Objective:To study the effect of p53-targeted small molecular reactivator of p53 and induction of tumor apoptosis (RITA) combined with temozolomide (TMZ) on the glioma cell growth in vitro.Methods:Human glioma cell li...Objective:To study the effect of p53-targeted small molecular reactivator of p53 and induction of tumor apoptosis (RITA) combined with temozolomide (TMZ) on the glioma cell growth in vitro.Methods:Human glioma cell lines U87 were cultured and randomly divided into RITA+TMZ group (treated with 5 μmol/L RITA and 10 μmol/L TMZ), TMZ group (treated with 10 μmol/L TMZ) and control group (treated with drug-free DMEM). After 24 h of treatment, the expression of p53 downstream cell cycle molecules, apoptosis molecules and invasion molecules in cells were measured.Results:p21cip1, Per2, ATM and E-cadherin protein expression in RITA+TMZ group and TMZ group were significantly higher than those in control group while CDK4, CDK6, p-Rb, E2F, MDM2, c-myc, ILK, Snail and Slug protein expression were significantly lower than those in control group;p21cip1, Per2, ATM and E-cadherin protein expression in RITA+TMZ group were significantly higher than those in TMZ group while CDK4, CDK6, p-Rb, E2F, MDM2, c-myc, ILK, Snail and Slug protein expression were significantly lower than those in TMZ group.Conclusion:p53-targeted small molecular RITA combined with temozolomide treatment of glioma cells can induce p53-mediated cell cycle arrest, cell apoptosis activation and cell invasion inhibition.展开更多
The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular an...The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.展开更多
Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to impr...Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.展开更多
Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic ...Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.展开更多
Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expre...Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.展开更多
To study the volatile organic compounds(VOCs)emission characteristics of industrial enterprises in China,6 typical chemical industries in Yuncheng City were selected as research objects,including the modern coal chemi...To study the volatile organic compounds(VOCs)emission characteristics of industrial enterprises in China,6 typical chemical industries in Yuncheng City were selected as research objects,including the modern coal chemical industry(MCC),pharmaceutical industry(PM),pesticide industry(PE),coking industry(CO)and organic chemical industry(OC).The chemical composition of 91 VOCs was quantitatively analyzed.The results showed that the emission concentration of VOCs in the chemical industry ranged from 1.16 to 155.59 mg/m^(3).Alkanes were the main emission components of MCC(62.0%),PE(55.1%),and OC(58.5%).Alkenes(46.5%)were important components of PM,followed by alkanes(23.8%)and oxygenated volatile organic compounds(OVOCs)(21.2%).Halocarbons(8.6%-71.1%),OVOCs(9.7%-37.6%)and alkanes(11.2%-27.0%)were characteristic components of CO.The largest contributor to OFP was alkenes(0.6%-81.7%),followed by alkanes(9.3%-45.9%),and the lowest onewas alkyne(0%-0.5%).Aromatics(66.9%-85.4%)were the largest contributing components to SOA generation,followed by alkanes(2.6%-28.5%),and the lowest one was alkenes(0%-4.1%).Ethylene and BTEX were the key active species in various chemical industries.The human health risk assessment showed workers long-term exposed to the air in the chemical industrial zone had a high cancer and non-cancer risk during work,and BTEX and dichloromethane were the largest contributors.展开更多
An improved acetylcholinesterase liquid crystal(LC) biosensor has been developed for the identification of organophosphates(OPs) by using a reactivator. When the acetylcholinesterases(AChEs) inhibited by different kin...An improved acetylcholinesterase liquid crystal(LC) biosensor has been developed for the identification of organophosphates(OPs) by using a reactivator. When the acetylcholinesterases(AChEs) inhibited by different kinds of OPs are reactived by a reactivator, the catalytic activity of AChEs can be recovered with different activation efficiency because of the different phosphorylation structures formed in the inhibited AChEs. Accordingly, the reactived AChEs can catalyze the hydrolysis of acetylthiocholine to generate thiocholine product in different degrees, which will result in different catalytic growth of AuNPs and further form distinct orientational response of LCs. Based on such a reactivation mechanism, the AChE LC biosensor with a simple, rapid and visual procedure achieves an obvious identification of three OPs pesticides, methamidophos, trichlorfon and paraoxon, by using a pralidoxime reactivator.展开更多
In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostat...In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological,molecular,and functional changes to adopt so-called‘reactive’states in response to CNS injury or disease.In recent years,interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances.Here,we will review and discuss the wellestablished and emerging astroglial biology and functions,with emphasis on their potential as therapeutic targets for CNS injury,including traumatic and ischemic injury.This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.展开更多
Severe ground-level ozone(O_(3))pollution over major Chinese cities has become one of the most challenging problems,which have deleterious effects on human health and the sustainability of society.This study explored ...Severe ground-level ozone(O_(3))pollution over major Chinese cities has become one of the most challenging problems,which have deleterious effects on human health and the sustainability of society.This study explored the spatiotemporal distribution characteristics of ground-level O_(3) and its precursors based on conventional pollutant and meteorological monitoring data in Zhejiang Province from 2016 to 2021.Then,a high-performance convolutional neural network(CNN)model was established by expanding the moment and the concentration variations to general factors.Finally,the response mechanism of O_(3) to the variation with crucial influencing factors is explored by controlling variables and interpolating target variables.The results indicated that the annual average MDA8-90th concentrations in Zhejiang Province are higher in the northern and lower in the southern.When the wind direction(WD)ranges from east to southwest and the wind speed(WS)ranges between 2 and 3 m/sec,higher O_(3) concentration prone to occur.At different temperatures(T),the O_(3) concentration showed a trend of first increasing and subsequently decreasing with increasing NO_(2) concentration,peaks at the NO_(2) concentration around 0.02mg/m^(3).The sensitivity of NO_(2) to O_(3) formation is not easily affected by temperature,barometric pressure and dew point temperature.Additionally,there is a minimum IRNO_(2) at each temperature when the NO_(2) concentration is 0.03 mg/m^(3),and this minimum IRNO_(2) decreases with increasing temperature.The study explores the response mechanism of O_(3) with the change of driving variables,which can provide a scientific foundation and methodological support for the targeted management of O_(3) pollution.展开更多
The penetration-deflagration coupling damage performance of rod-like reactive shaped charge pene-trator(RRSCP)impacting thick steel plates is investigated by theoretical analysis and experiments.A penetration-deflagra...The penetration-deflagration coupling damage performance of rod-like reactive shaped charge pene-trator(RRSCP)impacting thick steel plates is investigated by theoretical analysis and experiments.A penetration-deflagration coupling damage model is developed to predict the penetration depth and cratering diameter.Four type of aluminum-polytetrafluoroethylene-copper(Al-PTFE-Cu)reactive liners with densities of 2.3,2.7,3.5,and 4.5 g·cm^(-3) are selected to conduct the penetration experiments.The comparison results show that model predictions are in good agreement with the experimental data.By comparing the penetration depth and cratering diameter in the inert penetration mode and the penetration-deflagration coupling mode,the influence mechanism that the penetration-induced chemical response is unfavorable to penetration but has an enhanced cratering effect is revealed.From the formation characteristics,penetration effect and penetration-induced chemical reaction be-haviors,the influence of reactive liner density on the penetration-deflagration performance is further analyzed.The results show that increasing the density of reactive liner significantly increases both the kinetic energy and length of the reactive penetrator,meanwhile effectively reduces the weakened effect of penetration-induced chemical response,resulting in an enhanced penetration capability.However,due to the decreased diameter and potential energy content of reactive penetrator,the cratering capa-bility is weakened significantly.展开更多
Emission characteristics of biogenic volatile organic compounds(BVOCs)from dominant tree species in the subtropical pristine forests of China are extremely limited.Here we conducted in situ field measurements of BVOCs...Emission characteristics of biogenic volatile organic compounds(BVOCs)from dominant tree species in the subtropical pristine forests of China are extremely limited.Here we conducted in situ field measurements of BVOCs emissions from representative mature evergreen trees by using dynamic branch enclosures at four altitude gradients(600-1690ma.s.l.)in the Nanling Mountains of southern China.Composition characteristics as well as seasonal and altitudinal variations were analyzed.Standardized emission rates and canopyscale emission factors were then calculated.Results showed that BVOCs emission intensities in the wet season were generally higher than those in the dry season.Monoterpenes were the dominant BVOCs emitted from most broad-leaved trees,accounting for over 70%of the total.Schima superba,Yushania basihirsuta and Altingia chinensis had relatively high emission intensities and secondary pollutant formation potentials.The localized emission factors of isoprene were comparable to the defaults in the Model of Emissions of Gases and Aerosols fromNature(MEGAN),while emission factors of monoterpenes and sesquiterpenes were 2 to 58 times of those in the model.Our results can be used to update the current BVOCs emission inventory in MEGAN,thereby reducing the uncertainties of BVOCs emission estimations in forested regions of southern China.展开更多
Advanced oxidation processes (AOPs) exhibit significant potential forwater disinfection dueto their generation of large quantities of highly oxidizing free radicals. However, the neglectof viable but nonculturable (VB...Advanced oxidation processes (AOPs) exhibit significant potential forwater disinfection dueto their generation of large quantities of highly oxidizing free radicals. However, the neglectof viable but nonculturable (VBNC) cells obscures their true disinfection efficacy and potentialenvironmental health risks. Therefore, the study evaluated the disinfection effectivenessand mechanisms of typical AOPs, including Fe/H_(2)O_(2), Fe/persulfate (PS), and O_(3), fromthe perspective of the production of VBNC bacteria. The results indicate that Fe/PS exhibitsthe strongest bacterial inactivation rate (99.94%), and the cells lose their ability to reactivate.Fe/H_(2)O_(2) and O_(3) induce more cells to enter the VBNC state compared to Fe/PS. Moreover,different AOPs result in varying levels of free radical production and utilization efficiency,with SO(4)^(·−) and O_(3) exhibiting greater selectivity in deactivating bacteria comparedto HO^(·). The inhibition of VBNC bacteria production by Fe/PS treatment may be attributed tothe combined action of HO^(·) and SO(4)^(·−) on microorganisms, leading to oxidative stress andmetabolic disruption in bacteria through the inhibition of biofilm formation and aminoacyltRNAbiosynthesis (p < 0.05), thereby causing direct bacterial death rather than entry intothe VBNC state. In contrast, Fe/H_(2)O_(2) and O_(3) result in the upregulation of the metabolismof alanine, aspartate, and glutamate, as well as styrene degradation capacity by the bacteria,leading to the production of more VBNC bacteria. Overall, the study offers insights intomitigating potential biological risks in water disinfection and developing environmentallyfriendly and efficient disinfection technologies.展开更多
Atmospheric chemistry research and atmospheric measurement techniques have mutually promoted each other and developed rapidly in China in recent years.Cavity-based absorption spectroscopy,which uses a high-finesse cav...Atmospheric chemistry research and atmospheric measurement techniques have mutually promoted each other and developed rapidly in China in recent years.Cavity-based absorption spectroscopy,which uses a high-finesse cavity to achieve very long absorption path-length,thereby achieving ultra-high detection sensitivity,plays an extremely important role in atmospheric chemistry research.Based on the Beer–Lambert law,this technology has the unique advantages of being non-destructive,chemical-free,and highly selective.It does not require any sample preparation and can quantitatively analyze atmospheric trace gases in real time and in situ.In this paper,we review the following:(1)key technological advances in different cavity-based absorption spectroscopy techniques,including cavity ring-down spectroscopy,cavityenhanced absorption spectroscopy,cavity attenuated phase shift spectroscopy,and their extensions;and(2)applications of these techniques in the detection of atmospheric reactive species,such as total peroxy radical,formaldehyde,and reactive nitrogen(e.g.,NOx,HONO,peroxy nitrates,and alkyl nitrates).The review systematically introduces cavity-based absorption spectroscopy techniques and their applications in atmospheric chemistry,which will help promote further communication and cooperation in the fields of laser spectroscopy and atmospheric chemistry.展开更多
