In a large ancient landslide,approximately 240,000 m3 of sediments were reactivated,posing a grave threat to the safety of iron ore stopes.To trace the deformation and evolution history of reactivated Landslide,we con...In a large ancient landslide,approximately 240,000 m3 of sediments were reactivated,posing a grave threat to the safety of iron ore stopes.To trace the deformation and evolution history of reactivated Landslide,we conducted geological surveys and combined real-time monitoring equipment to analyze the landslide data since 1986 and the deformation status of the reactivated Landslide.A multi-factor comprehensive landslide monitoring method and an Newton force early warning system(NFEWS)were established,focusing on underground stress,surface deformation information and landslide stability.Furthermore,we developed a four-level early warning grading standard,employing surface cracks and changes in underground stress thresholds as early warning indicators.This standard adds expert assessment to avoid false alarms and realize real-time dynamics of mining landslides during excavation and transportation.Through the case study and analysis of Nanfen open-pit mine,the NFEWS system offers valuable insights and solution for early warning of landslides in analogous open-pit mines.Finally,the evaluation index system of landslide hazard susceptibility was established by selecting the Newton force influence factor.A landslide susceptibility zoning map is constructed using the information value model.The rationality and accuracy are assessed from three perspectives:frequency ratio,landslide hazard point density,and receiver operating characteristic(ROC)curve.The improved Newton force landslide early warning system provides a good reference for the analysis and monitoring of the creep landslide evolution process.展开更多
In southwest of China, landslide reactivation caused by excavation has caused huge property and human losses, and posed severely threaten to the construction and operation of the man-made linear structures. A reactiva...In southwest of China, landslide reactivation caused by excavation has caused huge property and human losses, and posed severely threaten to the construction and operation of the man-made linear structures. A reactivated landslide is a complex process. The engineering practices have shown that a correct understanding of the reactivated mechanism of an ancient giant landslide is significant for the landslide mitigation. In this paper, a case study of the ancient Badu landslide that underwent multiple reactivations during the construction of Nanning-Kunming railway was discussed. The landslide characteristics are described and the reactivated features and progressive failure of the landslide are revealed. The reactivated mechanism of the landslide is analyzed by use of geological process analysis method and is simulated using the 3D FEM （finite element method）. At last, the reactivated mechanism mode of Badu giant landslide is put forward, namely ＂creeping-tensile cracking-shear breaking with zoning and grading features＂. The understanding of this kind of reactivated mechanism had helped engineers to take efficient and economic mitigation measures to stabilize the landslide.展开更多
Due to the complex geological processes of Qinghai-Tibet Plateau,numerous deposits,especially the large-scale ancient landslide deposits,are characteristic features of the valleys incised in southwestern China.Intense...Due to the complex geological processes of Qinghai-Tibet Plateau,numerous deposits,especially the large-scale ancient landslide deposits,are characteristic features of the valleys incised in southwestern China.Intense water level fluctuations since 2011 in Maoergai Reservoir,China,registered the reactivation of Xierguazi ancient landslide,and presented a significant risk to neighboring facilities.Based on detailed field survey and drilling exploration,the landslide was divided into Zone A and Zone B,and other characterizations of landslide were studied as well.To precisely measure the extent of landslide displacement during filling and drawdown stage,surface displacement monitoring system was deployed on the landslide.The monitoring analyses data reveal that reservoir fluctuation is the dominant factor influencing landslide displacement,especially during drawdown stage.Moreover,a future sliding is anticipated in Zone A,while a creep had already existed in Zone B.A reservoir regulation was then established using the lead-lag correlation between reservoir fluctuation and landslide displacement and landslide stability analysis.In the end,the follow-up deformation monitoring demonstrates that the reservoir regulation controlled the landslide effectively.Landslide control by reservoir regulation in Maoergai can serve as a case study for other settlements involved in similar construction activities.展开更多
The risk of reactivated ancient landslides in the Sichuan–Xizang transportation corridor in China is significantly increasing,primarily driven by the intensification of engineering activities and the increased freque...The risk of reactivated ancient landslides in the Sichuan–Xizang transportation corridor in China is significantly increasing,primarily driven by the intensification of engineering activities and the increased frequency of extreme weather events.This escalation has resulted in a considerable number of fatalities and extensive damage to critical engineering infrastructure.However,the factors contributing to the reactivation and modes of destruction of ancient landslides remain unknown.Therefore,it is imperative to systematically analyze the developmental characteristics and failure modes of reactivated ancient landslides to effectively mitigate disaster risks.Based on a combination of data collection,remote sensing interpretation,and field investigations,we delineated the developmental attributes of typical ancient landslides within the study area.These attributes encompass morphological and topographic aspects,material composition,and spatial structure of ancient landslides.Subsequently,we identified the key triggers for the reactivation of ancient landslides,including water infiltration,reservoir hydrodynamics,slope erosion,and excavation,by analyzing representative cases in the study area.Reactivation of ancient landslides is sometimes the result of the cumulative effects of multiple predisposing factors.Furthermore,our investigations revealed that the reactivation of these ancient landslides primarily led to local failures.However,over extended periods of dynamic action,the entire zone may experience gradual creep.We categorized the reactivation modes of ancient landslides into three distinct types based on the reactivation sequences:progressive retreat,backward thrusting,and forward pulling–backward thrusting.This study is of great significance for us to identify ancient landslides,deepen our understanding of the failure modes and risks of reactivated ancient landslides on the eastern margin of the Tibetan Plateau,and formulate effective disaster prevention and mitigation measures.展开更多
