Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha...Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.展开更多
EHL-2 is a compact,high-field spherical tokamak designed to explore the potential of an advanced p-11B nuclear fusion reactor.Due to its high plasma current and thermal energy,it is crucial to mitigate the impact asso...EHL-2 is a compact,high-field spherical tokamak designed to explore the potential of an advanced p-11B nuclear fusion reactor.Due to its high plasma current and thermal energy,it is crucial to mitigate the impact associated with disruptions to ensure the safe operation of EHL-2.This paper evaluates the performance requirements of the disruption prediction system on EHL-2,with a particular focus on applying generalizable knowledge transfer from existing devices to future ones.Furthermore,the key characteristics of disruption mitigation strategies are analyzed,and their overall mitigation performance on EHL-2 is assessed.This insight provides valuable guidance for optimizing the engineering design of EHL-2 and identifying its optimal operational regime.展开更多
A two-level supply chain model involving one supplier and one retailer with linear demand is developed, and supply chain coordination mechanisms under asymmetric information （the retailer＇ s cost structure is asymme...A two-level supply chain model involving one supplier and one retailer with linear demand is developed, and supply chain coordination mechanisms under asymmetric information （the retailer＇ s cost structure is asymmetric information） are proposed by employing game theory in two scenarios： coordination mechanisms under asymmetric information in a regular scenario （without disruption）; and coordination mechanisms under asymmetric information in an irregular scenario （ with retailer cost disruptions）. It is optimal for the supply chain to maintain the original production plan and to guarantee a steadily running system if variations of retailer costs are sufficiently low and do not exceed an upper bound. This shows that the original production plan has certain robustness under disruptions. Decisions must be re-made if a retailer＇ s cost change is greater and exceeds an upper bound. Impacts of retailer cost disruptions on the order quantity, the retail price, the wholesale price and each party＇ s as well as the system＇ s expected profits are investigated through numerical analyses.展开更多
Background:Circadian disruption has emerged as a significant risk factor for cancer,driven by mechanisms such as hormonal imbalances,impaired DNA repair,immune suppression,and metabolic dysregulation.Modern societal p...Background:Circadian disruption has emerged as a significant risk factor for cancer,driven by mechanisms such as hormonal imbalances,impaired DNA repair,immune suppression,and metabolic dysregulation.Modern societal patterns-shift work,artificial light at night,and irregular sleep schedules-have exacerbated these risks.Methods:We conducted a systematic review following Preferred Reporting Items for Systematic reviews and Meta-Analyses(PRISMA)guidelines,screening over 500 studies published between 2003 and 2023 from PubMed,Scopus,Embase,ScienceDirect,and Web of Science.Inclusion criteria focused on peer-reviewed epidemiological and mechanistic studies linking circadian disruption with cancer risk.The Newcastle-Ottawa Scale was used for methodological quality assessment.Results:A total of 75 high-quality studies were included.Strong evidence supports associations between circadian disruption and breast,prostate,and colorectal cancers,with limited but emerging evidence for melanoma and bladder cancer.Mechanistic pathways involve melatonin suppression,dysregulation of CLOCK and BMAL1 genes,reduced natural killer cell activity,and chronic inflammation due to metabolic imbalance.Light-at-night(LAN)exposure and prolonged night shift work were consistently identified as major risk factors.Furthermore,economic analyses reveal a substantial burden due to increased healthcare costs and productivity losses,particularly in shift work-dominated sectors.Conclusions:Circadian misalignment is a critical,yet often overlooked,contributor to cancer incidence and associated economic burdens.Public health strategies-such as regulating shift schedules,reducing LAN exposure,and promoting chronotherapy-are essential to mitigate these risks.Further research should address sex-based differences,improve exposure measurement,and extend investigations to low-and middle-income countries.展开更多
BACKGROUND L-arginine(L-Arg)is one of the most widely used amino acids in dietary and pharmacological products.However,the evidence on its usefulness and dose limitations,especially in diabetics is still controversial...BACKGROUND L-arginine(L-Arg)is one of the most widely used amino acids in dietary and pharmacological products.However,the evidence on its usefulness and dose limitations,especially in diabetics is still controversial.AIM To investigate the effects of chronic administration of different doses of L-Arg on the cardiac muscle of type 2 diabetic rats.METHODS Of 96 male rats were divided into 8 groups as follows(n=12):Control,0.5 g/kg L-Arg,1 g/kg L-Arg,1.5 g/kg L-Arg,diabetic,diabetic+0.5 g/kg L-Arg,diabetic+1 g/kg L-Arg,and diabetic+1.5 g/kg L-Arg;whereas L-Arg was orally administered for 3 months to all treated groups.RESULTS L-Arg produced a moderate upregulation of blood glucose levels to normal rats,but when given to diabetics a significant upregulation was observed,associated with increased nitric oxide,inflammatory cytokines,and malonaldehyde levels in diabetic rats treated with 1 g/kg L-Arg and 1.5 g/kg L-Arg.A substantial decrease in the antioxidant capacity,superoxide dismutase,catalase,glutathione peroxidase,reduced glutathione concentrations,and Nrf-2 tissue depletion were observed at 1 g/kg and 1.5 g/kg L-Arg diabetic treated groups,associated with myocardial injury,fibrosis,α-smooth muscle actin upregulation,and disruption of desmin cardiac myofilaments,and these effects were not noticeable at normal treated groups.On the other hand,L-Arg could significantly improve the lipid profile of diabetic rats and decrease their body weights.CONCLUSION L-Arg dose of 1 g/kg or more can exacerbates the diabetes injurious effects on the myocardium,while 0.5 g/kg dose can improve the lipid profile and decrease the body weight.展开更多
