Two long-term slow slip events(SSEs) in Lower Cook Inlet, Alaska, were identified by Li SS et al.(2016). The earlier SSE lasted at least 9 years with M_(w) ~7.8 and had an average slip rate of ~82 mm/year. The latter ...Two long-term slow slip events(SSEs) in Lower Cook Inlet, Alaska, were identified by Li SS et al.(2016). The earlier SSE lasted at least 9 years with M_(w) ~7.8 and had an average slip rate of ~82 mm/year. The latter SSE, occurring in a similar area, lasted approximately 2 years with M_(w) ~7.2 and an average slip rate of ~91 mm/year. To test whether these SSEs triggered earthquakes near the slow slip area, we calculated the Coulomb stressing rate changes on receiver faults by using two fault geometry definitions: nodal planes of focal mechanism solutions of past earthquakes, and optimally oriented fault planes. Regions in the shallow slab(30–60 km) that experienced a significant increase in the Coulomb stressing rate due to slip by the SSEs showed an increase in seismicity rates during SSE periods. No correlation was found in the volumes that underwent a significant increase in the Coulomb stressing rate during the SSE within the crust and the intermediate slab. We modeled variations in seismicity rates by using a combination of the Coulomb stress transfer model and the framework of rate-and-state friction. Our model indicated that the SSEs increased the Coulomb stress changes on adjacent faults,thereby increasing the seismicity rates even though the ratio of the SSE stressing rate to the background stressing rate was small. Each long-term SSE in Alaska brought the megathrust updip of the SSE areas closer to failure by up to 0.1–0.15 MPa. The volumes of significant Coulomb stress changes caused by the Upper and Lower Cook Inlet SSEs did not overlap.展开更多
Background: New normality is uncertain in every sense, specifically in education and for many health disciplines. Being immersed in COVID-19 pandemics brought serious consequences for mental health, and is very import...Background: New normality is uncertain in every sense, specifically in education and for many health disciplines. Being immersed in COVID-19 pandemics brought serious consequences for mental health, and is very important to handle emotions and stress coping strategies to obtain positive outcomes. Objective: To identify the most frequent emotions, as well as the adaptation strategies to the new normality faced by the students of nursing. Methods: Qualitative and phenomenological research, with the participation of 20 students from both genders in the middle term of nursing career at Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, from August to November 2021. Information was collected from a focal group for ten sessions;analysis was according to De Souza Minayo, and there was a signed informed consent letter from participants. Results: Four categories emerged with sub-categories. Category I Maximized emotions. Sub-categories: 1) Frustration, anger, disappointment;2) Personal disappointment, hopelessness, uncertainty;3) Depression. Category II Support elements close to the new normality. Sub-categories: 1) Family communication;2) Education for mental and physical health. Category III Stressing situations that exceeded the student. Sub-category: Disease in lovely ones. Category IV Stress coping strategies. Sub-categories: 1) Friends and relatives that help to get better;2) Family values. Informers pointed out to have maximized emotion, and having no self-control on its negative outcomes occurred;in addition, the situation was not favorable at home with several losses of loved ones, as well as a poor economy that threatened students to give up studies. Conclusion: Emotions facing this new normality are very important and should be attended to, their proper handling will result in a new learning of socio-emotional abilities, stress coping strategies development, better adaptation and informed decisions taken.展开更多
This article describes the effective channel length degradation under hot carrier stressing. The extraction is based on the IDs-Vcs characteristics by maximum transconductance （maximum slope of IDs ＆ VGS） in the li...This article describes the effective channel length degradation under hot carrier stressing. The extraction is based on the IDs-Vcs characteristics by maximum transconductance （maximum slope of IDs ＆ VGS） in the linear region. The transconductance characteristics are determine for the several devices of difference drawn channel length. The effective channel length of submicron LDD （Lightly Doped Drain） NMOSFETs （Metal Oxide Semiconductor Field Effect Transistor） under hot carrier stressing was measured at the stress time varying from zero to 10,000 seconds. It is shown that the effective channel length was increased with time. This is caused by charges trapping in the oxide during stress. The increased of effective channel length （△Leff） is seem to be increased sharply as the gate channel length is decrease.展开更多
This paper analyzes the influence of fatigue loading on the residual stress profile in high strength steel wires. To this end, different sinusoidal loads with diverse values of maximum loading level and number of cycl...This paper analyzes the influence of fatigue loading on the residual stress profile in high strength steel wires. To this end, different sinusoidal loads with diverse values of maximum loading level and number of cycles were simulated on wires in which several residual stress profiles had been previously introduced, some of them with a tensile state and others with a compressive state. An analysis was made of the evolution with time of such residual stress laws by comparing them at key instants of loading, that is, at initial instant, at maximum load, at minimum load and at final instant. Numerical results show only a minor influence of fatigue loading on the residual stress profile.展开更多
