To facilitate the low-noise design of tandem lift bodies as applied in aeroengines and aircraft,the acoustic features of tandem blades are investigated by wind-tunnel experiments.This is further specialized for the ro...To facilitate the low-noise design of tandem lift bodies as applied in aeroengines and aircraft,the acoustic features of tandem blades are investigated by wind-tunnel experiments.This is further specialized for the rotating blades applied in contra-rotating open rotors under the concept of frozen-rotor.A 70-channel phased microphone array and nine high-precision free-field microphones are employed.The beamforming method,enhanced by a source filtering technique,is employed to locate noise sources,providing insights into the source patterns of blade-blade interaction noise concerning flow speed,blade spacing,and aft blade clipping.The results show the following:(A)Sources of tandem-blade noise exist in the form of concentrated source clusters,resulting in two major clusters:the mid-span interaction noise and the tip-induced noise.(B)These source clusters tend to separate as flow speed or blade spacing increases.(C)By increasing blade spacing,the band-pass filtered overall sound pressure level is reduced by 2.9 dB.(D)A two-phase noise suppression pattern is observed with blade clipping,resulting in a total reduction of 3.0 dB for the interaction noise through the removal of tip-induced noise sources and the replacement of mid-span noise sources.Based on these findings,suggestions concerning blade spacing and clipping are discussed.展开更多
Large Eddy Simulation（LES） is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod wi...Large Eddy Simulation（LES） is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with a diameter of 10 mm. The incoming flow velocity is 40 m/s and the corresponding Reynolds numbers based on airfoil chord and rod diameter are about 397000 and 26000, respectively. The far-field acoustic field is predicted using an acoustic analogy method which has been validated by the experiment. A straight leading edge airfoil and a wavy leading edge airfoil are simulated. The results show that wavy leading edge increases the airfoil lift and drag whereas the lift and drag fluctuations are substantially reduced. In addition, wavy leading edge can significantly change the flow pattern around the leading edge and a pair of counter-rotating streamwise vortices stemming from each wavy leading edge peak are observed.An averaged noise reduction of 9.5 dB is observed with the wavy leading edge at the azimuthal angle of 90°. Moreover, the wavy leading edge can mitigate noise radiation at all the azimuthal angles without significantly changing the noise directivity. The underlying noise reduction mechanisms are then analyzed in detail.展开更多
Pressure-sensitive paint(PSP)is a global pressure measurement technique.Compared with pressure transducers,PSP has significant advantages such as high spatial resolution and a lack of contact when applied to fast-rota...Pressure-sensitive paint(PSP)is a global pressure measurement technique.Compared with pressure transducers,PSP has significant advantages such as high spatial resolution and a lack of contact when applied to fast-rotating blades.However,due to the limitations of other pressure measurement techniques,the validation of PSP measurements on fast-rotating blades is generally difficult.In this work,a comprehensive study including PSP measurement,force balance measurement,and simulation was conducted on a 1 m-diameter propeller at the China Aerodynamic Research and Development Center.First,our computational fluid dynamics(CFD)code was validated by comparing the calculated aerodynamic thrust with the results from force balance measurements.Then,the pressure distributions on the propeller blade obtained by PSP were carefully compared with the CFD results under different working conditions.The results of PSP measurements,force balance measurements,and CFD showed good agreement,and the PSP measurement errors were estimated to be less than 5% of the dynamic pressure at the blade tip.Finally,the variations in pressure distribution under different rotating speeds and free-stream velocities were discussed.展开更多
To better understand the outcomes of small cell lung cancer（SCLC）,we examined the clinical features and prognostic factors of SCLC in this study.A total of 148 patients who were diagnosed as having SCLC between Janu...To better understand the outcomes of small cell lung cancer（SCLC）,we examined the clinical features and prognostic factors of SCLC in this study.A total of 148 patients who were diagnosed as having SCLC between January 2009 and December 2013 in Cancer Center of Union Hospital,Wuhan,China,were enrolled and their clinical features and prognostic factors were retrospectively analyzed.Log-rank test and Cox regression model were employed for analysis of prognostic factors.The 1-and 2-year overall survival（OS） rates were 59.7% and 25.7%,respectively,for limited disease（LD） patients whose median survival time（MST） was 16 months.The 1-and 2-year OS rates were 29.5% and 5.3%,respectively,for extensive disease（ED） patients whose MST was 10 months.The univariate analysis and multivariate analysis revealed that age,tumor stage,serum CEA and Ki-67 antigen were significantly correlated to the outcomes of SCLC,and they were significant prognostic factors for SCLC.展开更多