Efficient siRNA delivery is highly desirable for disease treatment.However,the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes.Herein,we report a strategy using smal...Efficient siRNA delivery is highly desirable for disease treatment.However,the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes.Herein,we report a strategy using small-molecule drugs to enhance siRNA endo-lysosomal release,addressing this challenge.We encapsulated gentamicin(GM)into the marketed Onpattro■ formulation to establish LNP-siRNA/GM nanoparticles that promote siRNA endo-lysosomal escape through endosomal disruption,mechanistically exhibiting unique functionality and synergistic effects of LNP-siRNA/GM to improve cancer therapy.Besides,GM induced reactive oxygen species(ROS)and phospholipids accumulation in endolysosomes,as well as the physical characteristics of lipid nanoparticles(LNPs)were preserved.We also revealed that GM causes endo-lysosomal swelling and disrupts the endosomal membrane to enable siRNA release,as confirmed by Galectin 3 recruitment and acridine orange release.This approach achieved∼81%mRNA-EGFR silencing,which is more than LNP-siEGFR(∼56.23%)by enhancing siRNA endo-lysosomal escape efficiency.Meanwhile,LNP-siEGFR/GM exhibited significant biological activities in HepG2 cells,driven by the synergistic effects of siEGFR and GM with the VEGF and CXCL12 downregulation of,and ROS and phospholipids upregulation.Furthermore,tumor growth was notably suppressed after intravenous injection of LNP-siEGFR/GM in tumor-bearing nude mice.The combination of EGFR-siRNA and GM could also greatly inhibit angiogenesis,be antiproliferative,and induce tumor cells apoptosis.Therefore,this GM and siRNA co-delivery system would provide an efficient strategy for siRNA endosomal escape,significantly improving knockdown in various LNPs based siRNA delivery systems and efficiently enhancing cancer therapy.展开更多
Airport disruptions often pose challenges in assigning aircraft to gates,resulting in infeasible planned schedules.In particular,a large number of transfer passengers miss their connections in the context of disruptio...Airport disruptions often pose challenges in assigning aircraft to gates,resulting in infeasible planned schedules.In particular,a large number of transfer passengers miss their connections in the context of disruptions,which cause huge economic losses to airlines and serious passengers’dissatisfaction.This paper proposes a set-partitioning-based model to optimize Aircraft-Gate Reassignment with Transfer Passenger Connections(AGRP-TPC),which incorporates flexible gate-swap and aircraft-delay operations to mitigate the overall impact of disruptions.To efficiently solve the model,we introduce the concepts of additive-transfer and nonstop-transfer to handle passenger connections,and develop a Hierarchical Column-and-Row Generation(HCRG)approach guided by airport terminal space attribute.The column generation and row generation procedures solve iteratively until no new variables and constraints are generated.In addition,a follow-on strategy and a diving heuristic are designed to efficiently obtain high-quality solutions.We evaluate the proposed approach using various instances from a major Chinese international airport.Computational results demonstrate that our approach outperforms the comparison algorithms and produces good solutions within the time limit.Detailed results indicate that our approach effectively reduces overall losses in aircraft-gate reassignment following disruptions,and it can serve as an auxiliary decision-making tool for airport operators and airlines.展开更多
As a prominent mode of variability in the tropical stratosphere on the interannual timescale,the Quasi-Biennial Oscillation(QBO)can significantly influence global atmospheric circulation and weather patterns.This stud...As a prominent mode of variability in the tropical stratosphere on the interannual timescale,the Quasi-Biennial Oscillation(QBO)can significantly influence global atmospheric circulation and weather patterns.This study explores the dynamic processes of QBO disruptions using the integrated climate model of the China Meteorological Administration(CMA)by nudging the tropical zonal winds toward observations.A comparative analysis with ERA5 reanalysis data shows that the nudged runs accurately replicate the general characteristics of the QBO,including the alternating QBO wind regimes and QBO disruption events.The evolution of the QBO winds is diagnosed using empirical orthogonal function and root-mean-square difference analyses,and the rarity of the disruption events is confirmed in the CMA model.Different aspects of the QBO disruptions and the relevant dynamics are present in the model.Firstly,the momentum budget analysis highlights the crucial roles of extratropical Rossby waves and non-orographic gravity waves in the transition from westerly to easterly winds during a disruption.Secondly,Kelvin waves and non-orographic gravity waves explain much of the transition from easterly to westerly winds near 40 hPa.Thirdly,the positive tendency from enhanced vertical advection further accelerates westerly momentum development via secondary meridional circulation.These findings underscore the importance of nudging techniques in understanding QBO dynamics,which provides valuable insights for future climate model improvements toward better forecasting QBO-related climate variability.Notably,due to model limitations,no QBO disruptions were simulated in the free-run experiments.展开更多