Pregnancy, which is responsible for the decline in immunity, and the immediate postpartum period can lead to reactivation or worsening of tuberculosis. We report a case of a patient who consulted for neurological diso...Pregnancy, which is responsible for the decline in immunity, and the immediate postpartum period can lead to reactivation or worsening of tuberculosis. We report a case of a patient who consulted for neurological disorders in the context of a deterioration in general condition. The CT scan revealed a brainstem lesion which was successfully treated like a tuberculosis. However, reactivation has been observed in the postpartum period of a pregnancy contracted during anti-tuberculosis treatment. Further clinical improvement has been achieved with anti-tuberculosis treatment. Pregnancy and the immediate postpartum had led to a transient decline in immunity in part by decreasing in the inflammatory activity of type 1 helper T cells so that the fetus, which is a foreign body, was accepted by the maternal body. This decline in immunity during pregnancy and the immediate postpartum period due to immune reconstitution had been responsible for a high degree of vulnerability, usually characterized by a significant exacerbation of tuberculosis symptoms and an unfavorable course of disease.展开更多
Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remai...Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.展开更多
Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidat...Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidative stress,and mitochondrial dysfunction.Regrettably,there is a paucity of clinically available therapeutics to address these issues.Emerging evidence underscores the pivotal roles of astrocytes,the most abundant glial cells in the brain,throughout the various stages of ischemic stroke.In this comprehensive review,we initially provide an overview of the fundamental physiological functions of astrocytes in the brain,emphasizing their critical role in modulating neuronal homeostasis,synaptic activity,and blood-brain barrier integrity.We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke.Their well-established contributions to energy provision,metabolic regulation,and neurotransmitter homeostasis,as well as their emerging roles in mitochondrial recovery,neuroinflammation regulation,and oxidative stress modulation following ischemic injury,are discussed in detail.We also explore the cellular and molecular mechanisms underpinning these functions,with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention.In the final section of this review,we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke.These astrocyte-targeting strategies are categorized into traditional small-molecule drugs,microRNAs(miRNAs),stem cell-based therapies,cellular reprogramming,hydrogels,and extracellular vesicles.By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches,we aim to highlight the critical roles of astrocytes during and after stroke,particularly in the pathophysiological development in ischemic stroke.We also emphasize promising avenues for novel,astrocyte-targeted therapeutics that could become clinically available options,ultimately improving outcomes for patients with stroke.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
The reactive materials filled structure(RMFS)is a structural penetrator that replaces high explosive(HE)with reactive materials,presenting a novel self-distributed initiation,multiple deflagrations behavior during pen...The reactive materials filled structure(RMFS)is a structural penetrator that replaces high explosive(HE)with reactive materials,presenting a novel self-distributed initiation,multiple deflagrations behavior during penetrating multi-layered plates,and generating a multipeak overpressure behind the plates.Here analytical models of RMFS self-distributed energy release and equivalent deflagration are developed.The multipeak overpressure formation model based on the single deflagration overpressure expression was promoted.The impact tests of RMFS on multi-layered plates at 584 m/s,616 m/s,and819 m/s were performed to validate the analytical model.Further,the influence of a single overpressure peak and time intervals versus impact velocity is discussed.The analysis results indicate that the deflagration happened within 20.68 mm behind the plate,the initial impact velocity and plate thickness are the crucial factors that dominate the self-distributed multipeak overpressure effect.Three formation patterns of multipeak overpressure are proposed.展开更多
Molten salt reactors,being the only reactor type among Generation Ⅳ advanced nuclear reactors that utilize liquid fuels,offer inherent safety,high-temperature,and low-pressure operation,as well as the capability for ...Molten salt reactors,being the only reactor type among Generation Ⅳ advanced nuclear reactors that utilize liquid fuels,offer inherent safety,high-temperature,and low-pressure operation,as well as the capability for online fuel reprocessing.However,the fuel-salt flow results in the decay of delayed neutron precursors(DNPs)outside the core,causing fluctuations in the effective delayed neutron fraction and consequently impacting the reactor reactivity.Particularly in accident scenarios—such as a combined pump shutdown and the inability to rapidly scram the reactor—the sole reliance on negative temperature feedback may cause a significant increase in core temperature,posing a threat to reactor safety.To address these problems,this paper introduces an innovative design for a passive fluid-driven suspended control rod(SCR)to dynamically compensate for reactivity fluctuations caused by DNPs flowing with the fuel.The control rod operates passively by leveraging the combined effects of gravity,buoyancy,and fluid dynamic forces,thereby eliminating the need for an external drive mechanism and enabling direct integration within the active region of the core.Using a 150 MWt thorium-based molten salt reactor as the reference design,we develop a mathematical model to systematically analyze the effects of key parameters—including the geometric dimensions and density of the