The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular ...The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization.To address this problem,we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency.Marked deficiencies in fatty acid oxidation(FAO)and other mitochondrial defects were observed in cells carrying one of these six variants(c.541 C>T,c.863 T>G,c.895 A>G,c.1238 T>C,c.1276 G>A,and c.1505 T>A),including reductions in mitochondrial respiratory-chain function and adenosine teriphosphate(ATP)production,and increased levels of mitochondrial reactive oxygen species(ROS).Intriguingly,higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress.Moreover,the stability of the mutant homodimer was disturbed,and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics(MD)simulation.The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.展开更多
The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immuno...The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune cells.To solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor site.Upon irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ICD.Moreover,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic tumors.In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.展开更多
Alzheimer’s disease(AD),characterized by b-amyloid(Ab)aggregation and neuroinflammation,remains a formidable clinical challenge.Herein,we present an innovative nose-to-brain delivery platform utilizing lactoferrin(Lf...Alzheimer’s disease(AD),characterized by b-amyloid(Ab)aggregation and neuroinflammation,remains a formidable clinical challenge.Herein,we present an innovative nose-to-brain delivery platform utilizing lactoferrin(Lf)-functionalized lipid nanoparticles(LNPs)co-encapsulating α-mangostin(α-M)and β-site APP cleaving enzyme 1(BACE1)siRNA(siB).This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α-M with the transcriptional silencing of BACE1 via siB,thereby simultaneously inhibiting Aβ production and enhancing its clearance.Fabricated via a microfluidic approach,the LNPs exhibited uniform particle size distribution,great encapsulation efficiency,and robust colloidal stability.Upon intranasal administration,Lf-functionalization enabled superior brain-targeting efficacy through receptormediated transcytosis.In vitro studies demonstrated that α-M reversed Aβ-induced low-density lipoprotein receptor downregulation,promoting microglial phagocytosis and autophagic degradation of Aβ,while siB effectively suppressed BACE1 expression,abrogating Aβ synthesis.In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery,substantial Aβ plaque reduction,and alleviation of neuroinflammation and oxidative stress.This intricately designed LNP system,exploiting a non-invasive and efficient nose-to-brain delivery route,provides a biocompatible,synergistic,and transformative therapeutic strategy for the multifaceted management of AD.展开更多
To the Editor:Lung cancer is characterized by its high incidence and mortality rates,imposing a significant burden of disease globally.[1]Liver metastasis is associated with poorer clinical outcomes and shorter life e...To the Editor:Lung cancer is characterized by its high incidence and mortality rates,imposing a significant burden of disease globally.[1]Liver metastasis is associated with poorer clinical outcomes and shorter life expectancy in non-small cell lung cancer(NSCLC).[2]Although immune checkpoint inhibitors(ICIs)have revolutionized the treatment of NSCLC,existing predictive and prognostic biomarkers have limited effectiveness and pose a clinical challenge,particularly for patients with liver metastasis.展开更多
Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation.However,its efficacy remains restricted by weak competitiveness in pathogen-rich n...Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation.However,its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers.Inspired by bacterial competitive interactions,we developed a multifunctional microneedle(MN)platform to overcome these limitations.Lactobacillus reuteri(Lr)was coated with poly-l-lysine-modified metal–phenolic networks(MPNs)encapsulating doxorubicin(DOX),yielding DOX@MPN–PLL@Lr(DMP@Lr).The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function.This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared(NIR)-promoted antibiotic release,thereby enhancing probiotic competitiveness.Meanwhile,MNs physically disrupt biofilms for precise delivery into deep infection sites.In vitro,DMP@Lr achieved>99.9%(5.5 log)bactericidal efficiency,and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs.In vivo,a single DMP@Lr MN patch promoted 93.9%wound closure,demonstrating potent antibacterial activity and accelerated healing.This study presents an innovative,translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.展开更多