Considering the uncertainty of grid connection of electric vehicle charging stations and the uncertainty of new energy and residential electricity load,a spatio-temporal decoupling strategy of dynamic reactive power o...Considering the uncertainty of grid connection of electric vehicle charging stations and the uncertainty of new energy and residential electricity load,a spatio-temporal decoupling strategy of dynamic reactive power optimization based on clustering-local relaxation-correction is proposed.Firstly,the k-medoids clustering algorithm is used to divide the reduced power scene into periods.Then,the discrete variables and continuous variables are optimized in the same period of time.Finally,the number of input groups of parallel capacitor banks(CB)in multiple periods is fixed,and then the secondary static reactive power optimization correction is carried out by using the continuous reactive power output device based on the static reactive power compensation device(SVC),the new energy grid-connected inverter,and the electric vehicle charging station.According to the characteristics of the model,a hybrid optimization algorithm with a cross-feedback mechanism is used to solve different types of variables,and an improved artificial hummingbird algorithm based on tent chaotic mapping and adaptive mutation is proposed to improve the solution efficiency.The simulation results show that the proposed decoupling strategy can obtain satisfactory optimization resultswhile strictly guaranteeing the dynamic constraints of discrete variables,and the hybrid algorithm can effectively solve the mixed integer nonlinear optimization problem.展开更多
Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrog...Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.展开更多
The current single-atom catalysts(SACs)for medicine still suffer from the limited active site density.Here,we develop a synthetic method capable of increasing both the metal loading and mass-specific activity of SACs ...The current single-atom catalysts(SACs)for medicine still suffer from the limited active site density.Here,we develop a synthetic method capable of increasing both the metal loading and mass-specific activity of SACs by exchanging zinc with iron.The constructed iron SACs(h^(3)-FNC)with a high metal loading of 6.27 wt%and an optimized adjacent Fe distance of~4 A exhibit excellent oxidase-like catalytic performance without significant activity decay after being stored for six months and promising antibacterial effects.Attractively,a“density effect”has been found at a high-enough metal doping amount,at which individual active sites become close enough to interact with each other and alter the electronic structure,resulting in significantly boosted intrinsic activity of single-atomic iron sites in h^(3)-FNCs by 2.3 times compared to low-and medium-loading SACs.Consequently,the overall catalytic activity of h^(3)-FNC is highly improved,with mass activity and metal mass-specific activity that are,respectively,66 and 315 times higher than those of commercial Pt/C.In addition,h^(3)-FNCs demonstrate efficiently enhanced capability in catalyzing oxygen reduction into superoxide anion(O_(2)·^(−))and glutathione(GSH)depletion.Both in vitro and in vivo assays demonstrate the superior antibacterial efficacy of h^(3)-FNCs in promoting wound healing.This work presents an intriguing activity-enhancement effect in catalysts and exhibits impressive therapeutic efficacy in combating bacterial infections.展开更多
Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,...Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.展开更多
Memristive crossbar arrays(MCAs)offer parallel data storage and processing for energy-efficient neuromorphic computing.However,most wafer-scale MCAs that are compatible with complementary metal-oxide-semiconductor(CMO...Memristive crossbar arrays(MCAs)offer parallel data storage and processing for energy-efficient neuromorphic computing.However,most wafer-scale MCAs that are compatible with complementary metal-oxide-semiconductor(CMOS)technology still suffer from substantially larger energy consumption than biological synapses,due to the slow kinetics of forming conductive paths inside the memristive units.Here we report wafer-scale Ag_(2)S-based MCAs realized using CMOS-compatible processes at temperatures below 160℃.Ag_(2)S electrolytes supply highly mobile Ag+ions,and provide the Ag/Ag_(2)S interface with low silver nucleation barrier to form silver filaments at low energy costs.By further enhancing Ag+migration in Ag_(2)S electrolytes via microstructure modulation,the integrated memristors exhibit a record low threshold of approximately−0.1 V,and demonstrate ultra-low switching-energies reaching femtojoule values as observed in biological synapses.The low-temperature process also enables MCA integration on polyimide substrates for applications in flexible electronics.Moreover,the intrinsic nonidealities of the memristive units for deep learning can be compensated by employing an advanced training algorithm.An impressive accuracy of 92.6%in image recognition simulations is demonstrated with the MCAs after the compensation.The demonstrated MCAs provide a promising device option for neuromorphic computing with ultra-high energy-efficiency.展开更多
Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an imp...Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.展开更多
文摘Objective:To study the effect of p53-targeted small molecular reactivator of p53 and induction of tumor apoptosis (RITA) combined with temozolomide (TMZ) on the glioma cell growth in vitro.Methods:Human glioma cell lines U87 were cultured and randomly divided into RITA+TMZ group (treated with 5 μmol/L RITA and 10 μmol/L TMZ), TMZ group (treated with 10 μmol/L TMZ) and control group (treated with drug-free DMEM). After 24 h of treatment, the expression of p53 downstream cell cycle molecules, apoptosis molecules and invasion molecules in cells were measured.Results:p21cip1, Per2, ATM and E-cadherin protein expression in RITA+TMZ group and TMZ group were significantly higher than those in control group while CDK4, CDK6, p-Rb, E2F, MDM2, c-myc, ILK, Snail and Slug protein expression were significantly lower than those in control group;p21cip1, Per2, ATM and E-cadherin protein expression in RITA+TMZ group were significantly higher than those in TMZ group while CDK4, CDK6, p-Rb, E2F, MDM2, c-myc, ILK, Snail and Slug protein expression were significantly lower than those in TMZ group.Conclusion:p53-targeted small molecular RITA combined with temozolomide treatment of glioma cells can induce p53-mediated cell cycle arrest, cell apoptosis activation and cell invasion inhibition.
