TANK-binding kinase 1(TBK1)is an essential protein kinase for activation of interferon regulatory factor 3(IRF3)and induction of the type I interferons(IFN-I).Although the biochemical regulation of TBK1 activation has...TANK-binding kinase 1(TBK1)is an essential protein kinase for activation of interferon regulatory factor 3(IRF3)and induction of the type I interferons(IFN-I).Although the biochemical regulation of TBK1 activation has been studied,little is known about how enterovirus 71(EV71)employs the deubiquitinases(DUBs)to regulate TBK1 activation for viral immune evasion.Here,we found that EV71 infection upregulated the expression of ubiquitinspecific protease 24(USP24).Further studies revealed that USP24 physically interacted with TBK1,and can reduce K63-linked polyubiquitination of TBK1.Knockdown of USP24 upregulated TBK1 K63-linked polyubiquitination,promoted the phosphorylation and nuclear translocation of IRF3,and in turn improved IFN-I production during EV71 infection.As a consequence,USP24 knockdown dramatically inhibited EV71 infection.This study revealed USP24 as a novel regulator of TBK1 activation,which promotes the understanding of immune evasion mechanisms of EV71 and could provide a potential strategy for treatment of EV71 infection.展开更多
Multimodal imaging-guided chemo-photothermal therapy is an excellent cancer treatment,which can not only efficiently against tumor,but also can offer precise treatment window and real-time monitoring of the treatment ...Multimodal imaging-guided chemo-photothermal therapy is an excellent cancer treatment,which can not only efficiently against tumor,but also can offer precise treatment window and real-time monitoring of the treatment efficiency.In our work,polydopamine(PDA)-coated gold nanobones(AuNBs@PDA nanocomplexes)were designed for this approach.The AuNBs@PDA nanocomplexes have strong absorbance in the near infrared(NIR)region and higher photothermal conversion efficiency(75.48%)than gold nanobones alone,which was facilitated for photoacoustic imaging and photothermal therapy.Besides,the loading efficiency of doxorubicin(DOX)by AuNBs@PDA nanocomplexes could be up to about 70%and DOX release from AuNBs@PDA/DOX nanocomplexes sensitively response to the lower pH environment and NIR laser irradiation,which makes them become the excellent nano-carrier for the delivery of chemotherapy drug.In vitro and in vivo studies showed significant cytotoxicity and antitumor efficacy by the AuNBs@PDA/DOX nanoplatform with negligible side effects.Meanwhile,the nanoplatform was also successfully employed for computed tomography(CT)imaging,attributing to the high atomic number and high X-ray attenuation coefficient of gold.Therefore,we believed that the proposed PDA-coated gold nanobones would be a novel multifunctional theranostic nanoagent to realize the PA/CT imaging-guided chemo-photothermal therapy of cancer.展开更多
Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-targe...Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.展开更多
Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIK...Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIKV is a singlestranded positive-sense RNA virus encoding three structural proteins, including nucleocapsid protein C, prM/M,envelope glycoprotein E, and seven non-structural proteins.Since 2015.展开更多
Dear Editor,Since December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) induced human disease, the coronavirus disease 2019(COVID-19),has been reported in more than 200 countries a...Dear Editor,Since December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) induced human disease, the coronavirus disease 2019(COVID-19),has been reported in more than 200 countries and areas around the world(Wu et al. 2020).展开更多
Dear Editor,Rabies virus(RABV)is an enveloped,non-segmented,and singlestranded RNA virus that belongs to the genus Lyssavirus within the Rhabdoviridae family(Douglas et al.,2013).RABV causes rabies,and although vaccin...Dear Editor,Rabies virus(RABV)is an enveloped,non-segmented,and singlestranded RNA virus that belongs to the genus Lyssavirus within the Rhabdoviridae family(Douglas et al.,2013).RABV causes rabies,and although vaccines are available,rabies continues to be a global public health concern causing more than 60,000 human deaths each year(WHO,2013).There is a high prevalence especially in developing countries in Asia and Africa(Hampson et al.,2015;Singh et al.,2017).展开更多
Tumor-specific antigens,also known as neoantigens,have potential utility in anti-cancer immunotherapy,including immune checkpoint blockade(ICB),neoantigen-specific T cell receptor-engineered T(TCR-T),chimeric antigen ...Tumor-specific antigens,also known as neoantigens,have potential utility in anti-cancer immunotherapy,including immune checkpoint blockade(ICB),neoantigen-specific T cell receptor-engineered T(TCR-T),chimeric antigen receptor T(CAR-T),and therapeutic cancer vaccines(TCVs).After recognizing presented neoantigens,the immune system becomes activated and triggers the death of tumor cells.Neoantigens may be derived from multiple origins,including somatic mutations(single nucleotide variants,insertions/deletions,and gene fusions),circular RNAs,alternative splicing,RNA editing,and polymorphic microbiomes.An increasing amount of bioinformatics tools and algorithms are being developed to predict tumor neoantigens derived from different sources,which may require inputs from different multi-omics data.In addition,calculating the peptide-major histocompatibility complex(MHC)affinity can aid in selecting putative neoantigens,as high binding affinities facilitate antigen presentation.Based on these approaches and previous experiments,many resources have been developed to reveal the landscape of tumor neoantigens across multiple cancer types.Herein,we summarize these tools,algorithms,and resources to provide an overview of computational analysis for neoantigen discovery and prioritization,as well as the future development of potential clinical utilities in this field.展开更多
