Traditional Chinese medicine(TCM)exerts integrative effects on complex diseases owing to the characteristics of multiple components with multiple targets.However,the syndrome-based system of diagnosis and treatment in...Traditional Chinese medicine(TCM)exerts integrative effects on complex diseases owing to the characteristics of multiple components with multiple targets.However,the syndrome-based system of diagnosis and treatment in TCM can easily lead to bias because of varying medication preferences among physicians,which has been a major challenge in the global acceptance and application of TCM.Therefore,a standardized TCM prescription system needs to be explored to promote its clinical application.In this study,we first developed a gradient weighted disease-target-herbal ingredient-herb network to aid TCM formulation.We tested its efficacy against intracerebral hemorrhage(ICH).First,the top 100 ICH targets in the GeneCards database were screened according to their relevance scores.Then,SymMap and Traditional Chinese Medicine Systems Pharmacology(TCMSP)databases were applied to find out the target-related ingredients and ingredient-containing herbs,respectively.The relevance of the resulting ingredients and herbs to ICH was determined by adding the relevance scores of the corresponding targets.The top five ICH therapeutic herbs were combined to form a tailored TCM prescriptions.The absorbed components in the serum were detected.In a mouse model of ICH,the new prescription exerted multifaceted effects,including improved neurological function,as well as attenuated neuronal damage,cell apoptosis,vascular leakage,and neuroinflammation.These effects matched well with the core pathological changes in ICH.The multi-targets-directed gradient-weighting strategy presents a promising avenue for tailoring precise,multipronged,unbiased,and standardized TCM prescriptions for complex diseases.This study provides a paradigm for advanced achievements-driven modern innovation in TCM concepts.展开更多
Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challengin...Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.展开更多
As a crucial process in the coordinated strikes of unmanned aerial vehicles(UAVs), weapon-target assignment is vital for optimizing the allocation of available weapons and effectively exploiting the capabilities of UA...As a crucial process in the coordinated strikes of unmanned aerial vehicles(UAVs), weapon-target assignment is vital for optimizing the allocation of available weapons and effectively exploiting the capabilities of UAVs. Existing weapon-target assignment methods primarily focus on macro cluster constraints while neglecting individual strategy updates. This paper proposes a novel weapon-target assignment method for UAVs based on the multi-strategy threshold public goods game(PGG). By analyzing the concept mapping between weapon-target assignment for UAVs and multi-strategy threshold PGG, a weapon-target assignment model for UAVs based on the multi-strategy threshold PGG is established, which is adaptively complemented by the diverse cooperation-defection strategy library and the utility function based on the threshold mechanism. Additionally, a multi-chain Markov is formulated to quantitatively describe the stochastic evolutionary dynamics, whose evolutionary stable distribution is theoretically derived through the development of a strategy update rule based on preference-based aspiration dynamic. Numerical simulation results validate the feasibility and effectiveness of the proposed method, and the impacts of selection intensity, preference degree and threshold on the evolutionary stable distribution are analyzed. Comparative simulations show that the proposed method outperforms GWO, DE, and NSGA-II, achieving 17.18% higher expected utility than NSGA-II and reducing evolutionary stable times by 25% in large-scale scenario.展开更多
When the space robot captures a floating target, contact impact occurs inevitably and frequently between the manipulator hand and the target, which seriously impacts the position and attitude of the robot and grasping...When the space robot captures a floating target, contact impact occurs inevitably and frequently between the manipulator hand and the target, which seriously impacts the position and attitude of the robot and grasping security. ＂Dynamic grasping area＂ is introduced to describe the collision process of manipulator grasping target, and grasping area control equation is established. By analyzing the impact of grasping control parameters, base and target mass on the grasping process and combining the life experience, it is found that if the product of speed control parameter and dB adjustment parameter is close to but smaller than the minimum grasping speed, collision impact in the grasping process could be reduced greatly, and then an ideal grasping strategy is proposed. Simulation results indicate that during the same period, the strategy grasping is superior to the accelerating grasping, in that the amplitude of impact force is reduced to 20%, and the attitude control torque is reduced to 15%, and the impact on the robot is eliminated significantly. The results would have important academic value and engineering significance.展开更多
Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxyge...Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.展开更多
A situation maintenance-based cooperative guidance strategy is proposed to intercept a high-speed and high-maneuverability target via inferior missiles.Reachability and relative motion analyses are conducted to develo...A situation maintenance-based cooperative guidance strategy is proposed to intercept a high-speed and high-maneuverability target via inferior missiles.Reachability and relative motion analyses are conducted to develop and pursue virtual targets,respectively.A two-stage guidance strategy under nonlinear kinematics is developed on the basis of virtual targets.The first stage optimizes the coverage and collision situation by pursuing virtual targets under specific angular constraints.The second stage subsequently intercepts the superior target based on the handover condition optimized by the first stage.Numerical simulation results are provided to compare the effectiveness and superiority of the proposed strategy with those of the reachability-based cooperative strategy(RCS),coverage-based cooperative guidance(CBCG)and augmented proportional navigation(APN)under various maneuvering modes.展开更多