Electric vehicles(EVs)with managed charging and discharging schedules have the potential to reduce costs,enhance grid resilience,and facilitate integration of renewable energy sources.However,the heterogeneity of cons...Electric vehicles(EVs)with managed charging and discharging schedules have the potential to reduce costs,enhance grid resilience,and facilitate integration of renewable energy sources.However,the heterogeneity of consumer travel patterns and the variability of renewable energy generation present significant challenges to existing control strategies,often resulting in issues such as the“curse of dimensionality.”This study proposes a mobility-aware deep reinforcement learning-based charging control strategy using the Deep Q-Network(DQN)algorithm to minimize charging costs and maximize photovoltaic(PV)energy utilization.Leveraging real-time electricity prices,real-world EV travel data,and actual PV generation profiles,the proposed framework achieves low charging costs,high solar energy utilization,and reduced carbon emissions—approaching the performance of an ideal offline optimization algorithm with perfect foresight,and substantially outperforming baseline strategies such as random charging,Charge-As-Soon-As-Possible(CASAP),and greedy charging.Specifically,the RL-based approach reduces charging costs by 55%and lowers carbon emission by 11.6%compared to random charging,and achieves a PV utilization rate of 95%.Furthermore,the value of information regarding EV’s travel time and the building’s electricity demand is 2.4CNY/vehicle/day and$0.7/vehicle/day,respectively,underscoring the importance of addressing uncertainty in EV charging management.These findings demonstrate the feasibility and effectiveness of reinforcement learning in optimizing EV operations within integrated vehicle-grid-building-PV systems.展开更多
Background:The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy(RT)following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell l...Background:The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy(RT)following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer(ES-SCLC).Methods:A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed.Inverse probability of treatment weighting(IPTW)analysis was performed to address potential confounding factors.The primary focus of our evaluation was to assess the impact of RT on progression-free survival(PFS)and overall survival(OS).Results:After IPTW analysis,49 patients received durvalumab plus platinum-etoposide(EP)chemotherapy followed by RT(Durva+EP+RT)and 72 patients received immunochemotherapy(Durva+EP).The median OS was 17.2 months vs.12.3 months(hazard ratio[HR]:0.38,95%confidence interval[CI]:0.17-0.85,P=0.020),and the median PFS was 8.9 months vs.5.9 months(HR:0.56,95%CI:0.32-0.97,P=0.030)in Durva+EP+RT and Durva+EP groups,respectively.Thoracic radiation therapy(TRT)resulted in longer OS(17.2 months vs.14.7 months)and PFS(9.1 months vs.7.2 months)compared to RT directed to other metastatic sites.Among patients with oligo-metastasis,RT also showed significant benefits,with a median OS of 17.4 months vs.13.7 months and median PFS of 9.8 months vs.5.9 months compared to no RT.Continuous durvalumab treatment beyond progression(TBP)prolonged OS compared to patients without TBP,in both the Durva+EP+RT(NA vs.15.8 months,HR:0.48,95%CI:0.14-1.63,P=0.238)and Durva+EP groups(12.3 months vs.4.3 months,HR:0.29,95%CI:0.10-0.81,P=0.018).Grade 3 or 4 adverse events occurred in 13(26.5%)and 13(18.1%)patients,respectively,in the two groups;pneumonitis was mostly low-grade.Conclusion:Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.展开更多
Adeno-associated virus(AAV)is one of the best viral vectors for the drug delivery in gene therapy.Several U.S.Food and Drug Administration(FDA)proved drugs such as Luxturna,Zolgensma,Hemgenix or Elevidys are based on ...Adeno-associated virus(AAV)is one of the best viral vectors for the drug delivery in gene therapy.Several U.S.Food and Drug Administration(FDA)proved drugs such as Luxturna,Zolgensma,Hemgenix or Elevidys are based on wild-type AAV2,AAV9,AAV5 or AAVrh74,respectively.However,the highly liver bio-distribution and tropism generate high toxicity which leads to serious adverse events(SAE)or deaths in many clinical cases.展开更多
Insurmountable blood-brain barrier(BBB)and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectivenes...Insurmountable blood-brain barrier(BBB)and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβdeposition or TAU protein need to be resolved urgently.Herein,a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide[R@(ox-PLGA)-KcD].DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions,and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma.Then exposed KLVFF can capture and carry Aβto microglia,attenuating Aβ-induced neurotoxicity.Strikingly,rapamycin,an autophagy promoter,is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβdegradation and normalize inflammatory condition.This design altogether accelerates Aβdegradation and alleviates oxidative stress and excessive inflammatory response.Collectively,our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment,to achieve efficient AD therapy.展开更多
Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during t...Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].展开更多
Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the re...Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.展开更多
Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through...Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.展开更多
Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-pa...Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.展开更多
基金supported by grants from the National Natural Science Foundation of China(Nos.12102451,12072186)the National Science and Technology Major Project,China(No.J2019-II-0006-0026)AVIC Aerodynamics Research Institute,China(No.XFX20220201).