China Network Communications Group Corporation (CNC) proposed and reaffirmed for many times the strategic objective of transferring to a broadband communication and multimedia service provider since the beginning of t...China Network Communications Group Corporation (CNC) proposed and reaffirmed for many times the strategic objective of transferring to a broadband communication and multimedia service provider since the beginning of this year. CNC, insisting on self-innovation, is going to forge itself into a domestically high-class and internationally influential innovative company within five years.展开更多
How to put forward advisory suggestions regarded as feasible, workable and acceptable by the State leaders through the integration of the goodwill cherished by our scientists with the blueprint masterminded by the hos...How to put forward advisory suggestions regarded as feasible, workable and acceptable by the State leaders through the integration of the goodwill cherished by our scientists with the blueprint masterminded by the hosts of various R&D projects? It seems to me a problem worthy of our serious consideration. Here I would like to suggest that under the leading group of national S&T affairs, a new organ functionally similar to the State R&D Center be set up. Acting as a counselling team to the group, it must be small in payroll and include by strategists spe-展开更多
In order to investigate the ratcheting behavior of T225NG alloy, a series of ratcheting tests under uniaxial long-cyclic stressing were performed. The results show that the ratcheting strain of this alloy can get into...In order to investigate the ratcheting behavior of T225NG alloy, a series of ratcheting tests under uniaxial long-cyclic stressing were performed. The results show that the ratcheting strain of this alloy can get into shakedown after tens （or hundreds） of thousand cycles. After the ratcheting strain is saturated under the condition that stress amplitude is half of peak stress, it will bring about subsequent fatigue failure, and relationship between fatigue life and one of peak stress and saturated ratcheting （SR） strain meets power law. As the alloy is under stress jiggling with stress amplitude that is 1%-2.5% of peak stress, the ratcheting strain still become remarkable and goes into shakedown after several hundreds of thousand cycles but there exists little accessional strain caused by creep effect. It is notable that, when the peak stress is 85%-100% of yield stress, the long-cyclic stressing will lead SR strain to be from 1.4% to 2.5% even if the initial ratio of ratcheting strain is zero. Based on ratcheting threshold property of peak stress and monotonicity of relationship between the peak stress and SR strain, a saturated ratcheting model （SRM） is developed to predict SR strain and to estimate saturated creep strain also. In addition, the classes of ratcheting evolutions of metals are discussed.展开更多
Non-invasive cardiac stress imaging plays a central role in the assessment of patients with known or suspected coronary artery disease.The current guidelines suggest estimation of the myocardial ischaemic burden as a ...Non-invasive cardiac stress imaging plays a central role in the assessment of patients with known or suspected coronary artery disease.The current guidelines suggest estimation of the myocardial ischaemic burden as a criterion for revascularisation on prognostic grounds despite the lack of standardised reporting of the magnitude of ischaemia on various non-invasive imaging methods.Future studies should aim to accurately describe the relationship between myocardial ischaemic burden as assessed by cardiovascular magnetic resonance imaging and mortality.展开更多
Abstract:Microwave-based destressing is regarded as a promising approach for proactively preventing and controlling rockbursts in deep hard rock.As the fracturing degree of microwave-induced boreholes is affected by b...Abstract:Microwave-based destressing is regarded as a promising approach for proactively preventing and controlling rockbursts in deep hard rock.As the fracturing degree of microwave-induced boreholes is affected by borehole diameter,water content,mineral content,etc.,it is difficult to establish relationships between them.The research aims to unify various factors with heating rate and temperature,and establish a microwave parameter design method based thereon.Tests on microwave-induced borehole fracturing in hard rock with different or similar heating rates and temperatures under true triaxial stress were conducted.The test results show that both heating rate and temperature promote radial fracture of the rock,but have little effect on the development of axial fractures.Compared with heating rate,temperature is a more critical factor influencing microwave-induced fracturing.The effects of the heating rate on rock fracturing become noticeable only at higher temperatures.When the heating rate and temperature are similar but the diameter of the boreholes is different,the crack distribution,total length,wave velocity attenuation,and fracture process are similar.It is feasible to reverse-design microwave parameters under different borehole diameters based on the heating rate and temperature.Thermal fracturing of basalt shows a distinct threshold effect between 150℃ and 195℃(with an average of about 175℃),and the heating rate and borehole diameter exert minor influences thereon.The results provide guidance for the design of microwave parameters in practice.展开更多
In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quali...In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.展开更多
Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a...Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.展开更多
Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen...Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.展开更多
The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response pla...Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.展开更多
Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological d...Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.展开更多
Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in...Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.展开更多
Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroa...Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroacupuncture and explore its potential mechanisms in animal models of ischemic stroke.The PubMed,EMBASE,Web of Science,CENTRAL,and CINAHL databases were comprehensively searched up to May 1,2024.This review included articles on preclinical investigations of the efficacy and mechanisms of electroacupuncture in treating ischemic stroke.Data from 70 eligible studies were analyzed in Stata 18.0,using a random-effects model to calculate the standardized mean difference(Hedge’s g).The risk of bias was assessed using RevMan 5.4 software,and the quality of evidence was rated according to the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)system.Subgroup analyses were conducted to test the consistency of the results and sensitivity analyses were used to assess their robustness.The quality assessment revealed that most studies adequately handled incomplete data and selective reporting.However,several methodological limitations were identified:only 4 studies demonstrated a low risk of allocation concealment,26 achieved a low risk of outcome assessment bias,and 9 had a high risk of randomization bias.Additionally,there was an unclear risk regarding participant blinding and other methodological aspects.The GRADE assessment rated 12 outcomes as moderate quality and 6 as low quality.The mechanisms of electroacupuncture treatment for ischemic stroke can be categorized as five primary pathways:(1)Electroacupuncture significantly reduced infarct volume and apoptotic cell death(P<0.01)in ischemic stroke models;(2)electroacupuncture significantly decreased the levels of pro-inflammatory factors(P<0.01)while increasing the levels of anti-inflammatory factors(P=0.02);(3)electroacupuncture reduced the levels of oxidative stress indicators(P<0.01)and enhanced the expression of antioxidant enzymes(P<0.01);(4)electroacupuncture significantly promoted nerve regeneration(P<0.01);and(5)electroacupuncture influenced blood flow remodeling(P<0.01)and angiogenesis(P<0.01).Subgroup analyses indicated that electroacupuncture was most effective in the transient middle cerebral artery occlusion model(P<0.01)and in post-middle cerebral artery occlusion intervention(P<0.01).Dispersive waves were found to outperform continuous waves with respect to neuroprotection and anti-inflammatory effects(P<0.01),while scalp acupoints demonstrated greater efficacy than body acupoints(P<0.01).The heterogeneity among the included studies was minimal,and sensitivity analyses indicated stable results.Their methodological quality was generally satisfactory.In conclusion,electroacupuncture is effective in treating cerebral ischemia by modulating cell apoptosis,oxidative stress,inflammation,stroke-induced nerve regeneration,blood flow remodeling,and angiogenesis.The efficacy of electroacupuncture may be influenced by factors such as the middle cerebral artery occlusion model,the timing of intervention onset,waveform,and acupoint selection.Despite the moderate to low quality of evidence,these findings suggest that electroacupuncture has clinical potential for improving outcomes in ischemic stroke.展开更多
Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is cha...Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.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
Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal deg...Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.展开更多
基金supported by the National Natural Science Foundation of China (Grant No. 42104001)。
文摘Two long-term slow slip events(SSEs) in Lower Cook Inlet, Alaska, were identified by Li SS et al.(2016). The earlier SSE lasted at least 9 years with M_(w) ~7.8 and had an average slip rate of ~82 mm/year. The latter SSE, occurring in a similar area, lasted approximately 2 years with M_(w) ~7.2 and an average slip rate of ~91 mm/year. To test whether these SSEs triggered earthquakes near the slow slip area, we calculated the Coulomb stressing rate changes on receiver faults by using two fault geometry definitions: nodal planes of focal mechanism solutions of past earthquakes, and optimally oriented fault planes. Regions in the shallow slab(30–60 km) that experienced a significant increase in the Coulomb stressing rate due to slip by the SSEs showed an increase in seismicity rates during SSE periods. No correlation was found in the volumes that underwent a significant increase in the Coulomb stressing rate during the SSE within the crust and the intermediate slab. We modeled variations in seismicity rates by using a combination of the Coulomb stress transfer model and the framework of rate-and-state friction. Our model indicated that the SSEs increased the Coulomb stress changes on adjacent faults,thereby increasing the seismicity rates even though the ratio of the SSE stressing rate to the background stressing rate was small. Each long-term SSE in Alaska brought the megathrust updip of the SSE areas closer to failure by up to 0.1–0.15 MPa. The volumes of significant Coulomb stress changes caused by the Upper and Lower Cook Inlet SSEs did not overlap.