In the process of spraying coating perovskite films,the"coffee ring"effect(CRE)leads to the problem of excessive organic ammonium salt accumulation in local areas that cannot be completely eliminated.We intr...In the process of spraying coating perovskite films,the"coffee ring"effect(CRE)leads to the problem of excessive organic ammonium salt accumulation in local areas that cannot be completely eliminated.We introduce an in-situ targeted defect-healing strategy by incorporating butylamine formate(BAFa)ionic liquid into the spray ink.Ionic liquids,due to their long carbon chain structure,tend to target flow towards the CRE region during the droplet evaporation process.The coordination between the lone pair electrons in the C=O group of BAFa and Pb^(2+)effectively reduces defects in perovskite and suppresses non-radiative recombination losses.Simultaneously,amine ligands,which are repelled to the film surface and grain boundaries,form a thin insulating monolayer in the CRE areas,forcing charge carriers to transport through areas of the perovskite with fewer defects.This approach enables the crystallization control and defect-heal over the Cs_(0.19)FA_(0.81)PbI_(3-x-y)Br_(x)Cl_(y)perovskite films.Consequently,the champion perovskite solar cell achieved a power conversion efficiency of 22.04%,while mini-modules with an effective area of 64.8 cm^(2)reached a peak power conversion efficiency of 18.35%,demonstrating the significant potential for commercializing large-area perovskite solar cells.展开更多
In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to elimin...In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.展开更多
Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic dru...Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic drugs with minimal side effects[1].Recently,natural medicine has garnered significant attention due to its remarkable efficacy and limited side effects.Icariin,a naturally occurring flavonoid,exhibits excellent potential as a therapeutic agent for neurodegenerative disease[2].However,its clinical application is limited by poor water solubility,low bioavailability,and high clearance rates.Here,an aqueous formulation of icariin/hydroxypropyl-β-cyclodextrin(HP-β-CD)supramolecular inclusion complex was obtained to optimize icariin properties.Furthermore,icariin cyclodextrin supramolecular inclusion complex based thermosensitive(icariin gels)was innovated.At lower temperatures,it remained in a liquid phase with high fluidity.Upon reaching the gelation temperature,it underwent a transition to a gel phase with significantly reduced fluidity,which may be suitable for the design of an intranasal delivery system for PD treatment.The innovative approach capitalizes on the exceptional characteristics of HP-β-CD,which was utilized to synergize with nasal delivery for targeted brain delivery and with icariin for PD treatment[3,4].展开更多
Traditional Chinese medicine(TCM),especially the plant-based,represents complex chemical system containing various primary and secondary metabolites.These botanical metabolites are structurally diversified and exhibit...Traditional Chinese medicine(TCM),especially the plant-based,represents complex chemical system containing various primary and secondary metabolites.These botanical metabolites are structurally diversified and exhibit significant difference in the acidity,alkalinity,molecular weight,polarity,and content,etc,which thus poses great challenges in assessing the quality of TCM[1].展开更多
This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulato...This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.展开更多
Cooperative interception of the target with strong maneuverability by multiple missiles with weak maneuverability in the three-dimensional nonlinear model is studied.Firstly,the three-dimensional nonlinear model of co...Cooperative interception of the target with strong maneuverability by multiple missiles with weak maneuverability in the three-dimensional nonlinear model is studied.Firstly,the three-dimensional nonlinear model of cooperative guidance is established.The three-dimensional reachable region is represented composed of lateral acceleration and longitudinal acceleration in the two-dimensional coordinate system.Secondly,the problem of the multiple missile’s reachable coverage area is transformed into the problem of cooperative coverage.A cooperative coverage strategy is proposed and an algorithm for quickly calculating the number of required missiles is designed.Then,the guidance law based on the cooperative coverage strategy is proposed,and it is proved that cooperative interception of the target can be achieved under the acceleration limit.Moreover,the relations among the number of missiles,the initial array position of terminal guidance and the coverage area of the target’s large maneuver are analyzed.The dynamic adjustment strategy of guidance parameters is proposed to reduce the guidance error.Finally,simulation results show that multiple missiles with low maneuverability can achieve effective interception of target with strong maneuverability through the proposed cooperative strategy and cooperative guidance method.展开更多
The rotational motion of a tumbling target brings great challenges to space robot on successfully capturing the tumbling target.Therefore,it is necessary to reduce the target's rotation to a rate at which capture ...The rotational motion of a tumbling target brings great challenges to space robot on successfully capturing the tumbling target.Therefore,it is necessary to reduce the target's rotation to a rate at which capture can be accomplished by the space robot.In this paper,a detumbling strategy based on friction control of dual-arm space robot for capturing tumbling target is proposed.This strategy can reduce the target's rotational velocity while maintaining base attitude stability through the establishment of the rotation attenuation controller and base attitude adjustment controller.The rotation attenuation controller adopts the multi-space hybrid impedance control method to control the friction precisely.The base attitude adjustment controller applies the dual-arm extended Jacobian matrix to stabilize the base attitude.The main contributions of this paper are as follows:(1)The compliant control method is adopted to achieve a precise friction control,which can reduce the target angular velocity steadily;(2)The dual-arm extended Jacobian matrix is applied to stabilize the base attitude without affecting the target capture task;(3)The detumbling strategy of dualarm space robot is designed considering base attitude stabilization,realizing coordinated planning of the base attitude and the arms.The strategy is verified by a dual-arm space robot with two 7-DOF(degrees of freedom)arms.Simulation results show that,target with a rotation velocity of 20(°)/s can be effectively controlled to stop within 30 s,and the final deflection of the base attitude is less than 0.15°without affecting the target capture task,verifying the correctness and effectiveness of the strategy.Except to the tumbling target capture task,the control strategy can also be applied to other typical on-orbit operation tasks such as space debris removal and spacecraft maintenance.展开更多
Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in cl...Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.展开更多