[Objective] The aim was to improve the quality of the duck blood tofu by ultrasonic technology. [Method] Ultrasonic technology was used to break the blood cell membrane. The optimal ultrasonic condition was determined...[Objective] The aim was to improve the quality of the duck blood tofu by ultrasonic technology. [Method] Ultrasonic technology was used to break the blood cell membrane. The optimal ultrasonic condition was determined by single factor de- sign, and the differences in sensory quality and nutritional value between the duck blood tofu treated with and without ultrasonication were studied. [Result] The optimal ultrasonic power was 400 W and the optimal ultrasonic time was 6 min. Under these conditions, the content of duck blood haemoglobin increased by 43.46%, the content of iron increased by 10.85%, and the breakage rate was 100%. The a＊ value of the duck blood tofu increased significantly under ultrasonic treatment. Both internal micro-structure and texture parameters proved that the ultrasonic contributed to the formation of gel structure. After treatment by artificial gastric juice and artifi- cial intestinal juice, the total amino acids in the digestive juice were 9.25% higher than that of the duck blood tofu without ultrasonic treatment. [Conclusion] The duck blood tofu under ultrasonic treatment would be beneficial to human body absorption, and the nutrition value would be higher as well.展开更多
Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cance...Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells.Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome.Here,we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala(CREKA,which can specifically target tumor vessels and stroma)and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride(AQ4N)and a VDA combretastatin A4(CA4),respectively.CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels,which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region.As a consequence,AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment.The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro.In addition,in vivo experiments confirm the excellent tumortargeting/accumulation,tumor vasculature-damaging,and tumor inhibition effects of the liposome.This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection,and is expected to benefit the future development of effective antitumor liposomal drugs.展开更多
The coordinating pricing strategies with asymmetric cost information under disruptions are investigated in a one-supplier-one-retailer supply chain system.While the retailer's cost structure is asymmetric informat...The coordinating pricing strategies with asymmetric cost information under disruptions are investigated in a one-supplier-one-retailer supply chain system.While the retailer's cost structure is asymmetric information,supply chain pricing contract models(a wholesale price contract and an all-unit quantity discount contract)under asymmetric information are proposed by employing the principal-agent principle in a regular scenario.When the retailer's cost distribution is fluctuated by disruptions,we obtain the optimal emergency strategies of the supply chain under asymmetric information by considering deviation costs and show how to effectively handle the cost uncertainty.Using numerical methods,impacts of cost disruptions on the optimal wholesale price,the retailer price,the order quantity and the expected profits of the retailer,the supplier,as well as the total system are analyzed.It is found that the all-unit quantity discount policy can obtain better performance than the wholesale pricing policy.展开更多
As for the supply chain consisting of a manufacturer and multiple competing retailers, the disruption management decision is considered for the demand disruption that both the investment sensitivity coefficient and th...As for the supply chain consisting of a manufacturer and multiple competing retailers, the disruption management decision is considered for the demand disruption that both the investment sensitivity coefficient and the investment-elasticity are changed simultaneously. Meanwhile, the corresponding solutions are given for different cases of the disruption, and the characteristics of the solutions are analyzed. The production plan is proved to he robustness under certain conditions, and the production plan of the coordination strategy is investigated for the disruption with appropriate contractual arrangement, i. e. , a subside rate schedule. Mutual restraints exist between the changed investment sensitivity coefficient and the investment-elasticity when the coordination mecha- nism is used. And the more the number of the retailers in the system, the more the subside provided by the suppler on the coordinaton strategy.展开更多
Injection of high-Z impurities into plasma has been proved to be able to reduce the localized thermal load and mechanical forces on the in-vessel components and the vacuum vessel, caused by disruptions in Tokamaks. An...Injection of high-Z impurities into plasma has been proved to be able to reduce the localized thermal load and mechanical forces on the in-vessel components and the vacuum vessel, caused by disruptions in Tokamaks. An advanced prediction and mitigation system of disruption is implemented in HL-2A to safely shut down plasmas by using the laser ablation of high-Z impurities with a perturbation real-time measuring and processing system. The injection is usually triggered by the amplitude and frequency of the MHD perturbation field which is detected with a Mirnov coil and leads to the onset of a mitigated disruption within a few milliseconds. It could be a simple and potential approach to significantly reducing the plasma thermal energy and magnetic energy before a disruption, thereby achieving safe plasma termination. The plasma response to impurity injection, a mechanism for improving plasma thermal and current quench in major disruptions, the design of the disruption prediction warner, and an evaluation of the mitigation success rate are discussed in the present paper.展开更多