文摘To facilitate the low-noise design of tandem lift bodies as applied in aeroengines and aircraft,the acoustic features of tandem blades are investigated by wind-tunnel experiments.This is further specialized for the rotating blades applied in contra-rotating open rotors under the concept of frozen-rotor.A 70-channel phased microphone array and nine high-precision free-field microphones are employed.The beamforming method,enhanced by a source filtering technique,is employed to locate noise sources,providing insights into the source patterns of blade-blade interaction noise concerning flow speed,blade spacing,and aft blade clipping.The results show the following:(A)Sources of tandem-blade noise exist in the form of concentrated source clusters,resulting in two major clusters:the mid-span interaction noise and the tip-induced noise.(B)These source clusters tend to separate as flow speed or blade spacing increases.(C)By increasing blade spacing,the band-pass filtered overall sound pressure level is reduced by 2.9 dB.(D)A two-phase noise suppression pattern is observed with blade clipping,resulting in a total reduction of 3.0 dB for the interaction noise through the removal of tip-induced noise sources and the replacement of mid-span noise sources.Based on these findings,suggestions concerning blade spacing and clipping are discussed.
基金supported by the National Natural Science Foundation of China (Nos.51776174,51476134,51276149 and 11602290)State Key Laboratory of Aerodynamics of China Aerodynamics Research and Development Center (No.SKLA20160201)+1 种基金Key Laboratory of Aerodynamic Noise Control of China Aerodynamics Research and Development Center (No.ANCL20170201)China-Europe IMAGE (Innovative Methodologies and Technologies for Reducing Aircraft Noise Generation and Emission) program (No.688971-IMAGE-H2020MG-20141015)
文摘Large Eddy Simulation（LES） is performed to investigate the airfoil broadband noise reduction with wavy leading edge under anisotropic incoming turbulence. The anisotropic incoming turbulence is generated by a rod with a diameter of 10 mm. The incoming flow velocity is 40 m/s and the corresponding Reynolds numbers based on airfoil chord and rod diameter are about 397000 and 26000, respectively. The far-field acoustic field is predicted using an acoustic analogy method which has been validated by the experiment. A straight leading edge airfoil and a wavy leading edge airfoil are simulated. The results show that wavy leading edge increases the airfoil lift and drag whereas the lift and drag fluctuations are substantially reduced. In addition, wavy leading edge can significantly change the flow pattern around the leading edge and a pair of counter-rotating streamwise vortices stemming from each wavy leading edge peak are observed.An averaged noise reduction of 9.5 dB is observed with the wavy leading edge at the azimuthal angle of 90°. Moreover, the wavy leading edge can mitigate noise radiation at all the azimuthal angles without significantly changing the noise directivity. The underlying noise reduction mechanisms are then analyzed in detail.
基金supported by the Foundation of the State Key Laboratory of Aerodynamics(Grant No.SKLA2019040302)the National Natural Science Foundation of China(Grant No.11872038).
文摘Pressure-sensitive paint(PSP)is a global pressure measurement technique.Compared with pressure transducers,PSP has significant advantages such as high spatial resolution and a lack of contact when applied to fast-rotating blades.However,due to the limitations of other pressure measurement techniques,the validation of PSP measurements on fast-rotating blades is generally difficult.In this work,a comprehensive study including PSP measurement,force balance measurement,and simulation was conducted on a 1 m-diameter propeller at the China Aerodynamic Research and Development Center.First,our computational fluid dynamics(CFD)code was validated by comparing the calculated aerodynamic thrust with the results from force balance measurements.Then,the pressure distributions on the propeller blade obtained by PSP were carefully compared with the CFD results under different working conditions.The results of PSP measurements,force balance measurements,and CFD showed good agreement,and the PSP measurement errors were estimated to be less than 5% of the dynamic pressure at the blade tip.Finally,the variations in pressure distribution under different rotating speeds and free-stream velocities were discussed.
基金supported by the National Natural Science Foundation of China(No.81172595 and No.81573090)
文摘To better understand the outcomes of small cell lung cancer（SCLC）,we examined the clinical features and prognostic factors of SCLC in this study.A total of 148 patients who were diagnosed as having SCLC between January 2009 and December 2013 in Cancer Center of Union Hospital,Wuhan,China,were enrolled and their clinical features and prognostic factors were retrospectively analyzed.Log-rank test and Cox regression model were employed for analysis of prognostic factors.The 1-and 2-year overall survival（OS） rates were 59.7% and 25.7%,respectively,for limited disease（LD） patients whose median survival time（MST） was 16 months.The 1-and 2-year OS rates were 29.5% and 5.3%,respectively,for extensive disease（ED） patients whose MST was 10 months.The univariate analysis and multivariate analysis revealed that age,tumor stage,serum CEA and Ki-67 antigen were significantly correlated to the outcomes of SCLC,and they were significant prognostic factors for SCLC.
