Explore the vast range of titles available.

Endogenous retroviruses (ERVs) are integrated retroviral elements that make up 8% of the human genome. However, the impact of ERVs on human health and disease is not well understood. While select ERVs have been implicated in diseases, including autoimmune disease and cancer, the lack of tools to analyze genome-wide, locus-specific expression of proviral autonomous ERVs has hampered the progress in the field. Here we describe a method called ERVmap, consisting of an annotated database of 3,220 human proviral ERVs and a pipeline that allows for locus-specific genome-wide identification of proviral ERVs that are transcribed based on RNA-sequencing data, and provide examples of the utility of this tool. Using ERVmap, we revealed cell-type–specific ERV expression patterns in commonly used cell lines as well as in primary cells. We identified 124 unique ERV loci that are significantly elevated in the peripheral blood mononuclear cells of patients with systemic lupus erythematosus that represent an IFN-independent signature. Finally, we identified additional tumor-associated ERVs that correlate with cytolytic activity represented by granzyme and perforin expression in breast cancer tissue samples. The open-source code of ERVmap and the accompanied web tool are made publicly available to quantify proviral ERVs in RNA-sequencing data with ease. Use of ERVmap across a range of diseases and experimental conditions has the potential to uncover novel diseaseassociated antigens and effectors involved in human health that is currently missed by focusing on protein-coding sequences.

Post-acute infection syndromes may develop after acute viral disease 1 . Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions 2 – 4 . However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein–Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers. Individuals with long COVID show marked biological changes in cortisol and immune factors relative to convalescent populations.

In the temperate regions, seasonal influenza virus outbreaks correlate closely with decreases in humidity. While low ambient humidity is known to enhance viral transmission, its impact on host response to influenza virus infection and disease outcome remains unclear. Here, we showed that housing Mx1 congenic mice in low relative humidity makes mice more susceptible to severe disease following respiratory challenge with influenza A virus. We find that inhalation of dry air impairs mucociliary clearance, innate antiviral defense, and tissue repair. Moreover, disease exacerbated by low relative humidity was ameliorated in caspase-1/11–deficient Mx1 mice, independent of viral burden. Single-cell RNA sequencing revealed that induction of IFN-stimulated genes in response to viral infection was diminished in multiple cell types in the lung of mice housed in low humidity condition. These results indicate that exposure to dry air impairs host defense against influenza infection, reduces tissue repair, and inflicts caspase-dependent disease pathology.

In this letter, the investigators report that saliva specimens and nasopharyngeal swab specimens had similar sensitivity in the detection of SARS-CoV-2 RNA in both symptomatic and asymptomatic persons.

Expression Quantitative Trait Loci (eQTLs) are critical to understanding the mechanisms underlying disease-associated genomic loci. Nearly all protein-coding genes in the human genome have been associated with one or more eQTLs. Here we introduce a multi-variant generalization of allelic Fold Change (aFC), aFC-n, to enable quantification of the cis -regulatory effects in multi-eQTL genes under the assumption that all eQTLs are known and conditionally independent. Applying aFC-n to 458,465 eQTLs in the Genotype-Tissue Expression (GTEx) project data, we demonstrate significant improvements in accuracy over the original model in estimating the eQTL effect sizes and in predicting genetically regulated gene expression over the current tools. We characterize some of the empirical properties of the eQTL data and use this framework to assess the current state of eQTL data in terms of characterizing cis -regulatory landscape in individual genomes. Notably, we show that 77.4% of the genes with an allelic imbalance in a sample show 0.5 log 2 fold or more of residual imbalance after accounting for the eQTL data underlining the remaining gap in characterizing regulatory landscape in individual genomes. We further contrast this gap across tissue types, and ancestry backgrounds to identify its correlates and guide future studies. Genetic variants that influence gene expression play a major role in human phenotypic variability and disease susceptibility. Here, the authors introduce a computational method to estimate the regulatory effect size in genes with multiple conditionally independent regulatory variants.

Antibodies secreted into mucosal barriers serve to protect the host from a variety of pathogens, and are the basis for successful vaccines 1 . In type I mucosa (such as the intestinal tract), dimeric IgA secreted by local plasma cells is transported through polymeric immunoglobulin receptors 2 and mediates robust protection against viruses 3 , 4 . However, owing to the paucity of polymeric immunoglobulin receptors and plasma cells, how and whether antibodies are delivered to the type II mucosa represented by the lumen of the lower female reproductive tract remains unclear. Here, using genital herpes infection in mice, we show that primary infection does not establish plasma cells in the lamina propria of the female reproductive tract. Instead, upon secondary challenge with herpes simplex virus 2, circulating memory B cells that enter the female reproductive tract serve as the source of rapid and robust antibody secretion into the lumen of this tract. CD4 tissue-resident memory T cells secrete interferon-γ, which induces expression of chemokines, including CXCL9 and CXCL10. Circulating memory B cells are recruited to the vaginal mucosa in a CXCR3-dependent manner, and secrete virus-specific IgG2b, IgG2c and IgA into the lumen. These results reveal that circulating memory B cells act as a rapidly inducible source of mucosal antibodies in the female reproductive tract. In a mouse model of herpes simplex 2 virus infection, circulating memory B cells—rather than plasma cells—are shown to be the source of antibody secretion in the vaginal lumen following secondary infection.

