Induction of IL-17A Precedes Development of Airway Hyperresponsiveness during Diet-Induced Obesity and Correlates with Complement Factor D

Obesity is a risk factor for the development of asthma. Obese mice exhibit innate airway hyperresponsiveness (AHR), a characteristic feature of asthma, and IL-17A is required for development of AHR in obese mice. The purpose of this study was to examine the temporal association between the onset of AHR and changes in IL-17A during the development of obesity by high-fat feeding in mice. At weaning, C57BL/6J mice were placed either on mouse chow or on a high-fat diet (HFD) and examined 9, 12, 15, 18, or 24 weeks later. Airway responsiveness to aerosolized methacholine (assessed via the forced oscillation technique) was greater in mice fed HFD versus chow for 24 weeks but not at earlier time points. Bronchoalveolar lavage and serum IL-17A were not affected by either the type or duration of diet, but increased pulmonary IL17a mRNA abundance was observed in HFD versus chow fed mice after both 18 and 24 weeks. Flow cytometry also confirmed an increase in IL-17A+ γδ T cells and IL-17A+ CD4+ T (Th17) cells in lungs of HFD versus chow fed mice. Pulmonary expression of Cfd (complement factor D, adipsin), a gene whose expression can be reduced by IL-17A, decreased after both 18 and 24 weeks in HFD versus chow fed mice. Furthermore, pulmonary Cfd mRNA abundance correlated with elevations in pulmonary Il17a mRNA expression and with AHR. Serum levels of TNFα, MIP-1α, and MIP-1β, and classical markers of systemic inflammation of obesity were significantly greater in HFD than chow fed mice after 24 weeks, but not earlier. In conclusion, our data indicate that pulmonary rather than systemic IL-17A is important for obesity-related AHR and suggest that changes in pulmonary Cfd expression contribute to these effects of IL-17A. Further, the observation that increases in Il17a preceded the development of AHR by several weeks suggests that IL-17A interacts with other factors to promote AHR. The observation that the onset of the systemic inflammation of obesity coincided temporally with the development of AHR suggest that systemic inflammation may be one of these factors

γδ T Cells Are Required for Pulmonary IL-17A Expression after Ozone Exposure in Mice: Role of TNFα

Ozone is an air pollutant that causes pulmonary symptoms. In mice, ozone exposure causes pulmonary injury and increases bronchoalveolar lavage macrophages and neutrophils. We have shown that IL-17A is important in the recruitment of neutrophils after subacute ozone exposure (0.3 ppm for 24–72 h). We hypothesized that γδ T cells are the main producers of IL-17A after subacute ozone. To explore this hypothesis we exposed wildtype mice and mice deficient in γδ T cells (TCRδ−/−) to ozone or room air. Ozone-induced increases in BAL macrophages and neutrophils were attenuated in TCRδ−/− mice. Ozone increased the number of γδ T cells in the lungs and increased pulmonary Il17a mRNA expression and the number of IL-17A+ CD45+ cells in the lungs and these effects were abolished in TCRδ−/− mice. Ozone-induced increases in factors downstream of IL-17A signaling, including G-CSF, IL-6, IP-10 and KC were also decreased in TCRδ−/− versus wildtype mice. Neutralization of IL-17A during ozone exposure in wildtype mice mimicked the effects of γδ T cell deficiency. TNFR2 deficiency and etanercept, a TNFα antagonist, also reduced ozone-induced increases in Il17a mRNA, IL-17A+ CD45+ cells and BAL G-CSF as well as BAL neutrophils. TNFR2 deficient mice also had decreased ozone-induced increases in Ccl20, a chemoattractant for IL-17A+ γδ T cells. Il17a mRNA and IL-17A+ γδ T cells were also lower in obese Cpefat versus lean WT mice exposed to subacute ozone, consistent with the reduced neutrophil recruitment observed in the obese mice. Taken together, our data indicate that pulmonary inflammation induced by subacute ozone requires γδ T cells and TNFα-dependent recruitment of IL-17A+ γδ T cells to the lung

γδ T Cells Are Required for M2 Macrophage Polarization and Resolution of Ozone-Induced Pulmonary Inflammation in Mice

