Inosine:A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)-induced cytokine storms constitute the primary cause of coronavirus disease 19(COVID-19)progression,severity,criticality,and death.Glucocorticoid and anti-cytokine therapies are frequently administered to treat COVID-19,but have limited clinical efficacy in severe and critical cases.Nevertheless,the weaknesses of these treatment modalities have prompted the development of anti-inflammatory therapy against this infection.We found that the broad-spectrum anti-inflammatory agent inosine downregulated proinflammatory interleukin(IL)-6,upregulated anti-inflammatory IL-10,and ameliorated acute inflammatory lung injury caused by multiple infectious agents.Inosine significantly improved survival in mice infected with SARS-CoV-2.It indirectly impeded TANK-binding kinase 1(TBK1)phosphorylation by binding stimulator of interferon genes(STING)and glycogen synthase kinase-3β(GSK3β),inhibited the activation and nuclear translocation of the downstream transcription factors interferon regulatory factor(IRF3)and nuclear factor kappa B(NF-κB),and downregulated IL-6 in the sera and lung tissues of mice infected with lipopolysaccharide(LPS),H1N1,or SARS-CoV-2.Thus,inosine administration is feasible for clinical anti-inflammatory therapy against severe and critical COVID-19.Moreover,targeting TBK1 is a promising strategy for inhibiting cytokine storms and mitigating acute inflammatory lung injury induced by SARS-CoV-2 and other infectious agents.

Microstructural evolution and tensile properties of low-carbon steel with martensitic microstructure during warm deforming and annealing

For preparing large-scale nano-grained and ultrafine-grained steel sheets by warm rolling and annealing, the effects of deforming temperature on both the flow stress and the microstructure evolution of 09MnNiD steel with lath martensitic microstructure were studied by warm-compression test and transmission electron microscopy （TEM） observation. Thereafter, the steel with the lath martensitic structure was multi-pass warm-rolled and then annealed. TEM results indicate that nano-grained and ultrafine-grained steel sheets are formed by warm rolling at 400℃ and annealing at 400-600℃. In comparison with the as-warm-rolled specimen, the tensile strength at room temperature changes a little when the rolled samples are annealed below 450℃, and the tensile strength is greatly lowered as the annealing temperature increases to above 550℃.

Multiporphyrinic architectures:Advances in structural design for photodynamic therapy

Rationally designed multiporphyrinic architectures for boosting photodynamic therapy(PDT)have attracted significant attentions recently years due to their great potential for light-mediated generation of reactive oxygen species.However,there is still a gap between the structure design and their PDT performance for biomedical applications.This tutorial review provides a historical overview on(i)the basic concept of PDT for deeply understanding the porphyrin-mediated PDT reactions,(ii)developing strategies for constructing porphyrinic architectures,like nanorings,boxes,metal-organic frameworks(MOFs),covalent-organic frameworks(COFs),vesicles,etc.,where we classified into the following three categories:multiporphyrin arrays,porphyrinic frameworks,and others porphyrin assemblies,(iii)the various application scenarios for clinical cancer therapy and antibacterial infection.Also,the existing challenges and future perspectives on the innovation of porphyrinic architectures for clinical PDT applications are mentioned in the end section.Moreover,the porphyrinic nanomaterials with atomically precise architectures provide an ideal platform for investigating the relationship between structures and PDT outputs,design of personalized“all-in-one”theranostic agents,and the popularization and application in wider biomedical fields.

THSD7A相关性膜性肾病:一例报告及文献复习

膜性肾病(membranous nephropathy,MN)是成人肾病综合征(nephrotic syndrome,NS)的主要原因,约80%的MN没有明确的继发性病因,称为特发性膜性肾病(idiopathic membranous nephropathy,IMN),病理特征为肾小球基底膜增厚、上皮下免疫复合物沉积。约20%的MN病例继发于自身免疫性疾病、感染、恶性肿瘤、药物和重金属中毒等,称为继发性膜性肾病。1型血小板反应蛋白7A域(thrombospondin type 1 domain-containing 7A,THSD7A)是近年发现的IMN第二个靶抗原,文献报道THSD7A可用于诊断、病情评估,尤其与肿瘤关系密切,但目前尚未在临床上广泛应用。现将我们诊治的1例THSD7A相关性膜性肾病患者并结合文献回顾阐述报告。

