Efficient exploration in complex coordination tasks has been considered a challenging problem in multi-agent reinforcement learning(MARL). It is significantly more difficult for those tasks with latent variables that ...Efficient exploration in complex coordination tasks has been considered a challenging problem in multi-agent reinforcement learning(MARL). It is significantly more difficult for those tasks with latent variables that agents cannot directly observe. However, most of the existing latent variable discovery methods lack a clear representation of latent variables and an effective evaluation of the influence of latent variables on the agent. In this paper, we propose a new MARL algorithm based on the soft actor-critic method for complex continuous control tasks with confounders. It is called the multi-agent soft actor-critic with latent variable(MASAC-LV) algorithm, which uses variational inference theory to infer the compact latent variables representation space from a large amount of offline experience.Besides, we derive the counterfactual policy whose input has no latent variables and quantify the difference between the actual policy and the counterfactual policy via a distance function. This quantified difference is considered an intrinsic motivation that gives additional rewards based on how much the latent variable affects each agent. The proposed algorithm is evaluated on two collaboration tasks with confounders, and the experimental results demonstrate the effectiveness of MASAC-LV compared to other baseline algorithms.展开更多
Polyploidy occurs frequently in plants and is an important force in plant evolution and crop breeding.New polyploids face various challenges due to genome duplication and subsequent changes in epigenetic modifications...Polyploidy occurs frequently in plants and is an important force in plant evolution and crop breeding.New polyploids face various challenges due to genome duplication and subsequent changes in epigenetic modifications,nucleus/cell size and gene expression.How polyploids produce evolutionary novelty remains to be understood.In this study,a transcriptome comparison between 21-day-old diploid and autotetraploid pak choi seedlings revealed that there are few differentially expressed genes(DEGs),with a greater proportion of DEGs downregulated in response to genome duplication.Genome-wide DNA methylation analysis indicated that the level of DNA methylation is obviously increased,especially in transposable elements(TEs)and 1 kb flanking regions,upon genome doubling.The differentially methylated regions between diploid and autotetraploid pak choi were related to 12,857 differentially hypermethylated genes and 8,451 hypomethylated genes,and the DEGs were negatively correlated with the differential methylation in the regions across the DEGs.Notably,TE methylation increases significantly in regions flanking neighboring non-DEGs rather than those flanking DEGs.These results shed light on the role of DNA methylation in the transcriptional regulation of genes in polyploids and the mechanism of coping with“genome shock”due to genome doubling in cruciferous plants.展开更多
Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic vir...Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.展开更多
In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.A...In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.Although a growing number of therapeutic targets have been identified in preclinical studies,the ones that can ultimately be used in the clinic are limited.Therefore,the research process and clinical application of drugs for treating CNS diseases are still large challenges.Physiological barriers such as the blood‒brain barrier(BBB)act as selective permeable membranes,allowing only certain molecules to enter the brain;this barrier is the major obstacle restricting the arrival of most drugs to brain lesions.Recently,nanoparticles,including lipid-based,cell-derived biomimetic,polymeric and inorganic nanoparticles,have gained increasing attention because of their ability to cross physiological barriers,and could play an important role as delivery carriers and immunomodulators.Additionally,clinical applications of nanoparticles in CNS diseases are underway.This review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases.展开更多
基金supported in part by the National Natural Science Foundation of China (62136008,62236002,61921004,62173251,62103104)the “Zhishan” Scholars Programs of Southeast Universitythe Fundamental Research Funds for the Central Universities (2242023K30034)。
文摘Efficient exploration in complex coordination tasks has been considered a challenging problem in multi-agent reinforcement learning(MARL). It is significantly more difficult for those tasks with latent variables that agents cannot directly observe. However, most of the existing latent variable discovery methods lack a clear representation of latent variables and an effective evaluation of the influence of latent variables on the agent. In this paper, we propose a new MARL algorithm based on the soft actor-critic method for complex continuous control tasks with confounders. It is called the multi-agent soft actor-critic with latent variable(MASAC-LV) algorithm, which uses variational inference theory to infer the compact latent variables representation space from a large amount of offline experience.Besides, we derive the counterfactual policy whose input has no latent variables and quantify the difference between the actual policy and the counterfactual policy via a distance function. This quantified difference is considered an intrinsic motivation that gives additional rewards based on how much the latent variable affects each agent. The proposed algorithm is evaluated on two collaboration tasks with confounders, and the experimental results demonstrate the effectiveness of MASAC-LV compared to other baseline algorithms.
基金supported by the Agriculture Research System of Shanghai,China(Grant No.202402 to H.Z.)the National Science Foundation of China(Grant Nos.32170585 and 31871230 to Y.F.).
文摘Polyploidy occurs frequently in plants and is an important force in plant evolution and crop breeding.New polyploids face various challenges due to genome duplication and subsequent changes in epigenetic modifications,nucleus/cell size and gene expression.How polyploids produce evolutionary novelty remains to be understood.In this study,a transcriptome comparison between 21-day-old diploid and autotetraploid pak choi seedlings revealed that there are few differentially expressed genes(DEGs),with a greater proportion of DEGs downregulated in response to genome duplication.Genome-wide DNA methylation analysis indicated that the level of DNA methylation is obviously increased,especially in transposable elements(TEs)and 1 kb flanking regions,upon genome doubling.The differentially methylated regions between diploid and autotetraploid pak choi were related to 12,857 differentially hypermethylated genes and 8,451 hypomethylated genes,and the DEGs were negatively correlated with the differential methylation in the regions across the DEGs.Notably,TE methylation increases significantly in regions flanking neighboring non-DEGs rather than those flanking DEGs.These results shed light on the role of DNA methylation in the transcriptional regulation of genes in polyploids and the mechanism of coping with“genome shock”due to genome doubling in cruciferous plants.
基金funded by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018-013)by Natural Science Foundation Project of Sichuan(No.2022NSFSC0848)+1 种基金as well as supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD18007)The Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC202310005).
文摘Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
基金supported by the National Natural Science Foundation of China(Nos.82073366 and 32100748)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD18007)the National Natural Science Foundation of Sichuan Province(No.2022NSFSC1642).
文摘In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired effect.Although a growing number of therapeutic targets have been identified in preclinical studies,the ones that can ultimately be used in the clinic are limited.Therefore,the research process and clinical application of drugs for treating CNS diseases are still large challenges.Physiological barriers such as the blood‒brain barrier(BBB)act as selective permeable membranes,allowing only certain molecules to enter the brain;this barrier is the major obstacle restricting the arrival of most drugs to brain lesions.Recently,nanoparticles,including lipid-based,cell-derived biomimetic,polymeric and inorganic nanoparticles,have gained increasing attention because of their ability to cross physiological barriers,and could play an important role as delivery carriers and immunomodulators.Additionally,clinical applications of nanoparticles in CNS diseases are underway.This review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases.