文摘Background: New normality is uncertain in every sense, specifically in education and for many health disciplines. Being immersed in COVID-19 pandemics brought serious consequences for mental health, and is very important to handle emotions and stress coping strategies to obtain positive outcomes. Objective: To identify the most frequent emotions, as well as the adaptation strategies to the new normality faced by the students of nursing. Methods: Qualitative and phenomenological research, with the participation of 20 students from both genders in the middle term of nursing career at Faculty of Higher Studies Iztacala, National Autonomous University of Mexico, from August to November 2021. Information was collected from a focal group for ten sessions;analysis was according to De Souza Minayo, and there was a signed informed consent letter from participants. Results: Four categories emerged with sub-categories. Category I Maximized emotions. Sub-categories: 1) Frustration, anger, disappointment;2) Personal disappointment, hopelessness, uncertainty;3) Depression. Category II Support elements close to the new normality. Sub-categories: 1) Family communication;2) Education for mental and physical health. Category III Stressing situations that exceeded the student. Sub-category: Disease in lovely ones. Category IV Stress coping strategies. Sub-categories: 1) Friends and relatives that help to get better;2) Family values. Informers pointed out to have maximized emotion, and having no self-control on its negative outcomes occurred;in addition, the situation was not favorable at home with several losses of loved ones, as well as a poor economy that threatened students to give up studies. Conclusion: Emotions facing this new normality are very important and should be attended to, their proper handling will result in a new learning of socio-emotional abilities, stress coping strategies development, better adaptation and informed decisions taken.
文摘This article describes the effective channel length degradation under hot carrier stressing. The extraction is based on the IDs-Vcs characteristics by maximum transconductance （maximum slope of IDs ＆ VGS） in the linear region. The transconductance characteristics are determine for the several devices of difference drawn channel length. The effective channel length of submicron LDD （Lightly Doped Drain） NMOSFETs （Metal Oxide Semiconductor Field Effect Transistor） under hot carrier stressing was measured at the stress time varying from zero to 10,000 seconds. It is shown that the effective channel length was increased with time. This is caused by charges trapping in the oxide during stress. The increased of effective channel length （△Leff） is seem to be increased sharply as the gate channel length is decrease.
文摘This paper analyzes the influence of fatigue loading on the residual stress profile in high strength steel wires. To this end, different sinusoidal loads with diverse values of maximum loading level and number of cycles were simulated on wires in which several residual stress profiles had been previously introduced, some of them with a tensile state and others with a compressive state. An analysis was made of the evolution with time of such residual stress laws by comparing them at key instants of loading, that is, at initial instant, at maximum load, at minimum load and at final instant. Numerical results show only a minor influence of fatigue loading on the residual stress profile.
文摘China Network Communications Group Corporation (CNC) proposed and reaffirmed for many times the strategic objective of transferring to a broadband communication and multimedia service provider since the beginning of this year. CNC, insisting on self-innovation, is going to forge itself into a domestically high-class and internationally influential innovative company within five years.
文摘How to put forward advisory suggestions regarded as feasible, workable and acceptable by the State leaders through the integration of the goodwill cherished by our scientists with the blueprint masterminded by the hosts of various R&D projects? It seems to me a problem worthy of our serious consideration. Here I would like to suggest that under the leading group of national S&T affairs, a new organ functionally similar to the State R&D Center be set up. Acting as a counselling team to the group, it must be small in payroll and include by strategists spe-
文摘In order to investigate the ratcheting behavior of T225NG alloy, a series of ratcheting tests under uniaxial long-cyclic stressing were performed. The results show that the ratcheting strain of this alloy can get into shakedown after tens （or hundreds） of thousand cycles. After the ratcheting strain is saturated under the condition that stress amplitude is half of peak stress, it will bring about subsequent fatigue failure, and relationship between fatigue life and one of peak stress and saturated ratcheting （SR） strain meets power law. As the alloy is under stress jiggling with stress amplitude that is 1%-2.5% of peak stress, the ratcheting strain still become remarkable and goes into shakedown after several hundreds of thousand cycles but there exists little accessional strain caused by creep effect. It is notable that, when the peak stress is 85%-100% of yield stress, the long-cyclic stressing will lead SR strain to be from 1.4% to 2.5% even if the initial ratio of ratcheting strain is zero. Based on ratcheting threshold property of peak stress and monotonicity of relationship between the peak stress and SR strain, a saturated ratcheting model （SRM） is developed to predict SR strain and to estimate saturated creep strain also. In addition, the classes of ratcheting evolutions of metals are discussed.
