Children have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and a substantially lower risk for developing severe coronavirus disease 2019 compared with adults. ...However, the molecular mechanisms underlying protection in younger age groups remain unknown. Here we characterize the single-cell transcriptional landscape in the upper airways of SARS-CoV-2-negative (n = 18) and age-matched SARS-CoV-2-positive (n = 24) children and corresponding samples from adults (n = 44), covering an age range of 4 weeks to 77 years. Children displayed higher basal expression of relevant pattern recognition receptors such as MDA5 (IFIH1) and RIG-I (DDX58) in upper airway epithelial cells, macrophages and dendritic cells, resulting in stronger innate antiviral responses upon SARS-CoV-2 infection than in adults. We further detected distinct immune cell subpopulations including KLRC1 (NKG2A)
cytotoxic T cells and a CD8
T cell population with a memory phenotype occurring predominantly in children. Our study provides evidence that the airway immune cells of children are primed for virus sensing, resulting in a stronger early innate antiviral response to SARS-CoV-2 infection than in adults.
The MLKL pseudokinase is the terminal effector in the necroptosis cell death pathway. Phosphorylation by its upstream regulator, RIPK3, triggers MLKL's conversion from a dormant cytoplasmic protein ...into oligomers that translocate to, and permeabilize, the plasma membrane to kill cells. The precise mechanisms underlying these processes are incompletely understood, and were proposed to differ between mouse and human cells. Here, we examine the divergence of activation mechanisms among nine vertebrate MLKL orthologues, revealing remarkable specificity of mouse and human RIPK3 for MLKL orthologues. Pig MLKL can restore necroptotic signaling in human cells; while horse and pig, but not rat, MLKL can reconstitute the mouse pathway. This selectivity can be rationalized from the distinct conformations observed in the crystal structures of horse and rat MLKL pseudokinase domains. These studies identify important differences in necroptotic signaling between species, and suggest that, more broadly, divergent regulatory mechanisms may exist among orthologous pseudoenzymes.
Background
Vitamin D levels are known to be associated with atopic disease development; however, existing data are controversial. The aim of this study was to investigate whether corresponding ...maternal and cord blood vitamin D levels are associated with atopic outcomes in early infancy.
Methods
Within the LINA cohort study (Lifestyle and environmental factors and their Influence on Newborns Allergy risk), 25(OH)D was measured in blood samples of 378 mother–child pairs during pregnancy and at birth. Information about children's atopic manifestations during the first 2 years of life was obtained from questionnaires filled out by the parents during pregnancy and annually thereafter. Cord blood regulatory T cells (Treg) were detected by methylation‐specific PCR using a Treg‐specific demethylated region in the FOXP3 gene.
Results
The median maternal 25(OH)D3 level was 22.19 ng/ml (IQR 14.40–31.19 ng/ml); the median cord blood 25(OH)D3 10.95 ng/ml (6.99–17.39 ng/ml). A high correlation was seen between maternal and cord blood 25(OH)D3 levels, both showing a seasonal distribution. Maternal and cord blood 25(OH)D3 was positively associated with children's risk for food allergy within the first 2 years. Further, higher maternal 25(OH)D3 resulted in a higher risk for sensitization against food allergens at the age of two. Cord blood 25(OH)D3 levels were negatively correlated with regulatory T cell numbers.
Conclusion
Our study demonstrates that high vitamin D levels in pregnancy and at birth may contribute to a higher risk for food allergy and therefore argues against vitamin D supplement to protect against allergy.
Background
Cross‐sectional studies suggested that allergy prevalence in childhood is higher in boys compared to girls, but it remains unclear whether this inequality changes after puberty. We ...examined the sex‐specific prevalence of asthma and rhinitis as single and as multimorbid diseases before and after puberty onset in longitudinal cohort data.
Methods
In six European population‐based birth cohorts of MeDALL, we assessed the outcomes: current rhinitis, current asthma, current allergic multimorbidity (ie, concurrent asthma and rhinitis), puberty status and allergic sensitization by specific serum antibodies (immunoglobulin E) against aero‐allergens. With generalized estimating equations, we analysed the effects of sex, age, puberty (yes/no) and possible confounders on the prevalence of asthma and rhinitis, and allergic multimorbidity in each cohort separately and performed individual participant data meta‐analysis.
Findings
We included data from 19 013 participants from birth to age 14‐20 years. Current rhinitis only affected girls less often than boys before and after puberty onset: adjusted odds ratio for females vs males 0.79 (95%‐confidence interval 0.73‐0.86) and 0.86 (0.79‐0.94), respectively (sex‐puberty interaction P = .089). Similarly, for current asthma only, females were less often affected than boys both before and after puberty onset: 0.71, 0.63‐0.81 and 0.81, 0.64‐1.02, respectively (sex‐puberty interaction P = .327). The prevalence of allergic multimorbidity showed the strongest sex effect before puberty onset (female‐male‐OR 0.55, 0.46‐0.64) and a considerable shift towards a sex‐balanced prevalence after puberty onset (0.89, 0.74‐1.04); sex‐puberty interaction: P < .001.
Interpretation
The male predominance in prevalence before puberty and the “sex‐shift” towards females after puberty onset were strongest in multimorbid patients who had asthma and rhinitis concurrently.
The OLYMPUS Collaboration reports on a precision measurement of the positron-proton to electron-proton elastic cross section ratio, R_{2γ}, a direct measure of the contribution of hard two-photon ...exchange to the elastic cross section. In the OLYMPUS measurement, 2.01 GeV electron and positron beams were directed through a hydrogen gas target internal to the DORIS storage ring at DESY. A toroidal magnetic spectrometer instrumented with drift chambers and time-of-flight scintillators detected elastically scattered leptons in coincidence with recoiling protons over a scattering angle range of ≈20° to 80°. The relative luminosity between the two beam species was monitored using tracking telescopes of interleaved gas electron multiplier and multiwire proportional chamber detectors at 12°, as well as symmetric Møller or Bhabha calorimeters at 1.29°. A total integrated luminosity of 4.5 fb^{-1} was collected. In the extraction of R_{2γ}, radiative effects were taken into account using a Monte Carlo generator to simulate the convolutions of internal bremsstrahlung with experiment-specific conditions such as detector acceptance and reconstruction efficiency. The resulting values of R_{2γ}, presented here for a wide range of virtual photon polarization 0.456<ε<0.978, are smaller than some hadronic two-photon exchange calculations predict, but are in reasonable agreement with a subtracted dispersion model and a phenomenological fit to the form factor data.
A
bstract
A comprehensive set of azimuthal single-spin and double-spin asymmetries in semi-inclusive leptoproduction of pions, charged kaons, protons, and antiprotons from transversely polarized ...protons is presented. These asymmetries include the previously published HERMES results on Collins and Sivers asymmetries, the analysis of which has been extended to include protons and antiprotons and also to an extraction in a three-dimensional kinematic binning and enlarged phase space. They are complemented by corresponding results for the remaining four single-spin and four double-spin asymmetries allowed in the one-photon-exchange approximation of the semi-inclusive deep-inelastic scattering process for target-polarization orientation perpendicular to the direction of the incoming lepton beam. Among those results, significant non-vanishing cos (
ϕ−ϕ
S
) modulations provide evidence for a sizable worm-gear (II) distribution,
g
1
T
q
x
p
T
2
. Most of the other modulations are found to be consistent with zero with the notable exception of large sin (
ϕ
S
) modulations for charged pions and
K
+
.
Background:
Regulatory T cells (Tregs) with stable FOXP3 expression are characterized by a specific demethylated region in the FOXP3 gene (Treg‐specific demethylated region, TSDR). The aim of this ...study was to analyse the influence of prenatal factors on cord blood Treg numbers, as detected by changes in the TSDR demethylation, and the subsequent risk for allergic diseases.
Methods:
Analyses were performed within the LINA study in blood samples from pregnant women (34th gestational week) and in cord blood (n = 346 mother–child pairs). Treg numbers were detected via DNA demethylation in the FOXP3 TSDR. At age 1, total and specific IgE was measured in children's blood. In addition, maternal cytokine production (Th1/Th2/Th17) was analysed. Exposure and disease outcomes were assessed by questionnaires.
Results:
Boys had lower Treg numbers compared with girls (P < 0.001). Parental atopy history, particularly maternal hay fever and paternal asthma were related to lower Treg numbers in cord blood (adj. MR = 0.81, 95% CI = 0.68–0.97; adj. MR = 0.60, 95% CI = 0.45–0.81). Maternal cytokines (IL‐13, IL‐17E and IFN‐γ) and maternal smoking/exposure to tobacco smoke during pregnancy were also associated with decreased cord blood Treg numbers (adj. MR = 0.89, 95% CI = 0.97–1.00). Children with lower Treg numbers at birth had a higher risk to develop atopic dermatitis (adj. OR = 1.55, 95% CI = 1.00–2.41) and sensitization to food allergens (adj. OR = 1.55, 95% CI = 1.06–2.25) during the first year of life.
Conclusions:
These results indicate that both genetic and environmental factors presumably influence the development of foetal Tregs. Low cord blood Treg numbers may predict early atopic dermatitis.