As a core component of the network,web applications have become one of the preferred targets for attackers because the static configuration of web applications simplifies the exploitation of vulnerabilities by attacke...As a core component of the network,web applications have become one of the preferred targets for attackers because the static configuration of web applications simplifies the exploitation of vulnerabilities by attackers.Although the moving target defense(MTD)has been proposed to increase the attack difficulty for the attackers,there is no solo approach can cope with different attacks;in addition,it is impossible to implement all these approaches simultaneously due to the resource limitation.Thus,the selection of an optimal defense strategy based on MTD has become the focus of research.In general,the confrontation of two players in the security domain is viewed as a stochastic game,and the reward matrices are known to both players.However,in a real security confrontation,this scenario represents an incomplete information game.Each player can only observe the actions performed by the opponent,and the observed actions are not completely accurate.To accurately describe the attacker’s reward function to reach the Nash equilibrium,this work simulated and updated the strategy selection distribution of the attacker by observing and investigating the strategy selection history of the attacker.Next,the possible rewards of the attacker in each confrontation via the observation matrix were corrected.On this basis,the Nash-Q learning algorithm with reward quantification was proposed to select the optimal strategy.Moreover,the performances of the Minimax-Q learning algorithm and Naive-Q learning algorithm were compared and analyzed in the MTD environment.Finally,the experimental results showed that the strategy selection algorithm can enable defenders to select a more reasonable defensive strategy and achieve the maximum possible reward.展开更多
The methods of Traditional Chinese Medicine(TCM)’s diagnosis and treatment have undergone several changes.It is crucial to build a proper model which is capable to modernize TCM into a both standardized and individua...The methods of Traditional Chinese Medicine(TCM)’s diagnosis and treatment have undergone several changes.It is crucial to build a proper model which is capable to modernize TCM into a both standardized and individualized treatment.Tong xiao-lin proposed the state-target strategy to build a bridge for the integration of Chinese and Western medicine.It is a model based on modern medical disease concepts and using the method of TCM to balance the pathological states and adopting the achievements of pharmacology of Chinese medicine to focus on the disease targets,symptom targets,and biochemical indicator targets.The reconstruction of TCM diagnosis and treatment system for diabetes is a good example to demonstrate this theory.It could improve the clinical efficacy,support the scientific research,and reinforce the standardization of TCM.展开更多
Qi-Yu-San-Long decoction(QYSLD)is a traditional Chinese medicine that has been clinically used in the treatment of non-small-cell lung cancer(NSCLC)for more than 20 years.However,to date,metabolicrelated studies on QY...Qi-Yu-San-Long decoction(QYSLD)is a traditional Chinese medicine that has been clinically used in the treatment of non-small-cell lung cancer(NSCLC)for more than 20 years.However,to date,metabolicrelated studies on QYSLD have not been performed.In this study,a post-targeted screening strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight full information tandem mass spectrometry(UPLC-QTOF-MS^(E))was developed to identify QYSLD-related xenobiotics in rat urine.The chemical compound database of QYSLD constituents was established from previous research,and metabolites related to these compounds were predicted in combination with their possible metabolic pathways.The metabolites were identified by extracted ion chromatograms using predicted m/z values as well as retention time,excimer ions,and fragmentation behavior.Overall,85 QYSLD-related xenobiotics(20 prototype compounds and 65 metabolites)were characterized from rat urine.The main metabolic reactions and elimination features of QYSLD included oxidation,reduction,decarboxylation,hydrolysis,demethylation,glucuronidation,sulfation,methylation,deglycosylation,acetylation,and associated combination reactions.Of the identified molecules,14 prototype compounds and 58 metabolites were slowly eliminated,thus accumulating in vivo over an extended period,while five prototypes and two metabolites were present in vivo for a short duration.Furthermore,one prototype and five metabolites underwent the process of“appearing-disappearing-reappearing”in vivo.Overall,the metabolic profile and characteristics of QYSLD in rat urine were determined,which is useful in elucidating the active components of the decoction in vivo,thus providing the basis for studying its mechanism of action.展开更多
Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are lacking.Proteolysis targeting ...Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are lacking.Proteolysis targeting chimera(PROTAC)technology is a novel strategy to solve this problem.PROTAC technology uses the ubiquitin-protease system to eliminate mutated,denatured,and harmful proteins in cells.It can be reused,and utilizes the protein destruction mechanism of the cells,thus making up for the deficiencies of traditional protein degradation methods.It can effectively target and degrade proteins,including proteins that are difficult to identify and bind.Therefore,it has extremely important implications for drug development and the treatment of neurological diseases.At present,the targeted degradation of mutant BTK,mHTT,Tau,EGFR,and other proteins using PROTAC technology is gaining attention.It is expected that corresponding treatment of nervous system diseases can be achieved.This review first focuses on the recent developments in PROTAC technology in terms of protein degradation,drug production,and treatment of central nervous system diseases,and then discusses its limitations.This review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases.展开更多
Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the dis...Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.展开更多
In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the...In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82174259 and 82304997)China Postdoctoral Followship Program of CPSF(Grant No.:GZC20233202)+4 种基金China Postdoctoral Science Foundation(Grant No.:2024M753698)the Key Research and Development Program of Hunan Province of China(Grant Nos.:2023SK2021 and 2022SK2015)the Natural Science Foundation of Hunan Province,China(Grant Nos.:2024JJ6632,2022JJ40853,and 2021JJ31117)the Hunan Traditional Chinese Medicine Scientific Research Program,China(Grant Nos.:B2024113,B2024114,and 2021032)the Fundamental Research Funds for the Central Universities of Central South University,China(Grant No.:1053320232786).
文摘Traditional Chinese medicine(TCM)exerts integrative effects on complex diseases owing to the characteristics of multiple components with multiple targets.However,the syndrome-based system of diagnosis and treatment in TCM can easily lead to bias because of varying medication preferences among physicians,which has been a major challenge in the global acceptance and application of TCM.Therefore,a standardized TCM prescription system needs to be explored to promote its clinical application.In this study,we first developed a gradient weighted disease-target-herbal ingredient-herb network to aid TCM formulation.We tested its efficacy against intracerebral hemorrhage(ICH).First,the top 100 ICH targets in the GeneCards database were screened according to their relevance scores.Then,SymMap and Traditional Chinese Medicine Systems Pharmacology(TCMSP)databases were applied to find out the target-related ingredients and ingredient-containing herbs,respectively.The relevance of the resulting ingredients and herbs to ICH was determined by adding the relevance scores of the corresponding targets.The top five ICH therapeutic herbs were combined to form a tailored TCM prescriptions.The absorbed components in the serum were detected.In a mouse model of ICH,the new prescription exerted multifaceted effects,including improved neurological function,as well as attenuated neuronal damage,cell apoptosis,vascular leakage,and neuroinflammation.These effects matched well with the core pathological changes in ICH.The multi-targets-directed gradient-weighting strategy presents a promising avenue for tailoring precise,multipronged,unbiased,and standardized TCM prescriptions for complex diseases.This study provides a paradigm for advanced achievements-driven modern innovation in TCM concepts.
基金supported by the Science and Technology Development Fund,Macao SAR,China(Grant Nos.:FDCT 0001/2020/AKP and 006/2023/SKL)Guangxi Science and Technology Major Program,China(Program No.:Guike AA22096022).
文摘Targeted covalent inhibitors,primarily targeting cysteine residues,have attracted great attention as potential drug candidates due to good potency and prolonged duration of action.However,their discovery is challenging.In this research,a database-assisted liquid chromatography-tandem mass spectrometry(LC-MS/MS)strategy was developed to quickly discover potential cysteine-targeting compounds.First,compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes.And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database.Second,substrate-independent product ions produced from N-acetyl-cysteine moiety were selected.Third,multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds.This strategy showed broad applicability,and covalent compounds with diverse structures were screened out,offering structural resources for covalent inhibitors development.Moreover,the screened compounds,norketamine and hydroxynorketamine,could modify synaptic transmission-related proteins in vivo,indicating their potential as covalent inhibitors.This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
基金supported by the National Natural Science Foundation of China (No. 62073267)。
文摘As a crucial process in the coordinated strikes of unmanned aerial vehicles(UAVs), weapon-target assignment is vital for optimizing the allocation of available weapons and effectively exploiting the capabilities of UAVs. Existing weapon-target assignment methods primarily focus on macro cluster constraints while neglecting individual strategy updates. This paper proposes a novel weapon-target assignment method for UAVs based on the multi-strategy threshold public goods game(PGG). By analyzing the concept mapping between weapon-target assignment for UAVs and multi-strategy threshold PGG, a weapon-target assignment model for UAVs based on the multi-strategy threshold PGG is established, which is adaptively complemented by the diverse cooperation-defection strategy library and the utility function based on the threshold mechanism. Additionally, a multi-chain Markov is formulated to quantitatively describe the stochastic evolutionary dynamics, whose evolutionary stable distribution is theoretically derived through the development of a strategy update rule based on preference-based aspiration dynamic. Numerical simulation results validate the feasibility and effectiveness of the proposed method, and the impacts of selection intensity, preference degree and threshold on the evolutionary stable distribution are analyzed. Comparative simulations show that the proposed method outperforms GWO, DE, and NSGA-II, achieving 17.18% higher expected utility than NSGA-II and reducing evolutionary stable times by 25% in large-scale scenario.