In this study,NIMROD simulations are performed to investigate the effects of massive helium gas injection level on the induced disruption on EAST tokamak.It is demonstrated in simulations that two different scenarios ...In this study,NIMROD simulations are performed to investigate the effects of massive helium gas injection level on the induced disruption on EAST tokamak.It is demonstrated in simulations that two different scenarios of plasma cooling(complete cooling and partial cooling)take place for different amounts of injected impurities.For the impurity injection above a critical level,a single MHD activity is able to induce a complete core temperature collapse.For impurity injection below the critical level,a series of multiple minor disruptions occur before the complete thermal quench.展开更多
The coordination problem of a supply chain comprising one supplier and one retailer under market demand disruption is studied in this article. A novel exponential demand function is adopted, and the penalty cost is in...The coordination problem of a supply chain comprising one supplier and one retailer under market demand disruption is studied in this article. A novel exponential demand function is adopted, and the penalty cost is introduced explicitly to capture the deviation production cost caused by the market demand disruption. The optimal strategies are obtained for different disruption scale under the centralized mode. For the decentralized mode, it is proved that the supply chain can be fully coordinated by adjusting the price discount policy appropriately when disruption occurs. Furthermore, the authors point out that similar results can be established for more general demand functions that represent different market circumstances if certain assumptions are satisfied.展开更多
This paper investigates the problem of how to handling demand disruptions ina one-supplier-one-retailer supply chain,where production cost is a convex function of productionquantity andprice-demand relationship is lin...This paper investigates the problem of how to handling demand disruptions ina one-supplier-one-retailer supply chain,where production cost is a convex function of productionquantity andprice-demand relationship is linear.Our results show that,ifdemand is disrupted,underthe new price-demand relationship,all-unit wholesale quantity discount policies combiningcapacitated linear pricingpolicies can also fully coordinate the supply chain.展开更多
Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease ...Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease.展开更多
Objective This study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane （DBDPE）. Methods In this study, Balb/C mice wer...Objective This study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane （DBDPE）. Methods In this study, Balb/C mice were treated orally by gavage with various doses of DBDPE. After 30 days of treatment, mice were sacrificed; blood, livers and thyroid glands were obtained, and hepatic microsomes were isolated. Biochemical parameters including 8 clinical chemistry parameters, blood glucose and hormone levels including insulin and thyroid hormone were assayed. The effects of DBDPE on hepatic cytochrome P450 （CYP） levels and activities and uridinediphosphate-glucuronosyltransferase （UDPGT） activities were investigated. Liver and thyroid glands were observed. Results There were no obvious signs of toxicity and no significant treatment effect on body weight, or liver-to-body weight ratios between treatment groups. The levels of ALT and AST of higher dose treatment groups were markedly increased. Blood glucose levels of treatment groups were higher than those of control group. There was also an induction in TSH, T3, and f T3. UDPGT, PROD, and EROD activities were found to have been increased significantly in the high dose group. Histopathologic liver changes were characterized by hepatocyte hypertrophy and cytoplasmic vacuolization. Our findings suggest that DBDPE can cause a certain degree of mouse liver damage and insufficiency. Conclusion DBDPE has the activity of endocrine disruptors in Bal/C mice, which may induce drug-metabolizing enzymes including CYPs and UDPGT, and interfere with thyroid hormone levels mediated by Ah R and CAR signaling pathways. Endocrine disrupting activity of DBDPE could also affect the glucose metabolism homeostasis.展开更多
The normal operation of aircraft and flights can be affected by various unpredictable factors,such as severe weather,airport closure,and corrective maintenance,leading to disruption of the planned schedule.When a disr...The normal operation of aircraft and flights can be affected by various unpredictable factors,such as severe weather,airport closure,and corrective maintenance,leading to disruption of the planned schedule.When a disruption occurs,the airline operation control center performs various operations to reassign resources(e.g.,flights,aircraft,and crews)and redistribute passengers to restore the schedule while minimizing costs.We introduce different sources of disruption and corresponding operations.Then,basic models and recently proposed extensions for aircraft recovery,crew recovery,and integrated recovery are reviewed,with the aim of providing models and methods for different disruption scenarios in the practical implementation of airlines.In addition,we provide suggestions for future research directions in these topics.展开更多
基金supported by the National Science Foundation of China,Nos.82325031(to FX),82030059(to YC),82102290(to YG),U23A20485(to YC)Noncommunicable Chronic Diseases-National Science and Technology Major Project,No.2023ZD0505504(to FX),2023ZD0505500(to YC)the Key R&D Program of Shandong Province,No.2022ZLGX03(to YC).
文摘Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest.
基金supported by the ENN Group,the ENN Energy Research Institute and National Natural Science Foundation of China(No.12205122).
