Integrated analysis of environmental and genetic influences on cord blood DNA methylation in new-borns

Epigenetic processes, including DNA methylation (DNAm), are among the mechanisms allowing integration of genetic and environmental factors to shape cellular function. While many studies have investigated either environmental or genetic contributions to DNAm, few have assessed their integrated effects. Here we examine the relative contributions of prenatal environmental factors and genotype on DNA methylation in neonatal blood at variably methylated regions (VMRs) in 4 independent cohorts (overall n = 2365). We use Akaike’s information criterion to test which factors best explain variability of methylation in the cohort-specific VMRs: several prenatal environmental factors (E), genotypes in cis (G), or their additive (G + E) or interaction (GxE) effects. Genetic and environmental factors in combination best explain DNAm at the majority of VMRs. The CpGs best explained by either G, G + E or GxE are functionally distinct. The enrichment of genetic variants from GxE models in GWAS for complex disorders supports their importance for disease risk

Inhibition of the human chemokine receptor CCR5 by variecolin and variecolol and isolation of four new variecolin analogues, emericolins A-D, from Emericella aurantiobrunnea

10.1021/np049844cJournal of Natural Products67101681-1684JNPR

What hinders pulmonary gas exchange and changes distribution of ventilation in immobilized white rhinoceroses (Ceratotherium simum) in lateral recumbency?

This study used electrical impedance tomography (EIT) measurements of regional ventilation and perfusion to elucidate the reasons for severe gas exchange impairment reported in rhinoceroses during opioid-induced immobilization. EIT values were compared with standard monitoring parameters to establish a new monitoring tool for conservational immobilization and future treatment options. Six male white rhinoceroses were immobilized using etorphine, and EIT ventilation variables, venous admixture, and dead space were measured 30, 40, and 50 min after becoming recumbent in lateral position. Pulmonary perfusion mapping using impedance-enhanced EIT was performed at the end of the study period. The measured impedance (∆Z) by EIT was compared between pulmonary regions using mixed linear models. Measurements of regional ventilation and perfusion revealed a pronounced disproportional shift of ventilation and perfusion toward the nondependent lung. Overall, the dependent lung was minimally ventilated and perfused, but remained aerated with minimal detectable lung collapse. Perfusion was found primarily around the hilum of the nondependent lung and was minimal in the periphery of the nondependent and the entire dependent lung. These shifts can explain the high amount of venous admixture and physiological dead space found in this study. Breath holding redistributed ventilation toward dependent and ventral lung areas. The findings of this study reveal important pathophysiological insights into the changes in lung ventilation and perfusion during immobilization of white rhinoceroses. These novel insights might induce a search for better therapeutic options and is establishing EIT as a promising monitoring tool for large animals in the field

Human haematopoietic stem cell lineage commitment is a continuous process

Blood formation is believed to occur through stepwise progression of haematopoietic stem cells (HSCs) following a tree-like hierarchy of oligo-, bi- and unipotent progenitors. However, this model is based on the analysis of predefined flow-sorted cell populations. Here we integrated flow cytometric, transcriptomic and functional data at single-cell resolution to quantitatively map early differentiation of human HSCs towards lineage commitment. During homeostasis, individual HSCs gradually acquire lineage biases along multiple directions without passing through discrete hierarchically organized progenitor populations. Instead, unilineage-restricted cells emerge directly from a 'continuum of low-primed undifferentiated haematopoietic stem and progenitor cells' (CLOUD-HSPCs). Distinct gene expression modules operate in a combinatorial manner to control stemness, early lineage priming and the subsequent progression into all major branches of haematopoiesis. These data reveal a continuous landscape of human steady-state haematopoiesis downstream of HSCs and provide a basis for the understanding of haematopoietic malignancies