基金Program for Innovative Research Team in University(IRT520)CAST of China (20090703)
文摘When the space robot captures a floating target, contact impact occurs inevitably and frequently between the manipulator hand and the target, which seriously impacts the position and attitude of the robot and grasping security. ＂Dynamic grasping area＂ is introduced to describe the collision process of manipulator grasping target, and grasping area control equation is established. By analyzing the impact of grasping control parameters, base and target mass on the grasping process and combining the life experience, it is found that if the product of speed control parameter and dB adjustment parameter is close to but smaller than the minimum grasping speed, collision impact in the grasping process could be reduced greatly, and then an ideal grasping strategy is proposed. Simulation results indicate that during the same period, the strategy grasping is superior to the accelerating grasping, in that the amplitude of impact force is reduced to 20%, and the attitude control torque is reduced to 15%, and the impact on the robot is eliminated significantly. The results would have important academic value and engineering significance.
基金support from the National Natural Science Foundation of China(Nos.22277056,21977052)the Distinguished Young Scholars of Jiangsu Province(No.BK20230006)+2 种基金the Natural Science Foundation of Jiangsu Province(Nos.BK20230977,BK20231090)the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province(No.23KJB150020)the Jiangsu Excellent Postdoctoral Program(No.2022ZB758)。
文摘Metal complexes hold significant promise in tumor diagnosis and treatment.However,their potential applications in photodynamic therapy(PDT)are hindered by issues such as poor photostability,low yield of reactive oxygen species(ROS),and aggregation-induced ROS quenching.To address these challenges,we present a molecular self-assembly strategy utilizing aggregation-induced emission(AIE)conjugates for metal complexes.As a proof of concept,we synthesized a mitochondrial-targeting cyclometalated Ir(Ⅲ)photosensitizer Ir-TPE.This approach significantly enhances the photodynamic effect while mitigating the dark toxicity associated with AIE groups.Ir-TPE readily self-assembles into nanoaggregates in aqueous solution,leading to a significant production of ROS upon light irradiation.Photoirradiated Ir-TPE triggers multiple modes of death by excessively accumulating ROS in the mitochondria,resulting in mitochondrial DNA damage.This damage can lead to ferroptosis and autophagy,two forms of cell death that are highly cytotoxic to cancer cells.The aggregation-enhanced photodynamic effect of Ir-TPE significantly enhances the production of ROS,leading to a more pronounced cytotoxic effect.In vitro and in vivo experiments demonstrate this aggregation-enhanced PDT approach achieves effective in situ tumor eradication.This study not only addresses the limitations of metal complexes in terms of low ROS production due to aggregation but also highlights the potential of this strategy for enhancing ROS production in PDT.
基金supported by the National Natural Science Foundation of China(Grant No.62203362)the Natural Science Basic Research Program of Shaanxi(Grant No.2023-JC-QN-0569)。
文摘A situation maintenance-based cooperative guidance strategy is proposed to intercept a high-speed and high-maneuverability target via inferior missiles.Reachability and relative motion analyses are conducted to develop and pursue virtual targets,respectively.A two-stage guidance strategy under nonlinear kinematics is developed on the basis of virtual targets.The first stage optimizes the coverage and collision situation by pursuing virtual targets under specific angular constraints.The second stage subsequently intercepts the superior target based on the handover condition optimized by the first stage.Numerical simulation results are provided to compare the effectiveness and superiority of the proposed strategy with those of the reachability-based cooperative strategy(RCS),coverage-based cooperative guidance(CBCG)and augmented proportional navigation(APN)under various maneuvering modes.
基金supported by the National Natural Science Foundation of China(U21A20171,U20A20245)Natural Scienceof Hubei Province(2023AFA010)Independent Innovation Projects of the Hubei Longzhong Laboratory。
文摘In the process of spraying coating perovskite films,the"coffee ring"effect(CRE)leads to the problem of excessive organic ammonium salt accumulation in local areas that cannot be completely eliminated.We introduce an in-situ targeted defect-healing strategy by incorporating butylamine formate(BAFa)ionic liquid into the spray ink.Ionic liquids,due to their long carbon chain structure,tend to target flow towards the CRE region during the droplet evaporation process.The coordination between the lone pair electrons in the C=O group of BAFa and Pb^(2+)effectively reduces defects in perovskite and suppresses non-radiative recombination losses.Simultaneously,amine ligands,which are repelled to the film surface and grain boundaries,form a thin insulating monolayer in the CRE areas,forcing charge carriers to transport through areas of the perovskite with fewer defects.This approach enables the crystallization control and defect-heal over the Cs_(0.19)FA_(0.81)PbI_(3-x-y)Br_(x)Cl_(y)perovskite films.Consequently,the champion perovskite solar cell achieved a power conversion efficiency of 22.04%,while mini-modules with an effective area of 64.8 cm^(2)reached a peak power conversion efficiency of 18.35%,demonstrating the significant potential for commercializing large-area perovskite solar cells.