基金the National Natural Science Foundation of China(No.81741090)the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talentsthe National KePy R&D Program of China(Nos.2017YFC1001703 and 2018YFC1002700)。
文摘The pathogenesis of very-long-chain acyl-CoA dehydrogenase(VLCAD)deficiency is highly heterogeneous and still unclear.Additional novel variants have been recently detected in the population.The molecular and cellular effects of these previously unreported variants are still poorly understood and require further characterization.To address this problem,we have evaluated the various functions and biochemical consequences of six novel missense variants that lead to mild VLCAD deficiency.Marked deficiencies in fatty acid oxidation(FAO)and other mitochondrial defects were observed in cells carrying one of these six variants(c.541 C>T,c.863 T>G,c.895 A>G,c.1238 T>C,c.1276 G>A,and c.1505 T>A),including reductions in mitochondrial respiratory-chain function and adenosine teriphosphate(ATP)production,and increased levels of mitochondrial reactive oxygen species(ROS).Intriguingly,higher apoptosis levels were found in cells carrying the mutant VLCAD under glucose-limited stress.Moreover,the stability of the mutant homodimer was disturbed,and major conformational changes in each mutant VLCAD structure were predicted by molecular dynamics(MD)simulation.The data presented here may provide valuable information for improving management of diagnosis and treatment of VLCAD deficiency and for a better understanding of the general molecular bases of disease variability.
基金supported by National Natural Science Foundation of China(No.82173762)Research Funds of Sichuan Science and Technology Department(Nos.2022JDJQ0050,2022YFS0334)111 Project(No.B18035)。
文摘The application of photothermal therapy(PTT)is greatly limited by the low accumulation of photothermal agents,uneven photothermal distribution,and heat endurance of cancer cells.Worse still,despite PTT enhances immunogenicity,the anti-tumor immune efficacy is still unsatisfactory due to the inefficient immunogenic cell death(ICD)induction and poor infiltration of immune cells.To solve the above problems of PTT,we developed hyaluronic acid(HA)modified hollow copper sulfide nanoparticles encapsulating diethyldithiocarbamate(DDTC)to construct a breast tumor targeting and near infrared(NIR)photo-responsive drug delivery system(D-HCuS@HA),which further combined with losartan to improve the accumulation and penetration in the tumor site.Upon irradiation,D-HCuS@HA realized enhanced PTT and released cytotoxic Cu(DDTC)_(2)to eliminate heat endurance tumor cells,thereby enhancing antitumor effect and inducing effective ICD.Moreover,the combination with losartan could remodel the tumor microenvironment,allowing more T cells to infiltrate into the tumor,and significantly inhibiting the occurrence and development of metastatic tumors.In vitro/vivo results revealed the great potential of D-HCuS@HA combined with losartan,which provides a new paradigm for anti-tumor and anti-metastases.
基金supported by the Research and Development Program of the Science and Technology Department of Sichuan Province(2022JDJQ0050,China)the Key Laboratory of Target Discovery and Protein Drug Development in Major Diseases at Chengdu Medical College of Sichuan Province 2023 Annual Project(23LHZY04,China).
文摘Alzheimer’s disease(AD),characterized by b-amyloid(Ab)aggregation and neuroinflammation,remains a formidable clinical challenge.Herein,we present an innovative nose-to-brain delivery platform utilizing lactoferrin(Lf)-functionalized lipid nanoparticles(LNPs)co-encapsulating α-mangostin(α-M)and β-site APP cleaving enzyme 1(BACE1)siRNA(siB).This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α-M with the transcriptional silencing of BACE1 via siB,thereby simultaneously inhibiting Aβ production and enhancing its clearance.Fabricated via a microfluidic approach,the LNPs exhibited uniform particle size distribution,great encapsulation efficiency,and robust colloidal stability.Upon intranasal administration,Lf-functionalization enabled superior brain-targeting efficacy through receptormediated transcytosis.In vitro studies demonstrated that α-M reversed Aβ-induced low-density lipoprotein receptor downregulation,promoting microglial phagocytosis and autophagic degradation of Aβ,while siB effectively suppressed BACE1 expression,abrogating Aβ synthesis.In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery,substantial Aβ plaque reduction,and alleviation of neuroinflammation and oxidative stress.This intricately designed LNP system,exploiting a non-invasive and efficient nose-to-brain delivery route,provides a biocompatible,synergistic,and transformative therapeutic strategy for the multifaceted management of AD.