SCR—on its performance.We examine its motion characteristics under different core flow conditions and assess its feasibility for the dynamic compensation of reactivity changes caused by fuel flow.The results of this study demonstrate that the SCR can effectively counteract reactivity fluctuations induced by fuel flow within molten salt reactors.A sensitivity analysis reveals that the SCR’s average density exerts a profound impact on its start-up flow threshold,channel flow rate,resistance to fuel density fluctuations,and response characteristics.This underscores the critical need to optimize this parameter.Moreover,by judiciously selecting the SCR’s length,number of deployed units,and the placement we can achieve the necessary reactivity control while maintaining a favorable balance between neutron economy and heat transfer performance.Ultimately,this paper provides an innovative solution for the passive reactivity control in molten salt reactors,offering significant potential for practical engineering applications.展开更多
Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and g...Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithel...BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithelial cells has a causal role leading to infiltration of neutrophils into the colonic mucosa and subsequent development of UC.This evidence-based mechanism identifies hydrogen peroxide as a therapeutic target for reducing agents in the treatment of UC.CASE SUMMARY Presented is a 41-year-old female with a 26-year history of refractory UC.Having developed steroid dependence and never achieving complete remission on treatment by conventional and advanced therapies,she began treatment with oral R-dihydrolipoic acid(RDLA),a lipid-soluble reducing agent with intracellular site of action.Within a week,rectal bleeding ceased.She was asymptomatic for three years until a highly stressful experience,when she noticed blood in her stool.RDLA was discontinued,and she began treatment with oral sodium thiosulfate pentahydrate(STS),a reducing agent with extracellular site of action.After a week,rectal bleeding ceased,and she resumed oral RDLA and discontinued STS.To date,she remains asymptomatic with normal stool calprotectin while on RDLA.CONCLUSION STS and RDLA are reducing agents that serve as highly effective and safe therapy for the induction and maintenance of remission in UC,even in patients refractory or poorly controlled by conventional and advanced therapies.Should preliminary findings be validated by subsequent clinical trials,the use of reducing agents could potentially prevent thousands of colectomies and represent a paradigm shift in the treatment of UC.展开更多
Modern power systems increasingly depend on interconnected microgrids to enhance reliability and renewable energy utilization.However,the high penetration of intermittent renewable sources often causes frequency devia...Modern power systems increasingly depend on interconnected microgrids to enhance reliability and renewable energy utilization.However,the high penetration of intermittent renewable sources often causes frequency deviations,voltage fluctuations,and poor reactive power coordination,posing serious challenges to grid stability.Conventional Interconnection FlowControllers(IFCs)primarily regulate active power flowand fail to effectively handle dynamic frequency variations or reactive power sharing in multi-microgrid networks.To overcome these limitations,this study proposes an enhanced Interconnection Flow Controller(e-IFC)that integrates frequency response balancing and an Interconnection Reactive Power Flow Controller(IRFC)within a unified adaptive control structure.The proposed e-IFC is implemented and analyzed in DIgSILENT PowerFactory to evaluate its performance under various grid disturbances,including frequency drops,load changes,and reactive power fluctuations.Simulation results reveal that the e-IFC achieves 27.4% higher active power sharing accuracy,19.6% lower reactive power deviation,and 18.2% improved frequency stability compared to the conventional IFC.The adaptive controller ensures seamless transitions between grid-connected and islanded modes and maintains stable operation even under communication delays and data noise.Overall,the proposed e-IFCsignificantly enhances active-reactive power coordination and dynamic stability in renewable-integrated multi-microgrid systems.Future research will focus on coupling the e-IFC with tertiary-level optimization frameworks and conducting hardware-in-the-loop validation to enable its application in large-scale smart microgrid environments.展开更多
Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,wi...Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.展开更多
Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-D-aspartate receptor(NMDAR). Age-related cognitive disorders includ...Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-D-aspartate receptor(NMDAR). Age-related cognitive disorders includes Alzheimer’s disease(AD), vascular dementia(VD), and age-associated memory impairment(AAMI). Based on the critical role of NMDAR-dependent long-term potentiation(LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is Hydrogen sulfidemore similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.展开更多
Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species （ROS） in infected cell...Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species （ROS） in infected cells, which may be closely related with their pathogenicity. In this report, chaetocin, a fimgal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus （EBV） in B95-8 cells. We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration （50 nmol L-l）. The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine （NAC）, an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.展开更多
Memory is a cognitive process through which past experiences are encoded,stored,and retrieved,playing a crucial role in intelligent behavior.It is well established that the hippocampus continues to reactivate memories...Memory is a cognitive process through which past experiences are encoded,stored,and retrieved,playing a crucial role in intelligent behavior.It is well established that the hippocampus continues to reactivate memories for several days after learning,and this process primarily occurs during sleep[1,2].The prevailing view suggests that sharp-wave ripples(SWRs)during non-rapid eye movement(NREM)sleep serve as key electrophysiological signatures of memory replay[3,4].However,only a small portion of SWRs contain memory replay[5].The direct relationship among SWRs,memory replay,and memory consolidation remains an open question.Another unresolved issue is how the hippocampus simultaneously reactivates both new and old memories while preventing interference.展开更多