文摘In this article,we make a comment on the recent article by Sun et al,focusing on the advances of neutrophil extracellular traps(NETs)formation in common osteoarticular diseases.Neutrophils are the first line to eliminate invading pathogens including fungal and bacterial infections via releasing hydrolytic enzymes and reactive oxygen species.Besides,neutrophils will accumulate at the inflammatory site and release NETs,which are composed of histones,DNA and granular proteins.Traumatic heterotopic ossification(THO)was generally believed to develop through four stages:Inflammation,chondrogenesis,osteogenesis,and bone maturation.Thus,it can be seen that THO was related to inflammation and bone formation.Apart from immune and infectious diseases,recent studies have also shown that NETs play a significant role in the pathogenesis of THO.This article focuses on elaborating the role of NETs in the onset of THO,discussing the existing problems in the current research and outlining future directions.
基金supported by the National Natural Science Foundation of China(Grant No.:82104399)the Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine,China(Grant No.:22HHZYSS00001).
文摘Parkinson's disease(PD)is a debilitating and progressive neurodegenerative disorder with complex pathology and multiple membrane barriers that hinder drug delivery,resulting in the absence of ideal therapeutic drugs with minimal side effects[1].Recently,natural medicine has garnered significant attention due to its remarkable efficacy and limited side effects.Icariin,a naturally occurring flavonoid,exhibits excellent potential as a therapeutic agent for neurodegenerative disease[2].However,its clinical application is limited by poor water solubility,low bioavailability,and high clearance rates.Here,an aqueous formulation of icariin/hydroxypropyl-β-cyclodextrin(HP-β-CD)supramolecular inclusion complex was obtained to optimize icariin properties.Furthermore,icariin cyclodextrin supramolecular inclusion complex based thermosensitive(icariin gels)was innovated.At lower temperatures,it remained in a liquid phase with high fluidity.Upon reaching the gelation temperature,it underwent a transition to a gel phase with significantly reduced fluidity,which may be suitable for the design of an intranasal delivery system for PD treatment.The innovative approach capitalizes on the exceptional characteristics of HP-β-CD,which was utilized to synergize with nasal delivery for targeted brain delivery and with icariin for PD treatment[3,4].
文摘Traditional Chinese medicine(TCM),especially the plant-based,represents complex chemical system containing various primary and secondary metabolites.These botanical metabolites are structurally diversified and exhibit significant difference in the acidity,alkalinity,molecular weight,polarity,and content,etc,which thus poses great challenges in assessing the quality of TCM[1].
基金Supported by Hubei Provincial Natural Science Foundation,No.2025AFB845Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology,No.JCX2024044.
文摘This editorial highlighted the central role of pancreatic β-cell dysfunction in the pathogenesis of diabetes mellitus and discussed the emerging significance of Ras homolog enriched in brain 1(Rheb1)as a key regulator of β-cell mass and insulinsecretory capacity.While molecular mechanisms governing β-cell homeostasis remain incompletely defined,Yang et al have recently demonstrated that Rheb1 could promote β-cell proliferation through dual activation of mechanistic target of rapamycin complex 1 and AMP-activated protein kinase signaling pathways,rather than relying solely on mechanistic target of rapamycin complex 1.Notably,Rheb1 expression is higher in pancreatic islets from younger individuals and upregulates hepatocyte nuclear factor 4 alpha,which is recognized as a transcription factor essential for β-cell identity and insulin production.These insights position Rheb1 as a pivotal regulator of β-cell growth and metabolic function,with potential therapeutic implications for diabetes.Targeting Rheb1 may shift treatment paradigms from conventional glucose-lowering strategies towardβ-cell restoration,providing a novel approach to preserve or enhance functionalβ-cell mass in diabetic patients.Further investigation into Rheb1’s upstream regulators and downstream effectors may provide innovative therapeutic directions.
基金supported by the Science and Technology Innovation 2030-Key Project of‘‘New Generation Artificial Intelligence”,China(No.2020AAA0108204)the National Natural Science Foundation of China(Nos.61922008,61973013,61873011,61803014)+4 种基金the Innovation Zone Project,China(No.18-163-00-TS-001-001-34)the Defense Industrial TechnologyDevelopmentProgram,China(No.JCKY2019601C106)the Beijing Natural Science Foundation(No.4182035the Special Research Project of Chinese Civil Aircraft,China National Postdoctoral Program for Innovative Talents(No.BX20200034)Project funded by China Postdoctoral Science Foundation(No.2020 M680297)。
文摘Cooperative interception of the target with strong maneuverability by multiple missiles with weak maneuverability in the three-dimensional nonlinear model is studied.Firstly,the three-dimensional nonlinear model of cooperative guidance is established.The three-dimensional reachable region is represented composed of lateral acceleration and longitudinal acceleration in the two-dimensional coordinate system.Secondly,the problem of the multiple missile’s reachable coverage area is transformed into the problem of cooperative coverage.A cooperative coverage strategy is proposed and an algorithm for quickly calculating the number of required missiles is designed.Then,the guidance law based on the cooperative coverage strategy is proposed,and it is proved that cooperative interception of the target can be achieved under the acceleration limit.Moreover,the relations among the number of missiles,the initial array position of terminal guidance and the coverage area of the target’s large maneuver are analyzed.The dynamic adjustment strategy of guidance parameters is proposed to reduce the guidance error.Finally,simulation results show that multiple missiles with low maneuverability can achieve effective interception of target with strong maneuverability through the proposed cooperative strategy and cooperative guidance method.