基金financially supported by the National Natural Science Foundation of China(Nos.82222048 and 82003206)the Natural Science Foundation of Hunan Province(No.2021RC3118).
文摘To the Editor:Lung cancer is characterized by its high incidence and mortality rates,imposing a significant burden of disease globally.[1]Liver metastasis is associated with poorer clinical outcomes and shorter life expectancy in non-small cell lung cancer(NSCLC).[2]Although immune checkpoint inhibitors(ICIs)have revolutionized the treatment of NSCLC,existing predictive and prognostic biomarkers have limited effectiveness and pose a clinical challenge,particularly for patients with liver metastasis.
基金supported by Hainan Provincial Natural Science Foundation of China(825MS071).
文摘Probiotic therapy offers a promising strategy for chronic infected wound management through pathogen suppression and immune modulation.However,its efficacy remains restricted by weak competitiveness in pathogen-rich niches and poor penetration across biofilm barriers.Inspired by bacterial competitive interactions,we developed a multifunctional microneedle(MN)platform to overcome these limitations.Lactobacillus reuteri(Lr)was coated with poly-l-lysine-modified metal–phenolic networks(MPNs)encapsulating doxorubicin(DOX),yielding DOX@MPN–PLL@Lr(DMP@Lr).The engineered probiotics were incorporated into dissolving MNs enriched with nutrient broth to ensure excellent microneedle performance and probiotic function.This design leverages MPN multifunctionality to reduce early-stage pathogenic burden via photothermal-assisted bacterial killing and near-infrared(NIR)-promoted antibiotic release,thereby enhancing probiotic competitiveness.Meanwhile,MNs physically disrupt biofilms for precise delivery into deep infection sites.In vitro,DMP@Lr achieved>99.9%(5.5 log)bactericidal efficiency,and its MNs exhibited a 1.4-fold higher biofilm clearance compared with blank MNs.In vivo,a single DMP@Lr MN patch promoted 93.9%wound closure,demonstrating potent antibacterial activity and accelerated healing.This study presents an innovative,translatable probiotic-based MN therapy for the effective treatment of chronically infected wounds.
基金funded by the National Natural Science Foundation of China(Grant No.72304028,72304031,W2412161)the National Key Research and Development Program of China(Grant No.2020YFA0608603)the Fundamental Research Funds for the Central Universities(Grant No.JKF-2025045909550,FRF-TP-22-024A1).
文摘Electric vehicles(EVs)with managed charging and discharging schedules have the potential to reduce costs,enhance grid resilience,and facilitate integration of renewable energy sources.However,the heterogeneity of consumer travel patterns and the variability of renewable energy generation present significant challenges to existing control strategies,often resulting in issues such as the“curse of dimensionality.”This study proposes a mobility-aware deep reinforcement learning-based charging control strategy using the Deep Q-Network(DQN)algorithm to minimize charging costs and maximize photovoltaic(PV)energy utilization.Leveraging real-time electricity prices,real-world EV travel data,and actual PV generation profiles,the proposed framework achieves low charging costs,high solar energy utilization,and reduced carbon emissions—approaching the performance of an ideal offline optimization algorithm with perfect foresight,and substantially outperforming baseline strategies such as random charging,Charge-As-Soon-As-Possible(CASAP),and greedy charging.Specifically,the RL-based approach reduces charging costs by 55%and lowers carbon emission by 11.6%compared to random charging,and achieves a PV utilization rate of 95%.Furthermore,the value of information regarding EV’s travel time and the building’s electricity demand is 2.4CNY/vehicle/day and$0.7/vehicle/day,respectively,underscoring the importance of addressing uncertainty in EV charging management.These findings demonstrate the feasibility and effectiveness of reinforcement learning in optimizing EV operations within integrated vehicle-grid-building-PV systems.
基金supported by the Bethune-Cancer Radiotherapy Translational Medicine Research Fund of China(No.flzh202117).
