prerequisite for preclinical evaluation in the future.
文摘Background:Neonatal-onset multisystem inflammatory disease is characterized by fever,urticarial rash,aseptic meningitis,deforming arthropathy,hearing loss,and mental retardation.Many patients have mutations in the cold-induced autoinflammatory syndrome 1(CIAS1)gene,encoding cryopyrin,a protein that regulates inflammation.
文摘Correction to:Neurosci.Bull.December,2016,32(6):577–584.https://doi.org/10.1007/s12264-016-0068-z In this article,in Fig 5A,the picture of the Vector+Nogo-66 group was incorrect and should have appeared as shown below.
基金Project(52004333)supported by the National Science Foundation of ChinaProject(2021CB1002)supported by Hunan International Joint Research Center for Efficient and Clean Utilization of Critical Metal Mineral Resources,China。
文摘The efficient recovery of fluorite is paid more and more attention with the increasing application especially in strategic emerging industries.In this study,acrylic acid-2-acrylamido-2-methylpropane sulfonic acid copolymer(AAAMPS)was first used as the depressant in fluorite flotation,and its effect on the flotation separation of fluorite and dolomite in sodium oleate(NaOL)system was investigated.The depression mechanism was analyzed by contact angle measurement,zeta potential test,FTIR and XPS analyses.The micro-flotation test results showed that dolomite can be inhibited in fluorite flotation system in the addition of 2 mg/L AA-AMPS and 20 mg/L NaOL at pH 10.The CaF_(2) grade increased from 49.85%in the artificial mixed mineral to 89.60%in the fluorite concentrate.The depression mechanism indicated that AA-AMPS could adsorb strongly on dolomite surface by the chelation with Ca and Mg active sites.Moreover,the further adsorption of NaOL on dolomite surface was prevented by the AA-AMPS adsorption,but that on fluorite surface was little affected,thereby increasing the difference in the hydrophobicity and floatability of the two minerals.
基金National Natural Science Foundation of China(No.52071067)Liaoning Revitalization Talents Program,China(No.XLYC2403026)+6 种基金Shenyang Young and Middle-aged Science and Technology Innovation Talent Support Program of China(No.RC231178)Natural Scienceof Liaoning Province,China(No.2022-YGJC-16)Fundamental Research Funds for the Central Universities,China(No.N2302019)financial supports by the National Natural Science Foundation of China(No.52101084)Guangdong Basic and Applied Basic Research Foundation,China(No.2023A1515011579)Guangzhou Basic and Applied Basic Research Foundation,China(No.2024A04J9889)National Key Research and Development Project of China(No.2023YFB3408200)。
文摘The influence of NaF on the microstructure,composition and corrosion performance of WE43 Mg alloy in 3.5 wt.%NaCl solution was systematically investigated by means of SEM,TEM,EPMA,XRD,XPS and electrochemical measurements.It was proved that NaF is an effective inhibitor for WE43 Mg alloy and the highest inhibition efficiency is 92.6%at its concentration of 40 mmol/L in neutral NaCl solution.The dissolution of WE43 alloy is inhibited by formation and deposition of a dense and protective double-layered corrosion film by chemical reaction between corrosion inhibitor and dissolved Mg^(2+).The microstructure and composition of this double-layered corrosion film were investigated by FIB and TEM.The outer layer of the corrosion film is found to be composed of NaMgF_(3),MgF_(2)and MgO,while the inner layer mainly consists of MgO and MgF_(2).
文摘Sclerosteosis,an ultra-rare disorder characterised by high bone mass(HBM)and skeletal overgrowth,leads to facial paralysis,hearing loss and raised intracranial pressure,which is currently managed only through high-risk surgery.Sclerosteosis is caused by SOST mutations and loss of functional sclerostin,a protein that suppresses osteogenesis by antagonising Wnt/β-catenin signalling.Herein,using in vitro and in vivo approaches,we explore whether LGK974,another potent Wnt inhibitor that targets porcupine(PORCN,Wnt-specific acyltransferase),is a promising sclerosteosis therapeutic.In vitro assays showed that 100 nmol/L LGK974 significantly reduced osteoblast alkaline phosphatase(ALP)activity/mineralisation,decreased Wnt/osteoblast marker(Axin2,Runx2 and Ocn)expression,and downregulated ossification and the Wnt signalling pathway,without affecting osteoclast numbers/resorption.To assess in vivo effects,6-week-old male and female Sost deficient(Sost-/-)mice received LGK974 for 4 weeks and right hindlimbs were subjected to 20 N peak loading to assess mechanoadaptive interactions.µCT revealed significant reductions in vertebral trabecular number and lower cortical bone volume in loaded and non-loaded tibiae in male and female LGK974-treated Sost-/-mice.Interestingly,the target engagement biomarker Axin2 was only significantly reduced in male vertebrae,which may indicate differences in male and female response to LGK974.This study also shows that PORCN inhibition may effectively limit characteristic HBM and skeletal overgrowth in sclerosteosis patients at sites with severe pathology.