基金supported by the National Natural Science Foundation of China,Nos.82271327 (to ZW),82072535 (to ZW),81873768 (to ZW),and 82001253 (to TL)。
文摘The pathophysiology of Huntington's disease involves high levels of the neurotoxin quinolinic acid. Quinolinic acid accumulation results in oxidative stress, which leads to neurotoxicity. However, the molecular and cellular mechanisms by which quinolinic acid contributes to Huntington's disease pathology remain unknown. In this study, we established in vitro and in vivo models of Huntington's disease by administering quinolinic acid to the PC12 neuronal cell line and the striatum of mice, respectively. We observed a decrease in the levels of hydrogen sulfide in both PC12 cells and mouse serum, which was accompanied by down-regulation of cystathionine β-synthase, an enzyme responsible for hydrogen sulfide production. However, treatment with NaHS(a hydrogen sulfide donor) increased hydrogen sulfide levels in the neurons and in mouse serum, as well as cystathionine β-synthase expression in the neurons and the mouse striatum, while also improving oxidative imbalance and mitochondrial dysfunction in PC12 cells and the mouse striatum. These beneficial effects correlated with upregulation of nuclear factor erythroid 2-related factor 2 expression. Finally, treatment with the nuclear factor erythroid 2-related factor 2inhibitor ML385 reversed the beneficial impact of exogenous hydrogen sulfide on quinolinic acid-induced oxidative stress. Taken together, our findings show that hydrogen sulfide reduces oxidative stress in Huntington's disease by activating nuclear factor erythroid 2-related factor 2,suggesting that hydrogen sulfide is a novel neuroprotective drug candidate for treating patients with Huntington's disease.
基金supported by the Natural Science Fund of Fujian Province,No.2020J011058(to JK)the Project of Fujian Provincial Hospital for High-level Hospital Construction,No.2020HSJJ12(to JK)+1 种基金the Fujian Provincial Finance Department Special Fund,No.(2021)848(to FC)the Fujian Provincial Major Scientific and Technological Special Projects on Health,No.2022ZD01008(to FC).
文摘Cardiac arrest can lead to severe neurological impairment as a result of inflammation,mitochondrial dysfunction,and post-cardiopulmonary resuscitation neurological damage.Hypoxic preconditioning has been shown to improve migration and survival of bone marrow–derived mesenchymal stem cells and reduce pyroptosis after cardiac arrest,but the specific mechanisms by which hypoxia-preconditioned bone marrow–derived mesenchymal stem cells protect against brain injury after cardiac arrest are unknown.To this end,we established an in vitro co-culture model of bone marrow–derived mesenchymal stem cells and oxygen–glucose deprived primary neurons and found that hypoxic preconditioning enhanced the protective effect of bone marrow stromal stem cells against neuronal pyroptosis,possibly through inhibition of the MAPK and nuclear factor κB pathways.Subsequently,we transplanted hypoxia-preconditioned bone marrow–derived mesenchymal stem cells into the lateral ventricle after the return of spontaneous circulation in an 8-minute cardiac arrest rat model induced by asphyxia.The results showed that hypoxia-preconditioned bone marrow–derived mesenchymal stem cells significantly reduced cardiac arrest–induced neuronal pyroptosis,oxidative stress,and mitochondrial damage,whereas knockdown of the liver isoform of phosphofructokinase in bone marrow–derived mesenchymal stem cells inhibited these effects.To conclude,hypoxia-preconditioned bone marrow–derived mesenchymal stem cells offer a promising therapeutic approach for neuronal injury following cardiac arrest,and their beneficial effects are potentially associated with increased expression of the liver isoform of phosphofructokinase following hypoxic preconditioning.
基金supported by Fondo Nacional de Desarrollo Científico y Tecnológico(FONDECYT)#1200836,#1210644,and#1240888,and Agencia Nacional de Investigación y Desarrollo(ANID)-FONDAP#15130011(to LL)FONDECYT#3230227(to MFG).
文摘Astrocytes are the most abundant type of glial cell in the central nervous system.Upon injury and inflammation,astrocytes become reactive and undergo morphological and functional changes.Depending on their phenotypic classification as A1 or A2,reactive astrocytes contribute to both neurotoxic and neuroprotective responses,respectively.However,this binary classification does not fully capture the diversity of astrocyte responses observed across different diseases and injuries.Transcriptomic analysis has revealed that reactive astrocytes have a complex landscape of gene expression profiles,which emphasizes the heterogeneous nature of their reactivity.Astrocytes actively participate in regulating central nervous system inflammation by interacting with microglia and other cell types,releasing cytokines,and influencing the immune response.The phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT)signaling pathway is a central player in astrocyte reactivity and impacts various aspects of astrocyte behavior,as evidenced by in silico,in vitro,and in vivo results.In astrocytes,inflammatory cues trigger a cascade of molecular events,where nuclear factor-κB serves as a central mediator of the pro-inflammatory responses.Here,we review the heterogeneity of reactive astrocytes and the molecular mechanisms underlying their activation.We highlight the involvement of various signaling pathways that regulate astrocyte reactivity,including the PI3K/AKT/mammalian target of rapamycin(mTOR),αvβ3 integrin/PI3K/AKT/connexin 43,and Notch/PI3K/AKT pathways.While targeting the inactivation of the PI3K/AKT cellular signaling pathway to control reactive astrocytes and prevent central nervous system damage,evidence suggests that activating this pathway could also yield beneficial outcomes.This dual function of the PI3K/AKT pathway underscores its complexity in astrocyte reactivity and brain function modulation.The review emphasizes the importance of employing astrocyte-exclusive models to understand their functions accurately and these models are essential for clarifying astrocyte behavior.The findings should then be validated using in vivo models to ensure real-life relevance.The review also highlights the significance of PI3K/AKT pathway modulation in preventing central nervous system damage,although further studies are required to fully comprehend its role due to varying factors such as different cell types,astrocyte responses to inflammation,and disease contexts.Specific strategies are clearly necessary to address these variables effectively.