The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystallin...The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystalline mineralogy,geochemistry,and Re-Os and U-Pb geochronology in the Dahu,Qinnan,and Yangzhaiyu deposits.The Xiaoqinling Orogen comprises an E-W-trending fold and thrust system with repeated structural reactivation and the Mo or Au orebodies in these deposits are dominantly controlled by E-W-trending and NW-SE-trending shear zones.Molybdenum mineralization related to K-feldspar alteration comprises early molybdenite,pyrite,rutile,and monazite within gray quartz veins plus late molybdenite and pyrite within white quartz veins in the Dahu and Qinnan Au-Mo deposits.Early and late Au mineralization events have similar mineral assemblages of pyrite,native gold±Au-Ag-Te minerals,rutile,and monazite associated with quartz-sericite alteration at Yangzhaiyu.The early dissem-inated molybdenite is characterized by rhombohedral polytype and oscillatory Re zoning,in contrast to the late molybdenite with a coexistence of rhombohedral and hexagonal polytypes and irregularly distributed Re.The early molybdenite has a Re-Os isochron age of 222.5±1.3 Ma,compatible with a monazite U-Pb age of 224±6.1 Ma,whereas late molybdenite provides a Re-Os isochron age of 185.0±12 Ma,with the implication that the 3R-polytype molybdenite with oscillatory Re zoning is more suitable for high-precision dating.The early and late Au mineralization have a pyrite Re-Os age of 202.0±5.9 Ma and U-Pb age of 124.0±1.3 Ma,respectively.In accordance with its complex geodynamic setting,geological and geochronological studies record a complicated 100-million-year mineralization history with multiple magmatic-hydrothermal Mo and orogenic Au mineralization events that formed within a structural framework of multiply reactivated shear zones.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
基金the National Natural Science Foundation of China(NSFC)(41941018 and 52304111)the Program of China Scholarship Council(202206430007)。
文摘In a large ancient landslide,approximately 240,000 m3 of sediments were reactivated,posing a grave threat to the safety of iron ore stopes.To trace the deformation and evolution history of reactivated Landslide,we conducted geological surveys and combined real-time monitoring equipment to analyze the landslide data since 1986 and the deformation status of the reactivated Landslide.A multi-factor comprehensive landslide monitoring method and an Newton force early warning system(NFEWS)were established,focusing on underground stress,surface deformation information and landslide stability.Furthermore,we developed a four-level early warning grading standard,employing surface cracks and changes in underground stress thresholds as early warning indicators.This standard adds expert assessment to avoid false alarms and realize real-time dynamics of mining landslides during excavation and transportation.Through the case study and analysis of Nanfen open-pit mine,the NFEWS system offers valuable insights and solution for early warning of landslides in analogous open-pit mines.Finally,the evaluation index system of landslide hazard susceptibility was established by selecting the Newton force influence factor.A landslide susceptibility zoning map is constructed using the information value model.The rationality and accuracy are assessed from three perspectives:frequency ratio,landslide hazard point density,and receiver operating characteristic(ROC)curve.The improved Newton force landslide early warning system provides a good reference for the analysis and monitoring of the creep landslide evolution process.
文摘In southwest of China, landslide reactivation caused by excavation has caused huge property and human losses, and posed severely threaten to the construction and operation of the man-made linear structures. A reactivated landslide is a complex process. The engineering practices have shown that a correct understanding of the reactivated mechanism of an ancient giant landslide is significant for the landslide mitigation. In this paper, a case study of the ancient Badu landslide that underwent multiple reactivations during the construction of Nanning-Kunming railway was discussed. The landslide characteristics are described and the reactivated features and progressive failure of the landslide are revealed. The reactivated mechanism of the landslide is analyzed by use of geological process analysis method and is simulated using the 3D FEM （finite element method）. At last, the reactivated mechanism mode of Badu giant landslide is put forward, namely ＂creeping-tensile cracking-shear breaking with zoning and grading features＂. The understanding of this kind of reactivated mechanism had helped engineers to take efficient and economic mitigation measures to stabilize the landslide.
基金the National Natural Science Foundation of China(No.41807292)the Opening Fund of the State Key Laboratory of Geohazard Prevention and Geoenvironment Protection(Chengdu University of Technology)(Nos.SKLGP2017K001,SKLGP2018K003)。
文摘Due to the complex geological processes of Qinghai-Tibet Plateau,numerous deposits,especially the large-scale ancient landslide deposits,are characteristic features of the valleys incised in southwestern China.Intense water level fluctuations since 2011 in Maoergai Reservoir,China,registered the reactivation of Xierguazi ancient landslide,and presented a significant risk to neighboring facilities.Based on detailed field survey and drilling exploration,the landslide was divided into Zone A and Zone B,and other characterizations of landslide were studied as well.To precisely measure the extent of landslide displacement during filling and drawdown stage,surface displacement monitoring system was deployed on the landslide.The monitoring analyses data reveal that reservoir fluctuation is the dominant factor influencing landslide displacement,especially during drawdown stage.Moreover,a future sliding is anticipated in Zone A,while a creep had already existed in Zone B.A reservoir regulation was then established using the lead-lag correlation between reservoir fluctuation and landslide displacement and landslide stability analysis.In the end,the follow-up deformation monitoring demonstrates that the reservoir regulation controlled the landslide effectively.Landslide control by reservoir regulation in Maoergai can serve as a case study for other settlements involved in similar construction activities.
