The rockefeller university

The Retroviridae are a family of viruses that reverse transcribe their RNA genome and integrate the resulting double-stranded DNA copy into the genome of the host cell. Retroviruses are well-documented pathogens that have been associated with a variety of diseases. The International Committee on Taxonomy of Viruses (ICTV) currently lists 65 species of retroviruses. As required by the ICTV, we have converted the species nomenclature to a binomial format comprised of the genus and a freeform epithet. Assigning binomial species names to classify new retroviruses will be facilitated when following the epithet rules described herein.

Bacterial sigma factors bind RNA polymerase (E) to form holoenzyme (E sigma), conferring promoter specificity to E and playing a key role in transcription bubble formation. sigma N is unique among sigma factors in its structure and functional mechanism, requiring activation by specialized AAA+ ATPases. E sigma N forms an inactive promoter complex where the N-terminal sigma N region I (sigma N-RI) threads through a small DNA bubble. On the opposite side of the DNA, the ATPase engages sigma N-RI within the pore of its hexameric ring. Here, we perform kinetics-guided structural analysis of de novo formed E sigma N initiation complexes and engineer a biochemical assay to measure ATPase-mediated sigma N-RI translocation during promoter melting. We show that the ATPase exerts mechanical action to translocate about 30 residues of sigma N-RI through the DNA bubble, disrupting inhibitory structures of sigma N to allow full transcription bubble formation. A local charge switch of sigma N-RI from positive to negative may help facilitate disengagement of the otherwise processive ATPase, allowing subsequent sigma N disentanglement from the DNA bubble.

Chronic inflammatory skin diseases arise from dysregulated interactions between tissue-resident and infiltrating cells, the complexity of which hinders disease understanding and treatment. To address this, here, we present a single-cell spatiotemporal atlas of murine type 2 skin inflammation using MERFISH and scRNA-seq. Analyzing similar to 430,000 cells during MC903-and oxazolone-induced dermatitis, we identify 39 cell types, including pro-inflammatory fibroblasts that resemble those in human atopic dermatitis. Spatial neighborhood analyses reveal basophils as potent activators of pro-inflammatory fibroblasts, with basophil-derived oncostatin-M (OSM) and IL-4 synergizing fibroblast-mediated feedforward basophil and immune recruitment. While fibroblast-specific deletion of the IL-4R alpha receptor disrupts inflammation in vivo, the addition of pharmacologic gp130 inhibition, a core component of the OSM receptor, results in synergistic reduction of inflammation. Our study establishes a basophil-fibroblast circuitry as a critical regulator of type 2 skin inflammation, redefining basophil biology and positioning fibroblasts as dynamic immune regulators and therapeutic targets in inflammatory skin disease.

The 5th International Symposium on Regulatory Autoantibodies Targeting GPCR (RAB-GPCRs) advanced the understanding of the significant role played by autoantibodies targeting G-protein-coupled receptors (GPCRs) in various human diseases. Once considered passive markers, RAB-GPCRs are now recognized as active modulators of cellular signaling, immune regulation, and inflammation. The symposium highlighted their involvement in multiple prominent pathologies, including autoimmune diseases, cardio-and cerebrovascular diseases, and neuroimmunologic disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 syndrome (ME/CFS/PCS), as well as solid organ and hematopoietic stem cell transplantation (SOT/HSCT). Experts from rheumatology, immunology, and neurology presented interdisciplinary discussions on the potential of RAB-GPCRs as biomarkers and therapeutic targets. Advances in screening methods, biomarker identification, and therapeutic strategies were shared, emphasizing their diagnostic potential and application in novel therapeutic interventions. This report summarizes key insights from the symposium, particularly focusing on the modulatory properties of RAB-GPCRs and their relevance in both immune-mediated diseases and other pathologies (e.g., vascular, degenerative) that are traditionally not considered primarily immune-mediated. Ongoing research is expected to further establish these autoantibodies as crucial components in disease modulation and systems biology contexts, offering new opportunities for precision medicine and improved clinical outcomes in immune-related disorders.