文摘Non-invasive cardiac stress imaging plays a central role in the assessment of patients with known or suspected coronary artery disease.The current guidelines suggest estimation of the myocardial ischaemic burden as a criterion for revascularisation on prognostic grounds despite the lack of standardised reporting of the magnitude of ischaemia on various non-invasive imaging methods.Future studies should aim to accurately describe the relationship between myocardial ischaemic burden as assessed by cardiovascular magnetic resonance imaging and mortality.
基金the financial support from the Na-tional Key Research and Development Program of China(Grant No.2023YFC2907202)the Postdoctoral Fellowship Program of CPSF(Grant No.GZB20240129).
文摘Abstract:Microwave-based destressing is regarded as a promising approach for proactively preventing and controlling rockbursts in deep hard rock.As the fracturing degree of microwave-induced boreholes is affected by borehole diameter,water content,mineral content,etc.,it is difficult to establish relationships between them.The research aims to unify various factors with heating rate and temperature,and establish a microwave parameter design method based thereon.Tests on microwave-induced borehole fracturing in hard rock with different or similar heating rates and temperatures under true triaxial stress were conducted.The test results show that both heating rate and temperature promote radial fracture of the rock,but have little effect on the development of axial fractures.Compared with heating rate,temperature is a more critical factor influencing microwave-induced fracturing.The effects of the heating rate on rock fracturing become noticeable only at higher temperatures.When the heating rate and temperature are similar but the diameter of the boreholes is different,the crack distribution,total length,wave velocity attenuation,and fracture process are similar.It is feasible to reverse-design microwave parameters under different borehole diameters based on the heating rate and temperature.Thermal fracturing of basalt shows a distinct threshold effect between 150℃ and 195℃(with an average of about 175℃),and the heating rate and borehole diameter exert minor influences thereon.The results provide guidance for the design of microwave parameters in practice.
基金supported by the Project of Sanya Yazhou Bay Science and Technology City (SKJC-JYRC-2024-26)the National Natural Science Foundation of China (32460072)+4 种基金Hainan Provincial Natural Science Foundation of China (323RC421)the Hainan Province Science and Technology Special Fund (ZDYF2022XDNY144)the Hainan Provincial Academician Innovation Platform Project (HDYSZX-202004)the Collaborative Innovation Center of Nanfan and High-Efficiency Tropical Agriculture, Hainan University (XTCX2022NYB06)Hainan Postdoctoral Research Grant Project
文摘In light of the pressing global challenges of climate change,declining crop resilience,and hidden hunger,it is imperative to overcome the limitations of conventional crop breeding to enhance both the nutritional quality and stress tolerance of crops.Synthetic metabolic engineering presents innovative strategies for the precision modification and de novo design of metabolic pathways.This approach generally encompasses three essential steps:identifying key metabolites through metabolomics,integrating multi-omics technologies to investigate the synthesis and regulation of these metabolites,and utilizing gene editing or de novo design to modify crop metabolic pathways associated with desirable agronomic traits.This review underscores the vital role of plant metabolite diversity in enhancing crop nutritional quality and stress resilience.Integrated multi-omics analyses facilitate the metabolic engineering by identifying key genes,transporters,and transcription factors that regulate metabolite biosynthesis.Precision modification strategies employ genome editing tools to reprogram endogenous metabolic networks,while de novo design reconstructs metabolic pathways through the introduction of exogenous biological elements—thereby both approaches enable the targeted enhancement of desired traits.These strategies have been effectively implemented in major food crops.However,simultaneously enhancing nutritional quality and stress resilience remains challenging due to inherent trade-offs and resource competition in distinct metabolic pathways within plants.Future research should integrate AI-driven predictive models with multi-omics datasets to decipher dynamic metabolic homeostasis and engineer climate-smart crops that maximize yield while preserving quality and environmental adaptability.
基金supported by the National Natural Science Foundation of China,82471345(to LC)the Key Research and Development Program for Social Development by the Jiangsu Provincial Department of Science and Technology.No.BE2022668(to LC).
文摘Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.82171387 and 31830111(both to SL).