文摘EHL-2 is a compact,high-field spherical tokamak designed to explore the potential of an advanced p-11B nuclear fusion reactor.Due to its high plasma current and thermal energy,it is crucial to mitigate the impact associated with disruptions to ensure the safe operation of EHL-2.This paper evaluates the performance requirements of the disruption prediction system on EHL-2,with a particular focus on applying generalizable knowledge transfer from existing devices to future ones.Furthermore,the key characteristics of disruption mitigation strategies are analyzed,and their overall mitigation performance on EHL-2 is assessed.This insight provides valuable guidance for optimizing the engineering design of EHL-2 and identifying its optimal operational regime.
基金The National Natural Science Foundation of China(No70671021)Jiangsu Postdoctoral Foundation (No0601015C)
文摘A two-level supply chain model involving one supplier and one retailer with linear demand is developed, and supply chain coordination mechanisms under asymmetric information （the retailer＇ s cost structure is asymmetric information） are proposed by employing game theory in two scenarios： coordination mechanisms under asymmetric information in a regular scenario （without disruption）; and coordination mechanisms under asymmetric information in an irregular scenario （ with retailer cost disruptions）. It is optimal for the supply chain to maintain the original production plan and to guarantee a steadily running system if variations of retailer costs are sufficiently low and do not exceed an upper bound. This shows that the original production plan has certain robustness under disruptions. Decisions must be re-made if a retailer＇ s cost change is greater and exceeds an upper bound. Impacts of retailer cost disruptions on the order quantity, the retail price, the wholesale price and each party＇ s as well as the system＇ s expected profits are investigated through numerical analyses.
文摘Background:Circadian disruption has emerged as a significant risk factor for cancer,driven by mechanisms such as hormonal imbalances,impaired DNA repair,immune suppression,and metabolic dysregulation.Modern societal patterns-shift work,artificial light at night,and irregular sleep schedules-have exacerbated these risks.Methods:We conducted a systematic review following Preferred Reporting Items for Systematic reviews and Meta-Analyses(PRISMA)guidelines,screening over 500 studies published between 2003 and 2023 from PubMed,Scopus,Embase,ScienceDirect,and Web of Science.Inclusion criteria focused on peer-reviewed epidemiological and mechanistic studies linking circadian disruption with cancer risk.The Newcastle-Ottawa Scale was used for methodological quality assessment.Results:A total of 75 high-quality studies were included.Strong evidence supports associations between circadian disruption and breast,prostate,and colorectal cancers,with limited but emerging evidence for melanoma and bladder cancer.Mechanistic pathways involve melatonin suppression,dysregulation of CLOCK and BMAL1 genes,reduced natural killer cell activity,and chronic inflammation due to metabolic imbalance.Light-at-night(LAN)exposure and prolonged night shift work were consistently identified as major risk factors.Furthermore,economic analyses reveal a substantial burden due to increased healthcare costs and productivity losses,particularly in shift work-dominated sectors.Conclusions:Circadian misalignment is a critical,yet often overlooked,contributor to cancer incidence and associated economic burdens.Public health strategies-such as regulating shift schedules,reducing LAN exposure,and promoting chronotherapy-are essential to mitigate these risks.Further research should address sex-based differences,improve exposure measurement,and extend investigations to low-and middle-income countries.
基金The Deputyship for Research and Innovation, Ministry of Education in Saudi Arabia, No. IF2/PSAU/2022/03/23339.
文摘BACKGROUND L-arginine(L-Arg)is one of the most widely used amino acids in dietary and pharmacological products.However,the evidence on its usefulness and dose limitations,especially in diabetics is still controversial.AIM To investigate the effects of chronic administration of different doses of L-Arg on the cardiac muscle of type 2 diabetic rats.METHODS Of 96 male rats were divided into 8 groups as follows(n=12):Control,0.5 g/kg L-Arg,1 g/kg L-Arg,1.5 g/kg L-Arg,diabetic,diabetic+0.5 g/kg L-Arg,diabetic+1 g/kg L-Arg,and diabetic+1.5 g/kg L-Arg;whereas L-Arg was orally administered for 3 months to all treated groups.RESULTS L-Arg produced a moderate upregulation of blood glucose levels to normal rats,but when given to diabetics a significant upregulation was observed,associated with increased nitric oxide,inflammatory cytokines,and malonaldehyde levels in diabetic rats treated with 1 g/kg L-Arg and 1.5 g/kg L-Arg.A substantial decrease in the antioxidant capacity,superoxide dismutase,catalase,glutathione peroxidase,reduced glutathione concentrations,and Nrf-2 tissue depletion were observed at 1 g/kg and 1.5 g/kg L-Arg diabetic treated groups,associated with myocardial injury,fibrosis,α-smooth muscle actin upregulation,and disruption of desmin cardiac myofilaments,and these effects were not noticeable at normal treated groups.On the other hand,L-Arg could significantly improve the lipid profile of diabetic rats and decrease their body weights.CONCLUSION L-Arg dose of 1 g/kg or more can exacerbates the diabetes injurious effects on the myocardium,while 0.5 g/kg dose can improve the lipid profile and decrease the body weight.