In conventional Bardeen–Cooper–Schrieffer superconductors 1 , electrons with opposite momenta bind into Cooper pairs due to an attractive interaction mediated by phonons in the material. Although superconductivity naturally emerges at thermal equilibrium, it can also emerge out of equilibrium when the system parameters are abruptly changed 2 – 8 . The resulting out-of-equilibrium phases are predicted to occur in real materials and ultracold fermionic atoms, but not all have yet been directly observed. Here we realize an alternative way to generate the proposed dynamical phases using cavity quantum electrodynamics (QED). Our system encodes the presence or absence of a Cooper pair in a long-lived electronic transition in 88 Sr atoms coupled to an optical cavity and represents interactions between electrons as photon-mediated interactions through the cavity 9 , 10 . To fully explore the phase diagram, we manipulate the ratio between the single-particle dispersion and the interactions after a quench and perform real-time tracking of the subsequent dynamics of the superconducting order parameter using nondestructive measurements. We observe regimes in which the order parameter decays to zero (phase I) 3 , 4 , assumes a non-equilibrium steady-state value (phase II) 2 , 3 or exhibits persistent oscillations (phase III) 2 , 3 . This opens up exciting prospects for quantum simulation, including the potential to engineer unconventional superconductors and to probe beyond mean-field effects like the spectral form factor 11 , 12 , and for increasing the coherence time for quantum sensing. The dynamical phases of out-of-equilibrium Bardeen–Cooper–Schrieffer superconductors have been simulated using cold atoms levitated inside an optical cavity.

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy–lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy–lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy–lysosomal biogenesis and show trehalose’s ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease. Dysfunction of autophagy in plaque macrophages aggravates atherosclerosis. Here the authors show that induction of macrophage autophagy–lysosomal biogenesis either genetically by overexpression of the master transcriptional regulator of this process, TFEB, or pharmacologically with trehalose is atheroprotective.

HIV-1 integrates into the genome of target cells and establishes latency indefinitely. Understanding the molecular mechanism of HIV-1 latency maintenance is needed for therapeutic strategies to combat existing infection. In this study, we found an unexpected role for Apobec3A (apolipoprotein B MRNA editing enzyme catalytic subunit 3A, abbreviated “A3A”) in maintaining the latency state within HIV-1–infected cells. Overexpression of A3A in latently infected cell lines led to lower reactivation, while knockdown or knockout of A3A led to increased spontaneous and inducible HIV-1 reactivation. A3A maintains HIV-1 latency by associating with proviral DNA at the 5′ long terminal repeat region, recruiting KAP1 and HP1, and imposing repressive histone marks. We show that knockdown of A3A in latently infected human primary CD4 T cells enhanced HIV-1 reactivation. Collectively, we provide evidence and a mechanism by which A3A reinforces HIV-1 latency in infected CD4 T cells.

Gene therapy has emerged as an alternative for the treatment of diseases refractory to conventional therapeutics. Synthetic nanoparticle-based gene delivery systems offer highly tunable platforms for the delivery of therapeutic genes. However, the inability to achieve sustained, high-level transgene expression in vivo presents a significant hurdle. The respiratory system, although readily accessible, remains a challenging target, as effective gene therapy mandates colloidal stability in physiological fluids and the ability to overcome biological barriers found in the lung. We formulated highly stable DNA nanoparticles based on state-of-the-art biodegradable polymers, poly(β-amino esters) (PBAEs), possessing a dense corona of polyethylene glycol. We found that these nanoparticles efficiently penetrated the nanoporous and highly adhesive human mucus gel layer that constitutes a primary barrier to reaching the underlying epithelium. We also discovered that these PBAE-based mucus-penetrating DNA nanoparticles (PBAE-MPPs) provided uniform and high-level transgene expression throughout the mouse lungs, superior to several gold standard gene delivery systems. PBAE-MPPs achieved robust transgene expression over at least 4 mo following a single administration, and their transfection efficiency was not attenuated by repeated administrations, underscoring their clinical relevance. Importantly, PBAE-MPPs demonstrated a favorable safety profile with no signs of toxicity following intratracheal administration.