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It is not fully understood why COVID-19 is typically milder in children 1-3 . Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children., (© 2021. The Author(s).)

Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time points ranging from 6.5 to 8.5 days post-fertilization. We construct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we use single-cell profiling to show that Tal1 -/- chimeric embryos display defects in early mesoderm diversification, and we thus demonstrate how combining temporal and transcriptional information can illuminate gene function. Together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development, as well as a roadmap for the optimization of in vitro differentiation protocols for regenerative medicine.

Although many aspects of blood production are well understood, the spatial organization of myeloid differentiation in the bone marrow remains unknown. Here we use imaging to track granulocyte/macrophage progenitor (GMP) behaviour in mice during emergency and leukaemic myelopoiesis. In the steady state, we find individual GMPs scattered throughout the bone marrow. During regeneration, we observe expanding GMP patches forming defined GMP clusters, which, in turn, locally differentiate into granulocytes. The timed release of important bone marrow niche signals (SCF, IL-1β, G-CSF, TGFβ and CXCL4) and activation of an inducible Irf8 and β-catenin progenitor self-renewal network control the transient formation of regenerating GMP clusters. In leukaemia, we show that GMP clusters are constantly produced owing to persistent activation of the self-renewal network and a lack of termination cytokines that normally restore haematopoietic stem-cell quiescence. Our results uncover a previously unrecognized dynamic behaviour of GMPs in situ, which tunes emergency myelopoiesis and is hijacked in leukaemia.

The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.

Increasing experimental evidence, including recently developed animal models support a causal role for uric acid in the development of hypertension. However, it is not clear whether serum uric acid levels are independently associated with the long-term incidence of hypertension. We examined the association between serum uric acid levels and 10-year incidence of hypertension in a population-based cohort study based in Beaver Dam city and township, Wisconsin, US. We studied 2520 hypertension-free individuals (56.3% women, age: 43-84 years, 98% Caucasian) at the baseline examination (1988-1990). The main outcome of interest was hypertension (systolic blood pressure (BP) of 140 mm Hg or higher, diastolic BP 90 mm Hg or higher, or combination of self-reported high BP diagnosis and use of antihypertensive medications) incidence over 10 years among baseline normotensive individuals. Nine hundred and fifty-six individuals developed hypertension over a 10-year follow-up period. The relative risk (RR) (95% confidence intervals (CI)) of incident hypertension increased in a dose-dependent manner (P-trend < 0.05 in all models) with increasing uric acid quartiles. Multivariable RR (95% CI) comparing the highest quartile of serum uric acid (> or =390 micromol/l) to the lowest quartile (< or =260 micromol/l) was 1.65 (1.41-1.93). This association persisted in subgroup analyses by categories of smoking, alcohol intake, body mass index, baseline blood pressure and estimated glomerular filtration rate (GFR). In conclusion, increasing quartiles of serum uric acid was associated with 10-year incidence of hypertension independent of smoking, alcohol intake and baseline kidney function suggesting an independent positive association between serum uric acid levels and hypertension development among community-dwelling older adults.

Objective: To examine associations between weight gain and changes in blood pressure and the incidence of hypertension in four ethnicity-gender groups., Design: Longitudinal closed cohort studied over an average of 6 y., Subjects: Total of 9309 white and African-American men and women 45-64 y of age who participated in the Atherosclerosis Risk in Communities (ARIC) Study., Methods: Weight and blood pressure were measured at baseline and after an average of 3 and 6 y of follow-up. Proportional hazard models with weight gain as a time-dependent variable were used to examine the association between weight gain and changes in blood pressure and hypertension. Multivariate models were used with baseline SBP, DBP, age, BMI, height, WHR, smoking, physical activity, education, caloric intake, fat intake and study center as covariates., Results: Weight gain was associated with increases in SBP and DBP in all groups. Hazard ratios for hypertension associated with 1 kg annual weight gain were 1.36 (95% CI, 1.29, 1.45) in white women, 1.12 (95% CI, 1.03, 1.21) in African-American women, 1.35 (95% CI, 1.27, 1.43) in white men and 1.43 (95% CI, 1.27,1.61) in African-American men., Conclusion: Weight gain was associated with increased blood pressure and increased incidence of hypertension. The association was weaker among African-American women compared to other ethnicity-gender groups.

The Caribbean nation of Cuba is comprised of over 10 million persons who trace their ancestry primarily to Africa and Spain. To date, little data on blood pressure (BP) or hypertension prevalence from Cuba have appeared in English language journals. Because the current government has pursued an active policy of reducing social differentiation on the basis of ethnic origin, Cuba provides an important population laboratory from which to advance the understanding of black-white differences in BP and hypertension. The authors conducted a population-based random sample among adults (aged > 15 years) in the city of Cienfuegos. Overall response rate was 95%, yielding 1633 participants who provided BP readings, self-reported racial group, demographic information, and treatment status. Overall prevalence of hypertension (SBP > or = 140 mm Hg or DBP > or = 90 mm Hg or currently treated) was 44% (46% among blacks and 43% whites; P = 0.19). Excess BP among black subjects was reduced slightly by excluding those under treatment, but attained statistical significance after adjustment for sex and age (P = 0.01). The black-white difference was small, however, relative to that observed in the United States. Racial differences in treatment status and control were also observed. Although there remains a difference in socioeconomic profile between those of African and of European origin in Cuba, this has decreased over recent decades. In the United States, the greater magnitude of social differentiation parallels a greater relative risk of BP elevation among blacks, suggesting that social, economic and psychological factors may play an important role in the observed racial gap in cardiovascular risk.