基金supported by National Natural Science Foundation of China(81502688)Cooperation Research Funding of Capital Medical University(2020KJ000514)+1 种基金Cooperation Research Funding of Capital Medical University(2023KJ000814)R&D Program of Beijing Municipal Education Commission(KM202210025024).
文摘Efficient siRNA delivery is highly desirable for disease treatment.However,the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes.Herein,we report a strategy using small-molecule drugs to enhance siRNA endo-lysosomal release,addressing this challenge.We encapsulated gentamicin(GM)into the marketed Onpattro■ formulation to establish LNP-siRNA/GM nanoparticles that promote siRNA endo-lysosomal escape through endosomal disruption,mechanistically exhibiting unique functionality and synergistic effects of LNP-siRNA/GM to improve cancer therapy.Besides,GM induced reactive oxygen species(ROS)and phospholipids accumulation in endolysosomes,as well as the physical characteristics of lipid nanoparticles(LNPs)were preserved.We also revealed that GM causes endo-lysosomal swelling and disrupts the endosomal membrane to enable siRNA release,as confirmed by Galectin 3 recruitment and acridine orange release.This approach achieved∼81%mRNA-EGFR silencing,which is more than LNP-siEGFR(∼56.23%)by enhancing siRNA endo-lysosomal escape efficiency.Meanwhile,LNP-siEGFR/GM exhibited significant biological activities in HepG2 cells,driven by the synergistic effects of siEGFR and GM with the VEGF and CXCL12 downregulation of,and ROS and phospholipids upregulation.Furthermore,tumor growth was notably suppressed after intravenous injection of LNP-siEGFR/GM in tumor-bearing nude mice.The combination of EGFR-siRNA and GM could also greatly inhibit angiogenesis,be antiproliferative,and induce tumor cells apoptosis.Therefore,this GM and siRNA co-delivery system would provide an efficient strategy for siRNA endosomal escape,significantly improving knockdown in various LNPs based siRNA delivery systems and efficiently enhancing cancer therapy.
基金supported by the National Natural Science Foundation of China(No.U2333218).
文摘Airport disruptions often pose challenges in assigning aircraft to gates,resulting in infeasible planned schedules.In particular,a large number of transfer passengers miss their connections in the context of disruptions,which cause huge economic losses to airlines and serious passengers’dissatisfaction.This paper proposes a set-partitioning-based model to optimize Aircraft-Gate Reassignment with Transfer Passenger Connections(AGRP-TPC),which incorporates flexible gate-swap and aircraft-delay operations to mitigate the overall impact of disruptions.To efficiently solve the model,we introduce the concepts of additive-transfer and nonstop-transfer to handle passenger connections,and develop a Hierarchical Column-and-Row Generation(HCRG)approach guided by airport terminal space attribute.The column generation and row generation procedures solve iteratively until no new variables and constraints are generated.In addition,a follow-on strategy and a diving heuristic are designed to efficiently obtain high-quality solutions.We evaluate the proposed approach using various instances from a major Chinese international airport.Computational results demonstrate that our approach outperforms the comparison algorithms and produces good solutions within the time limit.Detailed results indicate that our approach effectively reduces overall losses in aircraft-gate reassignment following disruptions,and it can serve as an auxiliary decision-making tool for airport operators and airlines.
基金funded by the National Natural Science Foundation of China(Grant No.42275056).
文摘As a prominent mode of variability in the tropical stratosphere on the interannual timescale,the Quasi-Biennial Oscillation(QBO)can significantly influence global atmospheric circulation and weather patterns.This study explores the dynamic processes of QBO disruptions using the integrated climate model of the China Meteorological Administration(CMA)by nudging the tropical zonal winds toward observations.A comparative analysis with ERA5 reanalysis data shows that the nudged runs accurately replicate the general characteristics of the QBO,including the alternating QBO wind regimes and QBO disruption events.The evolution of the QBO winds is diagnosed using empirical orthogonal function and root-mean-square difference analyses,and the rarity of the disruption events is confirmed in the CMA model.Different aspects of the QBO disruptions and the relevant dynamics are present in the model.Firstly,the momentum budget analysis highlights the crucial roles of extratropical Rossby waves and non-orographic gravity waves in the transition from westerly to easterly winds during a disruption.Secondly,Kelvin waves and non-orographic gravity waves explain much of the transition from easterly to westerly winds near 40 hPa.Thirdly,the positive tendency from enhanced vertical advection further accelerates westerly momentum development via secondary meridional circulation.These findings underscore the importance of nudging techniques in understanding QBO dynamics,which provides valuable insights for future climate model improvements toward better forecasting QBO-related climate variability.Notably,due to model limitations,no QBO disruptions were simulated in the free-run experiments.