The innate immune system plays a crucial role in the host defense against viral and microbial infection.Exosomes constitute a subset of extracellular vesicles(EVs)that can be released by almost all cell types.Owing to...The innate immune system plays a crucial role in the host defense against viral and microbial infection.Exosomes constitute a subset of extracellular vesicles(EVs)that can be released by almost all cell types.Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system,exosomes efficiently transport functional components to recipient cells.Accumulating evidence has recently shown that exosomes derived from tumor cells,host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules,modulating the innate immune responses of the host.In this review,we describe the current understanding of EVs(mainly focusing on exosomes)and summarize and discuss their crucial roles in determining innate immune responses.Additionally,we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.展开更多
Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transf...Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.展开更多
A systems biology approach was employed to gain insight into tick biology and interactions between vectors and pathogens.Haemaphysalis longicornis serves as one of the primary vectors of Babesia microti,significantly ...A systems biology approach was employed to gain insight into tick biology and interactions between vectors and pathogens.Haemaphysalis longicornis serves as one of the primary vectors of Babesia microti,significantly impacting human and animal health.Obtaining more information about their relationship is crucial for a comprehensive un-derstanding of tick and pathogen biology,pathogen transmission dynamics,and potential control strategies.RNA sequencing of uninfected and B.microti-infected ticks resulted in the identification of 15056 unigenes.Among these,1051 were found to be differentially expressed,with 796 being upregulated and 255 downregulated(P<0.05).Integrated tran-scriptomics datasets revealed the pivotal role of immune-related pathways,including the Toll,Janus kinase/signal transducer and activator of transcription(JAK-STAT),immunod-eficiency,and RNA interference(RNAi)pathways,in response to infection.Consequently,3 genes encoding critical transcriptional factor Dorsal,Relish,and STAT were selected for RNAi experiments.The knockdown of Dorsal,Relish,and STAT resulted in a substantial increase in Babesia infection levels compared to the respective controls.These findings significantly advanced our understanding of tick–Babesia molecular interactions and pro-posed novel tick antigens as potential vaccine targets against tick infestations and pathogen transmission.展开更多
Serine proteinase inhibitors(serpins),identified from the hard tick Haemaphysalis longicornis of China,play significant roles in various animal physiological processes.In this study,we showed that H.longicornis serpin...Serine proteinase inhibitors(serpins),identified from the hard tick Haemaphysalis longicornis of China,play significant roles in various animal physiological processes.In this study,we showed that H.longicornis serpins(Hlserpin-a and Hlserpin-b)were induced during blood-feeding in nymph ticks and exhibited anticoagulation activity in vitro.Silencing Hlserpins through RNA interference(RNAi)significantly impaired tick feeding.Immunization of mice with recombinant Hlserpins or passive transfer of Hlserpin antiserum significantly curtails the efficacy of tick feeding.Concurrently,the transmission of the Langat virus(LGTV)from ticks to mice witnessed a substantial decrease when Hlserpins were silenced.Our findings suggest that inhibiting Hlserpins can hamper tick engorgement and pathogen transmission,indicating the potential of Hlserpins as a vaccine to countertick-borne diseases.展开更多
FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors...FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.展开更多
