Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness ...Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.展开更多
Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-tar...Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.展开更多
Theranostic visualization of dextran at the nanoscale is beneficial for understanding the bioregulatory mechanisms of this molecule. In this study, we applied structured illumination microscopy(SIM) to capture the dis...Theranostic visualization of dextran at the nanoscale is beneficial for understanding the bioregulatory mechanisms of this molecule. In this study, we applied structured illumination microscopy(SIM) to capture the distribution of Cy5-Dextran at different incubation periods in living cells. The results showed that Cy5-Dextran could be absorbed by He La cells. In addition, we clarified that Cy5-Dextran exhibited differential organelle distribution(lysosomal or mitochondrial) in a time-dependent manner. Moreover,lysosomal Cy5-Dextran localization was found to be independent of the autophagy process, while Cy5-Dextran localized to the mitochondria triggered a pro-apoptotic event, upregulating the levels of reactive oxygen species(ROS) to accelerate mitochondrial fragmentation. This work uses a visualized strategy to reveal the anti-tumor bioactivity of dextran, which was achieved by regulating apoptosis and autophagy.展开更多
Equilibrium analysis has been widely studied as an effective tool to model gaming interactions and predict market results.However,as competition modes are fundamentally changed by the decarbonization and decentralizat...Equilibrium analysis has been widely studied as an effective tool to model gaming interactions and predict market results.However,as competition modes are fundamentally changed by the decarbonization and decentralization of power systems,analysis techniques must evolve.This article comprehensively reviews recent developments in modelling methods,practical settings and solution tech-niques in equilibrium analysis.Firstly,we review equilibrium in the evolving wholesale power markets which feature new entrants,novel trading products and multi-stage clearing.Secondly,the competition modes in the emerging distribution market and distributed resource aggregation are reviewed,and we compare peer-to-peer clearing,cooperative games and Stackelberg games.Further-more,we summarize the methods to treat various information acquisition degrees,risk preferences and rationalities of market par-ticipants.To deal with increasingly complex market settings,this review also covers refined analytical techniques and agent-based models used to compute the equilibrium.Finally,based on this review,this paper summarizes key issues in the gaming and equilibrium analysis in power markets under decarbonization and decentralization.展开更多
In this work,high-fidelity full-dimensional potential energy surfaces(PESs)of the ground(X^(2)A′)and first doublet excited(A^(2)A″)electronic states of HCO were constructed using neural network method.In total,4624 ...In this work,high-fidelity full-dimensional potential energy surfaces(PESs)of the ground(X^(2)A′)and first doublet excited(A^(2)A″)electronic states of HCO were constructed using neural network method.In total,4624 high-level ab initio points have been used which were calculated at Davidson corrected internally contracted MRCI-F12 level of theory with a quite large basis set(ACV5Z)without any scaling scheme.Compared with the results obtained from the scaled PESs of Ndenguéet al.,the absorption spectrum based on our PESs has slightly larger intensity,and the peak positions are shifted to smaller energy for dozens of wavenumbers.It is indicated that the scaling of potential energy may make some unpredictable difference on the dynamical results.However,the resonance energies based on those scaled PESs are slightly closer to the current available experimental values than ours.Nevertheless,the unscaled high-level PESs developed in this work might provide a platform for further experimental and theoretical photodissociation and collisional dynamic studies for HCO system.展开更多
Unlike chemosynthetic drugs designed for specific molecular and disease targets,active small-molecule natural products typically have a wide range of bioactivities and multiple targets,necessitating extensive screenin...Unlike chemosynthetic drugs designed for specific molecular and disease targets,active small-molecule natural products typically have a wide range of bioactivities and multiple targets,necessitating extensive screening and development.To address this issue,we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action.As a proof-of-concept,we investigated the behavior of mussel oligosaccharide(MOS-1)by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells.We recorded the entire dynamic process of the localization of fluorescein isothiocyanate(FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the cell.Remarkably,lysosomes containing FITC-MOS-1 actively recruited lipid droplets,leading to fusion events and increased cellular lipid consumption.These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases.Furthermore,in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E(ApoE)^(-/-)mice,MOS-1 significantly promoted triglyceride degradation,reduced lipid droplet accumulation,lowered serum triglyceride levels,and mitigated liver damage and steatosis.Overall,our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase,as this methodology contributes to the rapid identification of drug indications.Collectively,this methodology is significant for the screening and development of selective small-molecule drugs,and is expected to expedite the identification of candidate molecules with medicinal effects.展开更多
Scarring is an insurmountable obstacle for axonal regeneration in recovery from spinal cord injury(SCI).It impedes the repair effects of therapeutic targets in cortical neurons,such as PTEN^(-/-)and hyper-IL-6,which c...Scarring is an insurmountable obstacle for axonal regeneration in recovery from spinal cord injury(SCI).It impedes the repair effects of therapeutic targets in cortical neurons,such as PTEN^(-/-)and hyper-IL-6,which cannot break through dense scar barriers to reconstruct neural circuits.However,methods for eliminating this process remain elusive.Here,we conducted a multiomics analysis of SCI and identified FBXL12 as an effective target for inhibiting scarring,further promoting spontaneous crossing of axons at the epicenter.We identified N6-Methyladenosine(m6A)modification as the predominant mRNA modification in SCI,with Fbxl12 being a major modification target.Furthermore,m6A modification specifically promoted FBXL12 synthesis in activated microglia.The overexpression of FBXL12 in microglia contributed to its homogeneous distribution and maintained a“scar-less healing”phenotype.Remarkably,FBXL12 therapy effectively reduced extracellular matrix deposition and decreased the scar area by~70%.Importantly,axons grew through the epicenter and reached a length of more than 2.4 mm 56 days post-SCI,significantly improving motor function and reconstructing the neural circuit.Mechanistically,FBXL12 promoted cytoskeletal reorganization and migration in microglia by catalyzing the K63-linked ubiquitylation of Myosin heavy chain 14(MYH14).Together,our results identify m6A-FBXL12-MYH14 axis as a novel cytoskeletal reorganization pathway in activated microglia and suggest FBXL12 as an effective target for a novel microglia-based approach to facilitate scarless functional recovery in SCI.展开更多
Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anti...Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs.In this study,we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug,namely long-term lysosome-targeting anticancer drug(LLAD).It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes.Upon short term and low-dose treatment of HeLa cells,at passage 0,with LLAD,it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15.LLAD induced apoptosis in HeLa cells through long-term lysosomal damage,and showed better long-term anticancer effect than cisplatin in vivo.Overall,our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells,and also provides a candidate drug,LLAD,for treating cancer.展开更多
The optimal dispatch of energy storage systems(ESSs)in distribution networks poses significant challenges,primarily due to uncertainties of dynamic pricing,fluctuating demand,and the variability inherent in renewable ...The optimal dispatch of energy storage systems(ESSs)in distribution networks poses significant challenges,primarily due to uncertainties of dynamic pricing,fluctuating demand,and the variability inherent in renewable energy sources.By exploiting the generalization capabilities of deep neural networks(DNNs),the deep reinforcement learning(DRL)algorithms can learn good-quality control models that adapt to the stochastic nature of distribution networks.Nevertheless,the practical deployment of DRL algorithms is often hampered by their limited capacity for satisfying operational constraints in real time,which is a crucial requirement for ensuring the reliability and feasibility of control actions during online operations.This paper introduces an innovative framework,named mixed-integer programming based deep reinforcement learning(MIP-DRL),to overcome these limitations.The proposed MIP-DRL framework can rigorously enforce operational constraints for the optimal dispatch of ESSs during the online execution.This framework involves training a Q-function with DNNs,which is subsequently represented in a mixed-integer programming(MIP)formulation.This unique combination allows for the seamless integration of operational constraints into the decision-making process.The effectiveness of the proposed MIP-DRL framework is validated through numerical simulations,demonstrating its superior capability to enforce all operational constraints and achieve high-quality dispatch decisions and showing its advantage over existing DRL algorithms.展开更多
Deep learning technology is identified as a valid tool for transient stability assessment(TSA).Moreover,the superior performance of the TSA model depends on generously labeled samples.However,the power grid is dynamic...Deep learning technology is identified as a valid tool for transient stability assessment(TSA).Moreover,the superior performance of the TSA model depends on generously labeled samples.However,the power grid is dynamic,and some topologies or operation conditions change substantially.The traditional method generates a significant quantity of samples for each specific topology.Nonetheless,generating these labeled samples and establishing TSA models is very time-consuming.This paper proposes a high-quality sample generation framework based on data-driven methods to build a high-quality offline samples database for TSA model training and updating.Firstly,the representative topologies provided by the system operator are clustered into four different categories by density-based spatial clustering of applications with noise(DBSCAN).Thus the corresponding samples are collected.Then,when a new topology is encountered in the online application,scenario matching is used to match the most similar topology category.After that,instance-based transfer learning is implemented from a database of the best-matched topology category.Finally,a deep convolutional generative adversarial network(DCGAN)is constructed to mitigate the class imbalance problem.That is,unstable scenarios occur far more rarely than stable scenarios.Consequently,a high-quality and balanced TSA model training and updating database is constructed.The comprehensive test results on the Central China Power Grid illustrate that the proposed framework can generate high-quality and balanced TSA samples.Furthermore,the sample generation time is dramatically shortened.In addition,the metrics of accuracy,reliability and adaptability of the TSA model are significantly enhanced.展开更多
The COVID-19 pandemic has underscored the importance of in-depth research into the proteins encoded by coronaviruses(CoV),particularly the highly conserved nonstructural CoV proteins(nsp).Among these,the nsp13 helicas...The COVID-19 pandemic has underscored the importance of in-depth research into the proteins encoded by coronaviruses(CoV),particularly the highly conserved nonstructural CoV proteins(nsp).Among these,the nsp13 helicase of severe pathogenic MERS-CoV,SARS-CoV-2,and SARS-CoV is one of the most preserved CoV nsp.Utilizing single-molecule FRET,we discovered that MERS-CoV nsp13 unwinds DNA in distinct steps of about 9 bp when ATP is employed.If a different nucleotide is introduced,these steps diminish to 3−4 bp.Dwell-time analysis revealed 3−4 concealed steps within each unwinding process,which suggests the hydrolysis of 3−4 dTTP.Combining our observations with previous studies,we propose an unwinding model of CoV nsp13 helicase.This model suggests that the elongated and adaptable 1B-stalk of nsp13 may enable the 1B remnants to engage with the unwound single-stranded DNA,even as the helicase core domain has advanced over 3−4 bp,thereby inducing accumulated strain on the nsp13-DNA complex.Our findings provide a foundational framework for determining the unwinding mechanism of this unique helicase family.展开更多
The integration of distributed energy resources(DERs)has escalated the challenge of voltage magnitude regulation in distribution networks.Model-based approaches,which rely on complex sequential mathematical formulatio...The integration of distributed energy resources(DERs)has escalated the challenge of voltage magnitude regulation in distribution networks.Model-based approaches,which rely on complex sequential mathematical formulations,cannot meet the real-time demand.Deep reinforcement learning(DRL)offers an alternative by utilizing offline training with distribution network simulators and then executing online without computation.However,DRL algorithms fail to enforce voltage magnitude constraints during training and testing,potentially leading to serious operational violations.To tackle these challenges,we introduce a novel safe-guaranteed reinforcement learning algorithm,the Dist Flow safe reinforcement learning(DF-SRL),designed specifically for real-time voltage magnitude regulation in distribution networks.The DF-SRL algorithm incorporates a Dist Flow linearization to construct an expert-knowledge-based safety layer.Subsequently,the DF-SRL algorithm overlays this safety layer on top of the agent policy,recalibrating unsafe actions to safe domains through a quadratic programming formulation.Simulation results show the DF-SRL algorithm consistently ensures voltage magnitude constraints during training and real-time operation(test)phases,achieving faster convergence and higher performance,which differentiates it apart from(safe)DRL benchmark algorithms.展开更多