基金Supported by National Agricultural Scientific and Technological Achievements Transformation Program of China(2012GB2C100165)~~
文摘[Objective] The aim was to improve the quality of the duck blood tofu by ultrasonic technology. [Method] Ultrasonic technology was used to break the blood cell membrane. The optimal ultrasonic condition was determined by single factor de- sign, and the differences in sensory quality and nutritional value between the duck blood tofu treated with and without ultrasonication were studied. [Result] The optimal ultrasonic power was 400 W and the optimal ultrasonic time was 6 min. Under these conditions, the content of duck blood haemoglobin increased by 43.46%, the content of iron increased by 10.85%, and the breakage rate was 100%. The a＊ value of the duck blood tofu increased significantly under ultrasonic treatment. Both internal micro-structure and texture parameters proved that the ultrasonic contributed to the formation of gel structure. After treatment by artificial gastric juice and artifi- cial intestinal juice, the total amino acids in the digestive juice were 9.25% higher than that of the duck blood tofu without ultrasonic treatment. [Conclusion] The duck blood tofu under ultrasonic treatment would be beneficial to human body absorption, and the nutrition value would be higher as well.
基金supported by the Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor(Guangxi Medical University),Ministry of Education(No.GKE-KF202305)the Guangxi Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor,and the Natural Science Foundation of Jiangsu Province(No.BK20211510)。
文摘Vascular disrupting agents(VDAs)can destroy tumor vasculature and lead to tumor ischemia and hypoxia,resulting in tumor necrosis.However,VDAs are easy to induce the upregulation of genes that are associated with cancer cell drug resistance and angiogenesis in tumor cells.Hypoxia-activated chemotherapy will be an ideal supplement to VDAs therapy since it can help to fully utilize the ischemia and hypoxia induced by VDAs to realize a synergistic antitumor therapeutic outcome.Here,we design a liposome whose surface is modified with a tumor-homing peptide Cys-Arg-Glu-Lys-Ala(CREKA,which can specifically target tumor vessels and stroma)and whose aqueous cavity and lipid bilayer are loaded by a hypoxia-activatable drug banoxantrone dihydrochloride(AQ4N)and a VDA combretastatin A4(CA4),respectively.CA4 can selectively target vascular endothelial cells and destroy the tumor blood vessels,which will cause the rapid inhibition of blood flow in tumor and enhance the hypoxia in the tumor region.As a consequence,AQ4N can exert its boosted cytotoxicity under the enhanced hypoxic environment.The as-prepared liposome with a uniform particle size exhibits good stability and high cancer cell killing efficacy in vitro.In addition,in vivo experiments confirm the excellent tumortargeting/accumulation,tumor vasculature-damaging,and tumor inhibition effects of the liposome.This work develops a liposomal which can achieve safe and effective tumor suppression without external stimulus excitation by only single injection,and is expected to benefit the future development of effective antitumor liposomal drugs.
基金The National Key Technology R&D Program of China during the11th Five-Year Plan Period(No.2006BAH02A06)Jiangsu Postdoctoral Foundation(No.0601015C)
文摘The coordinating pricing strategies with asymmetric cost information under disruptions are investigated in a one-supplier-one-retailer supply chain system.While the retailer's cost structure is asymmetric information,supply chain pricing contract models(a wholesale price contract and an all-unit quantity discount contract)under asymmetric information are proposed by employing the principal-agent principle in a regular scenario.When the retailer's cost distribution is fluctuated by disruptions,we obtain the optimal emergency strategies of the supply chain under asymmetric information by considering deviation costs and show how to effectively handle the cost uncertainty.Using numerical methods,impacts of cost disruptions on the optimal wholesale price,the retailer price,the order quantity and the expected profits of the retailer,the supplier,as well as the total system are analyzed.It is found that the all-unit quantity discount policy can obtain better performance than the wholesale pricing policy.
基金Supported by the Scientific Research Foundation for Young Faulty of Nanjing University of Aeronautics & Astronautics(S0670-082)~~
文摘As for the supply chain consisting of a manufacturer and multiple competing retailers, the disruption management decision is considered for the demand disruption that both the investment sensitivity coefficient and the investment-elasticity are changed simultaneously. Meanwhile, the corresponding solutions are given for different cases of the disruption, and the characteristics of the solutions are analyzed. The production plan is proved to he robustness under certain conditions, and the production plan of the coordination strategy is investigated for the disruption with appropriate contractual arrangement, i. e. , a subside rate schedule. Mutual restraints exist between the changed investment sensitivity coefficient and the investment-elasticity when the coordination mecha- nism is used. And the more the number of the retailers in the system, the more the subside provided by the suppler on the coordinaton strategy.
