A bulge uridine in the HIF2a IRE allows IRP1 but not IRP2 to selectively regulate HIF2a expression and ensuing EPO levels.

Iron regulatory proteins (IRP1 and IRP2) play a pivotal role in maintaining cellular iron homeostasis by binding to iron-responsive elements (IREs) of target mRNAs and regulating the expression of these iron-related genes. Mice and humans that lack functional IRP1 develop erythrocytosis due to erythropoietin overproduction, whereas those that lack IRP2 develop microcytic anemia believed to result from iron deficiency of erythroblasts. Here, we discovered that IRP2 deficiency reduced the expression of hypoxia inducible factor 2 alpha (HIF2a) and its transcriptional target, erythropoietin (EPO), thereby compromising the stress erythropoiesis response to generate RBCs upon anemia.

Dysfunction of CD169 macrophages and blockage of erythrocyte maturation as a mechanism of anemia in infection.

parasites cause malaria with disease outcomes ranging from mild illness to deadly complications such as severe malarial anemia (SMA), pulmonary edema, acute renal failure, and cerebral malaria. In young children, SMA often requires blood transfusion and is a major cause of hospitalization. Malaria parasite infection leads to the destruction of infected and noninfected erythrocytes as well as dyserythropoiesis; however, the mechanism of dyserythropoiesis accompanied by splenomegaly is not completely understood.

MAVS Positively Regulates Mitochondrial Integrity and Metabolic Fitness in B Cells.

Activated B cells experience metabolic changes that require mitochondrial remodeling, in a process incompletely defined. In this study, we report that mitochondrial antiviral signaling protein (MAVS) is involved in BCR-initiated cellular proliferation and prolonged survival. MAVS is well known as a mitochondrial-tethered signaling adaptor with a central role in viral RNA-sensing pathways that induce type I IFN.

Intra-Sac Injection of Thrombin During Endovascular Aneurysm Repair to Remedy Type II Endoleak and Promote Sac Shrinkage.

Purpose: To evaluate the safety and effectiveness of intra-sac thrombin injection to remedy type II endoleaks (T2ELs) during endovascular aneurysm repair (EVAR).

Materials And Methods: 224 cases abdominal aortic aneurysm (AAA) were treated with EVAR. For the 52 cases of intra-operative type II endoleaks and 8 cases of ruptured AAAs, after the grafts were deployed, thrombin was injected into the aneurysm sac through a preset catheter.

curtails autoimmune nephritis via lasting bone marrow alterations, independent of hemozoin accumulation.

The host response against infection with commonly raises self-reactivity as a side effect, and antibody deposition in kidney has been cited as a possible cause of kidney injury during severe malaria. In contrast, animal models show that infection with the parasite confers long-term protection from lethal lupus nephritis initiated by autoantibody deposition in kidney. We have limited knowledge of the factors that make parasite infection more likely to induce kidney damage in humans, or the mechanisms underlying protection from autoimmune nephritis in animal models.

Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of T9 cells to promote allergic inflammation.

Allergic diseases are a major global health issue. Interleukin (IL)-9-producing helper T (T9) cells promote allergic inflammation, yet T9 cell effector functions are incompletely understood because their lineage instability makes them challenging to study. Here we found that resting T9 cells produced IL-9 independently of T cell receptor (TCR) restimulation, due to STAT5- and STAT6-dependent bystander activation.

Cerebral Malaria Is Regulated by Host-Mediated Changes in Gene Expression.

Cerebral malaria (CM), the deadliest complication of infection, is a complex and unpredictable disease. However, our understanding of the host and parasite factors that cause CM is limited. Using a mouse model of CM, experimental CM (ECM), we performed a three-way comparison between ECM-susceptible C57BL/6 mice infected with ECM-causing ANKA parasites [ANKA], ECM-resistant BALB/c mice infected with ANKA [ANKA], and C57BL/6 mice infected with NK65 that does not cause ECM [NK65].

CCL17-producing cDC2s are essential in end-stage lupus nephritis and averted by a parasitic infection.

Lupus nephritis is a severe organ manifestation in systemic lupus erythematosus leading to kidney failure in a subset of patients. In lupus-prone mice, controlled infection with Plasmodium parasites protects against the progression of autoimmune pathology including lethal glomerulonephritis. Here, we demonstrate that parasite-induced protection was not due to a systemic effect of infection on autoimmunity as previously assumed, but rather to specific alterations in immune cell infiltrates into kidneys and renal draining lymph nodes.