Background: Ticks are hematophagous parasites that transmit an extensive range of pathogens to their vertebrate hosts.Ticks can destroy invading microorganisms or alleviate infection via their rudimentary but orchestr...Background: Ticks are hematophagous parasites that transmit an extensive range of pathogens to their vertebrate hosts.Ticks can destroy invading microorganisms or alleviate infection via their rudimentary but orchestrated innate immune system.Antimicrobial peptides(AMPs)are important components of tick innate immunity.Among these humoral effector molecules,defensins are well-studied and widely identified in various species of Ixodidae(hard ticks)and Argasidae(soft ticks).This review was aimed at presenting the characterization of tick defensins from structure-based taxonomic status to antimicrobial function.Main text: All published papers written in English from 2001 to May 2022 were searched through PubMed and Web of Science databases with the combination of relevant terms on tick defensins.Reports on identification and characterization of tick defensins were included.Of the 329 entries retrieved,57 articles were finally eligible for our scoping review.Tick defensins mainly belong to the antibacterial ancient invertebrate-type defensins of the cis-defensins superfamily.They are generally small,cationic,and amphipathic,with six cysteine residues forming three intra-molecular disulfide bonds.Tick defensins primarily target membranes of a variety of pathogens,including Gram-positive and Gram-negative bacteria,fungi,viruses,and protozoa.Since tick defensins have a high degree of variability,we summarize their common biological properties and enumerate representative peptides.Along with the various and potent antimicrobial activities,the role of tick defensins in determining vector competence is discussed.Conclusions: Due to their broad-spectrum antimicrobial activities,tick defensins are considered novel candidates or targets for controlling infectious diseases.展开更多
Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better st...Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better strategy for cancer therapy.The canonical activities of p53,such as cell cycle arrest,senescence,and apoptosis,are well accepted as the major checkpoints in stress responses and tumor suppression.展开更多
C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic ...C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA(apopDNA)could induce macrophage activation and contribute to the initiation and progression of lupus nephritis.It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation.Herein,CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA(CRP/apopDNA complex).Notably,CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone.Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner.These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.展开更多
Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral ac...Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral activity.SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling.Mechanistically,SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8,consequently restricting the interaction between USP8 and IFNAR2.The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation,thus attenuating IFN-I antiviral activity.Correspondingly,the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2,leading to a reduction in IFNAR2 ubiquitination and,consequently,an enhancement in IFN-I-induced signaling.This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.展开更多
C-type lectins(CTLs)are a family of proteins that contain 1 or more carbohydrate-recognition domains(CRDs)and bind to a broad repertoire of ligands in the presence of calcium ions.CTLs play important roles in innate i...C-type lectins(CTLs)are a family of proteins that contain 1 or more carbohydrate-recognition domains(CRDs)and bind to a broad repertoire of ligands in the presence of calcium ions.CTLs play important roles in innate immune defenses against microorganisms by acting as pattern-recognition receptors(PRRs)for invading pathogens,such as bacteria,viruses,and parasites.After binding to pathogen-associated ligands,CTLs mediate immune responses,such as agglutination,phagocytosis,and the activation of phenol oxidase progenitors,thereby clearing pathogens.CTLs are an evolutionarily conserved family found in almost all vertebrates and invertebrates.Medical arthropods can acquire and transmit a range pathogens through various approaches,such as bloodsucking,lancing,and parasitism,thus infecting humans and animals with related diseases,some of which can be life-threatening.Recent studies have shown that lectins are important components of the arthropod immune system and are essential for the immune responses of arthropods to arthropod-borne pathogens.This article reviews the current understanding of the structure,function,and signaling pathways involved in CTLs derived from important medical arthropods.展开更多
The adoptive transfer of engineered chimeric antigen receptor(CAR)T cells has yielded impressive clinical results for targeting hematological cancers.1 However,the advancement of CAR T-cell therapy in solid tumors rem...The adoptive transfer of engineered chimeric antigen receptor(CAR)T cells has yielded impressive clinical results for targeting hematological cancers.1 However,the advancement of CAR T-cell therapy in solid tumors remains limited,due to the scarcity of tumor antigens that are deemed safe for targeting.Moreover,the requirement of patient-specific autologous T cells for the current standard treatment has also hampered its application.Oncolytic virus(OV)therapy has been classified as another form of novel immunotherapy.展开更多
基金support was provided by the National Natural Science Foundation of China(81572052 and 82102473)Changzhou science and technology support plan(CE20225036,CJ20210141)Young Talent Development Plan of Changzhou Health Commission(2020-233).
文摘TANK-binding kinase 1(TBK1)is an essential protein kinase for activation of interferon regulatory factor 3(IRF3)and induction of the type I interferons(IFN-I).Although the biochemical regulation of TBK1 activation has been studied,little is known about how enterovirus 71(EV71)employs the deubiquitinases(DUBs)to regulate TBK1 activation for viral immune evasion.Here,we found that EV71 infection upregulated the expression of ubiquitinspecific protease 24(USP24).Further studies revealed that USP24 physically interacted with TBK1,and can reduce K63-linked polyubiquitination of TBK1.Knockdown of USP24 upregulated TBK1 K63-linked polyubiquitination,promoted the phosphorylation and nuclear translocation of IRF3,and in turn improved IFN-I production during EV71 infection.As a consequence,USP24 knockdown dramatically inhibited EV71 infection.This study revealed USP24 as a novel regulator of TBK1 activation,which promotes the understanding of immune evasion mechanisms of EV71 and could provide a potential strategy for treatment of EV71 infection.
基金financially supported by the National Key R&D Program of China(No.2018YFB1105700)the National Natural Science Foundation of China(Nos.81902913,81930048 and 81627805)+9 种基金the Guangdong Basic and Applied Basic Research Foundation for Distinguished Young Scholars(No.2020B1515020027)the Fundamental Research Funds for the Central Universities(No.19ykpy108)the Natural Science Foundation of Jiangsu Province(No.BK20190821)the Postdoctoral Science Foundation of China(No.2019M651953)the Open Project Program of the State Key Laboratory of Radiation Medicine and Protection,Soochow University(No.GZK1201909)the Guangdong Science and Technology Department(No.2020B1212060018)the Science and Technology Project from Suzhou City Commission of Health and Family Planning(No.LCZX201712)the grants from Guangzhou Science and Technology Bureau(202002020070,201902020015)Opening Foundation of Hubei Province Key Laboratory of Molecular Imaginga Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Multimodal imaging-guided chemo-photothermal therapy is an excellent cancer treatment,which can not only efficiently against tumor,but also can offer precise treatment window and real-time monitoring of the treatment efficiency.In our work,polydopamine(PDA)-coated gold nanobones(AuNBs@PDA nanocomplexes)were designed for this approach.The AuNBs@PDA nanocomplexes have strong absorbance in the near infrared(NIR)region and higher photothermal conversion efficiency(75.48%)than gold nanobones alone,which was facilitated for photoacoustic imaging and photothermal therapy.Besides,the loading efficiency of doxorubicin(DOX)by AuNBs@PDA nanocomplexes could be up to about 70%and DOX release from AuNBs@PDA/DOX nanocomplexes sensitively response to the lower pH environment and NIR laser irradiation,which makes them become the excellent nano-carrier for the delivery of chemotherapy drug.In vitro and in vivo studies showed significant cytotoxicity and antitumor efficacy by the AuNBs@PDA/DOX nanoplatform with negligible side effects.Meanwhile,the nanoplatform was also successfully employed for computed tomography(CT)imaging,attributing to the high atomic number and high X-ray attenuation coefficient of gold.Therefore,we believed that the proposed PDA-coated gold nanobones would be a novel multifunctional theranostic nanoagent to realize the PA/CT imaging-guided chemo-photothermal therapy of cancer.
基金supported by the National Natural Science Foundation of China(Grant Nos.:32271292,31872723,32200778,and 22377089)the Jiangsu Students Innovation and Entrepre-neurship Training Program,China(Program No.:202210285081Z)+6 种基金the Project of MOE Key Laboratory of Geriatric Diseases and Immunology,China(Project No.:JYN202404)Proj-ect Funded by the Priority Academic Program Development(PAPD)of Jiangsu Higher Education Institutions,Natural Science Foundation of Jiangsu Province,China(Project No.:BK20220494)Suzhou Medical and Health Technology Innovation Project,China(Grant No.:SKY2022107)the Clinical Research Center of Neuro-logical Disease in The Second Affiliated Hospital of Soochow University,China(Grant No.:ND2022A04)State Key Laboratory of Drug Research(Grant No.:SKLDR-2023-KF-05)Jiangsu Shuang-chuang Program for Doctor,Young Science Talents Promotion Project of Jiangsu Science and Technology Association(Program No.:TJ-2023-019)Young Science Talents Promotion Project of Suzhou Science and Technology Association,Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases,and startup funding(Grant Nos.:NH21500221,NH21500122,and NH21500123)to Qifei Cong.
文摘Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the“therapeutic module”of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.
基金supported by the National Natural Science Foundation of China (31470848, 31470880, 31670898, and 31870867)Open Research Fund Program of the State Key Laboratory of Virology of China (2017IOV003)Jiangsu Provincial Innovative Research Team
文摘Dear Editor,Zika virus (ZIKV) is a mosquito-borne virus that belongs to the Flavivirus family along with dengue virus (DENV),yellow fever virus, West Nile virus, and Japanese encephalitis virus (Ming et al. 2016). ZIKV is a singlestranded positive-sense RNA virus encoding three structural proteins, including nucleocapsid protein C, prM/M,envelope glycoprotein E, and seven non-structural proteins.Since 2015.
基金supported by a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions, National Natural Science Foundation of China (31770933, 81971917 and 81872103)Natural Science Foundation of Colleges in Jiangsu Province (17KJA310005)+1 种基金Open Project Fund from State Key Laboratory of Genetic Engineering, Fudan University (No. SKLGE1903)Key Laboratory of Reproduction Regulation of NHC (No. KF2018-01)。
文摘Dear Editor,Since December 2019, the outbreak of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) induced human disease, the coronavirus disease 2019(COVID-19),has been reported in more than 200 countries and areas around the world(Wu et al. 2020).
基金supported by the National Natural Science Foundation of China(31870867,81802083,and 31970844)Open Research Fund Program of the State Key Laboratory of Virology of China(2020IOV003)the Priority Academic Program Development of Jiangsu Higher Education Institutions。
文摘Dear Editor,Rabies virus(RABV)is an enveloped,non-segmented,and singlestranded RNA virus that belongs to the genus Lyssavirus within the Rhabdoviridae family(Douglas et al.,2013).RABV causes rabies,and although vaccines are available,rabies continues to be a global public health concern causing more than 60,000 human deaths each year(WHO,2013).There is a high prevalence especially in developing countries in Asia and Africa(Hampson et al.,2015;Singh et al.,2017).
基金supported by the National Natural Science Foundation of China(Grant Nos.32270708 and 82203195)supported by the Medical Science Data Center at Shanghai Medical College of Fudan University,China.
文摘Tumor-specific antigens,also known as neoantigens,have potential utility in anti-cancer immunotherapy,including immune checkpoint blockade(ICB),neoantigen-specific T cell receptor-engineered T(TCR-T),chimeric antigen receptor T(CAR-T),and therapeutic cancer vaccines(TCVs).After recognizing presented neoantigens,the immune system becomes activated and triggers the death of tumor cells.Neoantigens may be derived from multiple origins,including somatic mutations(single nucleotide variants,insertions/deletions,and gene fusions),circular RNAs,alternative splicing,RNA editing,and polymorphic microbiomes.An increasing amount of bioinformatics tools and algorithms are being developed to predict tumor neoantigens derived from different sources,which may require inputs from different multi-omics data.In addition,calculating the peptide-major histocompatibility complex(MHC)affinity can aid in selecting putative neoantigens,as high binding affinities facilitate antigen presentation.Based on these approaches and previous experiments,many resources have been developed to reveal the landscape of tumor neoantigens across multiple cancer types.Herein,we summarize these tools,algorithms,and resources to provide an overview of computational analysis for neoantigen discovery and prioritization,as well as the future development of potential clinical utilities in this field.
基金supported by a special program from the Chinese National Natural Science Funds(31701232 to F.X.,31671457 and 91753139 to L.Z.,and 31871405 and 31571460 to F.Z.)the National Postdoctoral Program for Innovative Talents(BX201700165 to F.X.)+4 种基金the National Science Foundation for Postdoctoral Scientists of China(BX201700165 to F.X.)Distinguished Young Scholars of Jiangsu Province(BK20180043 to F.Z.)the Key Project of University Natural Science Foundation of Jiangsu Province(19KJA550003 to F.Z.)the Shenzhen Basic Research Program(JCYJ20180507182203049 to S.Z.)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The innate immune system plays a crucial role in the host defense against viral and microbial infection.Exosomes constitute a subset of extracellular vesicles(EVs)that can be released by almost all cell types.Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system,exosomes efficiently transport functional components to recipient cells.Accumulating evidence has recently shown that exosomes derived from tumor cells,host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules,modulating the innate immune responses of the host.In this review,we describe the current understanding of EVs(mainly focusing on exosomes)and summarize and discuss their crucial roles in determining innate immune responses.Additionally,we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.
文摘Oncolytic virus(OV)is increasingly being recognized as a novel vector in cancer immunotherapy.Increasing evidence suggests that OV has the ability to change the immune status of tumor microenvironment,so called transformation of‘cold’tumors into‘hot’tumors.The improved anti-tumor immunity can be induced by OV and further enhanced through the combination of various immunomodulators.The Neo-2/15 is a newly de novo synthesized cytokine that functions as both IL-2 and IL-15.However,it specifically lacks the binding site of IL-2 receptorαsubunit(CD25),therefore unable to induce the Treg proliferation.In present study,a recombinant vesicular stomatitis virus expressing the Neo-2/15(VSVM51R-Neo-2/15)was generated.Intratumoral delivery of VSVM51R-Neo-2/15 efficiently inhibited tumor growth in mice without causing the IL-2-related toxicity previously observed in clinic.Moreover,treatment with VSVM51R-Neo-2/15 increased the number of activated CD8t T cells but not Treg cells in tumors.More tumor-bearing mice were survival with VSVM51R-Neo-2/15 treatment,and the surviving mice displayed enhanced protection against tumor cell rechallenge due to the induced anti-tumor immunity.In addition,combination therapy of OV and anti-PD-L1 immune checkpoint inhibitors further enhanced the anti-tumor immune response.These findings suggest that our novel VSVM51R-Neo-2/15 can effectively inhibit the tumor growth and enhance the sensitivity to immune checkpoint inhibitors,providing promising attempts for further clinical trials.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions,National Natural Science Foundation of China(32170142,81971917,81271792,81471571)Jiangsu Natural Science Foundation(BK20211310),and funding from Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases.
文摘A systems biology approach was employed to gain insight into tick biology and interactions between vectors and pathogens.Haemaphysalis longicornis serves as one of the primary vectors of Babesia microti,significantly impacting human and animal health.Obtaining more information about their relationship is crucial for a comprehensive un-derstanding of tick and pathogen biology,pathogen transmission dynamics,and potential control strategies.RNA sequencing of uninfected and B.microti-infected ticks resulted in the identification of 15056 unigenes.Among these,1051 were found to be differentially expressed,with 796 being upregulated and 255 downregulated(P<0.05).Integrated tran-scriptomics datasets revealed the pivotal role of immune-related pathways,including the Toll,Janus kinase/signal transducer and activator of transcription(JAK-STAT),immunod-eficiency,and RNA interference(RNAi)pathways,in response to infection.Consequently,3 genes encoding critical transcriptional factor Dorsal,Relish,and STAT were selected for RNAi experiments.The knockdown of Dorsal,Relish,and STAT resulted in a substantial increase in Babesia infection levels compared to the respective controls.These findings significantly advanced our understanding of tick–Babesia molecular interactions and pro-posed novel tick antigens as potential vaccine targets against tick infestations and pathogen transmission.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions,National Natural Science Foundation of China(81971917,32170142,81271792,and 81471571)Jiangsu Natural Science Foundation(BK20211310).