文摘Nitric oxide(NO)is a gaseous molecule produced by 3 different NO synthase(NOS)isoforms:Neural/brain NOS(nNOS/bNOS,type 1),endothelial NOS(eNOS,type 3)and inducible NOS(type 2).Type 1 and 3 NOS are constitutively expressed.NO can serve different purposes:As a vasoactive molecule,as a neurotransmitter or as an immunomodulator.It plays a key role in cerebral ischemia/reperfusion injury(CIRI).Hypoxic episodes simulate the production of oxygen free radicals,leading to mitochondrial and phospholipid damage.Upon reperfusion,increased levels of oxygen trigger oxide synthases;whose products are associated with neuronal damage by promoting lipid peroxidation,nitrosylation and excitotoxicity.Molecular pathways in CIRI can be altered by NOS.Neuroprotective effects are observed with eNOS activity.While nNOS interplay is prone to endothelial inflammation,oxidative stress and apoptosis.Therefore,nNOS appears to be detrimental.The interaction between NO and other free radicals develops peroxynitrite;which is a cytotoxic agent.It plays a main role in the likelihood of hemorrhagic events by tissue plasminogen activator(t-PA).Peroxynitrite scavengers are currently being studied as potential targets to prevent hemorrhagic transformation in CIRI.
基金supported by the National Natural Science Foundation of China(No.41905108)the National Research Program for Key Issues in Air Pollution Control(No.DQ GG0532).
文摘To study the volatile organic compounds(VOCs)emission characteristics of industrial enterprises in China,6 typical chemical industries in Yuncheng City were selected as research objects,including the modern coal chemical industry(MCC),pharmaceutical industry(PM),pesticide industry(PE),coking industry(CO)and organic chemical industry(OC).The chemical composition of 91 VOCs was quantitatively analyzed.The results showed that the emission concentration of VOCs in the chemical industry ranged from 1.16 to 155.59 mg/m^(3).Alkanes were the main emission components of MCC(62.0%),PE(55.1%),and OC(58.5%).Alkenes(46.5%)were important components of PM,followed by alkanes(23.8%)and oxygenated volatile organic compounds(OVOCs)(21.2%).Halocarbons(8.6%-71.1%),OVOCs(9.7%-37.6%)and alkanes(11.2%-27.0%)were characteristic components of CO.The largest contributor to OFP was alkenes(0.6%-81.7%),followed by alkanes(9.3%-45.9%),and the lowest onewas alkyne(0%-0.5%).Aromatics(66.9%-85.4%)were the largest contributing components to SOA generation,followed by alkanes(2.6%-28.5%),and the lowest one was alkenes(0%-4.1%).Ethylene and BTEX were the key active species in various chemical industries.The human health risk assessment showed workers long-term exposed to the air in the chemical industrial zone had a high cancer and non-cancer risk during work,and BTEX and dichloromethane were the largest contributors.
基金supported by the International Scientific and Technological Cooperation Projects of China(2012DFR40480)the National Natural Science Foundation of China(21175037,21277042 and J1210040)
文摘An improved acetylcholinesterase liquid crystal(LC) biosensor has been developed for the identification of organophosphates(OPs) by using a reactivator. When the acetylcholinesterases(AChEs) inhibited by different kinds of OPs are reactived by a reactivator, the catalytic activity of AChEs can be recovered with different activation efficiency because of the different phosphorylation structures formed in the inhibited AChEs. Accordingly, the reactived AChEs can catalyze the hydrolysis of acetylthiocholine to generate thiocholine product in different degrees, which will result in different catalytic growth of AuNPs and further form distinct orientational response of LCs. Based on such a reactivation mechanism, the AChE LC biosensor with a simple, rapid and visual procedure achieves an obvious identification of three OPs pesticides, methamidophos, trichlorfon and paraoxon, by using a pralidoxime reactivator.
基金supported by the National Natural Science Foundation of China(82171386,81971161,and 82201536)the Shanghai Science and Technology Development Foundation(22YF1458600)+1 种基金the Scientifc Foundation from Naval Medical University(2021QN08)the STI2030-Major Projects from Ministry of Science and Technology of China(2022ZD0204700).
文摘In the mammalian central nervous system(CNS),astrocytes are the ubiquitous glial cells that have complex morphological and molecular characteristics.These fascinating cells play essential neurosupportive and homeostatic roles in the healthy CNS and undergo morphological,molecular,and functional changes to adopt so-called‘reactive’states in response to CNS injury or disease.In recent years,interest in astrocyte research has increased dramatically and some new biological features and roles of astrocytes in physiological and pathological conditions have been discovered thanks to technological advances.Here,we will review and discuss the wellestablished and emerging astroglial biology and functions,with emphasis on their potential as therapeutic targets for CNS injury,including traumatic and ischemic injury.This review article will highlight the importance of astrocytes in the neuropathological process and repair of CNS injury.
基金supported by the National Key Research and Development Program of China (Nos.2022YFC3702000 and 2022YFC3703500)the Key R&D Project of Zhejiang Province (No.2022C03146).
文摘Severe ground-level ozone(O_(3))pollution over major Chinese cities has become one of the most challenging problems,which have deleterious effects on human health and the sustainability of society.This study explored the spatiotemporal distribution characteristics of ground-level O_(3) and its precursors based on conventional pollutant and meteorological monitoring data in Zhejiang Province from 2016 to 2021.Then,a high-performance convolutional neural network(CNN)model was established by expanding the moment and the concentration variations to general factors.Finally,the response mechanism of O_(3) to the variation with crucial influencing factors is explored by controlling variables and interpolating target variables.The results indicated that the annual average MDA8-90th concentrations in Zhejiang Province are higher in the northern and lower in the southern.When the wind direction(WD)ranges from east to southwest and the wind speed(WS)ranges between 2 and 3 m/sec,higher O_(3) concentration prone to occur.At different temperatures(T),the O_(3) concentration showed a trend of first increasing and subsequently decreasing with increasing NO_(2) concentration,peaks at the NO_(2) concentration around 0.02mg/m^(3).The sensitivity of NO_(2) to O_(3) formation is not easily affected by temperature,barometric pressure and dew point temperature.Additionally,there is a minimum IRNO_(2) at each temperature when the NO_(2) concentration is 0.03 mg/m^(3),and this minimum IRNO_(2) decreases with increasing temperature.The study explores the response mechanism of O_(3) with the change of driving variables,which can provide a scientific foundation and methodological support for the targeted management of O_(3) pollution.