文摘Background:The purpose of this study was to evaluate the safety and efficacy of subsequent radiotherapy(RT)following first-line treatment with durvalumab plus chemotherapy in patients with extensive-stage small cell lung cancer(ES-SCLC).Methods:A total of 122 patients with ES-SCLC from three hospitals during July 2019 to December 2021 were retrospectively analyzed.Inverse probability of treatment weighting(IPTW)analysis was performed to address potential confounding factors.The primary focus of our evaluation was to assess the impact of RT on progression-free survival(PFS)and overall survival(OS).Results:After IPTW analysis,49 patients received durvalumab plus platinum-etoposide(EP)chemotherapy followed by RT(Durva+EP+RT)and 72 patients received immunochemotherapy(Durva+EP).The median OS was 17.2 months vs.12.3 months(hazard ratio[HR]:0.38,95%confidence interval[CI]:0.17-0.85,P=0.020),and the median PFS was 8.9 months vs.5.9 months(HR:0.56,95%CI:0.32-0.97,P=0.030)in Durva+EP+RT and Durva+EP groups,respectively.Thoracic radiation therapy(TRT)resulted in longer OS(17.2 months vs.14.7 months)and PFS(9.1 months vs.7.2 months)compared to RT directed to other metastatic sites.Among patients with oligo-metastasis,RT also showed significant benefits,with a median OS of 17.4 months vs.13.7 months and median PFS of 9.8 months vs.5.9 months compared to no RT.Continuous durvalumab treatment beyond progression(TBP)prolonged OS compared to patients without TBP,in both the Durva+EP+RT(NA vs.15.8 months,HR:0.48,95%CI:0.14-1.63,P=0.238)and Durva+EP groups(12.3 months vs.4.3 months,HR:0.29,95%CI:0.10-0.81,P=0.018).Grade 3 or 4 adverse events occurred in 13(26.5%)and 13(18.1%)patients,respectively,in the two groups;pneumonitis was mostly low-grade.Conclusion:Addition of RT after first-line immunochemotherapy significantly improved survival outcomes with manageable toxicity in ES-SCLC.
文摘Adeno-associated virus(AAV)is one of the best viral vectors for the drug delivery in gene therapy.Several U.S.Food and Drug Administration(FDA)proved drugs such as Luxturna,Zolgensma,Hemgenix or Elevidys are based on wild-type AAV2,AAV9,AAV5 or AAVrh74,respectively.However,the highly liver bio-distribution and tropism generate high toxicity which leads to serious adverse events(SAE)or deaths in many clinical cases.
基金supported by National Natural Science Foundation of China(No.81872806)111 Project(No.B18035,China)the Fundamental of Research Funds for the Central University(China)。
文摘Insurmountable blood-brain barrier(BBB)and complex pathological features are the key factors affecting the treatment of Alzheimer's disease(AD).Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing Aβdeposition or TAU protein need to be resolved urgently.Herein,a nanocleaner is designed with a rapamycin-loaded ROS-responsive PLGA core and surface modification with KLVFF peptide and acid-cleavable DAG peptide[R@(ox-PLGA)-KcD].DAG can enhance the targeting and internalization effect of nanocleaner towards neurovascular unit endothelial cells in AD lesions,and subsequently detach from nanocleaner in response to acidic microenvironment of endosomes to promote the transcytosis of nanocleaner from endothelial cells into brain parenchyma.Then exposed KLVFF can capture and carry Aβto microglia,attenuating Aβ-induced neurotoxicity.Strikingly,rapamycin,an autophagy promoter,is rapidly liberated from nanocleaner in the high ROS level of lesions to improve Aβdegradation and normalize inflammatory condition.This design altogether accelerates Aβdegradation and alleviates oxidative stress and excessive inflammatory response.Collectively,our finding offers a strategy to target the AD lesions precisely and multi-pronged therapies for clearing the toxic proteins and modulating lesion microenvironment,to achieve efficient AD therapy.
文摘Newborn screening(NBS)refers to a maternal and newborn healthcare technology,in which special examinations of congenital and genetic diseases that could seriously impact the health of newborns,are implemented during the neonatal period to provide early diagnosis and treatment[1].With a history of more than 60 years,NBS has advanced greatly due to technological progress resulting in significant improvement in the number of diseases covered by NBS and in screening efficiency[2-7].