文摘Stroke,particularly ischemic stroke,is the leading cause of long-term disability and mortality worldwide.It occurs due to the occlusion of the cerebral arteries,which significantly reduces the delivery of blood,oxygen,and essential nutrients to brain tissues.This deprivation triggers a cascade of cellular events that ultimately leads to neuronal death.Recent studies have clarified the multifactorial pathogenesis of ischemic stroke,highlighting the roles of energy failure,excitotoxicity,oxidative stress,neuroinflammation,and apoptosis.This review aimed to provide a comprehensive insight into the fundamental mechanisms driving neuronal death triggered by ischemia and to examine the progress of neuroprotective therapeutic approaches designed to mitigate neuronal loss and promote neurological recovery after a stroke.Additionally,we explored widely accepted findings regarding the potential pathways implicated in neuronal death during ischemic stroke,including the interplay of apoptosis,autophagy,pyroptosis,ferroptosis,and necrosis,which collectively influence neuronal fate.We also discussed advancements in neuroprotective therapeutics,encompassing a range of interventions from pharmacological modulation to stem cell-based therapies,aimed at reducing neuronal injury and enhancing functional recovery following ischemic stroke.Despite these advancements,challenges remain in translating mechanistic insights into effective clinical therapies.Although neuroprotective strategies have shown promise in preclinical models,their efficacy in human trials has been inconsistent,often due to the complex pathology of ischemic stroke and the timing of interventions.In conclusion,this review synthesizes mechanistic insights into the intricate interplay of molecular and cellular pathways driving neuronal death post-ischemia.It sheds light on cutting-edge advancements in potential neuroprotective therapeutics,underscores the promise of regenerative medicine,and offers a forward-looking perspective on potential clinical breakthroughs.The ongoing evolution of precision-targeted interventions is expected to significantly enhance preventative strategies and improve clinical outcomes.
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
基金supported by European Union-NextGeneration EU under the Italian University and Research(MUR)National Innovation Ecosystem grant ECS00000041-VITALITY-CUP E13C22001060006(to MdA)。
文摘Stroke is a major cause of death and disability worldwide.It is characterized by a highly interconnected and multiphasic neuropathological cascade of events,in which an intense and protracted inflammatory response plays a crucial role in worsening brain injury.Neuroinflammation,a key player in the pathophysiology of stroke,has a dual role.In the acute phase of stroke,neuroinflammation exacerbates brain injury,contributing to neuronal damage and blood–brain barrier disruption.This aspect of neuroinflammation is associated with poor neurological outcomes.Conversely,in the recovery phase following stroke,neuroinflammation facilitates brain repair processes,including neurogenesis,angiogenesis,and synaptic plasticity.The transition of neuroinflammation from a harmful to a reparative role is not well understood.Therefore,this review seeks to explore the mechanisms underlying this transition,with the goal of informing the development of therapeutic interventions that are both time-and context-specific.This review aims to elucidate the complex and dual role of neuroinflammation in stroke,highlighting the main actors,biomarkers of the disease,and potential therapeutic approaches.
基金supported by AFM-Telethon grants N°21704 and 23264,Universite Paris Cite(Paris)the National Institute of Health and Medical Research(INSERM)+3 种基金the National Center for Scientific Research(CNRS)the French Association Connaître les Syndromes Cerebelleux(CSC)(to MCD)GV/2021/188 granted from Conselleria of Innovation,Universities,28 Science and Society digital of the Community of Valencia(Spain)(to ITC)Subprograma Atraccion de Talento-Contratos Postdoctorales de la Universitat de Valencia(to IMY).
文摘Neurodevelopmental and neurodegenerative illnesses constitute a global health issue and a foremost economic burden since they are a large cause of incapacity and death worldwide.Altogether,the burden of neurological disorders has increased considerably over the past 30 years because of population aging.Overall,neurological diseases significantly impair cognitive and motor functions and their incidence will increase as societies age and the world's population continues to grow.Autism spectrum disorder,motor neuron disease,encephalopathy,epilepsy,stroke,ataxia,Alzheimer's disease,amyotrophic lateral sclerosis,Huntington's disease,and Parkinson's disease represent a non-exhaustive list of neurological illnesses.These affections are due to perturbations in cellular homeostasis leading to the progressive injury and death of neurons in the nervous system.Among the common features of neurological handicaps,we find protein aggregation,oxidative stress,neuroinflammation,and mitochondrial impairment in the target tissues,e.g.,the brain,cerebellum,and spinal cord.The high energy requirements of neurons and their inability to produce sufficient adenosine triphosphate by glycolysis,are responsible for their dependence on functional mitochondria for their integrity.Reactive oxygen species,produced along with the respiration process within mitochondria,can lead to oxidative stress,which compromises neuronal survival.Besides having an essential role in energy production and oxidative stress,mitochondria are indispensable for an array of cellular processes,such as amino acid metabolism,iron-sulfur cluster biosynthesis,calcium homeostasis,intrinsic programmed cell death(apoptosis),and intraorganellar signaling.Despite the progress made in the last decades in the understanding of a growing number of genetic and molecular causes of central nervous diseases,therapies that are effective to diminish or halt neuronal dysfunction/death are rare.Given the genetic complexity responsible for neurological disorders,the development of neuroprotective strategies seeking to preserve mitochondrial homeostasis is a realistic challenge to lastingly diminish the harmful evolution of these pathologies and so to recover quality of life.A promising candidate is the neuroglobin,a globin superfamily member of 151 amino acids,which is found at high levels in the brain,the eye,and the cerebellum.The protein,which localizes to mitochondria,is involved in electron transfer,oxygen storage and defence against oxidative stress;hence,possessing neuroprotective properties.This review surveys up-to-date knowledge and emphasizes on existing investigations regarding neuroglobin physiological functions,which remain since its discovery in 2000 under intense debate and the possibility of using neuroglobin either by gene therapy or its direct delivery into the brain to treat neurological disorders.