基金supported by the National Natural Science Foundation of China(No.42207233,41731287)the National Key Research and Development Program of China(No.2021YFC3000505)the China Geological Survey projects(No.DD20221816)。
文摘The risk of reactivated ancient landslides in the Sichuan–Xizang transportation corridor in China is significantly increasing,primarily driven by the intensification of engineering activities and the increased frequency of extreme weather events.This escalation has resulted in a considerable number of fatalities and extensive damage to critical engineering infrastructure.However,the factors contributing to the reactivation and modes of destruction of ancient landslides remain unknown.Therefore,it is imperative to systematically analyze the developmental characteristics and failure modes of reactivated ancient landslides to effectively mitigate disaster risks.Based on a combination of data collection,remote sensing interpretation,and field investigations,we delineated the developmental attributes of typical ancient landslides within the study area.These attributes encompass morphological and topographic aspects,material composition,and spatial structure of ancient landslides.Subsequently,we identified the key triggers for the reactivation of ancient landslides,including water infiltration,reservoir hydrodynamics,slope erosion,and excavation,by analyzing representative cases in the study area.Reactivation of ancient landslides is sometimes the result of the cumulative effects of multiple predisposing factors.Furthermore,our investigations revealed that the reactivation of these ancient landslides primarily led to local failures.However,over extended periods of dynamic action,the entire zone may experience gradual creep.We categorized the reactivation modes of ancient landslides into three distinct types based on the reactivation sequences:progressive retreat,backward thrusting,and forward pulling–backward thrusting.This study is of great significance for us to identify ancient landslides,deepen our understanding of the failure modes and risks of reactivated ancient landslides on the eastern margin of the Tibetan Plateau,and formulate effective disaster prevention and mitigation measures.
文摘Pregnancy, which is responsible for the decline in immunity, and the immediate postpartum period can lead to reactivation or worsening of tuberculosis. We report a case of a patient who consulted for neurological disorders in the context of a deterioration in general condition. The CT scan revealed a brainstem lesion which was successfully treated like a tuberculosis. However, reactivation has been observed in the postpartum period of a pregnancy contracted during anti-tuberculosis treatment. Further clinical improvement has been achieved with anti-tuberculosis treatment. Pregnancy and the immediate postpartum had led to a transient decline in immunity in part by decreasing in the inflammatory activity of type 1 helper T cells so that the fetus, which is a foreign body, was accepted by the maternal body. This decline in immunity during pregnancy and the immediate postpartum period due to immune reconstitution had been responsible for a high degree of vulnerability, usually characterized by a significant exacerbation of tuberculosis symptoms and an unfavorable course of disease.
基金supported by the DFG(CRC 1279)the NIH(AI164570,P30 AI045008)+2 种基金the Robert I.Jacobs Fund of the Philadelphia Foundation(LM),and a Herbert Kean,M.D.,Family Professorship(LM)Additionally,we thank the Human Immunology Core(HIC)at the Perelman School of Medicine at the University of Pennsylvania for their support with the Simoa assay,with partial funding from NIH P30 AI045008 and P30 CA016520The HIC is also supported by NIH grants and is identified by RRID:SCR_022380.G.M.L.was supported by NIH U24AI143502.
文摘Reactivation of the latent viral reservoirs is crucial for a cure of HIV/AIDS.However,current latency reversing agents are inefficient,and the endogenous factors that have the potential to reactivate HIV in vivo remain poorly understood.To identify natural activators of latent HIV-1,we screened a comprehensive peptide/protein library derived from human hemofiltrate,representing the entire blood peptidome,using J-Lat cell lines harboring transcriptionally silent HIV-1 GFP reporter viruses.Fractions potently reactivating HIV-1 from latency contained human Retinol Binding Protein 4(RBP4),the carrier of retinol(Vitamin A).We found that retinol-bound holo-RBP4 but not retinol-free apo-RBP4 strongly reactivates HIV-1 in a variety of latently infected T cell lines.Functional analyses indicate that this reactivation involves activation of the canonical NF-κB pathway and is strengthened by JAK/STAT5 and JNK signalling but does not require retinoic acid production.High levels of RBP4 were detected in plasma from both healthy individuals and people living with HIV-1.Physiological concentrations of RBP4 induced significant viral reactivation in latently infected cells from individuals on long-term antiretroviral therapy with undetectable viral loads.As a potent natural HIV-1 latency-reversing agent,RBP4 offers a novel approach to activating the latent reservoirs and bringing us closer to a cure.
基金supported by the National Natural Science Foundation of China,No.82001325Visiting Scholar Foundation of Shandong Province,No.20236-01(both to CS).
