Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115

STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

Combined targeting of CCL7 and Flt3L to promote the expansion and infiltration of cDC1s in tumors enhances T-cell activation and anti-PD-1 therapy effectiveness in NSCLC

mmune checkpoint inhibitors(ICIs),represented by anti-PD-1/PD-L1 antibodies,have been widely applied in various cancers,and the efficacy of ICIs is closely associated with the tumor immune microenvironment(TIME)[1,2].We previously demonstrated that the alveolar macrophage-derived chemokine CCL7 recruited conventional type 1 dendritic cells(cDC1s)to remodel the TIME,thereby promoting the expansion of T cells to inhibit non-small cell lung cancer(NSCLC)progression in KrasLSL-G12D/+Tp53fl/fl(KP)and KrasLSL-G12D/+Lkb1fl/fl(KL)mouse models[3].Here,we showed that the fusion protein PD-1Ab7,in which CCL7 was fused with the single-chain variable fragment region(scFv)of an anti-PD-1 antibody(PD-1Ab),exhibited antitumor activity superior to that of PD-1Ab in a manner dependent on cDC1s.In addition,Fms-like tyrosine kinase 3 ligand(Flt3L)synergized with PD-1Ab7 to inhibit NSCLC progression in both the KP and the KL mouse models.Mechanistically,Flt3L promoted the generation and proliferation of cDC1s,whereas PD-1Ab7 increased the infiltration and migration of cDC1s in the TIME to potentiate the activation and proliferation of T cells.These findings not only highlight the essential roles of the PD-1Ab-based chemokine fusion strategy in targeting cDC1s and T cells to potentiate the efficacy of ICIs for cancer prevention but also provide therapeutic lead molecules for antitumor therapy.

MXRA7 is involved in megakaryocyte differentiation and platelet production

Matrix remodeling is a critical process in hematopoiesis.The biology of MXRA7,as a matrix remodeling associated gene,has still not been reported in hematopoietic process.Public databases showed that MXRA7 expressed in hematopoietic stem cells,suggesting that it may be involved in hematopoiesis.We found that the amounts of megakaryocytes were lower in bone marrow and spleen from Mxra7−/−mice compared with that from wild-type mice.Knock-out of MXRA7 also reduced the amount of platelet in peripheral blood and affected the function of platelets.Knock-out of MXRA7 inhibited hematopoietic stem/progenitor cells differentiate to megakaryocytes possibly through down-regulating the expression of GATA-1 and FOG-1.Moreover,knockdown of MXRA7 in MEG-01 cells could inhibit the cell proliferation and cell apoptosis.Knockdown of MXRA7 inhibited the differentiation of MEG-01 cells and proplatelet formation through suppressing the ERK/MAPK signaling pathway and the expression ofβ-tubulin.In conclusion,the current study demonstrated the potential significance of MXRA7 in megakaryocyte differentiation and platelet production.The novel findings proposed a new target for the treatment of platelet-related diseases,and much more investigations are guaranteed to dissect the mechanisms of MXRA7 in megakaryocyte differentiation and platelet production.

暗黑菌(Atribacteria)的环境分布和功能特征

暗黑菌门包括OP9和JS1两大分支,成员大多为未培养微生物,在自然环境中广泛分布,并且在部分环境如厌氧海洋沉积物、地热环境以及油藏中为优势微生物。基于基因组信息的研究表明,暗黑菌为严格的厌氧微生物,同时具有降解糖类、小分子酸、短链正构烷烃的能力,在地球碳循环过程中可能扮演着重要的角色。然而,由于缺乏相应代表性的纯培养菌株,对于暗黑菌的生理生化功能推测仍有待验证。文章概述了暗黑菌的发现及发展历史,分析了其环境分布和多样性,简述了目前提出的三种代谢方式,提出了未来暗黑菌的研究发展方向。

Electrospinning of ceramic nanofibers:Fabrication,assembly and applications

This paper provides a brief review of current research activities that focus on the synthesis and controlled assembly of inorganic nano-bers by electrospinning,their electrical,optical and magnetic properties,as well as their applications in various areas including sensors,catalysts,batteries,filters and separators.We begin with a brief introduction to electrospinning technology and a brief method to produce ceramic nanofibers from electrospinning.We then discuss approaches to the controlled assembly and patterning of electrospun ceramic nanofibers.We continue with a highlight of some recent applications enabled by electrospun ceramic nano-bers,with a focus on the physical properties of functional ceramic nanofibers as well as their applications in energy and environmental technologies.In the end,we conclude this review with some perspectives on the future directions and implications for this new class of functional nanomaterials.It is expected that this review paper can help the readers quickly become acquainted with the basic principles and particularly the experimental procedure for preparing and assembly of 1D ceramic nanofiber and its arrays.

The S 1P, receptor-selective agonist CYM-5442 reduces the severity of acute GVHD byinhibiting macrophage recruitment

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.

古丸菌Archaeoglobi的代谢特征

古丸菌纲(Archaeoglobi)是广古菌门下的纲级分类单元,包含古丸菌(Archaeoglobus)、地丸菌(Geoglobus)和铁丸菌(Ferroglobus)三个属,所属菌株均是严格嗜热厌氧菌,主要分布于海洋、陆地热液系统和油田环境中。Archaeoglobus属下的微生物是一类以硫酸盐、亚硫酸盐或硫代硫酸盐为电子受体代谢生成硫化氢(H2S)的化能自养或氢营养型微生物;而Geoglobus和Ferroglobus的成员则主要还原硝酸盐和铁离子。Archaeoglobi地理分布广泛,在元素生物地球化学循环过程中发挥着重要作用,是目前微生物生态学研究的一个热点。在进化方面,Archaeoglobi菌和产甲烷古菌具有较高的亲缘关系;同时,Archaeoglobi基因组中保留着部分产甲烷途径上的功能基因,最新研究表明部分未培养的Archaeoglobi基因组中含有完整的产甲烷通路。这些证据都表明Archaeoglobi菌的基因组特征可能是产甲烷古菌向硫酸盐还原菌进化的活化石。本文梳理了目前发现的11株Archaeoglobi菌株的生理生化特征和基因组分析结果,从化能自养、化能异养、硫化物呼吸、产乙酸、产甲烷等方面综述了已分离的Archaeoglobi菌的代谢特征,并基于宏基因组信息分析了未培养的Archaeoglobi菌基因组中的潜在代谢功能,为进一步分离培养此类未培养厌氧微生物提供理论指导。