We examined the role of γδ T cells in the induction of alternatively activated M2 macrophages and the resolution of inflammation after ozone exposure. Wildtype (WT) mice and mice deficient in γδ T cells (TCRδ-/- mice) were exposed to air or to ozone (0.3 ppm for up to 72h) and euthanized immediately or 1, 3, or 5 days after cessation of exposure. In WT mice, M2 macrophages accumulated in the lungs over the course of ozone exposure. Pulmonary mRNA abundance of the M2 genes, Arg1, Retnla, and Clec10a, also increased after ozone. In contrast, no evidence of M2 polarization was observed in TCRδ-/- mice. WT but not TCRδ-/- mice expressed the M2c polarizing cytokine, IL-17A, after ozone exposure and WT mice treated with an IL-17A neutralizing antibody exhibited attenuated ozone-induced M2 gene expression. In WT mice, ozone-induced increases in bronchoalveolar lavage neutrophils and macrophages resolved quickly after cessation of ozone exposure returning to air exposed levels within 3 days. However, lack of M2 macrophages in TCRδ-/- mice was associated with delayed clearance of inflammatory cells after cessation of ozone and increased accumulation of apoptotic macrophages in the lungs. Delayed restoration of normal lung architecture was also observed in TCRδ-/- mice. In summary, our data indicate that γδ T cells are required for the resolution of ozone-induced inflammation, likely because γδ T cells, through their secretion of IL-17A, contribute to changes in macrophage polarization that promote clearance of apoptotic cells

JWST Reveals Widespread AGN-Driven Neutral Gas Outflows in Massive z ~ 2 Galaxies

We use deep JWST/NIRSpec R~1000 slit spectra of 113 galaxies at 1.7 < z < 3.5, selected from the mass-complete Blue Jay survey, to investigate the prevalence and typical properties of neutral gas outflows at cosmic noon. We detect excess Na I D absorption (beyond the stellar contribution) in 46% of massive galaxies ($\log$ M$_*$/M$_\odot >$ 10), with similar incidence rates in star-forming and quenching systems. Half of the absorption profiles are blueshifted by at least 100 km/s, providing unambiguous evidence for neutral gas outflows. Galaxies with strong Na I D absorption are distinguished by enhanced emission line ratios consistent with AGN ionization. We conservatively measure mass outflow rates of 3 - 100 $M_\odot$ yr$^{-1}$; comparable to or exceeding ionized gas outflow rates measured for galaxies at similar stellar mass and redshift. The outflows from the quenching systems (log(sSFR)[yr$^{-1}$] $\lesssim$ -10) have mass loading factors of 4 - 360, and the energy and momentum outflow rates exceed the expected injection rates from supernova explosions, suggesting that these galaxies could possibly be caught in a rapid blowout phase powered by the AGN. Our findings suggest that AGN-driven ejection of cold gas may be a dominant mechanism for fast quenching of star formation at z~2.Comment: 16 pages, 8 figures, submitted to MNRA

A population of red candidate massive galaxies ~600 Myr after the Big Bang

Galaxies with stellar masses as high as roughly 1011 solar masses have been identified1,2,3 out to redshifts z of roughly 6, around 1 billion years after the Big Bang. It has been difficult to find massive galaxies at even earlier times, as the Balmer break region, which is needed for accurate mass estimates, is redshifted to wavelengths beyond 2.5 μm. Here we make use of the 1–5 μm coverage of the James Webb Space Telescope early release observations to search for intrinsically red galaxies in the first roughly 750 million years of cosmic history. In the survey area, we find six candidate massive galaxies (stellar mass more than 1010 solar masses) at 7.4 ≤ z ≤ 9.1, 500–700 Myr after the Big Bang, including one galaxy with a possible stellar mass of roughly 1011 solar masses. If verified with spectroscopy, the stellar mass density in massive galaxies would be much higher than anticipated from previous studies on the basis of rest-frame ultraviolet-selected samples.The Cosmic DAWN Center is funded by the Danish National Research Foundation. K.W. wishes to acknowledge funding from Alfred P. Sloan Foundation grant no. FG-2019-12514. M.S. acknowledges project no. PID2019-109592GB-I00/AEI/10.13039/501100011033 from the Spanish Ministerio de Ciencia e Innovacion - Agencia Estatal de Investigacion.Peer reviewe

JWST reveals a population of ultra-red, flattened disk galaxies at 2<z<6 previously missed by HST

