Recent evidence shows that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is sensitive to interferons (IFNs). However, the most effective types of IFNs and the underlying antiviral ...effectors remain to be defined. Here, we show that zinc finger antiviral protein (ZAP), which preferentially targets CpG dinucleotides in viral RNA sequences, restricts SARS-CoV-2. We further demonstrate that ZAP and its cofactors KHNYN and TRIM25 are expressed in human lung cells. Type I, II, and III IFNs all strongly inhibited SARS-CoV-2 and further induced ZAP expression. Comprehensive sequence analyses revealed that SARS-CoV-2 and its closest relatives from horseshoe bats showed the strongest CpG suppression among all known human and bat coronaviruses, respectively. Nevertheless, endogenous ZAP expression restricted SARS-CoV-2 replication in human lung cells, particularly upon treatment with IFN-α or IFN-γ. Both the long and the short isoforms of human ZAP reduced SARS-CoV-2 RNA expression levels, but the former did so with greater efficiency. Finally, we show that the ability to restrict SARS-CoV-2 is conserved in ZAP orthologues of the reservoir bat and potential intermediate pangolin hosts of human coronaviruses. Altogether, our results show that ZAP is an important effector of the innate response against SARS-CoV-2, although this pandemic pathogen emerged from zoonosis of a coronavirus that was preadapted to the low-CpG environment in humans.
Although interferons inhibit SARS-CoV-2 and have been evaluated for treatment of coronavirus disease 2019 (COVID-19), the most effective types and antiviral effectors remain to be defined. Here, we show that IFN-γ is particularly potent in restricting SARS-CoV-2 and in inducing expression of the antiviral factor ZAP in human lung cells. Knockdown experiments revealed that endogenous ZAP significantly restricts SARS-CoV-2. We further show that CpG dinucleotides which are specifically targeted by ZAP are strongly suppressed in the SARS-CoV-2 genome and that the two closest horseshoe bat relatives of SARS-CoV-2 show the lowest genomic CpG content of all coronavirus sequences available from this reservoir host. Nonetheless, both the short and long isoforms of human ZAP reduced SARS-CoV-2 RNA levels, and this activity was conserved in horseshoe bat and pangolin ZAP orthologues. Our findings indicating that type II interferon is particularly efficient against SARS-CoV-2 and that ZAP restricts this pandemic viral pathogen might promote the development of effective immune therapies against COVID-19.
An understanding of astrophysical feedback is important for constraining models of galaxy formation and for extracting cosmological information from current and future weak lensing surveys. The ...thermal Sunyaev-Zel'dovich effect, quantified via the Compton-y parameter, is a powerful tool for studying feedback, because it directly probes the pressure of the hot, ionized gas residing in dark matter halos. Cross-correlations between galaxies and maps of Compton-y obtained from cosmic microwave background surveys are sensitive to the redshift evolution of the gas pressure, and its dependence on halo mass. In this work, we use galaxies identified in year one data from the Dark Energy Survey and Compton-y maps constructed from Planck observations. We find highly significant (roughly 12σ) detections of galaxy-y cross-correlation in multiple redshift bins. By jointly fitting these measurements as well as measurements of galaxy clustering, we constrain the halo bias-weighted, gas pressure of the Universe as a function of redshift between 0.15≲z≲0.75. We compare these measurements to predictions from hydrodynamical simulations, allowing us to constrain the amount of thermal energy in the halo gas relative to that resulting from gravitational collapse.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Context:
Total 25-hydroxyvitamin D (25OHD) is a marker of vitamin D status and is lower in African Americans than in whites. Whether this difference holds for free 25OHOD (f25OHD) is unclear, ...considering reported genetic-racial differences in vitamin D binding protein (DBP) used to calculate f25OHD.
Objectives:
Our objective was to assess racial-geographic differences in f25OHD and to understand inconsistencies in racial associations with DBP and calculated f25OHD.
Design:
This study used a cross-sectional design.
Setting:
The general community in the United States, United Kingdom, and The Gambia were included in this study.
