Extrasinusoidal macrophages are a distinct subset of immunologically active dural macrophages.

Although macrophages in the meningeal compartments of the central nervous system (CNS) have been comprehensively characterized under steady state, studying their contribution to physiological and pathological processes has been hindered by the lack of specific targeting tools in vivo. Recent findings have shown that the dural sinus and its adjacent lymphatic vessels act as a neuroimmune interface. However, the cellular and functional heterogeneity of extrasinusoidal dural macrophages outside this immune hub is not fully understood.

Probing TCR Specificity Using Artificial In Vivo Diversification of CDR3 Regions.

The T-cell receptor sequences expressed on cells recognizing a specific peptide in the context of a given MHC molecule can be explored for common features that might explain their antigen specificity. However, despite the development of numerous experimental and bioinformatic strategies, the specificity problem remains unresolved. To address the need for additional experimental paradigms, we report here on an in vivo experimental strategy designed to artificially diversify a transgenic TCR by CRISPR/Cas9-mediated mutagenesis of Tcra and Tcrb chain genes.

The multifaceted role of vitreous hyalocytes: Orchestrating inflammation, angiomodulation and erythrophagocytosis in proliferative diabetic retinopathy.

Background: Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis.

Phosphorylation of disordered proteins tunes local and global intramolecular interactions.

Protein post-translational modifications, such as phosphorylation, are important regulatory signals for diverse cellular functions. In particular, intrinsically disordered protein regions (IDRs) are subject to phosphorylation as a means to modulate their interactions and functions. Toward understanding the relationship between phosphorylation in IDRs and specific functional outcomes, we must consider how phosphorylation affects the IDR conformational ensemble.

Foxi1 regulates multiple steps of mucociliary development and ionocyte specification through transcriptional and epigenetic mechanisms.

Foxi1 is a master regulator of ionocytes (ISCs / INCs) across species and organs. Two subtypes of ISCs exist, and both α- and β-ISCs regulate pH- and ion-homeostasis in epithelia. Gain and loss of FOXI1 function are associated with human diseases, including Pendred syndrome, male infertility, renal acidosis and cancers.

PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis.

Introduction: Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit.

Chronic obesity does not alter cancer survival in mice.

Obesity is a complex chronic disease characterized by excessive adiposity and associations with numerous co-morbidities, including cancer. Despite extensive research, we have limited understanding of the mechanisms coupling obesity to cancer risk, and, of the contexts in which obesity does or does not exacerbate disease. Here, we show that chronic high-fat diet (HFD)-induced obesity has no significant effect on the mouse, a model of human Li-Fraumeni multi-cancer syndrome.

ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA.

Although adenosine deaminase 2 (ADA2) is considered an extracellular ADA, evidence questions the physiological relevance of this activity. Our study reveals that ADA2 localizes within the lysosomes, where it is targeted through modifications of its glycan structures. We show that ADA2 interacts with DNA molecules, altering their sequences by converting deoxyadenosine (dA) to deoxyinosine (dI).

Understanding vertebrate immunity through comparative immunology.

Evolutionary immunology has entered a new era. Classical studies, using just a handful of model animal species, combined with clinical observations, provided an outline of how innate and adaptive immunity work together to ensure tissue homeostasis and to coordinate the fight against infections. However, revolutionary advances in cellular and molecular biology, genomics and methods of genetic modification now offer unprecedented opportunities.

Epigenetic inheritance and gene expression regulation in early Drosophila embryos.

Precise spatiotemporal regulation of gene expression is of paramount importance for eukaryotic development. The maternal-to-zygotic transition (MZT) during early embryogenesis in Drosophila involves the gradual replacement of maternally contributed mRNAs and proteins by zygotic gene products. The zygotic genome is transcriptionally activated during the first 3 hours of development, in a process known as "zygotic genome activation" (ZGA), by the orchestrated activities of a few pioneer factors.

The complete mitochondrial genome of the banana pathogen f. sp. M5.

We report the complete mitochondrial genome of a causal agent of banana fusarium wilt isolated in Mexico. The whole set of genes encoding proteins related to respiration and ATP synthesis, rRNAs, tRNAs are enlisted. Two open reading frames of unknown function conserved in were also identified.

MOF-mediated PRDX1 acetylation regulates inflammatory macrophage activation.

Signaling-dependent changes in protein phosphorylation are critical to enable coordination of transcription and metabolism during macrophage activation. However, the role of acetylation in signal transduction during macrophage activation remains obscure. Here, we identify the redox signaling regulator peroxiredoxin 1 (PRDX1) as a substrate of the lysine acetyltransferase MOF.

Accelerated differentiation of neo-W nuclear-encoded mitochondrial genes between two climate-associated bird lineages signals potential co-evolution with mitogenomes.

There is considerable evidence for mitochondrial-nuclear co-adaptation as a key evolutionary driver. Hypotheses regarding the roles of sex-linkage have emphasized Z-linked nuclear genes with mitochondrial function (N-mt genes), whereas it remains contentious whether the perfect co-inheritance of W genes with mitogenomes could hinder or facilitate co-adaptation. Young (neo-) sex chromosomes that possess relatively many N-mt genes compared to older chromosomes provide unprecedented hypothesis-testing opportunities.

Rapid phagosome isolation enables unbiased multiomic analysis of human microglial phagosomes.

Microglia are the resident macrophages of the central nervous system (CNS). Their phagocytic activity is central during brain development and homeostasis-and in a plethora of brain pathologies. However, little is known about the composition, dynamics, and function of human microglial phagosomes under homeostatic and pathological conditions.

Neuronal RNA processing: cross-talk between transcriptional regulation and RNA-binding proteins.

In the nervous system, alternative RNA processing is particularly prevalent, which results in the expression of thousands of transcript variants found in no other tissue. Neuron-specific RNA-binding proteins co-transcriptionally regulate alternative splicing, alternative polyadenylation, and RNA editing, thereby shaping the RNA identity of nervous system cells. Recent evidence suggests that interactions between RNA-binding proteins and cis-regulatory elements such as promoters and enhancers play a role in the determination of neuron-specific expression profiles.

Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them.

Vhl safeguards thymic epithelial cell identity and thymopoietic capacity by constraining Hif1a activity during development.

The thymus is a physiologically hypoxic organ and fulfills its role of generating T cells under low-oxygen conditions. We have therefore investigated how thymic epithelial cells (TECs) cope with physiological hypoxia by focusing on the role of the Hif1a-Vhl axis. In most cell types, the oxygen-labile transcriptional regulator Hif1a is a central player in co-ordinating responses to low oxygen: under normoxic conditions Hif1a is rapidly degraded in a Vhl-guided manner; however, under hypoxic conditions Hif1a is stabilized and can execute its transcriptional functions.

p16 immune cell - controlled disease tolerance as a broad defense and healthspan extending strategy.

The ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens. Accumulating evidence, however, indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we report that p16 immune cells play a key role in establishing disease tolerance.

YY1-mediated enhancer-promoter communication in the immunoglobulin μ locus is regulated by MSL/MOF recruitment.

The rearrangement and expression of the immunoglobulin μ heavy chain (Igh) gene require communication of the intragenic Eμ and 3' regulatory region (RR) enhancers with the variable (V) gene promoter. Eμ binding of the transcription factor YY1 has been implicated in enhancer-promoter communication, but the YY1 protein network remains obscure. By analyzing the comprehensive proteome of the 1-kb Eμ wild-type enhancer and that of Eμ lacking the YY1 binding site, we identified the male-specific lethal (MSL)/MOF complex as a component of the YY1 protein network.

Functional multi-organelle units control inflammatory lipid metabolism of macrophages.

Eukaryotic cells contain several membrane-separated organelles to compartmentalize distinct metabolic reactions. However, it has remained unclear how these organelle systems are coordinated when cells adapt metabolic pathways to support their development, survival or effector functions. Here we present OrgaPlexing, a multi-spectral organelle imaging approach for the comprehensive mapping of six key metabolic organelles and their interactions.

Oncogene-induced TIM-3 ligand expression dictates susceptibility to anti-TIM-3 therapy in mice.

Leukemia relapse is a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). We tested the potential of targeting T cell (Tc) immunoglobulin and mucin-containing molecule 3 (TIM-3) for improving graft-versus-leukemia (GVL) effects. We observed differential expression of TIM-3 ligands when hematopoietic stem cells overexpressed certain oncogenic-driver mutations.