基金co-supported by the National Natural Science Foundation of China(Nos.61403038 and 61573066)the Open Research Fund of Key Laboratory of Space Utilization,Chinese Academy of Sciences(Nos.LSU-2016-05-2 and LSUKJTS-2017-02)。
文摘The rotational motion of a tumbling target brings great challenges to space robot on successfully capturing the tumbling target.Therefore,it is necessary to reduce the target's rotation to a rate at which capture can be accomplished by the space robot.In this paper,a detumbling strategy based on friction control of dual-arm space robot for capturing tumbling target is proposed.This strategy can reduce the target's rotational velocity while maintaining base attitude stability through the establishment of the rotation attenuation controller and base attitude adjustment controller.The rotation attenuation controller adopts the multi-space hybrid impedance control method to control the friction precisely.The base attitude adjustment controller applies the dual-arm extended Jacobian matrix to stabilize the base attitude.The main contributions of this paper are as follows:(1)The compliant control method is adopted to achieve a precise friction control,which can reduce the target angular velocity steadily;(2)The dual-arm extended Jacobian matrix is applied to stabilize the base attitude without affecting the target capture task;(3)The detumbling strategy of dualarm space robot is designed considering base attitude stabilization,realizing coordinated planning of the base attitude and the arms.The strategy is verified by a dual-arm space robot with two 7-DOF(degrees of freedom)arms.Simulation results show that,target with a rotation velocity of 20(°)/s can be effectively controlled to stop within 30 s,and the final deflection of the base attitude is less than 0.15°without affecting the target capture task,verifying the correctness and effectiveness of the strategy.Except to the tumbling target capture task,the control strategy can also be applied to other typical on-orbit operation tasks such as space debris removal and spacecraft maintenance.
基金supported by the State Key Laboratory of Dampness Syndrome of Chinese Medicine,the Second Affiliated Hospital of Guangzhou University of Chinese Medicine(No.SZ2021ZZ51)the National Key R&D Program of China(No.2022YFC3501601)+1 种基金the National Natural Sciences Foundation of China(Nos.82174008,81973505)Jinan New 20 Policies for Higher Education Funding(No.202228048)and the Fundamental Research Funds for the Central Universities.
文摘Psoriasis,a prevalent inherited skin condition,involves an inflammatory response as a key pathogenic mechanism.The Optimized Yinxieling Formula(OYF),rooted in traditional Chinese medicine,is extensively utilized in clinical settings to treat psoriasis.Although previous studies have demonstrated OYF’s significant anti-inflammatory effects in psoriasis,its potential molecular targets and active components remain unexplored.This study aimed to unveil the anti-psoriasis molecular targets and active components of OYF.Our findings indicated that OYF extract markedly reduced the production of several inflammatory mediators,including IL-23,nitric oxide,TNF-α,and IL-1β,in LPS-induced RAW264.7 cells.We synthesized OYF extract-crosslinked beads to isolate pharmacological targets from RAW264.7 lysates using an affinity purification strategy,known as Target Fishing.The enriched target proteins were subsequently identified via LC-MS/MS,followed by bioinformatics analysis to map the psoriasis-associated pathway-gene network.We identified a total of 76 potential target proteins,which were highly associated with mRNA transcription mechanisms.In particular,pathway-gene network analysis revealed that the IL-23 inflammatory pathway was involved in the anti-psoriasis effect of OYF extract.We further utilized a target protein-based affinity capture strategy,combined with LC-MS and SPR analysis,to globally screen OYF’s active components,focusing on the mRNA transcription regulator,fused in sarcoma(FUS).This process led to the identification of umbelliferone,vanillic acid,protocatechuic acid,gentisic acid,and echinacoside as key compounds targeting FUS to inhibit IL-23 expression.Additionally,we formulated a compound cocktail(CpdC),which significantly reduced psoriasis area and severity index(PASI)scores and the expressions of IL-23 and Ki67 in an imiquimod(IMQ)-induced psoriasis mouse model.Collectively,our study elucidates the primary molecular targets and active components of OYF,offering novel insights for psoriasis treatment.
基金This paper is supported by the National Key R&D Program of China(2017YFB0802703)the National Nature Science Foundation of China(61602052).
文摘As a core component of the network,web applications have become one of the preferred targets for attackers because the static configuration of web applications simplifies the exploitation of vulnerabilities by attackers.Although the moving target defense(MTD)has been proposed to increase the attack difficulty for the attackers,there is no solo approach can cope with different attacks;in addition,it is impossible to implement all these approaches simultaneously due to the resource limitation.Thus,the selection of an optimal defense strategy based on MTD has become the focus of research.In general,the confrontation of two players in the security domain is viewed as a stochastic game,and the reward matrices are known to both players.However,in a real security confrontation,this scenario represents an incomplete information game.Each player can only observe the actions performed by the opponent,and the observed actions are not completely accurate.To accurately describe the attacker’s reward function to reach the Nash equilibrium,this work simulated and updated the strategy selection distribution of the attacker by observing and investigating the strategy selection history of the attacker.Next,the possible rewards of the attacker in each confrontation via the observation matrix were corrected.On this basis,the Nash-Q learning algorithm with reward quantification was proposed to select the optimal strategy.Moreover,the performances of the Minimax-Q learning algorithm and Naive-Q learning algorithm were compared and analyzed in the MTD environment.Finally,the experimental results showed that the strategy selection algorithm can enable defenders to select a more reasonable defensive strategy and achieve the maximum possible reward.
