T cells are classically recognized as distinct subsets that express αβ or γδ TCRs. We identify a novel population of T cells that coexpress αβ and γδ TCRs in mice and humans. These hybrid αβ-γδ T cells arose in the murine fetal thymus by day 16 of ontogeny, underwent αβ TCR-mediated positive selection into CD4+ or CD8+ thymocytes, and constituted up to 10% of TCRδ+ cells in lymphoid organs. They expressed

Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype

Ion channels represent a large class of drug targets, but their role in brain cancer is underexplored. Here, we identify that chloride intracellular channel 1 (CLIC1) is overexpressed in human central nervous system malignancies, including medulloblastoma, a common pediatric brain cancer. While global knockout does not overtly affect mouse development, genetic deletion of CLIC1 suppresses medulloblastoma

Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production

Remyelination requires innate immune system function, but how exactly microglia and macrophages clear myelin debris after injury and tailor a specific regenerative response is unclear. Here, we asked whether pro-inflammatory microglial/macrophage activation is required for this process. We established a novel toxin-based spinal cord model of de- and remyelination in zebrafish and showed that pro-inflammatory

The ubiquitin pathway has been shown to regulate iNKT cell immunity, but the deubiquitinase involved in this process has not been identified. Herein we found that ubiquitin-specific peptidase 22 (USP22) is highly expressed in iNKT cells during their early developmental stage 1. USP22 deficiency blocked the transition from stage 1 to 2 during iNKT cell development in a cell-intrinsic manner. USP22 suppression

In this issue of JEM, Reed-Geaghan et al. (https://doi.org/10.1084/jem.20191374) address the long-standing question about the primary source of myeloid cells located at β-amyloid deposits. Using genetic labeling experiments, the authors identify resident microglia as the only myeloid cells present at β-amyloid deposits.

Progressive loss of retinal ganglion cells (RGCs) leads to irreversible visual deficits in glaucoma. Here, we found that the level of cyclic AMP and the activity and expression of its mediator Epac1 were increased in retinas of two mouse models of ocular hypertension. Genetic depletion of Epac1 significantly attenuated ocular hypertension-induced detrimental effects in the retina, including vascular

The work by Etzerodt et al. in this issue of JEM (https://doi.org/10.1084/jem.20191869) identifies a distinct omentum-resident macrophage population of embryonic origin and demonstrates that these cells provide a niche for ovarian cancer metastasis and cancer stemness. This research opens up for many questions and therapeutic prospects.

Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells prominent at barrier sites. Although precursors are found in blood, mature ILC2s can enter the circulation after small intestinal perturbation by migratory helminths and move to distant tissues to influence the local reparative response. Using fate-mapping and methods to bypass the lung or intestinal phases of Nippostrongylus brasiliensis

Every day, megakaryocytes produce billions of platelets that circulate for several days and eventually are cleared by the liver. The exact removal mechanism, however, remains unclear. Loss of sialic acid residues is thought to feature in the aging and clearance of platelets. Using state-of-the-art spinning disk intravital microscopy to delineate the different compartments and cells of the mouse liver

In humans, psychological stress has been associated with a higher risk of infectious illness. However, the mechanisms by which the stress pathway interferes with host response to pathogens remain unclear. We demonstrate here a role for the β2-adrenergic receptor (β2-AR), which binds the stress mediators adrenaline and noradrenaline, in modulating host response to mouse cytomegalovirus (MCMV) infection

Natural killer (NK) cells are innate lymphocytes that exhibit adaptive features, such as clonal expansion and memory, during viral infection. Although activating receptor engagement and proinflammatory cytokines are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here, we describe one such signal that is provided by

Innate mechanisms in the tumor stroma play a crucial role both in the initial rejection of tumors and in cancer promotion. Here, we provide a concise overview of the innate system in cancer and recent advances in the field, including the activation and functions of innate immune cells and the emerging innate properties and modulatory roles of the fibroblastic mesenchyme. Novel insights into the diverse

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular

Dendritic cells (DCs) are critical for the differentiation of pathogen-specific CD4 T cells. However, to what extent innate cues from DCs dictate transcriptional changes in T cells remains elusive. Here, we used DCs stimulated with specific pathogens to prime CD4 T cells in vitro and found that these T cells express unique transcriptional profiles dictated by the nature of the priming pathogen. More

Aberrant NLRP3 inflammasome activation contributes to the development of endotoxemia. The importance of negative regulation of NLRP3 inflammasomes remains poorly understood. Here, we show that the E3 ubiquitin ligase Cbl-b is essential for preventing endotoxemia induced by a sub-lethal dose of LPS via a caspase-11/NLRP3-dependent manner. Further studies show that NLRP3 undergoes both K63- and K48-linked

In a forward genetic screen of N-ethyl-N-nitrosourea (ENU)-induced mutant mice for aberrant immune function, we identified mice with a syndromic disorder marked by growth retardation, diabetes, premature death, and severe lymphoid and myeloid hypoplasia together with diminished T cell-independent (TI) antibody responses. The causative mutation was in Pdia6, an essential gene encoding protein disulfide

Alzheimer's disease (AD) is accompanied by a robust inflammatory response mediated by plaque-associated myeloid cells of the brain. These cells exhibit altered gene expression profiles and serve as a barrier, preventing neuritic dystrophy. The origin of these cells has been controversial and is of therapeutic importance. Here, we genetically labeled different myeloid populations and unequivocally demonstrated

Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in

Macrophages play pleiotropic roles in maintaining the balance between immune tolerance and inflammatory responses in the gut. Here, we identified transcription factor RBP-J as a crucial regulator of colonic macrophage-mediated immune responses against the enteric pathogen Citrobacter rodentium. In the immune response phase, RBP-J promoted pathogen clearance by enhancing intestinal macrophage-elicited

Tumor-specific mutations can generate neoantigens that drive CD8 T cell responses against cancer. Next-generation sequencing and computational methods have been successfully applied to identify mutations and predict neoantigens. However, only a small fraction of predicted neoantigens are immunogenic. Currently, predicted peptide binding affinity for MHC-I is often the major criterion for prioritizing

Cells, and hence organisms, have biological memory, recording prior exposures to facilitate future responses.1 By linking this recall to gene expression, coordinated transcriptional programs are triggered that define normal function and adaptive responses. Efficient, integrated gene expression is essential, as evident with inflammatory responses to infection or tissue repair after injury. Cellular

In this issue of JAMA, Shen et al report findings from a preliminary study of 5 severely ill patients with coronavirus disease 2019 (COVID-19) who were treated in the Shenzhen Third People's Hospital, China, using plasma from recovered individuals.1 All patients had severe respiratory failure and were receiving mechanical ventilation; 1 needed extracorporeal membrane oxygenation (ECMO) and 2 had bacterial

The profound effects of sodium-glucose transporter 2 (SGLT2) inhibition on the risks of cardiovascular complications in patients with hyperglycemia have provided for rapid and substantive changes to diabetes guidelines from various countries. In this issue of JAMA, Petrie and colleagues1 report findings from a highly informative exploratory analysis of the most recent large-scale clinical trial of

As the coronavirus disease 2019 (COVID-19) pandemic intensifies, shortages of ventilators have occurred in Italy and are likely imminent in parts of the US. In ordinary clinical circumstances, all patients in need of mechanical ventilation because of potentially-reversible conditions receive it, unless they or their surrogates decline. However, there are mounting concerns in many countries that this

As the coronavirus disease 2019 (COVID-19) pandemic accelerates, global health care systems have become overwhelmed with potentially infectious patients seeking testing and care. Preventing spread of infection to and from health care workers (HCWs) and patients relies on effective use of personal protective equipment (PPE)—gloves, face masks, air-purifying respirators, goggles, face shields, respirators

Our past experiences shape our current and future behavior. These experiences must leave some enduring imprint on our brains, altering neural circuits that mediate behavior and contributing to our individual differences. As a framework for understanding how experiences might produce lasting changes in neural circuits, Clayton [D. F. Clayton, Neurobiol....

Prenatal stress exposure is associated with risk for psychiatric disorders later in life. This may be mediated in part via enhanced exposure to glucocorticoids (GCs), which are known to impact neurogenesis. We aimed to identify molecular mediators of these effects, focusing on long-lasting epigenetic changes. In a human hippocampal progenitor...

Prolonged social isolation has negative effects on brain and behavior in humans and other social organisms, but neural mechanisms leading to these effects are not understood. Here we tested the hypothesis that even brief periods of social isolation can alter gene expression and DNA methylation in higher cognitive centers of...

Neurodevelopmental spectrum disorders like autism (ASD) are diagnosed, on average, beyond age 4 y, after multiple critical periods of brain development close and behavioral intervention becomes less effective. This raises the urgent need for quantitative, noninvasive, and translational biomarkers for their early detection and tracking. We found that both idiopathic...

Painful or threatening experiences trigger escape responses that are guided by nociceptive neuronal circuitry. Although some components of this circuitry are known and conserved across animals, how this circuitry is regulated at the genetic and developmental levels is mostly unknown. To escape noxious stimuli, such as parasitoid wasp attacks, Drosophila...

In the development of photoelectrochemical cells for water splitting or CO2 reduction, a major challenge is O2 evolution at photoelectrodes that, in behavior, mimic photosystem II. At an appropriate semiconductor electrode, a water oxidation catalyst must be integrated with a visible light absorber in a stable half-cell configuration. Here, we...

Innate behavioral biases and preferences can vary significantly among individuals of the same genotype. Though individuality is a fundamental property of behavior, it is not currently understood how individual differences in brain structure and physiology produce idiosyncratic behaviors. Here we present evidence for idiosyncrasy in olfactory behavior and neural responses...

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene

This century will witness a major transformation in how energy is acquired, stored, and utilized globally. The impetus for this change comes from the deep impacts that both developed and developing societies have had on our planet’s environment during the past century, and the projections going forward of what will...

Cement production is currently the largest single industrial emitter of CO2, accounting for ∼8% (2.8 Gtons/y) of global CO2 emissions. Deep decarbonization of cement manufacturing will require remediation of both the CO2 emissions due to the decomposition of CaCO3 to CaO and that due to combustion of fossil fuels (primarily...

The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such...

Biological embedding occurs when life experience alters biological processes to affect later life health and well-being. Although extensive correlative data exist supporting the notion that epigenetic mechanisms such as DNA methylation underlie biological embedding, causal data are lacking. We describe specific epigenetic mechanisms and their potential roles in the biological...

Children from lower-income households are at increased risk for poor health, educational failure, and behavioral problems. This social gradient is one of the most reproduced findings in health and social science. How people view their position in social hierarchies also signals poor health. However, when adolescents’ views of their social...

Electrolysis converts electrical energy into chemical energy by storing electrons in the form of stable chemical bonds. The chemical energy can be used as a fuel or converted back to electricity when needed. Water electrolysis to hydrogen and oxygen is a well-established technology, whereas fundamental advances in CO2 electrolysis are still needed to enable short-term and seasonal energy storage in

Technoeconomic and life-cycle analyses are presented for catalytic conversion of ethanol to fungible hydrocarbon fuel blendstocks, informed by advances in catalyst and process development. Whereas prior work toward this end focused on 3-step processes featuring dehydration, oligomerization, and hydrogenation, the consolidated alcohol dehydration and oligomerization (CADO) approach described here results

The induction of immediate-early gene (IEG) expression in brain nuclei in response to an experience is necessary for the formation of long-term memories. Additionally, the rapid dynamics of IEG induction and decay motivates the common use of IEG expression as markers for identification of neuronal assemblies (“ensembles”) encoding recent experience....

Electrochemical CO reduction can serve as a sequential step in the transformation of CO2 into multicarbon fuels and chemicals. In this study, we provide insights on how to steer selectivity for CO reduction almost exclusively toward a single multicarbon oxygenate by carefully controlling the catalyst composition and its surrounding reaction conditions. Under alkaline reaction conditions, we demonstrate

MEDICAL SCIENCES Retraction for “Impaired lipid metabolism by age-dependent DNA methylation alterations accelerates aging,” by Xin Li, Jiaqiang Wang, Leyun Wang, Guihai Feng, Gen Li, Meixin Yu, Yufei Li, Chao Liu, Xuewei Yuan, Guangxi Zang, Zhihuan Li, Ling Zhao, Hong Ouyang, Qingli Quan, Guangyu Wang, Charlotte Zhang, Oulan Li, Junkai...

The small GTPase RABL3 is an oncogene of unknown physiological function. Homozygous knockout alleles of mouse Rabl3 were embryonic lethal, but a viable hypomorphic allele (xiamen [xm]) causing in-frame deletion of four amino acids from the interswitch region resulted in profound defects in lymphopoiesis. Impaired lymphoid progenitor development led to...

Natural and man-made robotic systems use the interfacial tension between two fluids to support dense objects on liquid surfaces. Here, we show that coacervate-encased droplets of an aqueous polymer solution can be hung from the surface of a less dense aqueous polymer solution using surface tension. The forces acting on...

Coproduction of high-value bioproducts at biorefineries is a key factor in making biofuels more cost-competitive. One strategy for generating coproducts is to directly engineer bioenergy crops to accumulate bioproducts in planta that can be fractionated and recovered at biorefineries. Here, we develop quantitative insights into the relationship between bioproduct market...

Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no...

Frogs (Anura) are one of the most diverse vertebrate orders, comprising more than 7,000 species with a worldwide distribution and extensive ecological diversity. In contrast to other tetrapods, frogs have a highly derived body plan and simplified skull. In many lineages of anurans, increased mineralization has led to hyperossified skulls,...

The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven...

To adapt to habitat temperature, vertebrates have developed sophisticated physiological and ecological mechanisms through evolution. Transient receptor potential melastatin 8 (TRPM8) serves as the primary sensor for cold. However, how cold activates TRPM8 and how this sensor is tuned for thermal adaptation remain largely unknown. Here we established a molecular...