基金Association Neurofibromatoses et Recklinghausen(C.C)Agence Nationale de la Recherche-18-CE14-0033(C.C.,P.T.)+2 种基金Agence Nationale de la Recherche-21-CE18-007-01(C.C.,P.T.)US Department of the Army NF220019(C.C.)supported by a PhD fellowship from the University Paris-Est Créteil and the Fondation pour la Recherche Médicale(FRM)(FDT202304016600 to FK and ECO202306017399 to CG)。
文摘Neurofibromatosis type 1(NF1)is a genetic disorder affecting 1 in 3000 people due to heterozygous mutations in the NF1 gene.Patients with NF1 can develop multiple symptoms,such as neurofibromas,skin hyperpigmentation,and bone abnormalities,including tibial pseudarthrosis and spine deformity.Here,we aimed to elucidate the cellular origin and pathogenic mechanism of NF1 spine deformity.We explored the Prss56-Nf1 knockout(KO)mouse model that recapitulates neurofibromas and pseudarthrosis by carrying Nf1 gene inactivation in Prss56-expressing boundary cap cells,a neural crest subset,and their derivatives.Micro-CT analyses showed that Prss56-Nf1 KO mice exhibit spine deformity from 12 months of age,associated with vertebral anomalies reminiscent of patients with NF1.Fate mapping revealed a significant increase in OSX^(+)osteoblasts of the Prss56 lineage in vertebrae of Prss56-Nf1 KO mice.Increased traced Nf1-deficient cells correlated with increased vertebral bone volume and kyphosis spine curvature.Finally,we showed that treating Prss56-Nf1 KO mice with RAS-MAPK pathway inhibitors prevented spine deformity.Overall,the Prss56-Nf1 KO mouse model unravels the role of osteoblasts from the Prss56 lineage as the cellular origin of NF1 spine deformity and highlights RAS-MAPK pathway inhibition as a promising therapeutic strategy for preventing NF1 spine deformity.
基金financially supported by the Major Basic Research Fund of Jiangsu Province Hospital(No.TS202401)Jiangsu Province Hospital High-level Talent Cultivation Program(PhaseⅠ)(No.CZ0121002010039)
文摘In the treatment of breast cancer,the combination of glutamine metabolism inhibition and photothermal therapy(PTT)is gaining increasing attention.This study developed a Janus nanomotor to enhance permeability in tumor tissues for nanomedicine applications by using mesoporous organic silica(PMO)anisotropic ally grown on the surface of the platinum(Pt)nanoparticles(PMO@Pt).The prepared PMO@Pt had unique Janus structure with an average size of approximately 236 nm.The loading capacity of V9302 was evaluated to be 44.37%when the mass ratio of V9302 to PMO@Pt was maintained at 2.0 and in vitro release studies demonstrated that acidic environments significantly enhanced the drug release.Then this nanomotor was loaded with perfluorohexane(PFH),a phase-change material,and the glutamine inhibitor V9302(denoted as Janus PMO@Pt@PFH@V9302,JPV).Janus PMO@Pt@PFH(JPP)nanomotors demonstrated enhanced fluorescence intensity and distribution within 3D tumor spheroids compared to Janus PMO@Pt nanomotors,attributed to the photothermal-induced phase change of PFH.The nanomotors exhibited high biocompatibility,with cell viability exceeding 98%at high concentrations.However,the incorporation of V9302 into the nanomotors(JPV)significantly reduced 4T1 cell viability under laser irradiation,indicating a cytotoxic effect resulting from the synergy between photothermal therapy and glutamine metabolism inhibition.In vivo,JPV nanomotors effectively inhibited tumor growth and induced apoptosis without causing significant systemic toxicity,showcasing their potential as a therapeutic agent for breast cancer.This integrated nanomotor offers a promising approach for enhanced ultrasound imaging and photothermal therapy in cancer treatment.