文摘Stroke is the leading cause of mortality globally,ultimately leading to severe,lifelong neurological impairments.Patients often suffer from a secondary cascade of damage,including neuroinflammation,cytotoxicity,oxidative stress,and mitochondrial dysfunction.Regrettably,there is a paucity of clinically available therapeutics to address these issues.Emerging evidence underscores the pivotal roles of astrocytes,the most abundant glial cells in the brain,throughout the various stages of ischemic stroke.In this comprehensive review,we initially provide an overview of the fundamental physiological functions of astrocytes in the brain,emphasizing their critical role in modulating neuronal homeostasis,synaptic activity,and blood-brain barrier integrity.We then delve into the growing body of evidence that highlights the functional diversity and heterogeneity of astrocytes in the context of ischemic stroke.Their well-established contributions to energy provision,metabolic regulation,and neurotransmitter homeostasis,as well as their emerging roles in mitochondrial recovery,neuroinflammation regulation,and oxidative stress modulation following ischemic injury,are discussed in detail.We also explore the cellular and molecular mechanisms underpinning these functions,with particular emphasis on recently identified targets within astrocytes that offer promising prospects for therapeutic intervention.In the final section of this review,we offer a detailed overview of the current therapeutic strategies targeting astrocytes in the treatment of ischemic stroke.These astrocyte-targeting strategies are categorized into traditional small-molecule drugs,microRNAs(miRNAs),stem cell-based therapies,cellular reprogramming,hydrogels,and extracellular vesicles.By summarizing the current understanding of astrocyte functions and therapeutic targeting approaches,we aim to highlight the critical roles of astrocytes during and after stroke,particularly in the pathophysiological development in ischemic stroke.We also emphasize promising avenues for novel,astrocyte-targeted therapeutics that could become clinically available options,ultimately improving outcomes for patients with stroke.
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the support received from the National Natural Science Foundation of China(Grant No.12302460)the State Key Laboratory of Explosion Science and Safety Protection(Grant No.YBKT24-02)。
文摘The reactive materials filled structure(RMFS)is a structural penetrator that replaces high explosive(HE)with reactive materials,presenting a novel self-distributed initiation,multiple deflagrations behavior during penetrating multi-layered plates,and generating a multipeak overpressure behind the plates.Here analytical models of RMFS self-distributed energy release and equivalent deflagration are developed.The multipeak overpressure formation model based on the single deflagration overpressure expression was promoted.The impact tests of RMFS on multi-layered plates at 584 m/s,616 m/s,and819 m/s were performed to validate the analytical model.Further,the influence of a single overpressure peak and time intervals versus impact velocity is discussed.The analysis results indicate that the deflagration happened within 20.68 mm behind the plate,the initial impact velocity and plate thickness are the crucial factors that dominate the self-distributed multipeak overpressure effect.Three formation patterns of multipeak overpressure are proposed.
基金supported by Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2020261)Strategic Priority Research Program of Chinese Academy of Sciences(No.XDA02010000)the Young Potential Program of Shanghai Institute of Applied Physics,Chinese Academy of Sciences(No.SINAP-YXJH-202412).
文摘Molten salt reactors,being the only reactor type among Generation Ⅳ advanced nuclear reactors that utilize liquid fuels,offer inherent safety,high-temperature,and low-pressure operation,as well as the capability for online fuel reprocessing.However,the fuel-salt flow results in the decay of delayed neutron precursors(DNPs)outside the core,causing fluctuations in the effective delayed neutron fraction and consequently impacting the reactor reactivity.Particularly in accident scenarios—such as a combined pump shutdown and the inability to rapidly scram the reactor—the sole reliance on negative temperature feedback may cause a significant increase in core temperature,posing a threat to reactor safety.To address these problems,this paper introduces an innovative design for a passive fluid-driven suspended control rod(SCR)to dynamically compensate for reactivity fluctuations caused by DNPs flowing with the fuel.The control rod operates passively by leveraging the combined effects of gravity,buoyancy,and fluid dynamic forces,thereby eliminating the need for an external drive mechanism and enabling direct integration within the active region of the core.Using a 150 MWt thorium-based molten salt reactor as the reference design,we develop a mathematical model to systematically analyze the effects of key parameters—including the geometric dimensions and density of the SCR—on its performance.We examine its motion characteristics under different core flow conditions and assess its feasibility for the dynamic compensation of reactivity changes caused by fuel flow.The results of this study demonstrate that the SCR can effectively counteract reactivity fluctuations induced by fuel flow within molten salt reactors.A sensitivity analysis reveals that the SCR’s average density exerts a profound impact on its start-up flow threshold,channel flow rate,resistance to fuel density fluctuations,and response characteristics.This underscores the critical need to optimize this parameter.Moreover,by judiciously selecting the SCR’s length,number of deployed units,and the placement we can achieve the necessary reactivity control while maintaining a favorable balance between neutron economy and heat transfer performance.Ultimately,this paper provides an innovative solution for the passive reactivity control in molten salt reactors,offering significant potential for practical engineering applications.