One-year outcomes of radiofrequency ablation of incompetent perforator veins using the radiofrequency stylet device: Cohort study from East Asia.

Objectives: The present study was designed to assess outcomes of patients undergone radiofrequency ablation (RFA) for their incompetent perforator veins (IPVs) with ClosureFast stylets.

Methods: Data of 165 IPVs in 138 limbs of 117 consecutive patients between July 2017 to Nov. 2019 were retrospectively reviewed.

Testing the impact of a single nucleotide polymorphism in a Plasmodium berghei ApiAP2 transcription factor on experimental cerebral malaria in mice.

Cerebral malaria (CM) is the deadliest form of severe Plasmodium infections. Currently, we have limited understanding of the mechanisms by which Plasmodium parasites induce CM. The mouse model of CM, experimental CM (ECM), induced by infection with the rodent parasite, Plasmodium berghei ANKA (PbANKA) has been extensively used to study the pathophysiology of CM.

RTP4 inhibits IFN-I response and enhances experimental cerebral malaria and neuropathology.

Infection by malaria parasites triggers dynamic immune responses leading to diverse symptoms and pathologies; however, the molecular mechanisms responsible for these reactions are largely unknown. We performed Trans-species Expression Quantitative Trait Locus analysis to identify a large number of host genes that respond to malaria parasite infections. Here we functionally characterize one of the host genes called receptor transporter protein 4 (RTP4) in responses to malaria parasite and virus infections.

The E3 ubiquitin ligase MARCH1 regulates antimalaria immunity through interferon signaling and T cell activation.

Malaria infection induces complex and diverse immune responses. To elucidate the mechanisms underlying host-parasite interaction, we performed a genetic screen during early (24 h) infection in mice and identified a large number of interacting host and parasite genes/loci after transspecies expression quantitative trait locus (Ts-eQTL) analysis. We next investigated a host E3 ubiquitin ligase gene () that was clustered with interferon (IFN)-stimulated genes (ISGs) based on the similarity of the genome-wide pattern of logarithm of the odds (LOD) scores (GPLS).

A single-nucleotide polymorphism in a ApiAP2 transcription factor alters the development of host immunity.

The acquisition of malaria immunity is both remarkably slow and unpredictable. At present, we know little about the malaria parasite genes that influence the host's ability to mount a protective immune response. Here, we show that a single-nucleotide polymorphism (SNP) resulting in a single amino acid change (S to F) in an ApiAP2 transcription factor in the rodent malaria parasite () NK65 allowed infected mice to mount a T helper cell 1 (T1)-type immune response that controlled subsequent infections.

Plasmodium yoelii Erythrocyte-Binding-like Protein Modulates Host Cell Membrane Structure, Immunity, and Disease Severity.

Erythrocyte-binding-like (EBL) proteins are known to play an important role in malaria parasite invasion of red blood cells (RBCs); however, any roles of EBL proteins in regulating host immune responses remain unknown. Here, we show that EBL (PyEBL) can shape disease severity by modulating the surface structure of infected RBCs (iRBCs) and host immune responses. We identified an amino acid substitution (a change of C to Y at position 741 [C741Y]) in the protein trafficking domain of PyEBL between isogenic strain N67 and N67C parasites that produce different disease phenotypes in C57BL/6 mice.

Antiviral Adaptor MAVS Promotes Murine Lupus With a B Cell Autonomous Role.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by increased production of autoantibodies, which commonly target nuclear antigens, and concomitant deposition of immune complexes that cause inflammation in tissues. SLE is often associated with increased systemic expression of type I interferons, in some cases due to dysregulation in nucleic acid-sensing innate pathways. There is strong genetic evidence for a link between cytoplasmic RNA sensing pathways (RIG-I/MDA5) and SLE, both in human patients and murine models, however questions still remain regarding pathway initiation, cell types involved and downstream effects.

Interleukin-1β-induced IRAK1 ubiquitination is required for T-GM-CSF cell differentiation in T cell-mediated inflammation.