Participants:
Men in Osteoporotic Fractures in Men and Medical Research Council studies (N = 1057) were included.
Exposures:
Total 25OHD concentration, race, and DBP (GC) genotype exposures were included.
Outcome Measures:
Directly measured f25OHD, DBP assessed by proteomics, monoclonal and polyclonal immunoassays, and calculated f25OHD were the outcome measures.
Results:
Total 25OHD correlated strongly with directly measured f25OHD (Spearman r = 0.84). Measured by monoclonal assay, mean DBP in African-ancestry subjects was approximately 50% lower than in whites, whereas DBP measured by polyclonal DBP antibodies or proteomic methods was not lower in African-ancestry. Calculated f25OHD (using polyclonal DBP assays) correlated strongly with directly measured f25OHD (r = 0.80–0.83). Free 25OHD, measured or calculated from polyclonal DBP assays, reflected total 25OHD concentration irrespective of race and was lower in African Americans than in US whites.
Conclusions:
Previously reported racial differences in DBP concentration are likely from monoclonal assay bias, as there was no racial difference in DBP concentration by other methods. This confirms the poor vitamin D status of many African-Americans and the utility of total 25OHD in assessing vitamin D in the general population.
We found no racial or genetic differences in serum vitamin D binding protein. Free 25OHD, directly measured or calculated from DBP (using polyclonal antibodies), was low in Afro-Americans, compared to US whites or blacks from The Gambia.
Increasing evidence suggests exposure to adverse conditions in intrauterine life may increase the risk of developing attention-deficit/hyperactivity disorder (ADHD) in childhood. High maternal ...pre-pregnancy body mass index (BMI) has been shown to predict child ADHD symptoms, however the neurocognitive processes underlying this relationship are not known. The aim of the present study was to test the hypothesis that this association is mediated by alterations in child executive function.
A population-based cohort of 174 children (mean age = 7.3 ± 0.9 (SD) yrs, 55% girls) was evaluated for ADHD symptoms using the Child Behavior Checklist, and for neurocognitive function using the Go/No-go task. This cohort had been followed prospectively from early gestation and birth through infancy and childhood with serial measures of maternal and child prenatal and postnatal factors. Maternal pre-pregnancy BMI was a significant predictor of child ADHD symptoms (F((1,158)) = 4.80, p = 0.03) and of child performance on the Go/No-go task (F((1,157)) = 8.37, p = 0.004) after controlling for key potential confounding variables. A test of the mediation model revealed that the association between higher maternal pre-pregnancy BMI and child ADHD symptoms was mediated by impaired executive function (inefficient/less attentive processing; Sobel Test: t = 2.39 (± 0.002, SEM), p = 0.02).
To the best of our knowledge this is the first study to report that maternal pre-pregnancy BMI-related alterations in child neurocognitive function may mediate its effects on ADHD risk. The finding is clinically significant and may extrapolate to an approximately 2.8-fold increase in the prevalence of ADHD among children of obese compared to those of non-obese mothers. These results add further evidence to the growing awareness that neurodevelopmental disorders such as ADHD may have their foundations very early in life.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT We report the discovery of eight new ultra-faint dwarf galaxy candidates in the second year of optical imaging data from the Dark Energy Survey (DES). Six of these candidates are detected at ...high confidence, while two lower-confidence candidates are identified in regions of non-uniform survey coverage. The new stellar systems are found by three independent automated search techniques and are identified as overdensities of stars, consistent with the isochrone and luminosity function of an old and metal-poor simple stellar population. The new systems are faint (MV > −4.7 ) and span a range of physical sizes (17 < r1/2 < 181 ) and heliocentric distances (25 kpc < D < 214 kpc). All of the new systems have central surface brightnesses consistent with known ultra-faint dwarf galaxies ( 27.5 −2). Roughly half of the DES candidates are more distant, less luminous, and/or have lower surface brightnesses than previously known Milky Way satellite galaxies. Most of the candidates are found in the southern part of the DES footprint close to the Magellanic Clouds. We find that the DES data alone exclude (p < 10−3) a spatially isotropic distribution of Milky Way satellites and that the observed distribution can be well, though not uniquely, described by an association between several of the DES satellites and the Magellanic system. Our model predicts that the full sky may hold ∼100 ultra-faint galaxies with physical properties comparable to the DES satellites and that 20%-30% of these would be spatially associated with the Magellanic Clouds.