文摘Spared regions of the damaged central nervous system undergo dynamic remodelling and exhibit a remarkable potential for therapeutic exploitation1.Lesion-remote astrocytes(LRAs),which interact with viable neurons and glia,undergo reactive transformations whose molecular and functional properties are poorly understood2.Here,using multiple transcriptional profiling methods,we investigated LRAs from spared regions of mouse spinal cord following traumatic spinal cord injury.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic and debilitating inflammatory bowel disease.Cumulative evidence indicates that excess hydrogen peroxide,a potent neutrophilic chemotactic agent,produced by colonic epithelial cells has a causal role leading to infiltration of neutrophils into the colonic mucosa and subsequent development of UC.This evidence-based mechanism identifies hydrogen peroxide as a therapeutic target for reducing agents in the treatment of UC.CASE SUMMARY Presented is a 41-year-old female with a 26-year history of refractory UC.Having developed steroid dependence and never achieving complete remission on treatment by conventional and advanced therapies,she began treatment with oral R-dihydrolipoic acid(RDLA),a lipid-soluble reducing agent with intracellular site of action.Within a week,rectal bleeding ceased.She was asymptomatic for three years until a highly stressful experience,when she noticed blood in her stool.RDLA was discontinued,and she began treatment with oral sodium thiosulfate pentahydrate(STS),a reducing agent with extracellular site of action.After a week,rectal bleeding ceased,and she resumed oral RDLA and discontinued STS.To date,she remains asymptomatic with normal stool calprotectin while on RDLA.CONCLUSION STS and RDLA are reducing agents that serve as highly effective and safe therapy for the induction and maintenance of remission in UC,even in patients refractory or poorly controlled by conventional and advanced therapies.Should preliminary findings be validated by subsequent clinical trials,the use of reducing agents could potentially prevent thousands of colectomies and represent a paradigm shift in the treatment of UC.
基金the Deanship of Scientific Research at Northern Border University,Arar,Saudi Arabia,for funding this research work through the project number“NBU-FFR-2025-3623-11”.
文摘Modern power systems increasingly depend on interconnected microgrids to enhance reliability and renewable energy utilization.However,the high penetration of intermittent renewable sources often causes frequency deviations,voltage fluctuations,and poor reactive power coordination,posing serious challenges to grid stability.Conventional Interconnection FlowControllers(IFCs)primarily regulate active power flowand fail to effectively handle dynamic frequency variations or reactive power sharing in multi-microgrid networks.To overcome these limitations,this study proposes an enhanced Interconnection Flow Controller(e-IFC)that integrates frequency response balancing and an Interconnection Reactive Power Flow Controller(IRFC)within a unified adaptive control structure.The proposed e-IFC is implemented and analyzed in DIgSILENT PowerFactory to evaluate its performance under various grid disturbances,including frequency drops,load changes,and reactive power fluctuations.Simulation results reveal that the e-IFC achieves 27.4% higher active power sharing accuracy,19.6% lower reactive power deviation,and 18.2% improved frequency stability compared to the conventional IFC.The adaptive controller ensures seamless transitions between grid-connected and islanded modes and maintains stable operation even under communication delays and data noise.Overall,the proposed e-IFCsignificantly enhances active-reactive power coordination and dynamic stability in renewable-integrated multi-microgrid systems.Future research will focus on coupling the e-IFC with tertiary-level optimization frameworks and conducting hardware-in-the-loop validation to enable its application in large-scale smart microgrid environments.
基金funded by Shanghai Yangpu District Science and Technology Commission(Grant No.YPQ202303(Xuejing Lin))Shanghai Yangpu Hospital Foundation(Grant No.Se1202420(Wenchao Wang)and Ye1202423(Juan Huang)).
文摘Background:Hepatocellular carcinoma(HCC)is one of the leading causes of cancer-related mortality worldwide.This study aimed to identify key genes involved in HCC development and elucidate their molecular mechanisms,with a particular focus on mitochondrial function and apoptosis.Methods:Differential expression analyses were performed across three datasets—The Cancer Genome Atlas(TCGA)-Liver Hepatocellular Carcinoma(LIHC),GSE36076,and GSE95698—to identify overlapping differentially expressed genes(DEGs).A prognostic risk model was then constructed.Cysteine/serine-rich nuclear protein 1(CSRNP1)expression levels in HCC cell lines were assessed via western blot(WB)and quantitative reverse transcription polymerase chain reaction(qRT-PCR).The effects of CSRNP1 knockdown or overexpression on cell proliferation,migration,and apoptosis were evaluated using cell counting-8(CCK-8)assays,Transwell assays,and flow cytometry.Mitochondrial ultrastructure was examined by transmission electron microscopy,and intracellular and mitochondrial reactive oxygen species(mROS)levels were measured using specific fluorescent probes.WB was used to assess activation of the c-Jun N-terminal kinase(JNK)/p38 mitogen-activated protein kinase(MAPK)pathway,and pathway dependence was examined using the ROS scavenger N-Acetylcysteine(NAC)and the JNK inhibitor SP600125.Results:A six-gene prognostic model was established,comprising downregulated genes(NR4A1 and CSRNP1)and upregulated genes(CENPQ,YAE1,FANCF,and POC5)in HCC.Functional experiments revealed that CSRNP1 knockdown promoted the proliferation of HCC cells and suppressed their apoptosis.Conversely,CSRNP1 overexpression impaired mitochondrial integrity,increased both mitochondrial and cytoplasmic ROS levels,and activated the JNK/p38 MAPK pathway.Notably,treatment with NAC or SP600125 attenuated CSRNP1-induced MAPK activation and apoptosis.Conclusion:CSRNP1 is a novel prognostic biomarker and tumor suppressor in HCC.It exerts anti-tumor effects by inducing oxidative stress and activating the JNK/p38 MAPK pathway in a ROS-dependent manner.These findings suggest that CSRNP1 may serve as a potential therapeutic target in the management of HCC.