基金supported by the National Natural Science Foundation of China,Nos.82371310(to YJ),82271306(to JP)the Sichuan Science and Technology Support Program,Nos.2023YFH0069(to JP),2023NSFSC0028(to YJ),2023NSFSC1559(to YJ),2022YFS0615(to JP),2022NSFSC1421(to JP)+1 种基金Scientific Research Project of Sichuan Provincial Health Commission,No.23LCYJ040(to YJ)Youth Foundation of Southwestern Medical University and Southwest Medical University Project,Nos.2020ZRQNA038(to JP),2021ZKZD013(to JP),2021LZXNYD-P01(to YJ),2023QN014(to JP).
文摘Neuronal cell death is a common outcome of multiple pathophysiological processes and a key factor in neurological dysfunction after subarachnoid hemorrhage.Neuronal ferroptosis in particular plays an important role in early brain injury.Bromodomain-containing protein 4,a member of the bromo and extraterminal domain family of proteins,participated in multiple cell death pathways,but the mechanisms by which it regulates ferroptosis remain unclear.The primary aim of this study was to investigate how bromodomain-containing protein 4 affects neuronal ferroptosis following subarachnoid hemorrhage in vivo and in vitro.Our findings revealed that endogenous bromodomain-containing protein 4 co-localized with neurons,and its expression was decreased 48 hours after subarachnoid hemorrhage of the cerebral cortex in vivo.In addition,ferroptosis-related pathways were activated in vivo and in vitro after subarachnoid hemorrhage.Targeted inhibition of bromodomain-containing protein 4 in neurons increased lipid peroxidation and intracellular ferrous iron accumulation via ferritinophagy and ultimately led to neuronal ferroptosis.Using cleavage under targets and tagmentation analysis,we found that bromodomain-containing protein 4 enrichment in the Raf-1 promoter region decreased following oxyhemoglobin stimulation in vitro.Furthermore,treating bromodomain-containing protein 4-knockdown HT-22 cell lines with GW5074,a Raf-1 inhibitor,exacerbated neuronal ferroptosis by suppressing the Raf-1/ERK1/2 signaling pathway.Moreover,targeted inhibition of neuronal bromodomain-containing protein 4 exacerbated early and long-term neurological function deficits after subarachnoid hemorrhage.Our findings suggest that bromodomain-containing protein 4 may have neuroprotective effects after subarachnoid hemorrhage,and that inhibiting ferroptosis could help treat subarachnoid hemorrhage.
基金supported by the National Natural Science Foundation of China,Nos.82174496(to NW),82374574(to NW),82302865(to LL)Shanghai Science and Technology Committee Sailing Program,Nos.23YF1403800(to LL),23YF1405200(to YX)Shanghai Hospital Development Center Foundation-Shanghai Municipal Hospital Rehabilitation Medicine Specialty Alliance,No.SHDC22023304(to YW).