With just a month of data, JWST is already transforming our view of the Universe, revealing and resolving starlight in unprecedented populations of galaxies. Although ``HST-dark" galaxies have previously been detected at long wavelengths, these observations generally suffer from a lack of spatial resolution which limits our ability to characterize their sizes and morphologies. Here we report on a first view of starlight from a subset of the HST-dark population that are bright with JWST/NIRCam (4.4$\mu$m<24.5mag) and very faint or even invisible with HST ($<$1.6$\mu$m). In this Letter we focus on a dramatic and unanticipated population of physically extended galaxies ($\gtrsim$0.17''). These 12 galaxies have photometric redshifts $2<z<6$, high stellar masses $M_{\star}\gtrsim 10^{10}~M_{\odot}$, and significant dust-attenuated star formation. Surprisingly, the galaxies have elongated projected axis ratios at 4.4$\mu$m, suggesting that the population is disk-dominated or prolate. Most of the galaxies appear red at all radii, suggesting significant dust attenuation throughout. We refer to these red, disky, HST-dark galaxies as Ultra-red Flattened Objects (UFOs). With $r_e$(F444W)$\sim1-2$~kpc, the galaxies are similar in size to compact massive galaxies at $z\sim2$ and the cores of massive galaxies and S0s at $z\sim0$. The stellar masses, sizes, and morphologies of the sample suggest that some could be progenitors of lenticular or fast-rotating galaxies in the local Universe. The existence of this population suggests that our previous censuses of the universe may have missed massive, dusty edge-on disks, in addition to dust-obscured starbursts

Impact of Emerging Antiviral Drug Resistance on Influenza Containment and Spread: Influence of Subclinical Infection and Strategic Use of a Stockpile Containing One or Two Drugs

BACKGROUND: Wide-scale use of antiviral agents in the event of an influenza pandemic is likely to promote the emergence of drug resistance, with potentially deleterious effects for outbreak control. We explored factors promoting resistance within a dynamic infection model, and considered ways in which one or two drugs might be distributed to delay the spread of resistant strains or mitigate their impact. METHODS AND FINDINGS: We have previously developed a novel deterministic model of influenza transmission that simulates treatment and targeted contact prophylaxis, using a limited stockpile of antiviral agents. This model was extended to incorporate subclinical infections, and the emergence of resistant virus strains under the selective pressure imposed by various uses of one or two antiviral agents. For a fixed clinical attack rate, R(0) rises with the proportion of subclinical infections thus reducing the number of infections amenable to treatment or prophylaxis. In consequence, outbreak control is more difficult, but emergence of drug resistance is relatively uncommon. Where an epidemic may be constrained by use of a single antiviral agent, strategies that combine treatment and prophylaxis are most effective at controlling transmission, at the cost of facilitating the spread of resistant viruses. If two drugs are available, using one drug for treatment and the other for prophylaxis is more effective at preventing propagation of mutant strains than either random allocation or drug cycling strategies. Our model is relatively straightforward, and of necessity makes a number of simplifying assumptions. Our results are, however, consistent with the wider body of work in this area and are able to place related research in context while extending the analysis of resistance emergence and optimal drug use within the constraints of a finite drug stockpile. CONCLUSIONS: Combined treatment and prophylaxis represents optimal use of antiviral agents to control transmission, at the cost of drug resistance. Where two drugs are available, allocating different drugs to cases and contacts is likely to be most effective at constraining resistance emergence in a pandemic scenario

Sixteen diverse laboratory mouse reference genomes define strain-specific haplotypes and novel functional loci.

We report full-length draft de novo genome assemblies for 16 widely used inbred mouse strains and find extensive strain-specific haplotype variation. We identify and characterize 2,567 regions on the current mouse reference genome exhibiting the greatest sequence diversity. These regions are enriched for genes involved in pathogen defence and immunity and exhibit enrichment of transposable elements and signatures of recent retrotransposition events. Combinations of alleles and genes unique to an individual strain are commonly observed at these loci, reflecting distinct strain phenotypes. We used these genomes to improve the mouse reference genome, resulting in the completion of 10 new gene structures. Also, 62 new coding loci were added to the reference genome annotation. These genomes identified a large, previously unannotated, gene (Efcab3-like) encoding 5,874 amino acids. Mutant Efcab3-like mice display anomalies in multiple brain regions, suggesting a possible role for this gene in the regulation of brain development

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe