Biomechanical forces promote embryonic haematopoiesis

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41(+)c-Kit(+) haematopoietic progenitor cells, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development

The transcriptional landscape of age in human peripheral blood

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.Peer reviewe

Renal tubular secretion in chronic kidney disease: description, determinants, and outcomes

Thesis (Ph.D.)--University of Washington, 2014Background The presence and severity of chronic kidney disease are currently assessed by glomerular filtration rate and urinary albumin excretion. Other kidney functions, such as proximal tubular secretion, are not typically quantified. Tubular secretion is capable of clearing metabolites from the blood more efficiently than filtration, suggesting important clinical consequences of secretion dysfunction. Measuring tubular secretion as an independent marker of kidney function may provide insight into kidney disease etiology and prediction of adverse outcomes. Methods We developed and validated mass spectrometry assays to measure hippurate and cinnamoylglycine, which are primarily cleared by renal tubular secretion. We estimated secretion function in a prospective cohort study of 298 CKD patients using timed urinary clearance of these molecules. We examined associations between renal secretion and estimated filtration (average of creatinine and urea clearance), related clinical characteristics, and mortality. Results Tubular secretion correlated with glomerular filtration, but considerable residual variability remained. Tubular secretion was significantly greater among men. For a given level of filtration function, diminished hippurate clearance was associated with increased risk of death (hazard ratio comparing low to high secretion groups: 2.3, 95% confidence interval: 1.1-4.7). Diminished cinnamoylglycine clearance, for a given level of filtration, was associated with increased risk of starting dialysis (hazard ratio comparing low to high secretion groups: 4.5, 95% confidence interval: 1.4-14.4). Conclusion Proximal tubular secretion function comprises a measurement of kidney function that modestly correlates with filtration function and may be associated with mortality and starting dialysis

Patient and Provider Factors Associated With American Indian and Alaska Native Adolescent Tobacco Use Screening

Introduction: Tobacco use is the leading behavioral cause of death among adults 25 years or older. American Indian (AI) and Alaska Native (AN) communities confront some of the highest rates of tobacco use and of its sequelae. Primary care–based screening of adolescents is an integral step in the reduction of tobacco use, yet remains virtually unstudied. We examined whether delivery of tobacco screening in primary care visits is associated with patient and provider characteristics among AI/AN adolescents. Methods: We used a cross-sectional analysis to examine tobacco screening among 4757 adolescent AI/AN patients served by 56 primary care providers at a large tribally managed health system between October 1, 2011 and May 31, 2014. Screening prevalence was examined in association with categorical patient characteristics (gender, age, clinic visited, insurance coverage) and provider characteristics (gender, age, tenure) using multilevel logistic regressions with individual provider identity as the nesting variable. Results: Thirty-seven percent of eligible patients were screened. Gender of both providers and patients was associated with screening. Male providers delivered screening more often than female providers (odds ratio [OR] 1.6, 95% confidence interval [CI] 0.7-3.9). Male patients had 20% lower odds of screening receipt (OR 0.8, 95% CI 0.7-0.9) than female patients, independent of patient age and provider characteristics. Individual provider identity significantly contributed to variability in the mixed-effects model (variance component 2.2; 95% CI 1.4-3.4), suggesting individual provider effect. Conclusions: Low tobacco screening delivery by female providers and the low receipt of screening among younger, male patients may identify targets for screening interventions

Gene expression in thiazide diuretic or statin users in relation to incident type 2 diabetes.

Thiazide diuretics and statins are used to improve cardiovascular outcomes, but may also cause type 2 diabetes (T2DM), although mechanisms are unknown. Gene expression studies may facilitate understanding of these associations. Participants from ongoing population-based studies were sampled for these longitudinal studies of peripheral blood microarray gene expression, and followed to incident diabetes. All sampled subjects were statin or thiazide users. Those who developed diabetes during follow-up comprised cases (44 thiazide users; 19 statin users), and were matched to drug-using controls who did not develop diabetes on several factors. Supervised normalization, surrogate variable analyses removed technical bias and confounding. Differentially-expressed genes were those with a false discovery rate Q-value<0.05. Among thiazide users, diabetes cases had significantly different expression of CCL14 (down-regulated 6%, Q-value=0.0257), compared with controls. Among statin users, diabetes cases had marginal but insignificantly different expression of ZNF532 (up-regulated 15%, Q-value=0.0584), CXORF21 (up-regulated 11%, Q-value=0.0584), and ZNHIT3 (up-regulated 19%, Q-value=0.0959), compared with controls. These genes comprise potential targets for future expression or mechanistic research on medication-related diabetes development