基金supported by National Natural Science Foundation of China(81961138009,China)the Key Research and Development Program of Science and Technology Department of Sichuan Province(No.2020YFS0570,China)+2 种基金111 Project(B18035,China)the Fundamental Research Funds for the Central Universities(China)the Open Research Fund of Chengdu University of Traditional Chinese Medicine State Key Laboratory of Characteristic Chinese Medicine Resources in Southwest China(China)。
文摘Considering that photodynamic therapy(PDT)-induced oxygen consumption and microvascular damage could exacerbate hypoxia to drive more glycolysis and angiogenesis, a novel approach to potentiate PDT and overcome the resistances of hypoxia is avidly needed. Herein, morpholine-modified PEGylated bilirubin was proposed to co-deliver chlorin e6, a photosensitizer, and diclofenac(Dc). In acidic milieu, the presence of morpholine could enable the nanocarriers to selectively accumulate in tumor cells, while PDT-generated reactive oxidative species(ROS) resulted in the collapse of bilirubin nanoparticles and rapid release of Dc. Combining with Dc showed a higher rate of apoptosis over PDT alone and simultaneously triggered a domino effect, including blocking the activity and expression of lactate dehydrogenase A(LDHA), interfering with lactate secretion, suppressing the activation of various angiogenic factors and thus obviating hypoxia-induced resistance-glycolysis and angiogenesis. In addition, inhibition of hypoxia-inducible factor-1a(HIF-1a) by Dc alleviated hypoxia-induced resistance. This study offered a sequentially responsive platform to achieve sufficient tumor enrichment, on-demand drug release and superior anti-tumor outcomes in vitro and in vivo.
基金the financial support from National Natural Science Foundation of China(Nos.8196113800982071915)+3 种基金Research Funds of Sichuan Science and Technology Department(No.19YYJC2250,China)111 Project(No.B18035,China)Fundamental Research Funds for the Central UniversitiesNatural Science Foundation of Heilongjiang Province of China(No.YQ2019H004)
文摘Accurate tumor targeting,deep penetration and superb retention are still the main pursuit of developing excellent nanomedicine.To achieve these requirements,a stepwise stimuli-responsive strategy was developed through co-administration tumor penetration peptide iRGD with shape-transformable and GSH-responsive SN38-dimer(d-SN38)-loaded nanoparticles(d-SN38@NPs/iRGD).Upon intravenous injection,d-SN38@NPs with high drug loading efficiency(33.92±1.33%)could effectively accumulate and penetrate into the deep region of tumor sites with the assistance of iRGD.The gathered nanoparticles simultaneously transformed into nanofibers upon 650 nm laser irradiation at tumor sites so as to promote their retention in the tumor and burst release of reactive oxygen species for photodynamic therapy.The loaded d-SN38 with disulfide bond responded to the high level of GSH in tumor cytoplasm,which consequently resulted in SN38 release and excellent chemo-photodynamic effect on tumor.In vitro,coadministering iRGD with d-SN38@NPs+laser showed higher cellular uptake,apoptosis ratio and multicellular spheroid penetration.In vivo,d-SN38@NPs/iRGD+laser displayed advanced penetration and accumulation in tumor,leading to 60.89%of tumor suppression in 4 T1 tumor-bearing mouse model with a favorable toxicity profile.Our new strategy combining iRGD with structural transformable nanoparticles greatly improves tumor targeting,penetrating and retention,and empowers anticancer efficacy.
基金National Key Research and Development Program of China(2020YFA0713804)the National Natural Science Foundation of China(82272811)+2 种基金Jiangsu Province Key Research and Development Program(BE2023654)Nanjing Jiangbei New Area Key Research and Development Program,Special Fund of Health Science and Technology Development of Nanjing(YKK20080)Fundings for Clinical Trials from the Affiliated Drum Tower Hospital,Medical School of Nanjing University(2023-LCYJ-PY-29).
文摘Metastatic pancreatic cancer(mPC)has a dismal prognosis.Herein,we conducted a prospective,multicentre,single-arm,phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine(PAAG)in patients with first-line mPC(NCT05493995).The primary endpoints included the objective response rate(ORR)and disease control rate(DCR),while secondary endpoints encompassed progression-free survival(PFS),overall survival(OS),and safety.In 66 patients analysed for efficacy,the best response,indicated by the ORR,was recorded at 50.0%(33/66)(95%CI,37.4–62.6%),with 33 patients achieving partial response(PR).Notably,the DCR was 95.5%(63/66,95%CI,87.3–99.1%).The median PFS(mPFS)and OS(mOS)were 8.8(95%CI,8.1–11.6),and 13.7(95%CI,12.4 to not reached)months,respectively.Grade 3/4 treatment-related adverse events(TRAEs)were reported in 39.4%of patients(26/66).In prespecified exploratory analysis,patients with altered SWI/SNF complex had a poorer PFS.Additionally,low serum CA724 level,high T-cell recruitment,low Th17 cell recruitment,and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy.In conclusion,PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC.The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.