基金supported by the National Natural Science Foundation of China(Grant No.12172052)the Foundation of State Key Laboratory of Explosion Science and Safety Protection(Grant No.QKKT24-02).
文摘The penetration-deflagration coupling damage performance of rod-like reactive shaped charge pene-trator(RRSCP)impacting thick steel plates is investigated by theoretical analysis and experiments.A penetration-deflagration coupling damage model is developed to predict the penetration depth and cratering diameter.Four type of aluminum-polytetrafluoroethylene-copper(Al-PTFE-Cu)reactive liners with densities of 2.3,2.7,3.5,and 4.5 g·cm^(-3) are selected to conduct the penetration experiments.The comparison results show that model predictions are in good agreement with the experimental data.By comparing the penetration depth and cratering diameter in the inert penetration mode and the penetration-deflagration coupling mode,the influence mechanism that the penetration-induced chemical response is unfavorable to penetration but has an enhanced cratering effect is revealed.From the formation characteristics,penetration effect and penetration-induced chemical reaction be-haviors,the influence of reactive liner density on the penetration-deflagration performance is further analyzed.The results show that increasing the density of reactive liner significantly increases both the kinetic energy and length of the reactive penetrator,meanwhile effectively reduces the weakened effect of penetration-induced chemical response,resulting in an enhanced penetration capability.However,due to the decreased diameter and potential energy content of reactive penetrator,the cratering capa-bility is weakened significantly.
基金supported by the National Natural Science Foundation of China (NSFC)Projects (Nos.42205105,42121004,and 42077190)the Science and Technology Project of Shaoguan (No.210811164532141)+3 种基金the National Key R&D Program of China (2022YFC3700604)the Science and Technology Program of Guangzhou City (No.202201010400)the Fundamental Research Funds for the Central Universities (No.21622319)the Research Center of Low Carbon Economy for Guangzhou Region (No.22JNZS50).
文摘Emission characteristics of biogenic volatile organic compounds(BVOCs)from dominant tree species in the subtropical pristine forests of China are extremely limited.Here we conducted in situ field measurements of BVOCs emissions from representative mature evergreen trees by using dynamic branch enclosures at four altitude gradients(600-1690ma.s.l.)in the Nanling Mountains of southern China.Composition characteristics as well as seasonal and altitudinal variations were analyzed.Standardized emission rates and canopyscale emission factors were then calculated.Results showed that BVOCs emission intensities in the wet season were generally higher than those in the dry season.Monoterpenes were the dominant BVOCs emitted from most broad-leaved trees,accounting for over 70%of the total.Schima superba,Yushania basihirsuta and Altingia chinensis had relatively high emission intensities and secondary pollutant formation potentials.The localized emission factors of isoprene were comparable to the defaults in the Model of Emissions of Gases and Aerosols fromNature(MEGAN),while emission factors of monoterpenes and sesquiterpenes were 2 to 58 times of those in the model.Our results can be used to update the current BVOCs emission inventory in MEGAN,thereby reducing the uncertainties of BVOCs emission estimations in forested regions of southern China.
基金supported by Shandong Provincial Natural Science Foundation,China(Nos.ZR2020ZD34 and ZR2023YQ031)the National Natural Science Foundation of China(Nos.42077391 and 42377428)the Instrument Improvement Funds of ShandongUniversity Public Technology Platform(No.ts20230108).
文摘Advanced oxidation processes (AOPs) exhibit significant potential forwater disinfection dueto their generation of large quantities of highly oxidizing free radicals. However, the neglectof viable but nonculturable (VBNC) cells obscures their true disinfection efficacy and potentialenvironmental health risks. Therefore, the study evaluated the disinfection effectivenessand mechanisms of typical AOPs, including Fe/H_(2)O_(2), Fe/persulfate (PS), and O_(3), fromthe perspective of the production of VBNC bacteria. The results indicate that Fe/PS exhibitsthe strongest bacterial inactivation rate (99.94%), and the cells lose their ability to reactivate.Fe/H_(2)O_(2) and O_(3) induce more cells to enter the VBNC state compared to Fe/PS. Moreover,different AOPs result in varying levels of free radical production and utilization efficiency,with SO(4)^(·−) and O_(3) exhibiting greater selectivity in deactivating bacteria comparedto HO^(·). The inhibition of VBNC bacteria production by Fe/PS treatment may be attributed tothe combined action of HO^(·) and SO(4)^(·−) on microorganisms, leading to oxidative stress andmetabolic disruption in bacteria through the inhibition of biofilm formation and aminoacyltRNAbiosynthesis (p < 0.05), thereby causing direct bacterial death rather than entry intothe VBNC state. In contrast, Fe/H_(2)O_(2) and O_(3) result in the upregulation of the metabolismof alanine, aspartate, and glutamate, as well as styrene degradation capacity by the bacteria,leading to the production of more VBNC bacteria. Overall, the study offers insights intomitigating potential biological risks in water disinfection and developing environmentallyfriendly and efficient disinfection technologies.
基金supported by the National Natural Science Foundation of China(Grant Nos.U21A2028,42022051,62275250,42030609,41627810,91644107,and 91544228).
