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Monkeypox virus (MPXV) is a cross-kingdom pathogen infecting both humans and wildlife, which poses a significant health risk to the public. Although MPXV attracts broad attention, there is a lack of adequate studies to elucidate pathogenic mechanisms associated with viral infections. In this study, a high-throughput RNA sequencing (RNA-seq) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach was used to explore the transcriptional and metabolic responses of MPXV A23 protein to HEK293T cells. The protein-protein interactions and signaling pathways were conducted by GO and KEGG analyses. The localization of A23 protein in HEK293T cells was detected by immunofluorescence. A total of 648 differentially expressed genes (DEGs) were identified in cells by RNA-Seq, including 314 upregulated genes and 334 downregulated genes. Additionally, liquid chromatography-tandem mass spectrometry (LC-MS/MS) detected 115 cellular proteins that interact with the A23 proteins. Transcriptomic sequencing analysis revealed that transfection of MPXV A23 protein modulated genes primarily associated with cellular apoptosis and DNA damage repair. Proteomic analysis indicated that this protein primarily interacted with host ribosomal proteins and histones. Following the identification of the nuclear localization sequence RKKR within the A23 protein, a truncated mutant A23ΔRKKR was constructed to investigate the subcellular localization of A23 protein. The wild-type A23 protein exhibits a significantly higher nuclear-to-cytoplasmic ratio, exceeding 1.5, in contrast to the mutant A23ΔRKKR, which has a ratio of approximately 1. Immunofluorescence assays showed that the A23 protein was mainly localized in the nucleus. The integration of transcriptomics and proteomics analysis provides a comprehensive understanding of the interaction between MPXV A23 protein and the host. Our findings highlight the potential role of this enzyme in suppressing host antiviral immune responses and modulating host gene expression.

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The cGAS-STING signaling pathway plays a pivotal role in sensing cytosolic DNA and initiating innate immune responses against various threats, with disruptions in this pathway being associated with numerous immune-related disorders. Therefore, precise regulation of the cGAS-STING signaling is crucial to ensure appropriate immune responses. Recent research, including ours, underscores the importance of protein condensation in driving the activation and maintenance of innate immune signaling within the cGAS-STING pathway. Consequently, targeting condensation processes in this pathway presents a promising approach for modulating the cGAS-STING signaling and potentially managing associated disorders. In this review, we provide an overview of recent studies elucidating the role and regulatory mechanism of protein condensation in the cGAS-STING signaling pathway while emphasizing its pathological implications. Additionally, we explore the potential of understanding and manipulating condensation dynamics to develop novel strategies for mitigating cGAS-STING-related disorders in the future.

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Mitochondria play an important and multifaceted role in cellular function, catering to the cell's energy and biosynthetic requirements. They modulate apoptosis while responding to diverse extracellular and intracellular stresses including reactive oxygen species (ROS), nutrient and oxygen scarcity, endoplasmic reticulum stress, and signaling via surface death receptors. Integral components of mitochondria, such as mitochondrial DNA (mtDNA), mitochondrial RNA (mtRNA), Adenosine triphosphate (ATP), cardiolipin, and formyl peptides serve as major damage-associated molecular patterns (DAMPs). These molecules activate multiple innate immune pathways both in the cytosol [such as Retionoic Acid-Inducible Gene-1 (RIG-1) and Cyclic GMP-AMP Synthase (cGAS)] and on the cell surface [including Toll-like receptors (TLRs)]. This activation cascade leads to the release of various cytokines, chemokines, interferons, and other inflammatory molecules and oxidative species. The innate immune pathways further induce chronic inflammation in the tumor microenvironment which either promotes survival and proliferation or promotes epithelial to mesenchymal transition (EMT), metastasis and therapeutic resistance in the cancer cell's. Chronic activation of innate inflammatory pathways in tumors also drives immunosuppressive checkpoint expression in the cancer cells and boosts the influx of immune-suppressive populations like Myeloid-Derived Suppressor Cells (MDSCs) and Regulatory T cells (Tregs) in cancer. Thus, sensing of cellular stress by the mitochondria may lead to enhanced tumor growth. In addition to that, the tumor microenvironment also becomes a source of immunosuppressive cytokines. These cytokines exert a debilitating effect on the functioning of immune effector cells, and thus foster immune tolerance and facilitate immune evasion. Here we describe how alteration of the mitochondrial homeostasis and cellular stress drives innate inflammatory pathways in the tumor microenvironment.