文摘The methods of Traditional Chinese Medicine(TCM)’s diagnosis and treatment have undergone several changes.It is crucial to build a proper model which is capable to modernize TCM into a both standardized and individualized treatment.Tong xiao-lin proposed the state-target strategy to build a bridge for the integration of Chinese and Western medicine.It is a model based on modern medical disease concepts and using the method of TCM to balance the pathological states and adopting the achievements of pharmacology of Chinese medicine to focus on the disease targets,symptom targets,and biochemical indicator targets.The reconstruction of TCM diagnosis and treatment system for diabetes is a good example to demonstrate this theory.It could improve the clinical efficacy,support the scientific research,and reinforce the standardization of TCM.
基金supported by grants from the National Natural Science Foundation of China(Grant No.:81903765)the Open Fund Project of Key Laboratory of Traditional Chinese Medicine for Prevention and Treatment of Major Pulmonary Diseases of the Anhui Provincial Department of Education(Grant No.:JYTKF2020-5)the Graduate Science and Technology Innovation Fund project of Anhui University of Chinese Medicine(Grant No.:2020YB06).
文摘Qi-Yu-San-Long decoction(QYSLD)is a traditional Chinese medicine that has been clinically used in the treatment of non-small-cell lung cancer(NSCLC)for more than 20 years.However,to date,metabolicrelated studies on QYSLD have not been performed.In this study,a post-targeted screening strategy based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight full information tandem mass spectrometry(UPLC-QTOF-MS^(E))was developed to identify QYSLD-related xenobiotics in rat urine.The chemical compound database of QYSLD constituents was established from previous research,and metabolites related to these compounds were predicted in combination with their possible metabolic pathways.The metabolites were identified by extracted ion chromatograms using predicted m/z values as well as retention time,excimer ions,and fragmentation behavior.Overall,85 QYSLD-related xenobiotics(20 prototype compounds and 65 metabolites)were characterized from rat urine.The main metabolic reactions and elimination features of QYSLD included oxidation,reduction,decarboxylation,hydrolysis,demethylation,glucuronidation,sulfation,methylation,deglycosylation,acetylation,and associated combination reactions.Of the identified molecules,14 prototype compounds and 58 metabolites were slowly eliminated,thus accumulating in vivo over an extended period,while five prototypes and two metabolites were present in vivo for a short duration.Furthermore,one prototype and five metabolites underwent the process of“appearing-disappearing-reappearing”in vivo.Overall,the metabolic profile and characteristics of QYSLD in rat urine were determined,which is useful in elucidating the active components of the decoction in vivo,thus providing the basis for studying its mechanism of action.
基金This work was supported by the National Natural Science Foundation of China,No.81870975(to SLZ)the Nantong Science and Technology Innovation Program,China,No.JC2019028(to XMY).
文摘Neurological diseases such as stroke,Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease are among the intractable diseases for which appropriate drugs and treatments are lacking.Proteolysis targeting chimera(PROTAC)technology is a novel strategy to solve this problem.PROTAC technology uses the ubiquitin-protease system to eliminate mutated,denatured,and harmful proteins in cells.It can be reused,and utilizes the protein destruction mechanism of the cells,thus making up for the deficiencies of traditional protein degradation methods.It can effectively target and degrade proteins,including proteins that are difficult to identify and bind.Therefore,it has extremely important implications for drug development and the treatment of neurological diseases.At present,the targeted degradation of mutant BTK,mHTT,Tau,EGFR,and other proteins using PROTAC technology is gaining attention.It is expected that corresponding treatment of nervous system diseases can be achieved.This review first focuses on the recent developments in PROTAC technology in terms of protein degradation,drug production,and treatment of central nervous system diseases,and then discusses its limitations.This review will provide a brief overview of the recent application of PROTAC technology in the treatment of central nervous system diseases.
文摘Alzheimer＇s disease （AD） is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progres- sive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death.
文摘In this paper we discuss the rationale of applying a “sequential” targeted therapy with a specific application in clinical practice, given our understanding of cancer heterogenous and dynamic biology. We explore the advantages of “single inhibition” to combinational therapies and dual inhibition on key pathways, as well as a multi-step approach to use “oncological addiction” and “oncogenic shock” as a suicide plan for cancer. We specifically explain how the downstream targets can be used to “create” feedback loops in an advantage for creating actionable targets in upstream signaling molecules. We apply this hypothesis in the clinical setting, with superior outcomes shown in a series of case studies. We conclude that “sequential and dual inhibition” can be considered a meaningful approach to checkmate the tumor, with minimum chance of tumor resistance. We recommend further clinical studies to generate further hypotheses based on each actionable target.