文摘Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroacupuncture and explore its potential mechanisms in animal models of ischemic stroke.The PubMed,EMBASE,Web of Science,CENTRAL,and CINAHL databases were comprehensively searched up to May 1,2024.This review included articles on preclinical investigations of the efficacy and mechanisms of electroacupuncture in treating ischemic stroke.Data from 70 eligible studies were analyzed in Stata 18.0,using a random-effects model to calculate the standardized mean difference(Hedge’s g).The risk of bias was assessed using RevMan 5.4 software,and the quality of evidence was rated according to the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)system.Subgroup analyses were conducted to test the consistency of the results and sensitivity analyses were used to assess their robustness.The quality assessment revealed that most studies adequately handled incomplete data and selective reporting.However,several methodological limitations were identified:only 4 studies demonstrated a low risk of allocation concealment,26 achieved a low risk of outcome assessment bias,and 9 had a high risk of randomization bias.Additionally,there was an unclear risk regarding participant blinding and other methodological aspects.The GRADE assessment rated 12 outcomes as moderate quality and 6 as low quality.The mechanisms of electroacupuncture treatment for ischemic stroke can be categorized as five primary pathways:(1)Electroacupuncture significantly reduced infarct volume and apoptotic cell death(P<0.01)in ischemic stroke models;(2)electroacupuncture significantly decreased the levels of pro-inflammatory factors(P<0.01)while increasing the levels of anti-inflammatory factors(P=0.02);(3)electroacupuncture reduced the levels of oxidative stress indicators(P<0.01)and enhanced the expression of antioxidant enzymes(P<0.01);(4)electroacupuncture significantly promoted nerve regeneration(P<0.01);and(5)electroacupuncture influenced blood flow remodeling(P<0.01)and angiogenesis(P<0.01).Subgroup analyses indicated that electroacupuncture was most effective in the transient middle cerebral artery occlusion model(P<0.01)and in post-middle cerebral artery occlusion intervention(P<0.01).Dispersive waves were found to outperform continuous waves with respect to neuroprotection and anti-inflammatory effects(P<0.01),while scalp acupoints demonstrated greater efficacy than body acupoints(P<0.01).The heterogeneity among the included studies was minimal,and sensitivity analyses indicated stable results.Their methodological quality was generally satisfactory.In conclusion,electroacupuncture is effective in treating cerebral ischemia by modulating cell apoptosis,oxidative stress,inflammation,stroke-induced nerve regeneration,blood flow remodeling,and angiogenesis.The efficacy of electroacupuncture may be influenced by factors such as the middle cerebral artery occlusion model,the timing of intervention onset,waveform,and acupoint selection.Despite the moderate to low quality of evidence,these findings suggest that electroacupuncture has clinical potential for improving outcomes in ischemic stroke.
基金supported by grants from the Zhejiang Provincial TCM Science and Technology Plan Project,No.2023ZL156(to YH)Ningbo Top Medical and Health Research Program,No.2022020304(to XG)+1 种基金the Natural Science Foundation of Ningbo,No.2023J019(to YH)Key Laboratory of Precision Medicine for Atherosclerotic Diseases of Zhejiang Province,No.2022E10026(to YH)。
文摘Strokes include both ischemic stroke,which is mediated by a blockade or reduction in the blood supply to the brain,and hemorrhagic stroke,which comprises intracerebral hemorrhage and subarachnoid hemorrhage and is characterized by bleeding within the brain.Stroke is a lifethreatening cerebrovascular condition characterized by intricate pathophysiological mechanisms,including oxidative stress,inflammation,mitochondrial dysfunction,and neuronal injury.Critical transcription factors,such as nuclear factor erythroid 2-related factor 2 and nuclear factor kappa B,play central roles in the progression of stroke.Nuclear factor erythroid 2-related factor 2 is sensitive to changes in the cellular redox status and is crucial in protecting cells against oxidative damage,inflammatory responses,and cytotoxic agents.It plays a significant role in post-stroke neuroprotection and repair by influencing mitochondrial function,endoplasmic reticulum stress,and lysosomal activity and regulating metabolic pathways and cytokine expression.Conversely,nuclear factor-kappa B is closely associated with mitochondrial dysfunction,the generation of reactive oxygen species,oxidative stress exacerbation,and inflammation.Nuclear factor-kappa B contributes to neuronal injury,apoptosis,and immune responses following stroke by modulating cell adhesion molecules and inflammatory mediators.The interplay between these pathways,potentially involving crosstalk among various organelles,significantly influences stroke pathophysiology.Advancements in single-cell sequencing and spatial transcriptomics have greatly improved our understanding of stroke pathogenesis and offer new opportunities for the development of targeted,individualized,cell typespecific treatments.In this review,we discuss the mechanisms underlying the involvement of nuclear factor erythroid 2-related factor 2 and nuclear factor-kappa B in both ischemic and hemorrhagic stroke,with an emphasis on their roles in oxidative stress,inflammation,and neuroprotection.
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 National Natural Science Foundation of China,Nos.82171076(to XS)and U22A20311(to XS),82101168(to TL)Shanghai Science and technology Innovation Action Plan,No.23Y11901300(to JS)+1 种基金Science and Technology Commission of Shanghai Municipality,No.21ZR1451500(to TL)Shanghai Pujiang Program,No.22PJ1412200(to BY)。
文摘Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss.Ferroptosis has been demonstrated to be associated with retinal degenerative diseases.However,the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored.Bioinformatics and biochemical analyses in this study revealed xC^(–),solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model.This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway,through which cystine depletion,iron ion accumulation,and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment.We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo.Conversely,solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H_(2)O_(2)-induced ferroptosis of 661W cells.These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.