The smart grid has been revolutionizing electrical generation and consumption through a two-way flow of power and information. As an important information source from the demand side, Advanced Metering Infrastructure ...The smart grid has been revolutionizing electrical generation and consumption through a two-way flow of power and information. As an important information source from the demand side, Advanced Metering Infrastructure （AMI） has gained increasing popularity all over the world. By making full use of the data gathered by AMI, stakeholders of the electrical industry can have a better understanding of electrical consumption behavior. This is a significant strategy to improve operation efficiency and enhance power grid reliability. To implement this strategy, researchers have explored many data mining techniques for load profiling. This paper performs a state-of-the-art, comprehensive review of these data mining techniques from the perspectives of different technical approaches including direct clustering, indirect clustering, clustering evaluation criteria, and customer segmentation. On this basis, the prospects for implementing load profiling to demand response applications, price-based and incentivebased, are further summarized. Finally, challenges and opportunities of load profiling techniques in future power industry, especially in a demand response world, are discussed.展开更多
The repair and motor functional recovery after spinal cord injury(SCI)remains a worldwide challenge.The inflammatory microenvironment is one of main obstacles on inhibiting the recovery of SCI.Using mesenchymal stem c...The repair and motor functional recovery after spinal cord injury(SCI)remains a worldwide challenge.The inflammatory microenvironment is one of main obstacles on inhibiting the recovery of SCI.Using mesenchymal stem cells(MSCs)derived extracellular vesicles to replace MSCs transplantation and mimic cell paracrine secretions provides a potential strategy for microenvironment regulation.However,the effective preservation and controlled release of extracellular vesicles in the injured spinal cord tissue are still not satisfied.Herein,we fabricated an injectable adhesive anti-inflammatory F127-polycitrate-polyethyleneimine hydrogel(FE)with sustainable and long term extracellular vesicle release(FE@EVs)for improving motor functional recovery after SCI.The orthotopic injection of FE@EVs hydrogel could encapsulate extracellular vesicles on the injured spinal cord,thereby synergistically induce efficient integrated regulation through suppressing fibrotic scar formation,reducing inflammatory reaction,promoting remyelination and axonal regeneration.This study showed that combining extracellular vesicles into bioactive multifunctional hydrogel should have great potential in achieving satisfactory locomotor recovery of central nervous system diseases.展开更多
The current effective method for treatment of spinal cord injury(SCI)is to reconstruct the biological microenvironment by filling the injured cavity area and increasing neuronal differentiation of neural stem cells(NS...The current effective method for treatment of spinal cord injury(SCI)is to reconstruct the biological microenvironment by filling the injured cavity area and increasing neuronal differentiation of neural stem cells(NSCs)to repair SCI.However,the method is characterized by several challenges including irregular wounds,and mechanical and electrical mismatch of the material-tissue interface.In the current study,a unique and facile agarose/gelatin/polypyrrole(Aga/Gel/PPy,AGP3)hydrogel with similar conductivity and modulus as the spinal cord was developed by altering the concentration of Aga and PPy.The gelation occurred through non-covalent interactions,and the physically crosslinked features made the AGP3 hydrogels injectable.In vitro cultures showed that AGP3 hydrogel exhibited excellent biocompatibility,and promoted differentiation of NSCs toward neurons whereas it inhibited over-proliferation of astrocytes.The in vivo implanted AGP3 hydrogel completely covered the tissue defects and reduced injured cavity areas.In vivo studies further showed that the AGP3 hydrogel provided a biocompatible microenvironment for promoting endogenous neurogenesis rather than glial fibrosis formation,resulting in significant functional recovery.RNA sequencing analysis further indicated that AGP3 hydrogel significantly modulated expression of neurogenesis-related genes through intracellular Ca2+signaling cascades.Overall,this supramolecular strategy produces AGP3 hydrogel that can be used as favorable biomaterials for SCI repair by filling the cavity and imitating the physiological properties of the spinal cord.展开更多
Technology advances in genomics,proteomics,and metabolomics largely expanded the pool of potential therapeutic targets.Compared with the in vitro setting,cell-based screening assays have been playing a key role in the...Technology advances in genomics,proteomics,and metabolomics largely expanded the pool of potential therapeutic targets.Compared with the in vitro setting,cell-based screening assays have been playing a key role in the processes of drug discovery and development.Besides the commonly used strategies based on colorimetric and cell viability,we reason that methods that capture the dynamic cellular events will facilitate optimal hit identification with high sensitivity and specificity.Herein,we propose a live-cell screening strategy using structured illumination microscopy (SIM) combined with an automated cell colocalization analysis software,CellprofilerTM,to screen and discover drugs for mitochondria and lysosomes interaction at a nanoscale resolution in living cells.This strategy quantitatively benchmarks the mitochondria-lysosome interactions such as mitochondria and lysosomes contact (MLC) and mitophagy.The automatic quantitative analysis also resolves fine changes of the mitochondria-lysosome interaction in response to genetic and pharmacological interventions.Super-resolution live-cell imaging on the basis of quantitative analysis opens up new avenues for drug screening and development by targeting dynamic organelle interactions at the nanoscale resolution,which could facilitate optimal hit identification and potentially shorten the cycle of drug discovery.展开更多
Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the ef...Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the efficiency of human adipose-derived stem cells(human ADSCs)transplantation therapy.It inhibits human ADSCs proliferation,and increases human ADSCs apoptosis.Herein,we firstly devised a novel amphiphilic copolymer PEG-PAPO,which could self-assemble into a nanosized micelle and load lipophilic kartogenin(KGN),as a single complex(PAKM).It was an injectable esterase-responsive micelle,and showed controlled release ability of KGN and apocynin(APO).Oxidative stimulation promoted the esterase activity in human ADSCs,which accelerate degradation of esterase-responsive micelle.Compared its monomer,the PAKM micelle possessed better bioactivities,which were attributed to their synergistic effect.It enhanced the viability,autophagic activation(P62,LC3 II),ECM-related transcription factor(SOX9),and ECM(Collagen II,Aggrecan)maintenance in human ADSCs.Furthermore,it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats.Therefore,PAKM micelles perform promoting cell survival and differentiation effects,and may be a potential therapeutic agent for IVDD.展开更多