基金supported by grants from the National Natural Science Foundation of China (No. 81773712 to Pengfei WuNos.81471377 and 81671438 to Fang Wang+1 种基金Nos. 81473198 and81673414 to Jianguo Chen)Foundation for Innovative Research Groups of NSFC (No. 81721005 to Jianguo Chen and Fang Wang, China)。
文摘Redox-altered plasticity refers to redox-dependent reversible changes in synaptic plasticity via altering functions of key proteins, such as N-methyl-D-aspartate receptor(NMDAR). Age-related cognitive disorders includes Alzheimer’s disease(AD), vascular dementia(VD), and age-associated memory impairment(AAMI). Based on the critical role of NMDAR-dependent long-term potentiation(LTP) in memory, the increase of reactive oxygen species in cognitive disorders, and the sensitivity of NMDAR to the redox status, converging lines have suggested the redox-altered NMDAR-dependent plasticity might underlie the synaptic dysfunctions associated with cognitive disorders. In this review, we summarize the involvement of redox-altered plasticity in cognitive disorders by presenting the available evidence. According to reports from our laboratory and other groups, this "redox-altered plasticity" is Hydrogen sulfidemore similar to functional changes rather than organic injuries, and strategies targeting redox-altered plasticity using pharmacological agents might reverse synaptic dysfunctions and memory abnormalities in the early stage of cognitive disorders. Targeting redox modifications for NMDARs may serve as a novel therapeutic strategy for memory deficits.
文摘Oxidative stress, regarded as a negative effect of free radicals in vivo, takes place when organisms suffer from harmful stimuli. Some viruses can induce the release of reactive oxygen species （ROS） in infected cells, which may be closely related with their pathogenicity. In this report, chaetocin, a fimgal metabolite reported to have antimicrobial and cytostatic activity, was studied for its effect on the activation of latent Epstein-Barr virus （EBV） in B95-8 cells. We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration （50 nmol L-l）. The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine （NAC）, an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.
基金supported by the National Natural Science Foundation of China(32371028,32300822,U24A20373,and 82071177)the Shanghai Rising-Star Program(24QA2704800)+2 种基金the Shanghai Jiao Tong University 2030 InitiativeShanghai Municipal Health Commission(202340046)the Fund for Excellent Young Scholars of Shanghai Ninth People's Hospital,Shanghai Jiao Tong University School of Medicine.
文摘Memory is a cognitive process through which past experiences are encoded,stored,and retrieved,playing a crucial role in intelligent behavior.It is well established that the hippocampus continues to reactivate memories for several days after learning,and this process primarily occurs during sleep[1,2].The prevailing view suggests that sharp-wave ripples(SWRs)during non-rapid eye movement(NREM)sleep serve as key electrophysiological signatures of memory replay[3,4].However,only a small portion of SWRs contain memory replay[5].The direct relationship among SWRs,memory replay,and memory consolidation remains an open question.Another unresolved issue is how the hippocampus simultaneously reactivates both new and old memories while preventing interference.
基金supported by the National Key Research and Development Project of China(2020YFA0714802)the National Natural Science Foundation of China(42330809)the 111 Project of the Ministry of Science and Technology(BP0719021).
文摘The timings and geodynamic controls of Mo,Au,and Au-Mo deposits in the Xiaoqinling Orogen(>630 t Au and 115,000 t Mo),a rare Au-Mo province globally,are addressed by a combination of mineral par-ageneses,crystalline mineralogy,geochemistry,and Re-Os and U-Pb geochronology in the Dahu,Qinnan,and Yangzhaiyu deposits.The Xiaoqinling Orogen comprises an E-W-trending fold and thrust system with repeated structural reactivation and the Mo or Au orebodies in these deposits are dominantly controlled by E-W-trending and NW-SE-trending shear zones.Molybdenum mineralization related to K-feldspar alteration comprises early molybdenite,pyrite,rutile,and monazite within gray quartz veins plus late molybdenite and pyrite within white quartz veins in the Dahu and Qinnan Au-Mo deposits.Early and late Au mineralization events have similar mineral assemblages of pyrite,native gold±Au-Ag-Te minerals,rutile,and monazite associated with quartz-sericite alteration at Yangzhaiyu.The early dissem-inated molybdenite is characterized by rhombohedral polytype and oscillatory Re zoning,in contrast to the late molybdenite with a coexistence of rhombohedral and hexagonal polytypes and irregularly distributed Re.The early molybdenite has a Re-Os isochron age of 222.5±1.3 Ma,compatible with a monazite U-Pb age of 224±6.1 Ma,whereas late molybdenite provides a Re-Os isochron age of 185.0±12 Ma,with the implication that the 3R-polytype molybdenite with oscillatory Re zoning is more suitable for high-precision dating.The early and late Au mineralization have a pyrite Re-Os age of 202.0±5.9 Ma and U-Pb age of 124.0±1.3 Ma,respectively.In accordance with its complex geodynamic setting,geological and geochronological studies record a complicated 100-million-year mineralization history with multiple magmatic-hydrothermal Mo and orogenic Au mineralization events that formed within a structural framework of multiply reactivated shear zones.
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.