文摘Serine proteinase inhibitors(serpins),identified from the hard tick Haemaphysalis longicornis of China,play significant roles in various animal physiological processes.In this study,we showed that H.longicornis serpins(Hlserpin-a and Hlserpin-b)were induced during blood-feeding in nymph ticks and exhibited anticoagulation activity in vitro.Silencing Hlserpins through RNA interference(RNAi)significantly impaired tick feeding.Immunization of mice with recombinant Hlserpins or passive transfer of Hlserpin antiserum significantly curtails the efficacy of tick feeding.Concurrently,the transmission of the Langat virus(LGTV)from ticks to mice witnessed a substantial decrease when Hlserpins were silenced.Our findings suggest that inhibiting Hlserpins can hamper tick engorgement and pathogen transmission,indicating the potential of Hlserpins as a vaccine to countertick-borne diseases.
基金This work has been supported by the grants from the National Natural Science Foundation of China （91029703, 81072436 and 81273268）, with project funding from Suzhou City （SWG0904, SZS201109）, Priority Academic Program Development of Jiangsu Higher Education Institutions, Qing Lan Project of Jiangsu Province, Jiangsu Provincial Innovative Research Team and the Program for Changjiang Scholars and Innovative Research Team in University （IRT1075）.
文摘FTY720, an agonist for four of the five known sphingosine- 1-phosphate （SIP） receptors, has been reported to inhibit acute graft-versus-host disease （aGVHD）. Because FTY720 functions through multiple SIP receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective SIP receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an SIPl-selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an SIPl-selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.
基金This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions,National Natural Science Foundation of China(81971917,32170142 and 81271792)Jiangsu Natural Science Foundation(BK20211310)+2 种基金Open Project Fund from State Key Laboratory of Genetic Engineering,Fudan University(SKLGE1903)the Jiangsu Undergraduate Training Program for Innovation and Entrepreneurship,Soochow University(202010285133Y)the 23rd Undergraduates Extracurricular Academic Research Fund,Soochow University(KY20210120A).
文摘Background: Ticks are hematophagous parasites that transmit an extensive range of pathogens to their vertebrate hosts.Ticks can destroy invading microorganisms or alleviate infection via their rudimentary but orchestrated innate immune system.Antimicrobial peptides(AMPs)are important components of tick innate immunity.Among these humoral effector molecules,defensins are well-studied and widely identified in various species of Ixodidae(hard ticks)and Argasidae(soft ticks).This review was aimed at presenting the characterization of tick defensins from structure-based taxonomic status to antimicrobial function.Main text: All published papers written in English from 2001 to May 2022 were searched through PubMed and Web of Science databases with the combination of relevant terms on tick defensins.Reports on identification and characterization of tick defensins were included.Of the 329 entries retrieved,57 articles were finally eligible for our scoping review.Tick defensins mainly belong to the antibacterial ancient invertebrate-type defensins of the cis-defensins superfamily.They are generally small,cationic,and amphipathic,with six cysteine residues forming three intra-molecular disulfide bonds.Tick defensins primarily target membranes of a variety of pathogens,including Gram-positive and Gram-negative bacteria,fungi,viruses,and protozoa.Since tick defensins have a high degree of variability,we summarize their common biological properties and enumerate representative peptides.Along with the various and potent antimicrobial activities,the role of tick defensins in determining vector competence is discussed.Conclusions: Due to their broad-spectrum antimicrobial activities,tick defensins are considered novel candidates or targets for controlling infectious diseases.
文摘Dear Editor,Inactivation of the tumor suppressor p53 is a pivotal event in the formation of most human cancers.Dissecting the precise mechanism of p53 in tumor suppression contributes to the development of a better strategy for cancer therapy.The canonical activities of p53,such as cell cycle arrest,senescence,and apoptosis,are well accepted as the major checkpoints in stress responses and tumor suppression.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.30890141,31100629,and 30671952)Shanghai STC grant(No.10JC1401400)+4 种基金The Program for Outstanding Medical Academic Leaders of Shanghai(Grant No.LJ06011)Jiangsu“Pan-Deng”Project(Grant No.BK2010004)Postdoctoral Science Foundation Funded Project of China(Grant No.20100480538)Shanghai(Grant No.11R21411000)The Research Fellow Fund and Startup Fund for Young Backbone Scholars of Shanghai Medical College,Fudan University.
文摘C-reactive protein(CRP),an acute-phase protein with an ability to bind to nuclear antigen,has been reported to regulate cytokine secretion and modulate immune responses.We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA(apopDNA)could induce macrophage activation and contribute to the initiation and progression of lupus nephritis.It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation.Herein,CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA(CRP/apopDNA complex).Notably,CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone.Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner.These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.
基金National Natural Science Foundation of China(31970844,32170927)to SDX.
文摘Type I interferon(IFN-I)exhibits broad-spectrum antiviral properties and is commonly employed in clinical for the treatment of viral infections.In this study,we unveil SENP6 as a potent regulator of IFN-I antiviral activity.SENP6 does not impact the production of IFN-I induced by viruses but rather modulates IFN-I-activated signaling.Mechanistically,SENP6 constitutively interacts with USP8 and inhibits the SUMOylation of USP8,consequently restricting the interaction between USP8 and IFNAR2.The dissociation of USP8 from IFNAR2 enhances IFNAR2 ubiquitination and degradation,thus attenuating IFN-I antiviral activity.Correspondingly,the downregulation of SENP6 promotes the interaction between USP8 and IFNAR2,leading to a reduction in IFNAR2 ubiquitination and,consequently,an enhancement in IFN-I-induced signaling.This study deciphers a critical deSUMOylation-deubiquitination crosstalk that finely regulates the IFN-I response to viral infection.
基金supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions,National Natural Science Foundation of China(81271792,81471571,81971917,and 32170142)Jiangsu Natural Science Foundation(BK20211310).
文摘C-type lectins(CTLs)are a family of proteins that contain 1 or more carbohydrate-recognition domains(CRDs)and bind to a broad repertoire of ligands in the presence of calcium ions.CTLs play important roles in innate immune defenses against microorganisms by acting as pattern-recognition receptors(PRRs)for invading pathogens,such as bacteria,viruses,and parasites.After binding to pathogen-associated ligands,CTLs mediate immune responses,such as agglutination,phagocytosis,and the activation of phenol oxidase progenitors,thereby clearing pathogens.CTLs are an evolutionarily conserved family found in almost all vertebrates and invertebrates.Medical arthropods can acquire and transmit a range pathogens through various approaches,such as bloodsucking,lancing,and parasitism,thus infecting humans and animals with related diseases,some of which can be life-threatening.Recent studies have shown that lectins are important components of the arthropod immune system and are essential for the immune responses of arthropods to arthropod-borne pathogens.This article reviews the current understanding of the structure,function,and signaling pathways involved in CTLs derived from important medical arthropods.
基金supported by the National Natural Science Foundation of China(31470848,31470880,31670898,81802083 and 31870867)State Key Laboratory of Veterinary Biotechnology Foundation(SKLVBF201916)Jiangsu Provincial Innovative Research Team,the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The adoptive transfer of engineered chimeric antigen receptor(CAR)T cells has yielded impressive clinical results for targeting hematological cancers.1 However,the advancement of CAR T-cell therapy in solid tumors remains limited,due to the scarcity of tumor antigens that are deemed safe for targeting.Moreover,the requirement of patient-specific autologous T cells for the current standard treatment has also hampered its application.Oncolytic virus(OV)therapy has been classified as another form of novel immunotherapy.
