Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 – 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human host cells via angiotensin-converting enzyme 2 (ACE2) and causes coronavirus disease 2019 (COVID-19). Here, through a genome-wide association study, we identify a variant (rs190509934, minor allele frequency 0.2–2%) that downregulates ACE2 expression by 37% (P = 2.7 × 10−8) and reduces the risk of SARS-CoV-2 infection by 40% (odds ratio = 0.60, P = 4.5 × 10−13), providing human genetic evidence that ACE2 expression levels influence COVID-19 risk. We also replicate the associations of six previously reported risk variants, of which four were further associated with worse outcomes in individuals infected with the virus (in/near LZTFL1, MHC, DPP9 and IFNAR2). Lastly, we show that common variants define a risk score that is strongly associated with severe disease among cases and modestly improves the prediction of disease severity relative to demographic and clinical factors alone.

BackgroundChildren often need support in health decision-making. The objective of this study was to review characteristics and effectiveness of interventions that support health decision-making of children.MethodsA systematic review. Electronic databases (PubMed, the Cochrane Library, Web of Science, Scopus, ProQuest Dissertations and Theses, CINAHL, PsycINFO, MEDLINE, and EMBASE) were searched from inception until March 2012. Two independent reviewers screened eligibility: a) intervention studies; b) involved supporting children (≤18 years) considering health-related decision(s); and c) measured decision quality or decision-making process outcomes. Data extraction and quality appraisal were conducted by one author and verified by another using a standardized data extraction form. Quality appraisal was based on the Cochrane Risk of Bias tool.ResultsOf 4313 citations, 5 studies were eligible. Interventions focused on supporting decisions about risk behaviors (n = 3), psycho-educational services (n = 1), and end of life (n = 1). Two of 5 studies had statistically significant findings: i) compared to attention placebo, decision coaching alone increased values congruence between child and parent, and child satisfaction with decision-making process (lower risk of bias); ii) compared to no intervention, a workshop with weekly assignments increased overall decision-making quality (higher risk of bias).ConclusionsFew studies have focused on interventions to support children’s participation in decisions about their health. More research is needed to determine effective methods for supporting children’s health decision-making.

The involvement of genes controlling embryonic processes in the etiology of diseases often escapes attention because of the focus given to their inherent developmental role. Hoxa5 belongs to the Hox gene family encoding transcription factors known for their role in skeletal patterning. Hoxa5 is required for embryonic respiratory tract morphogenesis. We now show that the loss of Hoxa5 function has severe repercussions on postnatal lung development. Hoxa5؊/؊ lungs present an emphysema-like morphology because of impaired alveogenesis. Chronic inflammation characteristics, including goblet cell hyperplasia, mucus hypersecretion, and recruitment of inflammatory cells, were also observed. Altered cell specification during lung morphogenesis triggered goblet cell anomalies. In addition, the defective motility of alveolar myofibroblast precursors in the embryonic lung led to the mispositioning of the alveolar myofibroblasts and to abnormal elastin deposition postnatally. Both goblet cell hyperplasia and elastic fiber abnormalities contributed to the chronic physiopathological features of Hoxa5 ؊/؊ lungs. They constituted an attractive stimulus to recruit activated macrophages that in turn generated a positive feedback loop that perpetuated macrophage accumulation in the lung. The present work corroborates the notion that altered Hox gene expression may predispose to lung pathologies. Lung morphogenesis relies on finely orchestrated processes that initiate from the outpocketing and the elongation of the foregut endoderm into the surrounding mesenchyme. The lung bud then branches extensively giving rise to saccules that expend and subdivide to ultimately produce alveoli. In the mouse, the main stem bronchi form at approximately embryonic day (E) 9.5, and ramification organized by signaling centers shapes the respiratory tree during the pseudoglandular period that extends from E14.0 to E16.5. At late gestational stages, saccules are found at the end of each terminus of the pulmonary tree. The last step of lung morphogenesis occurs between postnatal day (P) 5 and P30, and it aims at multiplying the respiratory surface for vital gas exchanges after birth by modifying the distal lung architecture through the process of alveogenesis. During each step of lung development, the concerted action of transcriptional regulators, signaling molecules, their associated receptors and downstream effectors governs branching morphogenesis and lung maturation by integrating cellular proliferation, differentiation, apoptosis, and migration.