In taking a goal pursuit perspective into account, the present study examined associations between the context, process and outcome evaluation of an organizational health intervention (OHI) ...implemented within 29 teams in a hospital setting. In doing so, team climate for innovation as a context factor was measured at baseline (
= 529). Four to six weeks after baseline,
= 250 team representatives participated in a 4-day workshop. During the workshop employees formulated collective goals as action plans to be implemented in the nursing wards. Goal pursuit as a process factor was differentiated into (a) a motivational "goal setting" and (b) a volitional "goal striving" phase. The scale of outcome expectancy (measured after the fourth day of the workshop) was used as an indicator for the goal setting phase. For the operationalization of the goal striving phase, action plans were coded with regard to the proportion of formulated implementation intentions ("if-then plans"). After 6 months, the outcome of the intervention was measured on a retrospective impact scale (
= 385). The results of the multiple regression analysis and of the multilevel analysis show that both team climate and goal pursuit (outcome expectancy and the proportion of if-then plans) were positively related to the perceived impact of the intervention. Furthermore, the results show that the relationship between team climate and the impact of the intervention was mediated by outcome expectancy. The results highlight the contribution of goal theory within context-process-outcome research that leads to a better understanding of when and why OHIs are effective.
Post-viral mental health problems (MHP) in COVID-19 patients and survivors were anticipated already during early stages of this pandemic. We aimed to synthesize the prevalence of the anxiety, ...depression, post-traumatic and general distress domain associated with virus epidemics since 2002.
In this systematic review and meta-analysis, we searched PubMed, PsycINFO, and Embase from 2002 to April 14, 2021 for peer-reviewed studies reporting prevalence of MHP in adults with laboratory-confirmed or suspected SARS-CoV-1, H1N1, MERS-CoV, H7N9, Ebolavirus, or SARS-CoV-2 infection. We included studies that assessed post-viral MHP with validated and frequently used scales. A three-level random-effects meta-analysis for dependent effect sizes was conducted to account for multiple outcome reporting. We pooled MHP across all domains and separately by severity (above mild or moderate-to-severe) and by acute (one month), ongoing (one to three months), and post-illness stages (longer than three months). A meta-regression was conducted to test for moderating effects, particularly for exploring estimate differences between SARS-Cov-2 and previous pandemics and epidemics. PROSPERO registration: CRD42020194535.
We identified 59 studies including between 14 and 1002 participants and providing 187 prevalence estimates. MHP, in general, decreased from acute to post-illness from 46.3% to 38.8% and for mild and moderate-to-severe from 22.3% to 18.8%, respectively. We found no evidence of moderating effects except for non-random sampling and H1N1 showing higher prevalence. There was a non-significant trend towards lower MHP for SARS-CoV-2 compared to previous epidemics.
MHP prevalence estimates decreased over time but were still on a substantial level at post-illness. Post-viral mental health problems caused by SARS-CoV-2 could have been expected much earlier, given the previous post-viral sequelae.
Assessing fatty acid (FA) composition in relation to inflammatory markers can shed light on the role of different FA and their metabolism in low-grade inflammation. Existing exploratory studies in ...children are scarce, and findings inconsistent. We hence aim to analyse associations of FA with common inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6), in 10-year-old children.
Complete data were available for 958 participants from the 10-year follow-up of the LISAplus (Influence of Lifestyle-Related Factors on the Immune System and the Development of Allergies in Childhood plus the Influence of Traffic Emissions and Genetics) birth cohort study. FA composition was assessed in serum glycerophospholipids. Hs-CRP and IL-6 were categorised into three levels. Associations of FA with inflammatory markers were assessed using multinomial logistic regression, adjusting for potential confounders. Additionally, sex-stratified analyses were carried out.
FA exposures associated with significantly higher low-grade inflammation, as indicated by higher hs-CRP or IL-6 levels, included: palmitic acid (PA) (IL-6: P<0.001, 95% confidence interval: 1.30; 2.43), arachidonic acid (AA) (hs-CRP: P=0.002, 1.07; 1.31), n-6 highly unsaturated FA (HUFA) (hs-CRP: P=0.002, 1.06; 1.27), ratio of AA to linoleic acid (AA/LA) (hs-CRP: P<0.001, 1.16; 1.62) and total saturated FA (SFA) (IL-6: P<0.001, 1.77; 3.15). FA exposures associated with reduced levels of inflammatory markers included LA (hs-CRP: P=0.001, 0.84; 0.96; IL-6: P<0.001, 0.69; 0.90) and total polyunsaturated FA (PUFA) (IL-6: P<0.001, 0.57; 0.78).
These findings suggest that higher SFA and minor n-6 HUFA, namely PA and AA, are associated with increased low-grade inflammation in children, whereas the major dietary n-6 PUFA and total PUFA are associated with reduced inflammation. Elevated desaturase activity, estimated by the ratio AA/LA, may be associated with higher inflammation, particularly in boys.
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