Mitonuclear discordance has been observed in several shark species. Female philopatry has often been invoked to explain such discordance but has never been explicitly tested. Here, we focus on the white shark, for which female philopatry has been previously proposed, and produced a chromosome-level genome, high-coverage whole-genome autosomal, and uniparental datasets to investigate mitonuclear discordance. We first reconstructed the historical population demography of the species based on autosomal data. We show that this species once comprised a single panmictic population, which experienced a steady decline until recent times when it fragmented into at least three main autosomal genetic groups. Mitochondrial data depict a strikingly different picture, inconsistent with the spatial distribution of autosomal diversity. Using the demographic scenario established from autosomal data, we performed coalescent and forward simulations to test for the occurrence of female philopatry. Coalescent simulations showed that the model can reproduce the autosomal variability, confirming its robustness. A forward simulation framework was further built to explicitly account for a sex-biased reproduction model and track both autosomal and uniparental markers (Y chromosome and mitochondrial DNA). While our model generates data that are consistent with the observed Y chromosome variation, the mitochondrial pattern is never reproduced even under extreme female philopatry (no female migration), strongly suggesting that demography alone cannot explain the mitonuclear discordance. Our framework could, and perhaps should, be extended to other shark species where philopatry has been suggested. It is possible that the proposed widespread occurrence of female philopatry in sharks should be revisited. Significance The mitonuclear discordance seen in sharks is widely attributed to female philopatry but has never been explicitly tested. Herein, we explore the issue in white sharks, for which we assembled a high-resolution genome and reconstructed the demographic history using resequencing data. We used backward and forward simulations to examine the genetic consequences of sex-specific migration patterns using parameter values derived from the demographic analyses of autosomal data. The mitochondrial variability observed in natural populations was never reproduced in any of the simulations-even under extreme female philopatry, suggesting that other forces have contributed to the discordance. The same approach would benefit other species of shark where female philopatry has previously been assumed based on genetic data.

Hyperactivation of the cystic fibrosis transmembrane conductance regulator (CFTR) contributes to secretory diarrhea, a major cause of pediatric mortality worldwide, and autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of end-stage renal disease. Selective CFTR inhibition is a potential therapeutic strategy, with (R)-BPO-27 emerging as a promising candidate. Here, we present a cryo-EM structure of CFTR bound to (R)-BPO-27 at an overall resolution of 2.1 & Aring;. Contrary to the previous hypothesis that it inhibits CFTR current by competition with ATP, we demonstrate that (R)-BPO-27 instead directly occludes the chloride-conducting pore while permitting ATP hydrolysis, thus uncoupling the two activities. Furthermore, we find that inhibitor binding requires some degree of NBD separation, as the inhibition rate inversely correlates with the probability NBD dimerization. These findings clarify the compound's mechanism and provide a molecular basis for optimizing its clinical potential.

A search for flavor-changing neutral current interactions of the top quark (t) and the Higgs boson (H) is presented. The search is based on proton-proton collision data collected in 2016-2018 at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, and corresponding to an integrated luminosity of 138 fb(-1). Events containing a pair of leptons with the same-sign electric charge and at least one jet are considered. The results are used to constrain the branching fraction (B) of the top quark decaying to a Higgs boson and an up (u) or charm (c) quark. No significant excess above the estimated background was found. The observed (expected) upper limits at a 95% confidence level are found to be 0.072% (0.059%) for B(t -> Hu) and 0.043% (0.062%) for B(t -> Hc). These results are combined with two other searches performed by the CMS Collaboration for flavor-changing neutral current interactions of top quarks and Higgs bosons in final states where the Higgs boson decays to either a pair of photons or a pair of bottom quarks. The resulting observed (expected) upper limits at the 95% confidence level are 0.019% (0.027%) for B(t -> Hu) and 0.037% (0.035%) for B(t -> Hc).

Effective vaccines elicit B cell clonal expansion in germinal centers (GCs) that produce memory B cells and antibody-secreting plasma cells. In mice, memory B cells rarely re-enter GCs upon boosting and instead differentiate into plasma cells. However, mouse circulating memory constitutes only 1%-2% of B cells, compared to 30%-50% in primates. We examine memory and GC B cell responses in rhesus macaques immunized and boosted ipsilaterally or contralaterally with an mRNA vaccine encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The neutralizing activity of antibodies cloned from the memory compartment, as well as the size of the compartment, was independent of the site of boosting. We show that memory B cells enter and undergo iterative expansion in newly developing GCs when boosting is at a site distal to the site of priming. Thus, in primates, high-affinity memory B cells constitute a reservoir that actively participates in further development of immunity irrespective of the anatomical site of vaccine boosting.

Postmitotic neurons have high levels of methylated cytosine and its oxidized intermediates such as 5-hydroxymethylcytosine1. However, the functional relevance of these epigenetic modifications of DNA are poorly understood. Here we show that some cytidine analogues, such as cytarabine, cause DNA double-strand breaks during TET-mediated active 5-methylcytosine demethylation by interrupting TDG-dependent base excision repair. These double-strand breaks are frequently converted into deletions and translocations by DNA ligase 4. In vivo, Purkinje and Golgi cells in the cerebellum are the only neuronal populations that exhibit high levels of DNA damage due to cytarabine. In Purkinje cells, TET targets highly expressed gene bodies marked by enhancer-associated histone modifications. Many of these genes control movement coordination, which explains the long-recognized cerebellar neurotoxicity of cytarabine2. We show that other cytidine analogues, such as gemcitabine, cause only single-strand breaks in neurons, which are repaired by DNA ligase 3 with minimal toxicity. Our findings uncover a mechanistic link between TET-mediated DNA demethylation, base excision repair and gene expression in neurons. The results also provide a rational explanation for the different neurotoxicity profiles of an important class of antineoplastic agents.