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Reprogramming scar fibroblasts into cardiomyocytes has been proposed to reverse the damage associated with myocardial infarction. However, the limited improvement in cardiac function calls for enhanced strategies. We reported enhanced efficacy of our miR reprogramming cocktail miR combo (miR-1, miR-133a, miR-208a, and miR-499) via RNA-sensing receptor stimulation. We hypothesized that we could combine RNA-sensing receptor activation with fibroblast reprogramming by chemically modifying miR combo. To test the hypothesis, miR combo was modified to enhance interaction with the RNA-sensing receptor Rig1 via the addition of a 5'-triphosphate (5'ppp) group. Importantly, when compared with unmodified miR combo, 5'ppp-modified miR combo markedly improved reprogramming efficacy in vitro. Enhanced reprogramming efficacy correlated with a type-I interferon immune response with strong and selective secretion of interferon ß (IFNß). Antibody blocking studies and media replacement experiments indicated that 5'ppp-miR combo utilized IFNß to enhance fibroblast reprogramming efficacy. In conclusion, miRs can acquire powerful additional roles through chemical modification that potentially increases their clinical applications.

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Background: Monkeypox or mpox virus (mpox) is a double-stranded DNA virus that poses a significant threat to global public health security. The F3 protein, encoded by mpox, is an apoenzyme believed to possess a double-stranded RNA-binding domain (dsRBD). However, limited research has been conducted on its function. In this study, we present data on the transcriptomics and proteomics of F3L-transfected HEK293T cells, aiming to enhance our comprehension of F3L. Methods: The gene expression profiles of pCAGGS-HA-F3L transfected HEK293T cells were analyzed using RNA-seq. Proteomics was used to identify and study proteins that interact with F3L. Real-time PCR was used to detect mRNA levels of several differentially expressed genes (DEGs) in HEK293T cells (or Vero cells) after the expression of F3 protein. Results: A total of 14,822 genes were obtained in cells by RNA-Seq and 1,672 DEGs were identified, including 1,156 up-regulated genes and 516 down-regulated genes. A total of 27 cellular proteins interacting with F3 proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and 19 cellular proteins with large differences in abundance ratios were considered to be candidate cellular proteins. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that the DEGs were significantly enriched in immune-related pathways, including type I interferon signaling pathway, response to virus, RIG-I-like receptor signaling pathway, NOD-like receptor signaling pathway, etc. Moreover, some selected DEGs were further confirmed by real-time PCR and the results were consistent with the transcriptome data. Proteomics data show that cellular proteins interacting with F3 proteins are mainly related to RNA splicing and protein translation. Conclusions: Our analysis of transcriptomic and proteomic data showed that (1) F3L up-regulates the transcript levels of key genes in the innate immune signaling pathway, such as RIGI, MDA5, IRF5, IRF7, IRF9, ISG15, IFNA14, and elicits a broad spectrum of antiviral immune responses in the host. F3L also increases the expression of the FOS and JNK genes while decreasing the expression of TNFR2, these factors may ultimately induce apoptosis. (2) F3 protein interacts with host proteins involved in RNA splicing and protein translation, such as SNRNP70, POLR2H, HNRNPA1, DDX17, etc. The findings of this study shed light on the function of the F3 protein.

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Alcoholic liver disease (ALD), which is induced by chronic heavy alcohol consumption, accompanies complicated pathological mechanisms, including oxidative stress, inflammation, cell death, epigenetic changes and acetaldehyde-mediated toxicity. Hydrogen (H2) is the lightest gas with multiple biological effects such as high selective anti-oxidation, anti-inflammation and anti-apoptosis. However, the dose effects and innate immune mechanisms of intraperitoneal injection of H2 on ALD are limited. Here, we used acute ethanol-induced hepatotoxicity mice models to estimate the actions of intraperitoneal injection of H2 on ALD. The effects of H2 on acute ethanol-induced liver damage were examined by hepatic oil red O staining, quantitative PCR (qPCR) for lipid metabolic genes, hepatic triglyceride (TG) and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Hepatic mitochondrial superoxide (MitoSOX), 3-nitrotyrosine (3-NT), malondialdehyde (MDA), and glutathione (GSH) levels were examined to evaluate oxidative stress. Immunoblot, and immunofluorescence staining were used to further confirm the innate immune molecular targets of H2. Our results showed that intraperitoneal injection of H2 improved acute ethanol-induced liver injury in mice in a dose dependent manner, as indicated by decreasing serum ALT and AST levels, hepatic TG levels, and increasing lipid export genes (Mttp and Apob) mRNA levels and reducing fatty acid uptake gene (CD36) mRNA levels. Mechanistically, H2 inhibited hepatic oxidative stress as indicated by reducing reactive oxygen species (ROS), 3-NT, and MDA levels in the liver, while increasing hepatic GSH levels; inhibited the overactived TLR4/9-NF-κB-TNF-α/IL-1ß/IL-18 innate immune signaling; suppressed the canonical Caspase-1-GSDMD pyroptosis signaling, and the non-canonical pyroptosis signaling, such as Caspase-11-GSDMD, Caspase-8-GSDMD and Caspase-3-GSDME signaling. Therefore, our study highlights that intraperitoneal injection of H2 may represent a novel therapeutic and safe strategy for ALD via modulating oxidative stress, innate immunity and pyroptosis.

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Exercise training can stimulate the formation of fatty-acid-oxidizing slow-twitch skeletal muscle fibers, which are inversely correlated with obesity, but the molecular mechanism underlying this transformation requires further elucidation. Here, we report that the downregulation of the mitochondrial disulfide relay carrier CHCHD4 by exercise training decreases the import of TP53-regulated inhibitor of apoptosis 1 (TRIAP1) into mitochondria, which can reduce cardiolipin levels and promote VDAC oligomerization in skeletal muscle. VDAC oligomerization, known to facilitate mtDNA release, can activate cGAS-STING/NFKB innate immune signaling and downregulate MyoD in skeletal muscle, thereby promoting the formation of oxidative slow-twitch fibers. In mice, CHCHD4 haploinsufficiency is sufficient to activate this pathway, leading to increased oxidative muscle fibers and decreased fat accumulation with aging. The identification of a specific mediator regulating muscle fiber transformation provides an opportunity to understand further the molecular underpinnings of complex metabolic conditions such as obesity and could have therapeutic implications.

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Background: Nuclear factor κB (NF-κB) signaling in cardiac myocytes causes disease in a mouse model of arrhythmogenic cardiomyopathy (ACM) by mobilizing CCR2-expressing macrophages that promote myocardial injury and arrhythmias. Buccal mucosa cells exhibit pathologic features similar to those seen in cardiac myocytes in patients with ACM. Objectives: We sought to determine if persistent innate immune signaling via NF-κB occurs in cardiac myocytes in patients with ACM and if this is associated with myocardial infiltration of proinflammatory cells expressing CCR2. We also determined if buccal mucosa cells from young subjects with inherited disease alleles exhibit NF-κB signaling. Methods: We analyzed myocardium from ACM patients who died suddenly or required cardiac transplantation. We also analyzed buccal mucosa cells from young subjects with inherited disease alleles. The presence of immunoreactive signal for RelA/p65 in nuclei of cardiac myocytes and buccal cells was used as a reliable indicator of active NF-κB signaling. We also counted myocardial CCR2-expressing cells. Results: RelA/p65 signal was seen in numerous cardiac myocyte nuclei in 34 of 36 cases of ACM but not in 19 age-matched control individuals. Cells expressing CCR2 were increased in patient hearts in numbers directly correlated with the number of cardiac myocytes showing NF-κB signaling. NF-κB signaling was observed in buccal cells in young subjects with active disease. Conclusions: Patients with clinically active ACM exhibit persistent innate immune responses in cardiac myocytes and buccal mucosa cells, reflecting a local and systemic inflammatory process. Such individuals may benefit from anti-inflammatory therapy.

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Interferon-alpha inducible protein 6 (IFI6) is an important interferon-stimulated gene. To date, research on IFI6 has mainly focused on human malignant tumors, virus-related diseases and autoimmune diseases. Previous studies have shown that IFI6 plays an important role in antiviral, antiapoptotic and tumor-promoting cellular functions, but few studies have focused on the structure or function of avian IFI6. Avian reovirus (ARV) is an important virus that can exert immunosuppressive effects on poultry. Preliminary studies have shown that IFI6 expression is upregulated in various tissues and organs of specific-pathogen-free chickens infected with ARV, suggesting that IFI6 plays an important role in ARV infection. To analyze the function of avian IFI6, particularly in ARV infection, the chicken IFI6 gene was cloned, a bioinformatics analysis was conducted, and the roles of IFI6 in ARV replication and the innate immune response were investigated after the overexpression or knockdown of IFI6 in vitro. The results indicated that the molecular weight of the chicken IFI6 protein was approximately 11 kDa and that its structure was similar to that of the human IFI27L1 protein. A phylogenetic tree analysis of the IFI6 amino acid sequence revealed that the evolution of mammals and birds was clearly divided into two branches. The evolutionary history and homology of chickens are similar to those of other birds. Avian IFI6 localized to the cytoplasm and was abundantly expressed in the chicken lung, intestine, pancreas, liver, spleen, glandular stomach, thymus, bursa of Fabricius and trachea. Further studies demonstrated that IFI6 overexpression in DF-1 cells inhibited ARV replication and that the inhibition of IFI6 expression promoted ARV replication. After ARV infection, IFI6 modulated the expression of various innate immunity-related factors. Notably, the expression patterns of MAVS and IFI6 were similar, and the expression patterns of IRF1 and IFN-ß were opposite to those of IFI6. The results of this study further advance the research on avian IFI6 and provide a theoretical basis for further research on the role of IFI6 in avian virus infection and innate immunity.

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APOBEC3A is an antiviral DNA deaminase often induced by virus infection. APOBEC3A is also a source of cancer mutation in viral and nonviral tumor types. It is therefore critical to identify factors responsible for APOBEC3A upregulation. Here, we test the hypothesis that leaked mitochondrial (mt) double-stranded (ds)RNA is recognized as foreign nucleic acid, which triggers innate immune signaling, APOBEC3A upregulation, and DNA damage. Knockdown of an enzyme responsible for degrading mtdsRNA, the exoribonuclease polynucleotide phosphorylase, results in mtdsRNA leakage into the cytosol and induction of APOBEC3A expression. APOBEC3A upregulation by cytoplasmic mtdsRNA requires RIG-I, MAVS, and STAT2 and is likely part of a broader type I interferon response. Importantly, although mtdsRNA-induced APOBEC3A appears cytoplasmic by subcellular fractionation experiments, its induction triggers an overt DNA damage response characterized by elevated nuclear γ-H2AX staining. Thus, mtdsRNA dysregulation may induce APOBEC3A and contribute to observed genomic instability and mutation signatures in cancer.

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The creation of safe and effective vaccines that induce potent cellular and humoral immune responses against SARS-CoV-2 is urgently needed to end the global COVID-19 epidemic. Here, we developed an alphavirus-derived self-replicating RNA (repRNA)-based vaccine platform encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike glycoprotein. The repRNA triggers prolonged antigen expression compared with conventional mRNA due to the replication machinery of repRNA. To improve the delivery and vaccine efficacy of repRNA, we developed a self-assembling liposome-protamine-RNA (LPR) nanoparticle with highly efficient encapsulation and transfection of repRNA. LPR-repRNA vaccines substantially activated type I interferon response and innate immune signaling pathways. Subcutaneous immunization of LPR-repRNA-RBD led to prolonged antigen expression, stimulation of innate immune cells, and induction of germinal center response in draining lymph nodes. LPR-repRNA-RBD induced antigen-specific T cell responses and skewed cellular immunity toward an effector memory CD8+ T cell response. Immunizations with LPR-repRNA-RBD triggered the production of anti-RBD IgG antibodies and induced neutralizing antibody response against SARS-CoV-2 pseudovirus. LPR-repRNA-RBD vaccines reduced SARS-CoV-2 infection and lung inflammation in mice. Altogether, these data suggest that the LPR-repRNA platform can be a promising avenue for COVID-19 vaccine development.

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Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.

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Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation and has become the leading chronic liver disease worldwide. NAFLD is viewed as the hepatic manifestation of metabolic syndrome, ranging from simple steatosis and nonalcoholic steatohepatitis (NASH) to advanced fibrosis, eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of NAFLD progression is still not clear. Pattern recognition receptor (PRR)-mediated innate immune responses play a critical role in the initiation of NAFLD and the progression of NAFLD-related HCC. Toll-like receptors (TLRs) and the cyclic GMP-AMP (cGAMP) synthase (cGAS) are the two major PRRs in hepatocytes and resident innate immune cells in the liver. Increasing evidence indicates that the overactivation of TLRs and the cGAS signaling pathways may contribute to the development of liver disorders, including NAFLD progression. However, induction of PRRs is critical for the release of type I interferons (IFN-I) and the maturation of dendritic cells (DCs), which prime systemic antitumor immunity in HCC therapy. In this review, we will summarize the emerging evidence regarding the molecular mechanisms of TLRs and cGAS in the development of NAFLD and HCC. The dysfunction of PRR-mediated innate immune response is a critical determinant of NAFLD pathology; targeting and selectively inhibiting TLRs and cGAS signaling provides therapeutic potential for treating NALF-associated diseases in humans.

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TAX1BP1 is a selective macroautophagy/autophagy receptor that plays a central role in host defense to pathogens and in regulating the innate immune system. TAX1BP1 facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis and regulates TLR3 (toll-like receptor 3)-TLR4 and DDX58/RIG-I-like receptor (RLR) signaling by targeting TICAM1 and MAVS for autophagic degradation respectively. In addition to these canonical autophagy receptor functions, TAX1BP1 can also exert multiple accessory functions that influence the biogenesis and maturation of autophagosomes. In this review, we will discuss and integrate recent findings related to the autophagy function of TAX1BP1 and highlight outstanding questions regarding its functions in autophagy and regulation of innate immunity and host defense.Abbreviations: ATG: autophagy related; CALCOCO: calcium binding and coiled-coil domain; CC: coiled-coil; CHUK/IKKα: conserved helix-loop-helix ubiquitous kinase; CLIR: noncanonical LC3-interacting region; GABARAP: gamma-aminobutyric acid receptor associated protein; HTLV-1: human T-lymphotropic virus 1; IFN: interferon; IL1B/IL1ß: interleukin 1 beta; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/JNK: mitogen-activated protein kinase; mATG8: mammalian Atg8 homolog; MAVS: mitochondrial antiviral signaling protein; MEF: mouse embryonic fibroblast; MTB: Mycobacterium tuberculosis; MYD88: myeloid differentiation primary response gene 88; NBR1: NBR1, autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; OPTN: optineurin; Poly(I:C): polyinosinic:polycytidylic acid; PTM: post-translational modification; RB1CC1: RB1-inducible coiled-coil 1; RIPK: receptor (TNFRSF)-interacting serine-threonine kinase; RLR: DDX58/RIG-I-like receptor; RSV: respiratory syncytia virus; SKICH: SKIP carboxyl homology; SLR: SQSTM1 like receptor; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TBK1: TANK-binding kinase 1; TICAM1: toll-like receptor adaptor molecule 1; TLR: toll-like receptor; TNF: tumor necrosis factor; TNFAIP3: TNF alpha induced protein 3; TNFR: tumor necrosis factor receptor; TOM1: target of myb1 trafficking protein; TRAF: TNF receptor-associated factor; TRIM32: tripartite motif-containing 32; UBD: ubiquitin binding domain; ZF: zinc finger.

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STING, an endoplasmic reticulum (ER)-resident receptor for cyclic di-nucleotides (CDNs), is essential for innate immune responses. Upon CDN binding, STING moves from the ER to the Golgi, where it activates downstream type-I interferon (IFN) signaling. General cargo proteins exit from the ER via concentration at ER exit sites. However, the mechanism of STING concentration is poorly understood. Here, we visualize the ER exit sites of STING by blocking its transport at low temperature or by live-cell imaging with the cell-permeable ligand bis-pivSATE-2'F-c-di-dAMP, which we have developed. After ligand binding, STING forms punctate foci at non-canonical ER exit sites. Unbiased proteomic screens and super-resolution microscopy show that the Golgi-resident protein ACBD3/GCP60 recognizes and concentrates ligand-bound STING at specialized ER-Golgi contact sites. Depletion of ACBD3 impairs STING ER-to-Golgi trafficking and type-I IFN responses. Our results identify the ACBD3-mediated non-canonical cargo concentration system that drives the ER exit of STING.

