Adaptive Autoimmunity and Foxp3-Based Immunoregulation in Zebrafish

Background: Jawed vertebrates generate their immune-receptor repertoire by a recombinatorial mechanism that has the potential to produce harmful autoreactive lymphocytes. In mammals, peripheral tolerance to self-antigens is enforced by Foxp3+ regulatory T cells. Recombinatorial mechanisms also operate in teleosts, but active immunoregulation is thought to be a late incorporation to the vertebrate lineage. Methods/Principal Findings: Here we report the characterization of adaptive autoimmunity and Foxp3-based immunoregulation in the zebrafish. We found that zebrafish immunization with an homogenate of zebrafish central nervous system (zCNS) triggered CNS inflammation and specific antibodies. We cloned the zebrafish ortholog for mammalian Foxp3 (zFoxp3) which induced a regulatory phenotype on mouse T cells and controlled IL-17 production in zebrafish embryos. Conclusions/Significance: Our findings demonstrate the acquisition of active mechanisms of self-tolerance early in vertebrate evolution, suggesting that active regulatory mechanisms accompany the development of the molecular potential for adaptive autoimmunity. Moreover, they identify the zebrafish as a tool to study the molecular pathways controlling adaptive immunity

IL-21 induces IL-22 production in CD4+ T-cells

IL-22 produced by innate lymphoid cells (ILCs) and CD4+ T cells plays an important role in host defense and mucosal homeostasis, thus it is important to investigate the mechanisms that regulate IL-22 production. We investigated the regulation IL-22 production by CD4+ T cells. Here we show that IL-21 triggers IL-22, but not IL-17 production by CD4+ T cells. STAT3, activated by IL-21, controls the epigenetic status of the il22 promoter and its interaction with the aryl hydrocarbon receptor (AhR). Moreover, IL-21 and AhR signaling in T cells control IL-22 production and the development of dextran sodium sulfate-induced colitis in ILC-deficient mice. Thus, we have identified IL-21 as an inducer of IL-22 production in CD4+ T cells in vitro and in vivo

Iterative methods for Navier-Stokes inverse problems

Even when the partial differential equation underlying a physical process can be evolved forward in time, the retrospective (backward in time) inverse problem often has its own challenges and applications. Direct adjoint looping (DAL) is the defacto approach for solving retrospective inverse problems, but it has not been applied to deterministic retrospective Navier–Stokes inverse problems in 2D or 3D. In this paper, we demonstrate that DAL is ill-suited for solving retrospective 2D Navier–Stokes inverse problems. Alongside DAL, we study two other iterative methods: simple backward integration (SBI) and the quasireversible method (QRM). As far as we know, our iterative SBI approach is novel, while iterative QRM has previously been used. Using these three iterative methods, we solve two retrospective inverse problems: 1D Korteweg–de Vries–Burgers (decaying nonlinear wave) and 2D Navier–Stokes (unstratified Kelvin–Helmholtz vortex). In both cases, SBI and QRM reproduce the target final states more accurately and in fewer iterations than DAL. We attribute this performance gap to additional terms present in SBI and QRM's respective backward integrations which are absent in DAL

The photometric variability of massive stars due to gravity waves excited by core convection

Massive stars die in catastrophic explosions, which seed the interstellar medium with heavy elements and produce neutron stars and black holes. Predictions of the explosion's character and the remnant mass depend on models of the star's evolutionary history. Models of massive star interiors can be empirically constrained by asteroseismic observations of gravity wave oscillations. Recent photometric observations reveal a ubiquitous red noise signal on massive main sequence stars; a hypothesized source of this noise is gravity waves driven by core convection. We present the first 3D simulations of massive star convection extending from the star's center to near its surface, with realistic stellar luminosities. Using these simulations, we make the first prediction of photometric variability due to convectively-driven gravity waves at the surfaces of massive stars, and find that gravity waves produce photometric variability of a lower amplitude and lower characteristic frequency than the observed red noise. We infer that the photometric signal of gravity waves excited by core convection is below the noise limit of current observations, so the red noise must be generated by an alternative process.Comment: As accepted for publication in Nature Astronomy except for final editorial revisions. Supplemental materials available online at https://doi.org/10.5281/zenodo.7764997 . We have also sonified our results to make them more accessible, see https://github.com/evanhanders/gmode_variability_paper/blob/main/sound/gmode_sonification.pd

SARS-CoV-2 mRNA vaccination elicits robust antibody responses in children

Publisher Copyright: Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY)Although children have been largely spared from coronavirus disease 2019 (COVID-19), the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) with increased transmissibility, combined with fluctuating mask mandates and school reopenings, has led to increased infections and disease among children. Thus, there is an urgent need to roll out COVID-19 vaccines to children of all ages. However, whether children respond equivalently to adults to mRNA vaccines and whether dosing will elicit optimal immunity remain unclear. Here, we aimed to deeply profile the vaccine-induced humoral immune response in 6- to 11-year-old children receiving either a pediatric (50 μg) or adult (100 μg) dose of the mRNA-1273 vaccine and to compare these responses to vaccinated adults, infected children, and children who experienced multisystem inflammatory syndrome in children (MIS-C). Children elicited an IgG-dominant vaccine-induced immune response, surpassing adults at a matched 100-μg dose but more variable immunity at a 50-μg dose. Irrespective of titer, children generated antibodies with enhanced Fc receptor binding capacity. Moreover, like adults, children generated cross-VOC humoral immunity, marked by a decline of omicron-specific receptor binding domain, but robustly preserved omicron spike protein binding. Fc receptor binding capabilities were also preserved in a dose-dependent manner. These data indicate that both the 50- and 100-μg doses of mRNA vaccination in children elicit robust cross-VOC antibody responses and that 100-μg doses in children result in highly preserved omicron-specific functional humoral immunity.publishersversionPeer reviewe

<i>De Novo</i> and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk

Catching Element Formation In The Act

Gamma-ray astronomy explores the most energetic photons in nature to address some of the most pressing puzzles in contemporary astrophysics. It encompasses a wide range of objects and phenomena: stars, supernovae, novae, neutron stars, stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays and relativistic-particle acceleration, and the evolution of galaxies. MeV gamma-rays provide a unique probe of nuclear processes in astronomy, directly measuring radioactive decay, nuclear de-excitation, and positron annihilation. The substantial information carried by gamma-ray photons allows us to see deeper into these objects, the bulk of the power is often emitted at gamma-ray energies, and radioactivity provides a natural physical clock that adds unique information. New science will be driven by time-domain population studies at gamma-ray energies. This science is enabled by next-generation gamma-ray instruments with one to two orders of magnitude better sensitivity, larger sky coverage, and faster cadence than all previous gamma-ray instruments. This transformative capability permits: (a) the accurate identification of the gamma-ray emitting objects and correlations with observations taken at other wavelengths and with other messengers; (b) construction of new gamma-ray maps of the Milky Way and other nearby galaxies where extended regions are distinguished from point sources; and (c) considerable serendipitous science of scarce events -- nearby neutron star mergers, for example. Advances in technology push the performance of new gamma-ray instruments to address a wide set of astrophysical questions.Comment: 14 pages including 3 figure

Identification of novel locus associated with coronary artery aneurysms and validation of loci for susceptibility to Kawasaki disease

Kawasaki disease (KD) is a paediatric vasculitis associated with coronary artery aneurysms (CAA). Genetic variants influencing susceptibility to KD have been previously identified, but no risk alleles have been validated that influence CAA formation. We conducted a genome-wide association study (GWAS) for CAA in KD patients of European descent with 200 cases and 276 controls. A second GWAS for susceptibility pooled KD cases with healthy paediatric controls from vaccine trials in the UK (n = 1609). Logistic regression mixed models were used for both GWASs. The susceptibility GWAS was meta-analysed with 400 KD cases and 6101 controls from a previous European GWAS, these results were further meta-analysed with Japanese GWASs at two putative loci. The CAA GWAS identified an intergenic region of chromosome 20q13 with multiple SNVs showing genome-wide significance. The risk allele of the most associated SNV (rs6017006) was present in 13% of cases and 4% of controls; in East Asian 1000 Genomes data, the allele was absent or rare. Susceptibility GWAS with meta-analysis with previously published European data identified two previously associated loci (ITPKC and FCGR2A). Further meta-analysis with Japanese GWAS summary data from the CASP3 and FAM167A genomic regions validated these loci in Europeans showing consistent effects of the top SNVs in both populations. We identified a novel locus for CAA in KD patients of European descent. The results suggest that different genes determine susceptibility to KD and development of CAA and future work should focus on the function of the intergenic region on chromosome 20q13

Trends in Use of Medication to Treat Opioid Use Disorder During the COVID-19 Pandemic in 10 State Medicaid Programs

Federal and state agencies granted temporary regulatory waivers to prevent disruptions in access to medication for opioid use disorder (MOUD) during the COVID-19 pandemic, including expanding access to telehealth for MOUD. Little is known about changes in MOUD receipt and initiation among Medicaid enrollees during the pandemic.To examine changes in receipt of any MOUD, initiation of MOUD (in-person vs telehealth), and the proportion of days covered (PDC) with MOUD after initiation from before to after declaration of the COVID-19 public health emergency (PHE).This serial cross-sectional study included Medicaid enrollees aged 18 to 64 years in 10 states from May 2019 through December 2020. Analyses were conducted from January through March 2022.Ten months before the COVID-19 PHE (May 2019 through February 2020) vs 10 months after the PHE was declared (March through December 2020).Primary outcomes included receipt of any MOUD and outpatient initiation of MOUD via prescriptions and office- or facility-based administrations. Secondary outcomes included in-person vs telehealth MOUD initiation and PDC with MOUD after initiation.Among a total of 8 167 497 Medicaid enrollees before the PHE and 8 181 144 after the PHE, 58.6% were female in both periods and most enrollees were aged 21 to 34 years (40.1% before the PHE; 40.7% after the PHE). Monthly rates of MOUD initiation, representing 7% to 10% of all MOUD receipt, decreased immediately after the PHE primarily due to reductions in in-person initiations (from 231.3 per 100 000 enrollees in March 2020 to 171.8 per 100 000 enrollees in April 2020) that were partially offset by increases in telehealth initiations (from 5.6 per 100 000 enrollees in March 2020 to 21.1 per 100 000 enrollees in April 2020). Mean monthly PDC with MOUD in the 90 days after initiation decreased after the PHE (from 64.5% in March 2020 to 59.5% in September 2020). In adjusted analyses, there was no immediate change (odds ratio [OR], 1.01; 95% CI, 1.00-1.01) or change in the trend (OR, 1.00; 95% CI, 1.00-1.01) in the likelihood of receipt of any MOUD after the PHE compared with before the PHE. There was an immediate decrease in the likelihood of outpatient MOUD initiation (OR, 0.90; 95% CI, 0.85-0.96) and no change in the trend in the likelihood of outpatient MOUD initiation (OR, 0.99; 95% CI, 0.98-1.00) after the PHE compared with before the PHE.In this cross-sectional study of Medicaid enrollees, the likelihood of receipt of any MOUD was stable from May 2019 through December 2020 despite concerns about potential COVID-19 pandemic–related disruptions in care. However, immediately after the PHE was declared, there was a reduction in overall MOUD initiations, including a reduction in in-person MOUD initiations that was only partially offset by increased use of telehealth