基金supported by the National Natural Science Foundation of China(Grant No:82474158)the Natural Science Foundation of Sichuan Province,China(Grant No.:2024NSFSC0708).
文摘The rising prevalence of multidrug-resistant pathogens poses a substantial threat to global healthcare systems,demanding urgent therapeutic interventions.Microorganisms exhibit diverse resistance mechanisms against various classes of antibiotics,highlighting the urgent need to discover novel antimicrobial agents for combating bacterial infections.Anti-virulence therapy has emerged as a promising therapeutic strategy that neutralizes pathogens by targeting their virulence determinants.The strategies for screening virulence arresting drugs(VADs)in bacteria represent a multifaceted approach that involves elucidating molecular pathogenesis mechanisms of bacterial pathogenicity,identifying evolutionarily conserved virulence factors across different pathogens,and employing integrated approaches combining in silico prediction with experimental validation.Recent technological advancements have established standardized protocols for effective identification and validation of anti-virulence compounds.This review systematically examines contemporary screening methodologies,primarily focusing on quorum-sensing disruption and biofilm suppression strategies,including in silico screening,activity-based screening with bioassays,in vitro and in vivo models.Additionally,we emphasize the imperative for standardized preclinical validation through physiologically relevant animal models,while proposing framework recommendations for developing next-generation VAD screening platforms.This synthesis not only outlines current best practices but also proposes innovative avenues for future antimicrobial discovery research.
基金financially supported by the National Natural Science Foundation of China(No.21606005)Beijing Municipal Natural Science Foundation(No.2192016)。
文摘The limited chemical and dispersive stabilities of transition metal carbides and nitrides(MXenes)significantly hinder their practical applications despite the demonstrated excellent performances.In this study,colloidally stable Ti_(2)CT_(x)-and Ti_(3)C_(2)T_(x)-MXene aqueous dispersions(0.1 mg.m L^(-1))were achieved through a corrosion inhibition strategy by incorporating sodium tartrate(ST).The addition of ST(0.3 mg.m L^(-1))effectively increased the activation energy and enthalpy for the degradation of Ti_(2)CT_(x)and Ti_(3)C_(2)T_(x)in aqueous solutions,largely extending their time constants to 565.5 h and 239.3 days,respectively.This strong oxidation inhibition effect of ST preserved the structural integrity and colloidal properties of both MXenes without compromising their electrical and electrochemical performances.The vacuum-filteredTi_(2)CT_(x)and Ti_(3)C_(2)T_(x)film electrodes demonstrated capacitance retentions of 96.7%and 88.5%after 96 h and 24 days of aging at 25°C,respectively.Multiscale simulations revealed that single-deprotonated ST-preferentially adsorbed onto edges and defect sites of MXene nanosheets via oxygen heteroatoms on the carbonyl moiety bonding to Ti vacancies.This work offers a promising and straightforward approach to stabilize the diluted MXene aqueous dispersions,fundamentally address their oxidation issues,and meet the requirements for temporary storage.
基金supported by the National General Projects in 2020 of the 13th Five Year Plan of National Education Science in China:A Study on Attention Training Interventions for ADHD Children in Regular Classes from the Perspective of Educational Neuroscience(BHA200123).
文摘The study investigated the effects of monetary rewards and punishments on the behavioral inhibition in children with attention deficit hyperactivity disorder(ADHD)tendencies.The present study adopted the signal stopping task paradigm,with 66 children with ADHD tendencies as the research subjects.A mixed design of 2(reward and punishment type:reward,punishment)×2(stimulus type:monetary stimulus,social stimulus)was used.The analysis applied a between intervention group(with reward and punishment type variables)and within type of reward approach(by stimulus type as intra subject variables).The results showed that monetary punishment better promotes behavioral inhibition in children with an ADHD tendency than does reward.In addition,this study showed that monetary punishment and social rewards affected the speed–accuracy trade-off of inhibited behavior in children with an ADHD tendency.Thesefindings suggest that withdrawal of a material token resulted in more behavioural compliance in children with an ADHD tendency.
基金financially supported by the National Natural Science Foundation of China (52474216 and 52374197)the Science&Technology Innovation Talents in Universities of Henan Province(22HASTIT027)the Scientific and Technological Key Project of Henan Province (222102320142)。
文摘To address the critical need for safer and cleaner explosion suppression technologies in industrial settings,the suppression differences and mechanisms of the flame acceleration characteristics of CH_(4),LPG and H_(2) explosions by N_(2)-water mist two-phase medium were investigated.The flame acceleration characteristics and suppression mechanism of methane,LPG and H_(2) explosions in N_(2)-water mist twophase medium were studied qualitatively and quantitatively from both experimental and simulation aspects.The experimental results show that compared with single N_(2) or water mist,the N_(2)-water mist two-phase medium is more effective in reducing the flame propagation speed and delaying the formation of flame hydrodynamic structure,thus slowing down the flame acceleration characteristics.The simulation results show that this two-phase medium exhibits a strong inhibitory effect on the thermal diffusion instability of CH_(4) and LPG,and significantly weakens the hydrodynamic instability of CH_(4),LPG,and H_(2) simultaneously.Mechanistic analysis confirms that the N_(2)-water mist two-phase medium has both chemical and physical inhibitory effects,among which the physical inhibition plays a dominant role.In addition,the study reveals a linear correlation between the concentration of H radicals in the three combustible gases and the laminar burning velocity.Moreover,this two-phase medium can significantly reduce the reaction rate of the H radical chain reaction,thereby effectively suppressing the laminar burning velocity.
基金the financial support from National Natural Science Foundation of China(Grant Nos.52278255 and 51878246)Postgraduate Research&Practice Innovation Program of Jiangsu Province(SJCX24_0195).
文摘A new type of corrosion-resistant alloyed-steel rebar,Cr10MoV,was researched using techniques such as corrosion electrochemistry,X-ray computed tomography,and zero resistance ammeter to systematically study the macro-cell corrosion behavior and corrosion resistance of alloyed-steel rebar in mortar and concrete samples induced by chloride ion concentration in the marine environment.The macro-cell corrosion characteristics and development patterns induced by chloride ion concentration in alloyed-steel rebar were preliminarily revealed.In the macro-cell corrosion system of rebar mortar samples induced by 29 times chloride ion concentration,the corrosion current density of the alloyed-steel rebar combination stabilizes at 1.6–2.4μA/cm^(2),which is only one-third of that of the carbon-steel rebar combination,while the dissimilar steel rebar combination stabilizes at 0–0.4μA/cm^(2).Alloyed-steel rebar and carbon-steel rebar are configured in high concentration and low concentration chlorine salt areas,respectively.With the help of high corrosion resistance,the long-term stable corrosion resistance of alloyed-steel rebar is ensured.The potential difference between carbon-steel rebar and alloyed-steel rebar is reduced to weaken the driving force of macro-cell corrosion.It is a useful way to inhibit the macro-cell corrosion of dissimilar steel rebar and ensure the high corrosion resistance and durability of marine reinforced concrete structures.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32171124,31871156,31971101,32271180,82272229,and 81471852)Hunan Provincial Natural Science Foundation of China(Grant No.:2021JJ31058).
文摘Repairing the endothelial barrier is essential for maintaining pulmonary fuid balance and regulating leukocyte infiltration during sepsis[1].Tissue kallikrein-related peptidases(KLKs)are secreted serine proteases involved in angiogenesis[2].However,their involvement in regulating endothelial regeneration remains largely unknown.
基金Project supported by the National Natural Science Foundation of China(U2002215)。
文摘Weathered crust elution-deposited rare earth ores(WREOs)are rich in medium and heavy rare earth.In order to improve the in-situ leaching process,which is prone to landslides and poor permeability,cationic hydroxyethyl cellulose(PQ-10)was used as a novel green swelling inhibitor and percolation promoter and was mixed with conventional leaching agent ammonium sulfate((NH_(4))_(2)SO_(4))to form a composite leaching agent to study the performance and mechanism of swelling inhibition and percolation promotion.Adding PQ-10 can inhibit the hydration swelling of WREOs,promote the percolation effect of the leaching agent,improve the rare earth(RE)leaching efficiency,and reduce the im purity aluminum(Al)leaching efficiency.Compared with the conventional leaching agent 2 wt%(NH_(4))_(2)SO_(4),the percolation time is reduced by 50%by using the composite leaching agent(0.02 wt%PQ-10+2 wt%(NH_(4))_(2)SO_(4)).PQ-10 has positively charged quaternary ammonium groups and hydrophilic group hydroxyl groups,which makes it easy to adsorb on WREOs multiple sites through electrostatic interaction and hydrogen bonding,weakening the electrostatic repulsion between mineral particles,reducing the WREOs interlayer spacing,compressing the double electric layer thickness at the solid-liquid interface,weakening the mineral hydration swelling and increasing the percolation rate.The long carbon chains of the polymer entangle and link the fine mineral particles to agglomerate them,increasing their particle size and reduc ing their hydration dispersion,and preventing blockage of the pe rcolation pores caused by migration of the fine particles through the ore body with the solution.PQ-10 molecules also insert the mine ral interlayer and expulsion of the internal water,further inhibiting the swelling of WREOs.Adding PQ-10 reduces the surface tension of(NH_(4))_(2)SO_(4)solution,improving the spreading and spreading ability of the solution,reducing the adhesion work between molecules in the solid-liquid phase and the adhesion work reduction factor.It proves that PQ-10 promotes the percolation effect of the leaching process of WREOs.In addition,PQ-10 expands the leaching pore size and seepage channels,further improving the percolation rate.
基金supported by the National Natural Science Foundation of China(Grant Number 52001141).
文摘Pinless friction stir spot welding(P-FSSW)was performed to manufacture Mg/steel lap joints.Orthogonal tests for P-FSSW of Mg/steel were investigated,and the main factors affecting the properties of Mg/steel lap joints were derived.The shear force of the Mg/steel lap joints gradually increased and then decreased as the welding time increased.Maximum shear force was 5.3 kN.Fe-Al intermetallic compound(IMC)was formed at the Mg/steel interface near the steel side,and Mg-Al IMCs were formed at the Mg/steel interface near the Mg alloy side.Mg/steel lap joint was transformed from an initial solid-state welding to fusion-brazing welding as the welding time increased.No hole defects were formed in Mg/steel solid-state welding joints,whereas hole defects appeared in Mg/steel fusion-brazing welding joints.The temperature field of Mg/steel lap joints was simulated to analyze hole defects generated during the welding process.Hole defects can be eliminated by changing the spindle deflection angle,and the shear force decreased.Excessive spindle deflection can also lead to failure to form a stable joint.Hole defects were removed because the spindle deflection angle reduced the interfacial reaction temperature,and a solid-state welding joint was formed,which resulted in an absence of fusion-brazing welding hole formation.
基金financially supported by the National Natural Science Foundation of China under Grant Nos.52305467,52188102,U22A20196,and 52075201the Guangdong Basic and Applied Basic Research Foundation Nos.2023A1515010081 and 2022B1212020003the Fundamental Research Funds for the Central Universities under Grant No.YCJJ20230360.
文摘Solidification cracking(SC)of 2024 high-strength aluminium alloy during fusion welding or additive manufacturing has been a long-term issue.In this work,crack-free weld could be obtained using a Zr-core-Alshell wire(ZCASW filler material,a novel filler)coupled with an oscillating laser-arc hybrid welding process,and we investigated the solidification cracking susceptibility(SCS)and cracking behavior of AA2024 weld fabricated with different filler materials.The cracking inhibition mechanism of the weld fabricated with ZCASW filler material was elucidated by combined experiments and phase-field simulation.The results show that the effectiveness of filler materials in reducing the SC gradually improves in the order of ER2319 filler material<ER4043 filler material<ZCASW filler material.The main cracking(when using the ER2319 filler material)branches and the micro cracking branches interact with each other to produce cracking coalescence,which aggravates the cracking propagation.The formation of the Al_(3) Zr phase(when using the ZCASW filler material)promotes heterogeneous nucleation of α-Al,thereby resulting in finer and equiaxed non-dendrite structures,which shortens the liquid phase channels and decreases cracking susceptibility index|d T/d(f_(s))^(1/2)|(T is temperature and f_(s) is solidification fraction)at final solidification.A higher proportion(7.65%area fraction)of inter-dendrite phase with spherical distribution state,a shorter(8.6 mm liquid channel length)inter-dendrite phase coupled with round non-dendrite structure(6μm dendrite size)effectively inhibit the SC.The present study can be a useful database for welding and additive manufacturing of AA2024.
基金supported by the National Natural Science Foundation of China(Nos.82172719,82102918)Joint Funds of Henan Province Foundation for Science and Technology(No.232301420011).
文摘The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.