基金Project supported by the National Natural Science Foundation of China (Grant No 10475023)
文摘Injection of high-Z impurities into plasma has been proved to be able to reduce the localized thermal load and mechanical forces on the in-vessel components and the vacuum vessel, caused by disruptions in Tokamaks. An advanced prediction and mitigation system of disruption is implemented in HL-2A to safely shut down plasmas by using the laser ablation of high-Z impurities with a perturbation real-time measuring and processing system. The injection is usually triggered by the amplitude and frequency of the MHD perturbation field which is detected with a Mirnov coil and leads to the onset of a mitigated disruption within a few milliseconds. It could be a simple and potential approach to significantly reducing the plasma thermal energy and magnetic energy before a disruption, thereby achieving safe plasma termination. The plasma response to impurity injection, a mechanism for improving plasma thermal and current quench in major disruptions, the design of the disruption prediction warner, and an evaluation of the mitigation success rate are discussed in the present paper.
基金supported by the National Magnetic Confinement Fusion Science Program of China(No.2019YFE03050004)National Natural Science Foundation of China(Nos.11775221 and 51821005)+1 种基金US DOE(Nos.DEFG02-86ER53218 and DESC0018001)the Fundamental Research Funds for the Central Universities at Huazhong University of Science and Technology(No.2019kfyXJJS193).
文摘In this study,NIMROD simulations are performed to investigate the effects of massive helium gas injection level on the induced disruption on EAST tokamak.It is demonstrated in simulations that two different scenarios of plasma cooling(complete cooling and partial cooling)take place for different amounts of injected impurities.For the impurity injection above a critical level,a single MHD activity is able to induce a complete core temperature collapse.For impurity injection below the critical level,a series of multiple minor disruptions occur before the complete thermal quench.
基金This research was supported by National Science Foundation of China (60274048)
文摘The coordination problem of a supply chain comprising one supplier and one retailer under market demand disruption is studied in this article. A novel exponential demand function is adopted, and the penalty cost is introduced explicitly to capture the deviation production cost caused by the market demand disruption. The optimal strategies are obtained for different disruption scale under the centralized mode. For the decentralized mode, it is proved that the supply chain can be fully coordinated by adjusting the price discount policy appropriately when disruption occurs. Furthermore, the authors point out that similar results can be established for more general demand functions that represent different market circumstances if certain assumptions are satisfied.
文摘This paper investigates the problem of how to handling demand disruptions ina one-supplier-one-retailer supply chain,where production cost is a convex function of productionquantity andprice-demand relationship is linear.Our results show that,ifdemand is disrupted,underthe new price-demand relationship,all-unit wholesale quantity discount policies combiningcapacitated linear pricingpolicies can also fully coordinate the supply chain.
基金supported by the Science and Technology Development Fund (Macao SAR)(120015/2019/ASC,0023/2020/AFJ,0035/2020/AGJ)the University of Macao Research Grant (MYRG2022-00248-ICMS)(all to MPMH)。
文摘Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease.
基金supported by the National Natural Science Foundation[No.21407179]
文摘Objective This study aimed to evaluate the hepatotoxicity, metabolic disturbance activity and endocrine disrupting activity of mice treated by Decabromodiphenyl ethane （DBDPE）. Methods In this study, Balb/C mice were treated orally by gavage with various doses of DBDPE. After 30 days of treatment, mice were sacrificed; blood, livers and thyroid glands were obtained, and hepatic microsomes were isolated. Biochemical parameters including 8 clinical chemistry parameters, blood glucose and hormone levels including insulin and thyroid hormone were assayed. The effects of DBDPE on hepatic cytochrome P450 （CYP） levels and activities and uridinediphosphate-glucuronosyltransferase （UDPGT） activities were investigated. Liver and thyroid glands were observed. Results There were no obvious signs of toxicity and no significant treatment effect on body weight, or liver-to-body weight ratios between treatment groups. The levels of ALT and AST of higher dose treatment groups were markedly increased. Blood glucose levels of treatment groups were higher than those of control group. There was also an induction in TSH, T3, and f T3. UDPGT, PROD, and EROD activities were found to have been increased significantly in the high dose group. Histopathologic liver changes were characterized by hepatocyte hypertrophy and cytoplasmic vacuolization. Our findings suggest that DBDPE can cause a certain degree of mouse liver damage and insufficiency. Conclusion DBDPE has the activity of endocrine disruptors in Bal/C mice, which may induce drug-metabolizing enzymes including CYPs and UDPGT, and interfere with thyroid hormone levels mediated by Ah R and CAR signaling pathways. Endocrine disrupting activity of DBDPE could also affect the glucose metabolism homeostasis.
基金This study is supported by the National Natural Science Foundation of China(71825001 and 71890973).
文摘The normal operation of aircraft and flights can be affected by various unpredictable factors,such as severe weather,airport closure,and corrective maintenance,leading to disruption of the planned schedule.When a disruption occurs,the airline operation control center performs various operations to reassign resources(e.g.,flights,aircraft,and crews)and redistribute passengers to restore the schedule while minimizing costs.We introduce different sources of disruption and corresponding operations.Then,basic models and recently proposed extensions for aircraft recovery,crew recovery,and integrated recovery are reviewed,with the aim of providing models and methods for different disruption scenarios in the practical implementation of airlines.In addition,we provide suggestions for future research directions in these topics.