A micro-sized vaccine based on recombinant Lactiplantibacillus plantarum fights against SARS-CoV-2 infection via intranasal immunization

COVID-19 has globally spread to burden the medical system.Even with a massive vaccination,a mucosal vaccine offering more comprehensive and convenient protection is imminent.Here,a micro-sized vaccine based on recombinant Lactiplantibacillus plantarum(rLP)displaying spike or receptor-binding domain(RBD)was characterized as microparticles,and its safety and protective effects against SARS-CoV-2 were evaluated.We found a 66.7%mortality reduction and 100%protection with rLP against SARS-CoV-2 in a mouse model.The histological analysis showed decreased hemorrhage symptoms and increased leukocyte infiltration in the lung.Especially,rLP:RBD significantly decreased pulmonary viral loads.For the first time,our study provides a L.plantarum-vectored vaccine to prevent COVID-19 progress and transmission via intranasal vaccination.

Taurolidine improved protection against highly pathogenetic avian influenza H5N1 virus lethal-infection in mouse model by regulating the NF-κB signaling pathway

Taurolidine(TRD),a derivative of taurine,has anti-bacterial and anti-tumor effects by chemically reacting with cell-walls,endotoxins and exotoxins to inhibit the adhesion of microorganisms.However,its application in antiviral therapy is seldom reported.Here,we reported that TRD significantly inhibited the replication of influenza virus H5N1 in MDCK cells with the half-maximal inhibitory concentration(EC_(50))of 34.45μg/mL.Furthermore,the drug inhibited the amplification of the cytokine storm effect and improved the survival rate of mice lethal challenged with H5N1(protection rate was 86%).Moreover,TRD attenuated virus-induced lung damage and reduced virus titers in mice lungs.Administration of TRD reduced the number of neutrophils and increased the number of lymphocytes in the blood of H5N1 virus-infected mice.Importantly,the drug regulated the NF-κB signaling pathway by inhibiting the separation of NF-κB and IκBa,thereby reducing the expression of inflammatory factors.In conclusion,our findings suggested that TRD could act as a potential anti-influenza drug candidate in further clinical studies.

CD97 negatively regulates the innate immune response against RNA viruses by promoting RNF125-mediated RIG-I degradation

The G protein-coupled receptor ADGRE5(CD97)binds to various metabolites that play crucial regulatory roles in metabolism.However,its function in the antiviral innate immune response remains to be determined.In this study,we report that CD97 inhibits virus-induced type-I interferon(IFN-I)release and enhances RNA virus replication in cells and mice.CD97 was identified as a new negative regulator of the innate immune receptor RIG-I,and RIG-1 degradation led to the suppression of the IFN-I signaling pathway.Furthermore,overexpression of CD97 promoted the ubiquitination of RIG-I,resulting in its degradation,but did not impact its mRNA expression.Mechanistically,CD97 upregulates RNF125 expression to induce RNF125-mediated RIG-I degradation via K48-linked ubiquitination at Lys181 after RNA virus infection.Most importantly,CD97-deficient mice are more resistant than wild-type mice to RNA virus infection.We also found that sanguinarine-mediated inhibition of CD97 effectively blocks VSV and SARS-CoV-2 replication.These findings elucidate a previously unknown mechanism through which CD97 negatively regulates RIG-I in the antiviral innate immune response and provide a molecular basis for the development of new therapeutic strategies and the design of targeted antiviral agents.

Mouse model for pangolin-origin coronavirus GX/P2V/2017 infection and cross-protection from COVID-19 ZF2001 subunit vaccine

Many severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)–related coronaviruses have been discovered,constituting potential threats to human health.However,it remains unclear whether the currently available vaccines are effective against these coronaviruses.Here,we constructed a wild-type mouse model to evaluate pathogenicity of the SARS-CoV-2-related pangolin coronavirus GX/P2V/2017 and neutralization efficacy of the approved tandemrepeat SARS-CoV-2 spike receptor-binding domain(RBD)vaccine ZF2001.We found that ZF2001-induced cross-reactive and cross-neutralizing antibodies against GX/P2V/2017,and the vaccination alleviated the pathological lung damage caused by GX/P2V/2017 in mice.These results indicate that RBD may work as a promising candidate for pan-coronavirus vaccine development.

SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy

The global coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has caused severe morbidity and mortality in humans.It is urgent to understand the function of viral genes.However,the function of open reading frame 10(ORF10),which is uniquely expressed by SARS-CoV-2,remains unclear.In this study,we showed that overexpression of ORF10 markedly suppressed the expression of type I interferon(IFN-I)genes and IFN-stimulated genes.Then,mitochondrial antiviral signaling protein(MAVS)was identified as the target via which ORF10 suppresses the IFN-I signaling pathway,and MAVS was found to be degraded through the ORF10-induced autophagy pathway.Furthermore,overexpression of ORF10 promoted the accumulation of LC3 in mitochondria and induced mitophagy.Mechanistically,ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X(NIX)and induced mitophagy through its interaction with both NIX and LC3B.Moreover,knockdown of NIX expression blocked mitophagy activation,MAVS degradation,and IFN-I signaling pathway inhibition by ORF10.Consistent with our observations,in the context of SARS-CoV-2 infection,ORF10 inhibited MAVS expression and facilitated viral replication.In brief,our results reveal a novel mechanism by which SARS-CoV-2 inhibits the innate immune response;that is,ORF10 induces mitophagy-mediated MAVS degradation by binding to NIX.

Recombinant vaccine containing an RBD-Fc fusion induced protection against SARS-CoV-2 in nonhuman primates and mice

The novel coronavirus SARS-CoV-2 has infected more than 104 million individuals and resulted in more than 2.2 million deaths worldwide as of February 7,2021(https://covid19.who.int).The COVID-19 pandemic highlights the need for safe and effective vaccines against SARS-CoV-2 infection.

Highly pathogenic coronavirus N protein aggravates inflammation by MASP-2-mediated lectin complement pathway overactivation

Excessive inflammatory responses contribute to the pathogenesis and lethality of highly pathogenic human coronaviruses,but the underlying mechanism remains unclear.In this study,the N proteins of highly pathogenic human coronaviruses,including severe acute respiratory syndrome coronavirus(SARS-CoV),middle east respiratory syndrome coronavirus(MERS-CoV)and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),were found to bind MASP-2,a key serine protease in the lectin pathway of complement activation,resulting in excessive complement activation by potentiating MBL-dependent MASP-2 activation,and the deposition of MASP-2,C4b,activated C3 and C5b-9.Aggravated inflammatory lung injury was observed in mice infected with adenovirus expressing the N protein.Complement hyperactivation was also observed in SARS-CoV-2-infected patients.Either blocking the N protein:MASP-2 interaction,MASP-2 depletion or suppressing complement activation can significantly alleviate N protein-induced complement hyperactivation and lung injury in vitro and in vivo.Altogether,these data suggested that complement suppression may represent a novel therapeutic approach for pneumonia induced by these highly pathogenic coronaviruses.

Rapidly developable therapeutic-grade equine immunoglobulin against the SARS-CoV-2 infection in rhesus macaques

Dear Editor,The unprecedented COVID-19 pandemic caused by SARS-CoV-2 remains ongoing,but there is a lack of fully effective treatments.Convalescent plasma-derived hyperimmune globulins have been a safe and effective treatment but restricted by the difficulties in obtaining sufficient plasma with high antibody titers from a large number of recovered patients.Heterologous antibodies,particularly equine antibodies,have been widely used for decades as the therapeutics against some viral infections or as antivenoms.1 Equine antibodies could be rapidly developed and manufactured into therapeutic antibodies in large quantities under WHO standardized guidelines.Here we explored the development of equine antibody-derived F(ab′)2 as an option to treat COVID-19 by targeting the receptor-binding domain(RBD)of the viral spike protein that is essential for the viral entry into the host cells.2 We observed excellent neutralization titers of the F(ab′)2 in vitro and high potency against SARS-CoV-2 infection in the nonhuman primate rhesus macaques.

The Application of a Safe Neutralization Assay for Ebola Virus Using Lentivirus-Based Pseudotyped Virus

Dear Editor,Zaire Ebola virus(EBOV)is a negative-sense singlestranded RNA virus that is capable of causing acute hemorrhagic fever with a frightening fatality rate that can reach up to 90%.Due to its high lethality and frequent recurrence,EBOV is a substantial threat to public health.Research about live EBOV is restricted to BSL-4 laboratories;therefore,conventional serological detection methods do not provide a safe way to evaluate neutralizing activity,resulting in a bottleneck in antibody-based detection of viruses such as EBOV.Here,we aim to develop and apply a neutralization assay for EBOV using a generated lentivirus-based pseudotyped EBOV bearing GP on its surface.

An updated RBD-Fc fusion vaccine booster increases neutralization of SARS-CoV-2 Omicron variants

Dear Editor,Coronavirus disease 2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which is a novel subset of coronavirus.To this day,the number of confirmed cases is over 500 million with more than 6 million deaths globally.SARSCoV-2 keeps on evolving into different variants,including Alpha,Beta,Gamma,Delta,and Omicron.

Prevention and control of zoonoses at their source:from the Chinese perspective

Zoonoses are a significant public health concern and cause considerable socioeconomic problems globally.The emergence of severe acute respiratory syndrome(SARS),highly pathogenic avian influenza(HPAI),and Ebola virus disease(EVD)has had a significant effect on the national economy and public health in China,and other countries.This review analyzed zoonotic disease issues faced by China,and the main factors contributing to the risk of zoonotic disease.The Chinese government has devised new strategies and has taken measures to deal with the challenges of these diseases,and the prevention and control of zoonoses at their source.A strategy that is suited to China’s national conditions,is proposed.

Neutralization activity of influenza A virus humanized antibodies against new subtypes of influenza viruses

Antibodies are ideal for controlling the influenza A virus,but their effect on newly emerging strains is unclear.Here,we assessed the neutralization activity of the humanized monoclonal antibodies(mAbs)F10,H98 and H40 against circulating influenza viruses(H5N1,H1N1,H3N2 and H7N7 and new subtypes viruses H5N6 and H7N9).The results showed that all the three humanized mAbs(F10,H98 and H40)displayed different degrees of virus neutralization activities when encountered with different subtypes of influenza viruses.Remarkably,the humanized monoclonal antibody F10 produced higher and broader neutralization titers(range 25–1.56μg/ml)than those of the other two humanized mAbs(H98(range 50–3.12μg/ml),H40(range 50–5.56μg/ml))to against the viruses H5N1,H1N1,H3N2,H7N7,H5N6 and H7N9.This mAb may represent a new class of heterosubtypic neutralizing humanized mAb that could replace vaccines and chemical drugs.

国家基础学科公共科学数据中心建设与发展实践

数智时代,科学数据作为国家重要战略性资源和生产要素之一,将对国家科技水平提升和经济发展提供重要动能.《科学数据管理办法》发布后,国家基础学科公共科学数据中心正式成立,旨在汇集管理我国基础学科领域及典型区域长期科研活动积累的科学数据,以及相关基础领域政府预算资金支持项目汇交的科学数据,具有基础性、跨学科性和前沿性特征.经过近五年的建设实践,目前已形成完善的基础学科数据资源体系,以及支持分布式科学数据资源统一管理、集成融合、分析挖掘和应用服务的标准体系、服务体系和技术体系,持续深化数据国际交流合作.同时,创新科学数据出版新模式,引领科学数据的高效汇聚、开放共享、多学科交叉融合分析和创新应用.未来将在基础学科高质量数据集构建、数据治理服务模式创新、多学科交叉融合应用等方面进一步开展工作.本文综述国家基础学科公共科学数据中心建设模式与实践成效,以期为科学数据管理机构建设运行提供通用参考.