文摘Atmospheric chemistry research and atmospheric measurement techniques have mutually promoted each other and developed rapidly in China in recent years.Cavity-based absorption spectroscopy,which uses a high-finesse cavity to achieve very long absorption path-length,thereby achieving ultra-high detection sensitivity,plays an extremely important role in atmospheric chemistry research.Based on the Beer–Lambert law,this technology has the unique advantages of being non-destructive,chemical-free,and highly selective.It does not require any sample preparation and can quantitatively analyze atmospheric trace gases in real time and in situ.In this paper,we review the following:(1)key technological advances in different cavity-based absorption spectroscopy techniques,including cavity ring-down spectroscopy,cavityenhanced absorption spectroscopy,cavity attenuated phase shift spectroscopy,and their extensions;and(2)applications of these techniques in the detection of atmospheric reactive species,such as total peroxy radical,formaldehyde,and reactive nitrogen(e.g.,NOx,HONO,peroxy nitrates,and alkyl nitrates).The review systematically introduces cavity-based absorption spectroscopy techniques and their applications in atmospheric chemistry,which will help promote further communication and cooperation in the fields of laser spectroscopy and atmospheric chemistry.
基金funded by the“Research and Application Project of Collaborative Optimization Control Technology for Distribution Station Area for High Proportion Distributed PV Consumption(4000-202318079A-1-1-ZN)”of the Headquarters of the State Grid Corporation.
文摘Considering the uncertainty of grid connection of electric vehicle charging stations and the uncertainty of new energy and residential electricity load,a spatio-temporal decoupling strategy of dynamic reactive power optimization based on clustering-local relaxation-correction is proposed.Firstly,the k-medoids clustering algorithm is used to divide the reduced power scene into periods.Then,the discrete variables and continuous variables are optimized in the same period of time.Finally,the number of input groups of parallel capacitor banks(CB)in multiple periods is fixed,and then the secondary static reactive power optimization correction is carried out by using the continuous reactive power output device based on the static reactive power compensation device(SVC),the new energy grid-connected inverter,and the electric vehicle charging station.According to the characteristics of the model,a hybrid optimization algorithm with a cross-feedback mechanism is used to solve different types of variables,and an improved artificial hummingbird algorithm based on tent chaotic mapping and adaptive mutation is proposed to improve the solution efficiency.The simulation results show that the proposed decoupling strategy can obtain satisfactory optimization resultswhile strictly guaranteeing the dynamic constraints of discrete variables,and the hybrid algorithm can effectively solve the mixed integer nonlinear optimization problem.
基金supported by the National Research Foundation of Korea (NRF)funded by the Ministry of Science,ICT&Future Planning (2022R1A2C2006229,2022R1A6A3A01086868)Korea Dementia Research Project through the Korea Dementia Research Center (KDRC)funded by the Ministry of Health&Welfare and Ministry of Science and ICT,Republic of Korea (RS-2024-00345328)KIST Institutional Grant (2E32851)。
文摘Alzheimer'sdisease(AD)isaprogressive neurodegenerative disorder characterized by cognitive impairment and distinct neuropathological features,including amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis.Developing effective diagnostic,preventative,and therapeutic strategies for AD necessitates the establishment of animal models that accurately recapitulate the pathophysiological processes of the disease.Existing transgenic mouse models have significantly contributed to understanding AD pathology but often fail to replicate the complexity of human AD.Additionally,these models are limited in their ability to elucidate the interplay among amyloid-βplaques,neurofibrillary tangles,and reactive astrogliosis due to the absence of spatially and temporally specific genetic manipulation.In this study,we introduce a novel AD mouse model(APP/PS1-TauP301L-Adeno mice)designed to rapidly induce pathological symptoms and enhance understanding of AD mechanisms.Neurofibrillary tangles and severe reactive astrogliosis were induced by injecting AAVDJ-EF1a-hTauP301L-EGFP and Adeno-GFAP-GFP viruses into the hippocampi of 5-month-old APP/PS1 mice.Three months post-injection,these mice exhibited pronounced astrogliosis,substantial amyloid-βplaque accumulation,extensiveneurofibrillarytangles,accelerated neuronal loss,elevated astrocytic GABA levels,and significant spatial memory deficits.Notably,these pathological features were less severe in AAVTauP301L-expressing APP/PS1 mice without augmented reactive astrogliosis.These findings indicate an exacerbating role of severe reactive astrogliosis in amyloid-βplaque and neurofibrillary tangle-associated pathology.The APP/PS1-TauP301L-Adeno mouse model provides a valuable tool for advancing therapeutic research aimed at mitigating the progression of AD.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFB3804500)the National Natural Science Foundation of China(Grant No.52202352,22335006)+4 种基金the Shanghai Municipal Health Commission(Grant No.20224Y0010)the CAMS Innovation Fund for Medical Sciences(Grant No.2021-I2M-5-012)the Basic Research Program of Shanghai Municipal Government(Grant No.21JC1406000)the Fundamental Research Funds for the Central Universities(Grant No.22120230237,2023-3-YB-11,22120220618)the Basic Research Program of Shanghai Municipal Government(23DX1900200).
文摘The current single-atom catalysts(SACs)for medicine still suffer from the limited active site density.Here,we develop a synthetic method capable of increasing both the metal loading and mass-specific activity of SACs by exchanging zinc with iron.The constructed iron SACs(h^(3)-FNC)with a high metal loading of 6.27 wt%and an optimized adjacent Fe distance of~4 A exhibit excellent oxidase-like catalytic performance without significant activity decay after being stored for six months and promising antibacterial effects.Attractively,a“density effect”has been found at a high-enough metal doping amount,at which individual active sites become close enough to interact with each other and alter the electronic structure,resulting in significantly boosted intrinsic activity of single-atomic iron sites in h^(3)-FNCs by 2.3 times compared to low-and medium-loading SACs.Consequently,the overall catalytic activity of h^(3)-FNC is highly improved,with mass activity and metal mass-specific activity that are,respectively,66 and 315 times higher than those of commercial Pt/C.In addition,h^(3)-FNCs demonstrate efficiently enhanced capability in catalyzing oxygen reduction into superoxide anion(O_(2)·^(−))and glutathione(GSH)depletion.Both in vitro and in vivo assays demonstrate the superior antibacterial efficacy of h^(3)-FNCs in promoting wound healing.This work presents an intriguing activity-enhancement effect in catalysts and exhibits impressive therapeutic efficacy in combating bacterial infections.