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The disorders known as bone marrow failure syndromes (BMFS) are life-threatening disorders characterized by absence of one or more hematopoietic lineages in the peripheral blood. Myelodysplastic syndromes (MDS) are now considered BMF disorders with associated cellular dysplasia. BMFs and MDS are caused by decreased fitness of hematopoietic stem cells (HSC) and poor hematopoiesis. BMF and MDS can occur de novo or secondary to hematopoietic stress, including following bone marrow transplantation or myeloablative therapy. De novo BMF and MDS are usually associated with specific genetic mutations. Genes that are commonly mutated in BMF/MDS are in DNA repair pathways, epigenetic regulators, heme synthesis. Despite known and common gene mutations, BMF and MDS are very heterogenous in nature and non-genetic factors contribute to disease phenotype. Inflammation is commonly found in BMF and MDS, and contribute to ineffective hematopoiesis. Another common feature of BMF and MDS, albeit less known, is abnormal mitochondrial functions. Mitochondria are the power house of the cells. Beyond energy producing machinery, mitochondrial communicate with the rest of the cells via triggering stress signaling pathways and by releasing numerous metabolite intermediates. As a result, mitochondria play significant roles in chromatin regulation and innate immune signaling pathways. The main goal of this review is to investigate BMF processes, with a focus mitochondria-mediated signaling in acquired and inherited BMF.

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Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated following bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we show that acute gut inflammation expands HSPCs in the BM and directs them to inflamed mesenteric lymph nodes through GM-CSFR activation for further expansion and potential differentiation into Ly6C+ /G+ myeloid cells specialized in gut tissue repair. We identified this process to be mediated by Bacteroides, a commensal gram-negative bacteria that activates innate immune signaling. These findings establish cross-organ communication between the BM and distant inflamed sites, whereby a certain subset of multipotent progenitors is specified to respond to imminent hematopoietic demands and to alleviate inflammatory symptoms.

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In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann's research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today.

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Viral infections of the central nervous system (CNS) are a significant cause of neurological impairment and mortality worldwide. As tissue resident macrophages, microglia are critical initial responders to CNS viral infection. Microglia seem to coordinate brain-wide antiviral responses of both brain resident cells and infiltrating immune cells. This review discusses how microglia may promote this antiviral response at a molecular level, from potential mechanisms of virus recognition to downstream cytokine responses and interaction with antiviral T cells. Recent advancements in genetic tools to specifically target microglia in vivo promise to further our understanding about the precise mechanistic role of microglia in CNS infection.

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The outbreak of white spot syndrome (WSS) is a looming challenge, due to dramatic losses to the crustacean aquaculture industry. However, at present, there are no prophylactic or therapeutic means to control this infectious viral disease. Here, we screened fifteen medicinal plants for their inhibitory activity on the white spot syndrome virus (WSSV), using red swamp crayfish (Procambarus clarkii) as a model species. The results showed that the crude extracts of Pinellia ternata (Thunb.) Breit. had the highest inhibitory effect (91.59%, 100 mg/kg) on WSSV proliferation, and its main component, beta-sitosterol, showed a much higher activity (95.79%, 50 mg/kg). Further, beta-sitosterol potently reduced (p < 0.01) viral loads and viral gene transcription levels in a concentration-dependent fashion, and significantly promoted the survival rate of WSSV-challenged crayfish (57.14%, 50 mg/kg). The co-incubation assay indicated that beta-sitosterol did not influence the infectivity of WSSV particles. Both pre- and post-treatment of beta-sitosterol exerted a significant inhibitory effect (p < 0.01) on the viral load in vivo. Mechanistically, beta-sitosterol not only interfered with the expression of viral genes (immediate early gene 1, ie1; DNA polymerase, DNApol) that are important in initiating WSSV transcription, but it also attenuated the hijacking of innate immune signaling pathways (Toll, IMD, and JAK/STAT pathways) by viral genes to block WSSV replication. Moreover, the expression of several antiviral immune, antioxidant, pro-inflammatory, and apoptosis-related genes changed significantly in beta-sitosterol-treated crayfish. Beta-sitosterol is a potent WSSV inhibitor and has the potential to be developed as an effective anti-WSSV agent against a WSS outbreak in crustacean aquaculture.

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