By March 2020, COVID-19 forced much of the world to stay at home to reduce the spread of the disease. Whereas some health care workers transitioned to working from home, many continued to report to ...work in person as essential employees. We sought to explore changes in sleep, health, work, and mood in health care workers during the stay-at-home orders.
We developed a cross-sectional online survey administered to health care workers. The survey assessed changes in sleep, work, screen time, media exposure, diet, exercise, substance use, and mood. The survey data were collected between March 28, 2020, and April 29, 2020.
A total of 834 of 936 individuals completed the entire survey. Respondents were from 41 US states. Mood after the stay-at-home orders worsened, and screen time and substance use increased. Total sleep time shortened in those continuing to work in person (P < .001), whereas it was unchanged in those working from home (P = .73). Those working from home went to bed later, woke up later, and worked fewer hours. Reduced total sleep time and increased screen time before bed were associated with worse mood and screen time. Longer sleep time was associated with better mood.
Health care workers' mood worsened regardless of whether work was in person or remote, although total sleep time was shorter for those working in person. Those working from home may have shifted their sleep time to be more in line with their endogenous circadian phase. Peer or other support services may be indicated to address sleep, mood, and health behaviors among health care workers during these unprecedented times.
CpG dinucleotides are suppressed in the genomes of many vertebrate RNA viruses, including HIV-1. The cellular antiviral protein ZAP (zinc finger antiviral protein) binds CpGs and inhibits HIV-1 ...replication when CpGs are introduced into the viral genome. However, it is not known if ZAP-mediated restriction is the only mechanism driving CpG suppression. To determine how CpG dinucleotides affect HIV-1 replication, we increased their abundance in multiple regions of the viral genome and analyzed the effect on RNA expression, protein abundance, and infectious-virus production. We found that the antiviral effect of CpGs was not correlated with their abundance. Interestingly, CpGs inserted into some regions of the genome sensitize the virus to ZAP antiviral activity more efficiently than insertions into other regions, and this sensitivity can be modulated by interferon treatment or ZAP overexpression. Furthermore, the sensitivity of the virus to endogenous ZAP was correlated with its sensitivity to the ZAP cofactor KHNYN. Finally, we show that CpGs in some contexts can also inhibit HIV-1 replication by ZAP-independent mechanisms, and one of these is the activation of a cryptic splice site at the expense of a canonical splice site. Overall, we show that the location and sequence context of the CpG in the viral genome determines its antiviral activity.
Some RNA virus genomes are suppressed in the nucleotide combination of a cytosine followed by a guanosine (CpG), indicating that they are detrimental to the virus. The antiviral protein ZAP binds viral RNA containing CpGs and prevents the virus from multiplying. However, it remains unknown how the number and position of CpGs in viral genomes affect restriction by ZAP and whether CpGs have other antiviral mechanisms. Importantly, manipulating the CpG content in viral genomes could help create new vaccines. HIV-1 shows marked CpG suppression, and by introducing CpGs into its genome, we show that ZAP efficiently targets a specific region of the viral genome, that the number of CpGs does not predict the magnitude of antiviral activity, and that CpGs can inhibit HIV-1 gene expression through a ZAP-independent mechanism. Overall, the position of CpGs in the HIV-1 genome determines the magnitude and mechanism through which they inhibit the virus.