Embryonic germ cell migration is a vital component of the germline lifecycle. The translocation of germ cells from the place of origin to the developing somatic gonad involves several processes including passive movements with underlying tissues, transepithelial migration, cell adhesion dynamics, the establishment of environmental guidance cues and the ability to sustain directed migration. How germ cells accomplish these feats in established model organisms will be discussed in this review, with a focus on recent discoveries and themes conserved across species.

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Mendenhall AR, LeBlanc MG, Mohan DP, Padilla PA. Reduction in ovulation or male sex phenotype increases long-term anoxia survival in a daf-16-independent manner in Caenorhabditis elegans. Physiol Genomics 36: 167-178, 2009. First published December 2, 2008 doi:10.1152/physiolgenomics.90278.2008.-Identifying genotypes and phenotypes that enhance an organism's ability to survive stress is of interest. We used Caenorhabditis elegans mutants, RNA interference (RNAi), and the chemical 5-fluorodeoxyuridine (FUDR) to test the hypothesis that a reduction in progeny would increase oxygen deprivation (anoxia) survival. In the hermaphrodite gonad, germ line processes such as spermatogenesis and oogenesis can be simultaneously as well as independently disrupted by genetic mutations. We analyzed genetic mutants [glp-1(q158), glp-4(bn2ts), plc-1(rx1), ksr-1(ku68), fog-2(q71), fem-3(q20), spe-9(hc52ts), fer-15(hc15ts)] with reduced progeny production due to various reproductive defects. Furthermore, we used RNAi to inhibit the function of gene products in the RTK/Ras/MAPK signaling pathway, which is known to be involved in a variety of developmental processes including gonad function. We determined that reduced progeny production or complete sterility enhanced anoxia survival except in the case of sterile hermaphrodites [spe-9(hc52ts), fer-15(hc15ts)] undergoing oocyte maturation and ovulation as exhibited by the presence of laid unfertilized oocytes. Furthermore, the fog-2(q71) long-term anoxia survival phenotype was suppressed when oocyte maturation and ovulation were induced by mating with males that have functional or nonfunctional sperm. The mutants with a reduced progeny production survive long-term anoxia in a daf-16-and hif-1-independent manner. Finally, we determined that wild-type males were able to survive long-term anoxia in a daf-16-independent manner. Together, these results suggest that the insulin signaling pathway is not the only mechanism to survive oxygen deprivation and that altering gonad function, in particular oocyte maturation and ovulation, leads to a physiological state conducive for oxygen deprivation survival. oxygen deprivation; germ line; insulin-like signaling; stress; anoxia METAZOANS INHABITING aquatic or subterranean ecosystems have evolved mechanisms to survive changes in oxygen levels. For example, repression of energy-requiring processes or reallocation of metabolism increases oxygen deprivation survival (21). Although most terrestrial organisms live in environments where the oxygen tension does not fluctuate much, they do have the capacity to sense and respond to oxygen deprivation. In humans, oxygen deprivation is central to various health conditions including myocardial infarction, stroke, blood loss, pulmonary disorders, and solid tumor progression (37, 62). Thus identifying the molecular mechanisms that govern metazoan response to and survival of oxygen deprivation is of great interest.Oxygen deprivation tolerance spans across various phyla (7,20,53,55,68). The comparison of oxygen d...

A 485 cm sediment core from a lake unoffcially called JR01, Boothia Peninsula, Nunavut, Canada, yielded a high-resolution diatom record documenting environmental change in the mid-arctic. Five radiocarbon dates provided the chronology. Changes in diatom composition and sediment character istics indicated distinct shifts in the Holocene climate. A more diverse and productive diatom flora implies warmer temperatures in the middle Holocene. A subsequent complete shift in diatom composition to a predominantly Fragilaria sensu lato flora and a reduction in diversity and production suggests cooler climates in this region after 4600cal. BP. Smaller-scale climatic fluctuations, such as the‘Little Ice Age’ (LIA, 600–150 cal. BP) and the‘Mediaeval Warm Period’ (MWP, 1150–600 cal. BP), caused shifts in the diatom flora and production. Subtle shifts in floristic diversity within the LIA may reflect climatic variability at a century scale. A gradual shift to a more diverse and productive flora in the last 150 years suggests a response to the recent warming trend.