Accumulating evidence suggests granulocyte macrophage-colony stimulating factor (GM-CSF) can function as an inflammatory mediator, but whether GM-CSF-producing CD4 T cells (T-GM-CSF) are a distinct T helper cell subset is lacking. Herein we demonstrate that interleukin (IL)-1β exclusively drives differentiation of naïve CD4 T cells into T-GM-CSF cells via inducing ubiquitination of IL-1 receptor-associated kinase 1 (IRAK1) and subsequent activation of the transcription factor NF-kappaB (NF-κB), independent of RAR-related orphan receptor gamma (RORγt) required for T17 differentiation. In vivo, T-GM-CSF cells are present in murine Citrobacter Rodentium infections and mediate colitis following adoptive transfer of CD4 T cells into Rag1 mice via GM-CSF-induced macrophage activation.

Duox1 Regulates Primary B Cell Function under the Influence of IL-4 through BCR-Mediated Generation of Hydrogen Peroxide.

Engagement of the BCR with Ags triggers signaling pathways for commitment of B lymphocyte responses that can be regulated, in part, by reactive oxygen species. To investigate the functional relevance of reactive oxygen species produced in primary B cells, we focused on the role of the hydrogen peroxide generator Duox1 in stimulated splenic B cells under the influence of the T2 cytokine IL-4. We found that HO production in wild type (WT) and Nox2-deficient CD19 B cells was boosted concomitantly with enhanced expression of Duox1 following costimulation with BCR agonists together with IL-4, whereas stimulated Duox1 cells showed attenuated HO release.

3' enhancers hs3b/hs4 are dispensable for deregulation in mouse plasmacytomas with T(12;15) translocations.

-deregulating T(12;15) chromosomal translocations are the hallmark cytogenetic abnormalities of murine plasmacytomas (PCTs). In most PCTs, the immunoglobulin heavy chain () locus is broken between the enhancer and the 3' regulatory region (), making the latter the major candidate for orchestrating deregulation. To elucidate the role of the in tumorigenesis, we induced PCTs in transgenic mice deficient for the major enhancer elements, and (hs3b-4).

T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.

The follicular helper T cell (T) are established regulators of germinal center (GC) B cells, whether T have pathogenic potential independent of B cells is unknown. Based on in vitro T cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, T and its functions in colitis development were analyzed by FACS, ChIP, ChIP-sequencing, WB, ELISA and PCR. Herein we demonstrate that intestinal tissues of patients and colon tissues obtained from Rag1 recipients of naïve CD4 T cells with colitis, each over-express T-associated gene products.

T cell-dependent antigen adjuvanted with DOTAP-CpG-B but not DOTAP-CpG-A induces robust germinal center responses and high affinity antibodies in mice.

The development of vaccines for infectious diseases for which we currently have none, including HIV, will likely require the use of adjuvants that strongly promote germinal center responses and somatic hypermutation to produce broadly neutralizing antibodies. Here we compared the outcome of immunization with the T-cell dependent antigen, NP-conjugated to chicken gamma globulin (NP-CGG) adjuvanted with the toll-like receptor 9 (TLR9) ligands, CpG-A or CpG-B, alone or conjugated with the cationic lipid carrier, DOTAP. We provide evidence that only NP-CGG adjuvanted with DOTAP-CpG-B was an effective vaccine in mice resulting in robust germinal center responses, isotype switching and high affinity NP-specific antibodies.

DNase-active TREX1 frame-shift mutants induce serologic autoimmunity in mice.

TREX1/DNASE III, the most abundant 3'-5' DNA exonuclease in mammalian cells, is tail-anchored on the endoplasmic reticulum (ER). Mutations at the N-terminus affecting TREX1 DNase activity are associated with autoimmune and inflammatory conditions such as Aicardi-Goutières syndrome (AGS). Mutations in the C-terminus of TREX1 cause loss of localization to the ER and dysregulation of oligosaccharyltransferase (OST) activity, and are associated with retinal vasculopathy with cerebral leukodystrophy (RVCL) and in some cases with systemic lupus erythematosus (SLE).

Non-pathogenic tissue-resident CD8 T cells uniquely accumulate in the brains of lupus-prone mice.

Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8 T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4 cells are predominant.

Reprogramming macrophage orientation by microRNA 146b targeting transcription factor IRF5.

The regulation of macrophage orientation pathological conditions is important but still incompletely understood. Here, we show that IL-10 and Rag1 double knockout mice spontaneously develop colitis with dominant M1 macrophage phenotype, suggesting that IL-10 regulates macrophage orientation in inflammation. We demonstrate that IL-10 stimulation induced miR-146b expression, and that the expression of miR-146b was impaired in IL-10 deficient macrophages.