We present the first results of a survey for high-redshift, z ≥ 6, quasars using izY multicolour photometric observations from the Dark Energy Survey (DES). Here we report the discovery and ...spectroscopic confirmation of the z
AB, Y
AB = 20.2, 20.2 (M
1450 = −26.5) quasar DES J0454−4448 with a redshift of z = 6.09±0.02 based on the onset of the Ly α forest and an H i near zone size of 4.1
$_{-1.2}^{+1.1}$
proper Mpc. The quasar was selected as an i-band drop out with i−z = 2.46 and z
AB < 21.5 from an area of ∼300 deg2. It is the brightest of our 43 candidates and was identified for spectroscopic follow-up solely based on the DES i−z and z−Y colours. The quasar is detected by WISE and has W1AB = 19.68. The discovery of one spectroscopically confirmed quasar with 5.7 < z < 6.5 and z
AB ≤ 20.2 is consistent with recent determinations of the luminosity function at z ∼ 6. DES when completed will have imaged ∼5000 deg2 to Y
AB = 23.0 (5σ point source) and we expect to discover 50–100 new quasars with z > 6 including 3–10 with z > 7 dramatically increasing the numbers of quasars currently known that are suitable for detailed studies.
Grotthuss shuttling of an excess proton charge defect through hydrogen bonded water networks has long been the focus of theoretical and experimental studies. In this work we show that there is a ...related process in which water molecules move (“shuttle”) through a hydrated excess proton charge defect in order to wet the path ahead for subsequent proton charge migration. This process is illustrated through reactive molecular dynamics simulations of proton transport through a hydrophobic nanotube, which penetrates through a hydrophobic region. Surprisingly, before the proton enters the nanotube, it starts “shooting” water molecules into the otherwise dry space via Grotthuss shuttling, effectively creating its own water wire where none existed before. As the proton enters the nanotube (by 2–3 Å), it completes the solvation process, transitioning the nanotube to the fully wet state. By contrast, other monatomic cations (e.g., K+) have just the opposite effect, by blocking the wetting process and making the nanotube even drier. As the dry nanotube gradually becomes wet when the proton charge defect enters it, the free energy barrier of proton permeation through the tube via Grotthuss shuttling drops significantly. This finding suggests that an important wetting mechanism may influence proton translocation in biological systems, i.e., one in which protons “create” their own water structures (water “wires”) in hydrophobic spaces (e.g., protein pores) before migrating through them. An existing water wire, e.g., one seen in an X-ray crystal structure or MD simulations without an explicit excess proton, is therefore not a requirement for protons to transport through hydrophobic spaces.
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IJS, KILJ, NUK, PNG, UL, UM
Abstract
We describe a multicomponent matched filter (MCMF) cluster confirmation tool designed for the study of large X-ray source catalogues produced by the upcoming X-ray all-sky survey mission ...eROSITA. We apply the method to confirm a sample of 88 clusters with redshifts 0.05 < z < 0.8 in the recently published 2RXS catalogue from the ROSAT All-Sky Survey (RASS) over the 208 deg2 region overlapped by the Dark Energy Survey (DES) Science Verification (DES-SV) data set. In our pilot study, we examine all X-ray sources, regardless of their extent. Our method employs a multicolour red sequence (RS) algorithm that incorporates the X-ray count rate and peak position in determining the region of interest for follow-up and extracts the positionally and colour-weighted optical richness λMCMF as a function of redshift for each source. Peaks in the λMCMF–redshift distribution are identified and used to extract photometric redshifts, richness and uncertainties. The significances of all optical counterparts are characterized using the distribution of richnesses defined along random lines of sight. These significances are used to extract cluster catalogues and to estimate the contamination by random superpositions of unassociated optical systems. The delivered photometric redshift accuracy is δz/(1 + z) = 0.010. We find a well-defined X-ray luminosity–λMCMF relation with an intrinsic scatter of δln (λMCMF|Lx) = 0.21. Matching our catalogue with the DES-SV redMaPPer catalogue yields good agreement in redshift and richness estimates; comparing our catalogue with the South Pole Telescope (SPT) selected clusters shows no inconsistencies. SPT clusters in our data set are consistent with the high-mass extension of the RASS-based λMCMF–mass relation.
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