The high penetration of distributed renewable energy raises a higher concern for the safe and economic operation of the smart grid. Distributed batteries equipped in demand-side can not only contribute to the reliabil...The high penetration of distributed renewable energy raises a higher concern for the safe and economic operation of the smart grid. Distributed batteries equipped in demand-side can not only contribute to the reliability and security of the grid, but also make profits by participating in the electricity market, especially when distributed batteries are combined and operated by an aggregator.Considering the well-operated mechanism of performance based regulation(PBR) in the U.S. electricity market, it becomes increasingly lucrative for batteries to participate not only in energy markets for energy arbitrage, but also in ancillary service markets to provide regulation and peakload shaving services. In this study, distributed batteries are operated and coordinated by the aggregator, which simultaneously submits offers to the energy and the ancillary service markets as an individual entity. An optimaldecision model is formulated for the aggregator to determine the operation and bidding strategy for the distributed batteries by considering the characteristics of batteries,including the terms of capacity, efficiency and degradation cost. Finally, a numerical case is conducted to evaluate the benefits of the decision model.展开更多
With the increasing penetration of renewables,power systems have to operate with greater flexibility to address the uncertainties of renewable output.This paper develops an uncertainty locational marginal price(ULMP)m...With the increasing penetration of renewables,power systems have to operate with greater flexibility to address the uncertainties of renewable output.This paper develops an uncertainty locational marginal price(ULMP)mechanism to price these uncertainties.They are denoted as box deviation intervals as suggested by the market participants.The ULMP model solves a robust optimal power flow(OPF)problem to clear market bids,aiming to minimize the system cost as a prerequisite that the reserve margin can address all the relevant uncertainties.The ULMP can be obtained as a by-product of the optimization problem from the Lagrange multipliers.Under the ULMP mechanism,renewables and consumers with uncertainty will make extra payments,and the thermals and financial transmission right(FTR)holders will be compensated.It is further shown that the proposed mechanism has preferable properties,such as social efficiency,budget balance and individual rationality.Numerical tests are conducted on the modified IEEE 5-bus and 118-bus systems to demonstrate the merits and applicability of the proposed mechanism.展开更多
Mitochondrial damage,characterized by altered morphological distribution and the damage of cristae,is closely associated with mitochondrial disease.However,imaging methods for capturing mitochondrial morphology at the...Mitochondrial damage,characterized by altered morphological distribution and the damage of cristae,is closely associated with mitochondrial disease.However,imaging methods for capturing mitochondrial morphology at the nanoscale level in live samples remain unavailable,which seriously hinders the accurate evaluation and diagnosis of mitochondrial-related diseases.In response,we propose a super-resolution quantification strategy based on structured illumination microscopy(SIM)for the rapid,accurate evaluation of mitochondrial morphology.Using the strategy,we accurately captured the morphological distribution of mitochondria at the nanoscale level in a way generally applicable to checking various cell processes and identifying patients with mitochondrial disease who exhibit the SLC25A46 mutation.We also used algorithm-assisted super-resolution imaging to quantitatively analyze damage to mitochondrial cristae,which supports a novel drug screening strategy—high-resolution drug screening—for investigating drugs’pharmacodynamics on organelles in living cells.In short,our strategy improves the accurate examination of changes in mitochondrial morphology in living cells and indicates new ways in which SIM-imaging can assist in diagnosing mitochondrial disease at the single-cell level.展开更多
基金supported by the National Natural Science Foundation of China,No.82202681(to JW)the Natural Science Foundation of Zhejiang Province,Nos.LZ22H090003(to QC),LR23H060001(to CL).
文摘Spinal cord injuries impose a notably economic burden on society,mainly because of the severe after-effects they cause.Despite the ongoing development of various therapies for spinal cord injuries,their effectiveness remains unsatisfactory.However,a deeper understanding of metabolism has opened up a new therapeutic opportunity in the form of metabolic reprogramming.In this review,we explore the metabolic changes that occur during spinal cord injuries,their consequences,and the therapeutic tools available for metabolic reprogramming.Normal spinal cord metabolism is characterized by independent cellular metabolism and intercellular metabolic coupling.However,spinal cord injury results in metabolic disorders that include disturbances in glucose metabolism,lipid metabolism,and mitochondrial dysfunction.These metabolic disturbances lead to corresponding pathological changes,including the failure of axonal regeneration,the accumulation of scarring,and the activation of microglia.To rescue spinal cord injury at the metabolic level,potential metabolic reprogramming approaches have emerged,including replenishing metabolic substrates,reconstituting metabolic couplings,and targeting mitochondrial therapies to alter cell fate.The available evidence suggests that metabolic reprogramming holds great promise as a next-generation approach for the treatment of spinal cord injury.To further advance the metabolic treatment of the spinal cord injury,future efforts should focus on a deeper understanding of neurometabolism,the development of more advanced metabolomics technologies,and the design of highly effective metabolic interventions.
基金supported by Young Elite Scientists Sponsorship Program by China Association for Science and Technology(No.CACM-2023-QNRC1–02)Shandong Province Key R&D Program(Major Technological Innovation Project)(No.2021CXGC010501)+6 种基金National Natural Science Foundation of China(No.22107059)Natural Science Foundation of Shandong Province(No.ZR2021QH057)Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China(No.2021KJ035)Taishan Scholars Program(No.TSQN202211221)Shandong Science Fund for Excellent Young Scholars(No.ZR2022YQ66)Funded by Shandong Postdoctoral Science Foundation(No.SDCX-ZG-202400084)the National Administration of Traditional Chinese Medicine Young Qihuang Scholar Project。
文摘Drug resistance poses a significant challenge to effective long-term treatment across various medical fields.This study proposed a feasible strategy to enhance lysosomal alkalinization by transporting mitochondria-targeting quaternary ammonium salts into lysosomes,creating a deprotonated environment.This environment allows drugs to bypass protonation issues in lysosomes,thereby reversing drug resistance and improving therapeutic efficacy.As a proof of concept,a quaternary ammonium salt-based pH indicator was developed,berberrubine(BRB),enhancing the action of the anticancer drug hydroxycamptothecin(HCPT)in resistant cells.BRB-induced alkalinization increased lysosomal pH and deactivated lysosomal activity,enabling HCPT to bypass protonation constraints.This enhancement markedly improved the anticancer efficacy of HCPT in resistant cells,providing an innovative approach to address drug resistance and advancing therapeutic technologies.
基金supported by National Natural Science Foundation of China (Nos. 22107059, 21801158, 81870283, 82070382)Program of Taishan Scholars Programme (No. 20190979)+3 种基金Academic Promotion Programme of Shandong First Medical University (No.2019LJ003)National Postdoctoral Program for Innovative Talents(No. BX2021123)The China Postdoctoral Science Foundation (No.2021M691505)the Jiangsu Postdoctoral Research Funding Program (No. 2021K125B)。
文摘Theranostic visualization of dextran at the nanoscale is beneficial for understanding the bioregulatory mechanisms of this molecule. In this study, we applied structured illumination microscopy(SIM) to capture the distribution of Cy5-Dextran at different incubation periods in living cells. The results showed that Cy5-Dextran could be absorbed by He La cells. In addition, we clarified that Cy5-Dextran exhibited differential organelle distribution(lysosomal or mitochondrial) in a time-dependent manner. Moreover,lysosomal Cy5-Dextran localization was found to be independent of the autophagy process, while Cy5-Dextran localized to the mitochondria triggered a pro-apoptotic event, upregulating the levels of reactive oxygen species(ROS) to accelerate mitochondrial fragmentation. This work uses a visualized strategy to reveal the anti-tumor bioactivity of dextran, which was achieved by regulating apoptosis and autophagy.
基金supported by NSFC-NWO International Cooper-ation project under Grant 52161135201by National Natural and Science Foundation of China under Grant U2066205。
文摘Equilibrium analysis has been widely studied as an effective tool to model gaming interactions and predict market results.However,as competition modes are fundamentally changed by the decarbonization and decentralization of power systems,analysis techniques must evolve.This article comprehensively reviews recent developments in modelling methods,practical settings and solution tech-niques in equilibrium analysis.Firstly,we review equilibrium in the evolving wholesale power markets which feature new entrants,novel trading products and multi-stage clearing.Secondly,the competition modes in the emerging distribution market and distributed resource aggregation are reviewed,and we compare peer-to-peer clearing,cooperative games and Stackelberg games.Further-more,we summarize the methods to treat various information acquisition degrees,risk preferences and rationalities of market par-ticipants.To deal with increasingly complex market settings,this review also covers refined analytical techniques and agent-based models used to compute the equilibrium.Finally,based on this review,this paper summarizes key issues in the gaming and equilibrium analysis in power markets under decarbonization and decentralization.
基金supported by the National Natural Science Foundation of China(Nos.22073042,22122302,U1932147 to Xixi Hu,and No.21733006 to Daiqian Xie)the Fundamental Research Funds for the central universities(No.14380020)。
文摘In this work,high-fidelity full-dimensional potential energy surfaces(PESs)of the ground(X^(2)A′)and first doublet excited(A^(2)A″)electronic states of HCO were constructed using neural network method.In total,4624 high-level ab initio points have been used which were calculated at Davidson corrected internally contracted MRCI-F12 level of theory with a quite large basis set(ACV5Z)without any scaling scheme.Compared with the results obtained from the scaled PESs of Ndenguéet al.,the absorption spectrum based on our PESs has slightly larger intensity,and the peak positions are shifted to smaller energy for dozens of wavenumbers.It is indicated that the scaling of potential energy may make some unpredictable difference on the dynamical results.However,the resonance energies based on those scaled PESs are slightly closer to the current available experimental values than ours.Nevertheless,the unscaled high-level PESs developed in this work might provide a platform for further experimental and theoretical photodissociation and collisional dynamic studies for HCO system.
基金supported by Shandong Province Key R&D Program,China(Major Technological Innovation Project)(Grant No.:2021CXGC010501)Young Elite Scientists Sponsorship Program by China Association of Chinese Medicine,China(Grant No.:CACM-2023-QNRC1-02)+8 种基金the National Natural Science Foundation of China(Grant Nos.:22107059,22007060,82302743)the Natural Science Foundation of Shandong Province,China(Grant Nos.:ZR2022QH304,ZR2021QH057,ZR2020QB166)the Program for Youth Innovation Technology in Colleges and Universities of Shandong Province of China(Grant No.:2021KJ035)Taishan Scholars Program,China(Grant Nos.:TSQN202211221,TSPD20181218)Shandong Science Fund for Excellent Young Scholars,China(Grant No.:ZR2022YQ66)Shandong Province Traditional Chinese Medicine Science and Technology Project,China(Grant No.:Q-2023059)Shenzhen Basic Research Project,China(Grant No.:JCYJ20190809160209449)the General Project of Shandong Natural Science Foundation,China(Grant No.:ZR2021MH341)Jinan Innovation Team Project of Colleges and Universities,China(Grant No.:2021GXRC072).
文摘Unlike chemosynthetic drugs designed for specific molecular and disease targets,active small-molecule natural products typically have a wide range of bioactivities and multiple targets,necessitating extensive screening and development.To address this issue,we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action.As a proof-of-concept,we investigated the behavior of mussel oligosaccharide(MOS-1)by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells.We recorded the entire dynamic process of the localization of fluorescein isothiocyanate(FITC)-MOS-1 to the lysosomes and visualized the distribution of the drug within the cell.Remarkably,lysosomes containing FITC-MOS-1 actively recruited lipid droplets,leading to fusion events and increased cellular lipid consumption.These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases.Furthermore,in a high-fat HepG2 cell model and in high-fat diet-fed apolipoprotein E(ApoE)^(-/-)mice,MOS-1 significantly promoted triglyceride degradation,reduced lipid droplet accumulation,lowered serum triglyceride levels,and mitigated liver damage and steatosis.Overall,our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase,as this methodology contributes to the rapid identification of drug indications.Collectively,this methodology is significant for the screening and development of selective small-molecule drugs,and is expected to expedite the identification of candidate molecules with medicinal effects.
基金financially supported by the National Key Research and Development Program(Grant Nos.2024YFA1108200 and 2021YFA1101301)the National Natural Science Foundation of China(Grant Nos.82225027,82330062,92468204,82271418,82001308,and 82271419)the Fundamental Research Funds for the Central Universities(Grant No.22120230292).
文摘Scarring is an insurmountable obstacle for axonal regeneration in recovery from spinal cord injury(SCI).It impedes the repair effects of therapeutic targets in cortical neurons,such as PTEN^(-/-)and hyper-IL-6,which cannot break through dense scar barriers to reconstruct neural circuits.However,methods for eliminating this process remain elusive.Here,we conducted a multiomics analysis of SCI and identified FBXL12 as an effective target for inhibiting scarring,further promoting spontaneous crossing of axons at the epicenter.We identified N6-Methyladenosine(m6A)modification as the predominant mRNA modification in SCI,with Fbxl12 being a major modification target.Furthermore,m6A modification specifically promoted FBXL12 synthesis in activated microglia.The overexpression of FBXL12 in microglia contributed to its homogeneous distribution and maintained a“scar-less healing”phenotype.Remarkably,FBXL12 therapy effectively reduced extracellular matrix deposition and decreased the scar area by~70%.Importantly,axons grew through the epicenter and reached a length of more than 2.4 mm 56 days post-SCI,significantly improving motor function and reconstructing the neural circuit.Mechanistically,FBXL12 promoted cytoskeletal reorganization and migration in microglia by catalyzing the K63-linked ubiquitylation of Myosin heavy chain 14(MYH14).Together,our results identify m6A-FBXL12-MYH14 axis as a novel cytoskeletal reorganization pathway in activated microglia and suggest FBXL12 as an effective target for a novel microglia-based approach to facilitate scarless functional recovery in SCI.
基金supported by the National Natural Science Foundation of China(No.82003566)Henan Excellent Youth Found(No.242300421091,China)Program for Inno-vative Research Team(in Science and Technology)in University of Henan Province(24IRTSTHN039,China).
文摘Lysosomes represent a promising target for cancer therapy and reducing drug resistance.However,the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs.In this study,we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug,namely long-term lysosome-targeting anticancer drug(LLAD).It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes.Upon short term and low-dose treatment of HeLa cells,at passage 0,with LLAD,it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15.LLAD induced apoptosis in HeLa cells through long-term lysosomal damage,and showed better long-term anticancer effect than cisplatin in vivo.Overall,our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells,and also provides a candidate drug,LLAD,for treating cancer.
基金supported by the DATALESs project(No.482.20.602)jointly financed by the Netherlands Organization for Scientific Research(NWO)and the National Natural Science Foundation of China.
文摘The optimal dispatch of energy storage systems(ESSs)in distribution networks poses significant challenges,primarily due to uncertainties of dynamic pricing,fluctuating demand,and the variability inherent in renewable energy sources.By exploiting the generalization capabilities of deep neural networks(DNNs),the deep reinforcement learning(DRL)algorithms can learn good-quality control models that adapt to the stochastic nature of distribution networks.Nevertheless,the practical deployment of DRL algorithms is often hampered by their limited capacity for satisfying operational constraints in real time,which is a crucial requirement for ensuring the reliability and feasibility of control actions during online operations.This paper introduces an innovative framework,named mixed-integer programming based deep reinforcement learning(MIP-DRL),to overcome these limitations.The proposed MIP-DRL framework can rigorously enforce operational constraints for the optimal dispatch of ESSs during the online execution.This framework involves training a Q-function with DNNs,which is subsequently represented in a mixed-integer programming(MIP)formulation.This unique combination allows for the seamless integration of operational constraints into the decision-making process.The effectiveness of the proposed MIP-DRL framework is validated through numerical simulations,demonstrating its superior capability to enforce all operational constraints and achieve high-quality dispatch decisions and showing its advantage over existing DRL algorithms.
基金supported by the Technology Project from China Electric Power Planning&Engineering Institute(No.K202312)。
文摘Deep learning technology is identified as a valid tool for transient stability assessment(TSA).Moreover,the superior performance of the TSA model depends on generously labeled samples.However,the power grid is dynamic,and some topologies or operation conditions change substantially.The traditional method generates a significant quantity of samples for each specific topology.Nonetheless,generating these labeled samples and establishing TSA models is very time-consuming.This paper proposes a high-quality sample generation framework based on data-driven methods to build a high-quality offline samples database for TSA model training and updating.Firstly,the representative topologies provided by the system operator are clustered into four different categories by density-based spatial clustering of applications with noise(DBSCAN).Thus the corresponding samples are collected.Then,when a new topology is encountered in the online application,scenario matching is used to match the most similar topology category.After that,instance-based transfer learning is implemented from a database of the best-matched topology category.Finally,a deep convolutional generative adversarial network(DCGAN)is constructed to mitigate the class imbalance problem.That is,unstable scenarios occur far more rarely than stable scenarios.Consequently,a high-quality and balanced TSA model training and updating database is constructed.The comprehensive test results on the Central China Power Grid illustrate that the proposed framework can generate high-quality and balanced TSA samples.Furthermore,the sample generation time is dramatically shortened.In addition,the metrics of accuracy,reliability and adaptability of the TSA model are significantly enhanced.
基金supported by CRP-ICGEB Research Grant 2019(Grant number:CRP/CHN19-02)National Key Research and Development Program of China(Grant number:2016YFD0500300)supported by the Special Coronavirus(COVID-19)Research Pilot Grant Program from University of Cincinnati College of Medicine.
文摘The COVID-19 pandemic has underscored the importance of in-depth research into the proteins encoded by coronaviruses(CoV),particularly the highly conserved nonstructural CoV proteins(nsp).Among these,the nsp13 helicase of severe pathogenic MERS-CoV,SARS-CoV-2,and SARS-CoV is one of the most preserved CoV nsp.Utilizing single-molecule FRET,we discovered that MERS-CoV nsp13 unwinds DNA in distinct steps of about 9 bp when ATP is employed.If a different nucleotide is introduced,these steps diminish to 3−4 bp.Dwell-time analysis revealed 3−4 concealed steps within each unwinding process,which suggests the hydrolysis of 3−4 dTTP.Combining our observations with previous studies,we propose an unwinding model of CoV nsp13 helicase.This model suggests that the elongated and adaptable 1B-stalk of nsp13 may enable the 1B remnants to engage with the unwound single-stranded DNA,even as the helicase core domain has advanced over 3−4 bp,thereby inducing accumulated strain on the nsp13-DNA complex.Our findings provide a foundational framework for determining the unwinding mechanism of this unique helicase family.
基金part of the DATALESs project(with project number 482.20.602)jointly financed by the Netherlands Organization for Scientific Research(NWO)the National Natural Science Foundation of China(NSFC)。
文摘The integration of distributed energy resources(DERs)has escalated the challenge of voltage magnitude regulation in distribution networks.Model-based approaches,which rely on complex sequential mathematical formulations,cannot meet the real-time demand.Deep reinforcement learning(DRL)offers an alternative by utilizing offline training with distribution network simulators and then executing online without computation.However,DRL algorithms fail to enforce voltage magnitude constraints during training and testing,potentially leading to serious operational violations.To tackle these challenges,we introduce a novel safe-guaranteed reinforcement learning algorithm,the Dist Flow safe reinforcement learning(DF-SRL),designed specifically for real-time voltage magnitude regulation in distribution networks.The DF-SRL algorithm incorporates a Dist Flow linearization to construct an expert-knowledge-based safety layer.Subsequently,the DF-SRL algorithm overlays this safety layer on top of the agent policy,recalibrating unsafe actions to safe domains through a quadratic programming formulation.Simulation results show the DF-SRL algorithm consistently ensures voltage magnitude constraints during training and real-time operation(test)phases,achieving faster convergence and higher performance,which differentiates it apart from(safe)DRL benchmark algorithms.
基金supported by the National Science Fund for Distinguished Young Scholars (No. 51325702)
文摘The smart grid has been revolutionizing electrical generation and consumption through a two-way flow of power and information. As an important information source from the demand side, Advanced Metering Infrastructure （AMI） has gained increasing popularity all over the world. By making full use of the data gathered by AMI, stakeholders of the electrical industry can have a better understanding of electrical consumption behavior. This is a significant strategy to improve operation efficiency and enhance power grid reliability. To implement this strategy, researchers have explored many data mining techniques for load profiling. This paper performs a state-of-the-art, comprehensive review of these data mining techniques from the perspectives of different technical approaches including direct clustering, indirect clustering, clustering evaluation criteria, and customer segmentation. On this basis, the prospects for implementing load profiling to demand response applications, price-based and incentivebased, are further summarized. Finally, challenges and opportunities of load profiling techniques in future power industry, especially in a demand response world, are discussed.
基金supported by National Natural Science Foundation of China(Grant No.51872224,81772379,81972096 and 81902238)Zhejiang Province Health Foundation,China(Grant No.2018KY092,WKJ-ZJ-1903)Nature Science Foundation of Zhejiang Province,China(Grant No.LQ18H060003).
文摘The repair and motor functional recovery after spinal cord injury(SCI)remains a worldwide challenge.The inflammatory microenvironment is one of main obstacles on inhibiting the recovery of SCI.Using mesenchymal stem cells(MSCs)derived extracellular vesicles to replace MSCs transplantation and mimic cell paracrine secretions provides a potential strategy for microenvironment regulation.However,the effective preservation and controlled release of extracellular vesicles in the injured spinal cord tissue are still not satisfied.Herein,we fabricated an injectable adhesive anti-inflammatory F127-polycitrate-polyethyleneimine hydrogel(FE)with sustainable and long term extracellular vesicle release(FE@EVs)for improving motor functional recovery after SCI.The orthotopic injection of FE@EVs hydrogel could encapsulate extracellular vesicles on the injured spinal cord,thereby synergistically induce efficient integrated regulation through suppressing fibrotic scar formation,reducing inflammatory reaction,promoting remyelination and axonal regeneration.This study showed that combining extracellular vesicles into bioactive multifunctional hydrogel should have great potential in achieving satisfactory locomotor recovery of central nervous system diseases.
基金supported by the Medical and Health Innovation Talent Support Program of Zhejiang Province,China[Grant No.2020RC011]the National Natural Science Foundation of China,China[Grant NO.81772379,81972096,81902238,82002327,82072465 and 82072481].
文摘The current effective method for treatment of spinal cord injury(SCI)is to reconstruct the biological microenvironment by filling the injured cavity area and increasing neuronal differentiation of neural stem cells(NSCs)to repair SCI.However,the method is characterized by several challenges including irregular wounds,and mechanical and electrical mismatch of the material-tissue interface.In the current study,a unique and facile agarose/gelatin/polypyrrole(Aga/Gel/PPy,AGP3)hydrogel with similar conductivity and modulus as the spinal cord was developed by altering the concentration of Aga and PPy.The gelation occurred through non-covalent interactions,and the physically crosslinked features made the AGP3 hydrogels injectable.In vitro cultures showed that AGP3 hydrogel exhibited excellent biocompatibility,and promoted differentiation of NSCs toward neurons whereas it inhibited over-proliferation of astrocytes.The in vivo implanted AGP3 hydrogel completely covered the tissue defects and reduced injured cavity areas.In vivo studies further showed that the AGP3 hydrogel provided a biocompatible microenvironment for promoting endogenous neurogenesis rather than glial fibrosis formation,resulting in significant functional recovery.RNA sequencing analysis further indicated that AGP3 hydrogel significantly modulated expression of neurogenesis-related genes through intracellular Ca2+signaling cascades.Overall,this supramolecular strategy produces AGP3 hydrogel that can be used as favorable biomaterials for SCI repair by filling the cavity and imitating the physiological properties of the spinal cord.
基金the National Basic Research Program of China (No. 2015CB856300)Natural Science Foundation of Shandong Province (Nos. ZR2017PH072, ZR2017BH051, and ZR2015QL007)Key Research and Development Plan of Shandong Province (No. 2018GSF121033). K. Z. was supported by the University of Illinois at Urbana-Champaign.The Light Microscopy Imaging Center (LMIC) is supported in part with funds from Indiana University Office of the Vice Provost for Research. The 3D-SIM microscope was provided by NIH grant NIH1S100D024988-01.
文摘Technology advances in genomics,proteomics,and metabolomics largely expanded the pool of potential therapeutic targets.Compared with the in vitro setting,cell-based screening assays have been playing a key role in the processes of drug discovery and development.Besides the commonly used strategies based on colorimetric and cell viability,we reason that methods that capture the dynamic cellular events will facilitate optimal hit identification with high sensitivity and specificity.Herein,we propose a live-cell screening strategy using structured illumination microscopy (SIM) combined with an automated cell colocalization analysis software,CellprofilerTM,to screen and discover drugs for mitochondria and lysosomes interaction at a nanoscale resolution in living cells.This strategy quantitatively benchmarks the mitochondria-lysosome interactions such as mitochondria and lysosomes contact (MLC) and mitophagy.The automatic quantitative analysis also resolves fine changes of the mitochondria-lysosome interaction in response to genetic and pharmacological interventions.Super-resolution live-cell imaging on the basis of quantitative analysis opens up new avenues for drug screening and development by targeting dynamic organelle interactions at the nanoscale resolution,which could facilitate optimal hit identification and potentially shorten the cycle of drug discovery.
基金This study was supported by grants from the Nature Science Foundation of Zhejiang Province(Y20H060063,LY19H060005,LQ18H060003,LR18E030002,LY18H060004)the Medical and Health Innovation Talent Support Program of Zhejiang Province(2020RC011)+5 种基金the National Natural Science Foundation of China(NO.82072465,NO.81772379,NO.81972096,NO.81902238,NO.21774109,NO.51973188,NO.51522304)the Health Foundation of Zhejiang Province(2018KY092,WKJ-ZJ-1903)the China Postdoctoral Science Foundation(2017M612011)the Zhejiang University Education Foundation Global Partnership Fund,a project supported by the Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476 and Y201941491)Zhejiang Undergraduate Talent Project(grant no.2020R401212)the Scientific Research Fund of Zhejiang Provincial Education Department(Y201941476).
文摘Cell transplantation has been proved the promising therapeutic effects on intervertebral disc degeneration(IVDD).However,the increased levels of reactive oxygen species(ROS)in the degenerated region will impede the efficiency of human adipose-derived stem cells(human ADSCs)transplantation therapy.It inhibits human ADSCs proliferation,and increases human ADSCs apoptosis.Herein,we firstly devised a novel amphiphilic copolymer PEG-PAPO,which could self-assemble into a nanosized micelle and load lipophilic kartogenin(KGN),as a single complex(PAKM).It was an injectable esterase-responsive micelle,and showed controlled release ability of KGN and apocynin(APO).Oxidative stimulation promoted the esterase activity in human ADSCs,which accelerate degradation of esterase-responsive micelle.Compared its monomer,the PAKM micelle possessed better bioactivities,which were attributed to their synergistic effect.It enhanced the viability,autophagic activation(P62,LC3 II),ECM-related transcription factor(SOX9),and ECM(Collagen II,Aggrecan)maintenance in human ADSCs.Furthermore,it is demonstrated that the injection of PAKM with human ADSCs yielded higher disc height and water content in rats.Therefore,PAKM micelles perform promoting cell survival and differentiation effects,and may be a potential therapeutic agent for IVDD.
基金supported by Major International (Regional) Joint Research Project of National Natural Science Foundation of China (No. 51620105007)Scientific Research Project of Guangdong Electric Power Research Institute
文摘The high penetration of distributed renewable energy raises a higher concern for the safe and economic operation of the smart grid. Distributed batteries equipped in demand-side can not only contribute to the reliability and security of the grid, but also make profits by participating in the electricity market, especially when distributed batteries are combined and operated by an aggregator.Considering the well-operated mechanism of performance based regulation(PBR) in the U.S. electricity market, it becomes increasingly lucrative for batteries to participate not only in energy markets for energy arbitrage, but also in ancillary service markets to provide regulation and peakload shaving services. In this study, distributed batteries are operated and coordinated by the aggregator, which simultaneously submits offers to the energy and the ancillary service markets as an individual entity. An optimaldecision model is formulated for the aggregator to determine the operation and bidding strategy for the distributed batteries by considering the characteristics of batteries,including the terms of capacity, efficiency and degradation cost. Finally, a numerical case is conducted to evaluate the benefits of the decision model.
基金supported in part by the National Natural Science Foundation of China(No.51620105007)in part the UNSW(University of New South Wales)&Tsinghua University Collaborative Research Fund(RG193827/2018Z)。
文摘With the increasing penetration of renewables,power systems have to operate with greater flexibility to address the uncertainties of renewable output.This paper develops an uncertainty locational marginal price(ULMP)mechanism to price these uncertainties.They are denoted as box deviation intervals as suggested by the market participants.The ULMP model solves a robust optimal power flow(OPF)problem to clear market bids,aiming to minimize the system cost as a prerequisite that the reserve margin can address all the relevant uncertainties.The ULMP can be obtained as a by-product of the optimization problem from the Lagrange multipliers.Under the ULMP mechanism,renewables and consumers with uncertainty will make extra payments,and the thermals and financial transmission right(FTR)holders will be compensated.It is further shown that the proposed mechanism has preferable properties,such as social efficiency,budget balance and individual rationality.Numerical tests are conducted on the modified IEEE 5-bus and 118-bus systems to demonstrate the merits and applicability of the proposed mechanism.
基金This work was supported by the Special Project for the Shandong Provincial Key Laboratory(No.SDKL2017023)the National key R&D Plan Key Research Projects of Modernization of Traditional Chinese Medicine(No.2019 YFC1711203)+1 种基金Shandong Provincial Enterprise Project for Talents Development to P.X.L.,Key Research and Development Plan of Shandong Province(Nos.2018GSF121033,2019GSF108225,and 2019JZZY010520)Outstanding Contribution to the Shandong Middle-aged and Young Experts to F.L.,Academic promotion program of Shandong First Medical University(No.2019LJ003)to Q.X.C.We also thank Dr.Taosheng Huang for kindly gifted SLC25A46 normal and mutant cell line.
文摘Mitochondrial damage,characterized by altered morphological distribution and the damage of cristae,is closely associated with mitochondrial disease.However,imaging methods for capturing mitochondrial morphology at the nanoscale level in live samples remain unavailable,which seriously hinders the accurate evaluation and diagnosis of mitochondrial-related diseases.In response,we propose a super-resolution quantification strategy based on structured illumination microscopy(SIM)for the rapid,accurate evaluation of mitochondrial morphology.Using the strategy,we accurately captured the morphological distribution of mitochondria at the nanoscale level in a way generally applicable to checking various cell processes and identifying patients with mitochondrial disease who exhibit the SLC25A46 mutation.We also used algorithm-assisted super-resolution imaging to quantitatively analyze damage to mitochondrial cristae,which supports a novel drug screening strategy—high-resolution drug screening—for investigating drugs’pharmacodynamics on organelles in living cells.In short,our strategy improves the accurate examination of changes in mitochondrial morphology in living cells and indicates new ways in which SIM-imaging can assist in diagnosing mitochondrial disease at the single-cell level.