基金supported by the National Natural Science Foundation of China,Nos.82172196(to KX),82372507(to KX)the Natural Science Foundation of Hunan Province,China,No.2023JJ40804(to QZ)the Key Laboratory of Emergency and Trauma(Hainan Medical University)of the Ministry of Education,China,No.KLET-202210(to QZ)。
文摘Ischemia–reperfusion injury is a common pathophysiological mechanism in retinal degeneration.PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis,apoptosis,and necroptosis.Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia–reperfusion injury.However,its role in PANoptosis remains largely unknown.In this study,we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia–reperfusion injury.Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia–reperfusion injury.Mechanistically,mitochondria-derived reactive oxygen species played a central role in the voltagedependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly.Moreover,inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia–reperfusion injury.Overall,our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia–reperfusion injury,highlighting voltage-dependent anion channel 1 as a promising therapeutic target.
基金supported by the Swedish Strategic Research Foundation(SSF FFL15-0174 to Zhen Zhang)the Swedish Research Council(VR 2018-06030 and 2019-04690 to Zhen Zhang)+1 种基金the Wallenberg Academy Fellow Extension Program(KAW 2020-0190 to Zhen Zhang)the Olle Engkvist Foundation(Postdoc grant 214-0322 to Zhen Zhang).
文摘Memristive crossbar arrays(MCAs)offer parallel data storage and processing for energy-efficient neuromorphic computing.However,most wafer-scale MCAs that are compatible with complementary metal-oxide-semiconductor(CMOS)technology still suffer from substantially larger energy consumption than biological synapses,due to the slow kinetics of forming conductive paths inside the memristive units.Here we report wafer-scale Ag_(2)S-based MCAs realized using CMOS-compatible processes at temperatures below 160℃.Ag_(2)S electrolytes supply highly mobile Ag+ions,and provide the Ag/Ag_(2)S interface with low silver nucleation barrier to form silver filaments at low energy costs.By further enhancing Ag+migration in Ag_(2)S electrolytes via microstructure modulation,the integrated memristors exhibit a record low threshold of approximately−0.1 V,and demonstrate ultra-low switching-energies reaching femtojoule values as observed in biological synapses.The low-temperature process also enables MCA integration on polyimide substrates for applications in flexible electronics.Moreover,the intrinsic nonidealities of the memristive units for deep learning can be compensated by employing an advanced training algorithm.An impressive accuracy of 92.6%in image recognition simulations is demonstrated with the MCAs after the compensation.The demonstrated MCAs provide a promising device option for neuromorphic computing with ultra-high energy-efficiency.
基金supported by the National Natural Science Foundation of China(82270386,82070252,and 8207025)the Zhejiang Provincial Medical and Health Science and Technology Plan(2023RC020)the Zhejiang Provincial Natural Science Foundation(LR21H020001).
文摘Background:Cardiac fibrosis following myocardial infarction(MI)drives adverse ventricular remodeling and heart failure,with cardiac fibroblasts(CFs)playing a central role.Glutathione S-transferase mu 1(GSTM1)is an important member of the glutathione S-transferase(GSTs)family,which plays an important role in maintaining cell homeostasis and detoxification.This study investigated the role and mechanism of GSTM1 in post-MI fibrosis.Methods:Multi-omics approaches(proteomics/scRNA-seq)identified GSTM1 as a dysregulated target in post-MI fibroblasts.Using a murine coronary ligation model,we assessed GSTM1 dynamics via molecular profiling,such as Western blotting,immunofluorescence,and real-time quantitative polymerase chain reaction.Adeno-associated virus serotype 9(AAV9)-mediated cardiac-specific GSTM1 overexpression was achieved through systemic delivery.In vitro studies employed transforming growth factor-β(TGF-β)-stimulated primary fibroblasts with siRNA/plasmid interventions.Mechanistic insights were derived from transcriptomics and lipid peroxidation assays.Results:The expression of GSTM1 in mouse CFs after MI was significantly down-regulated at both transcriptional and protein levels.In human dilated cardiomyopathy(DCM)patients with severe heart failure,GSTM1 expression was decreased alongside aggravated fibrosis.Overexpression of GSTM1 in post-MI mice improved cardiac function,while significantly reducing infarct size and fibrosis compared with the control group.In vitro models demonstrated that GSTM1 markedly attenuated collagen secretion and activation of fibroblasts,as well as suppressed their proliferation and migration.Further studies revealed that GSTM1 overexpression significantly inhibited the generation of intracellular and mitochondrial reactive oxygen species(ROS)under pathological conditions,suggesting that GSTM1 exerts an antioxidative stress effect in post-infarction fibroblasts.Further investigation of molecular mechanisms indicated that GSTM1 may suppress the initiation and progression of fibrosis by modulating lipid metabolism and ferroptosis-related pathways.Overexpression of GSTM1 significantly reduced lipid peroxidation and free ferrous iron levels in fibroblasts and mitochondria,markedly decreased ferroptosis-related indicators,and alleviated oxidative lipid levels[such as 12-hydroxyeicosapentaenoic acid(HEPE)and 9-,10-dihydroxy octadecenoic acid(DHOME)]under fibrotic conditions.GSTM1 enhanced the phosphorylation of signal transducer and activator of transcription 3(STAT3),thereby upregulating the downstream expression of glutathione peroxidase 4(GPX4),reducing ROS production,and mitigating fibroblast activation and phenotypic transformation by inhibiting lipid peroxidation.Conclusions:This study identifies GSTM1 as a key inhibitor of fibroblast activation and cardiac fibrosis,highlighting its ability to target ferroptosis through redox regulation.AAV-mediated GSTM1 therapy demonstrates significant therapeutic potential for improving outcomes post-MI.
