The sequences of 150,119 genomes in the UK Biobank

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data(1,2). Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank(3). This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation

MiR-126 and miR-126* regulate shear-resistant firm leukocyte adhesion to human brain endothelium

Leukocyte adhesion to brain endothelial cells, the blood-brain barrier main component, is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Leukocyte adhesion is mediated mainly by selectins, cell adhesion molecules and chemokines induced by pro-inflammatory cytokines such as TNFα and IFNγ, but the regulation of this process is not fully clear. This study investigated the regulation of firm leukocyte adhesion to human brain endothelium by two different brain endothelial microRNAs (miRs), miR-126 and miR-126*, that are downregulated by TNFα and IFNγ in a human brain endothelial cell line, hCMEC/D3. Using a leukocyte adhesion in vitro assay under shear forces mimicking blood flow, we observed that reduction of endothelial miR-126 and miR-126* enhanced firm monocyte and T cell adhesion to hCMEC/D3 cells, whereas their increased expression partially prevented THP1, Jurkat and primary MS patient-derived PBMC firm adhesion. Furthermore, we observed that miR-126* and miR-126 downregulation increased E-selectin and VCAM1, respectively, while miR-126 overexpression reduced VCAM1 and CCL2 expression by hCMEC/D3 cells, suggesting that these miRs regulate leukocyte adhesion by modulating the expression of adhesion-associated endothelial mRNA targets. Hence, human brain endothelial miR-126 and miR-126* could be used as a therapeutic tool to reduce leukocyte adhesion and thus reduce neuroinflammation

Spiritual well-being and quality of life among Icelanders receiving palliative care: data from Icelandic pilot-testing of a provisional measure of spiritual well-being from the European Organisation for Research and Treatment of Cancer.

To access publisher's full text version of this article click on the hyperlink below.Palliative care focuses on improving quality of life (QoL). This study examined the feasibility of the Icelandic version of a provisional European Organisation for Research and Treatment of Cancer (EORTC) measure of spiritual well-being (SWB), and explored the relationship between SWB and QoL for palliative care patients in Iceland. Instruments from the EORTC were used: the provisional measure of SWB, which was undergoing pilot-testing in Iceland, and the EORTC QLQ C15-PAL. The correlation between scores was examined and descriptive statistics were used. Structured interviews explored feasibility. Thirty persons participated with average age 72 years. Belief in God or a higher power had the mean 3.33 on a 1-4 scale and the mean for overall SWB was 5.73 on a 1-7 scale. The mean score for global health/QoL was 59.4, physical functioning 48.5 and emotional functioning 78.9 on a 0-100 scale. Overall QoL was positively correlated with SWB showing r(30) = 0.386, P = 0.035. The participants found that answering the provisional EORTC QLQ-SWB prompted an emotional response and took the opportunity to discuss the subject. The provisional SWB measure was found relevant for the Icelandic context, and the study indicates that SWB and QoL are closely connected.Science Fund of Landspitali - The National University Hospital of Iceland Science Fund of The Icelandic Pastoral Associatio

Economic conditions, hypertension, and cardiovascular disease: analysis of the Icelandic economic collapse

Previous research has found a positive short-term relationship between the 2008 collapse and hypertension in Icelandic males. With Iceland's economy experiencing a phase of economic recovery, an opportunity to pursue a longer-term analysis of the collapse has emerged. Using data from a nationally representative sample, fixed-effect estimations and mediation analyses were performed to explore the relationship between the Icelandic economic collapse in 2008 and the longer-term impact on hypertension and cardiovascular health. A sensitivity analysis was carried out with pooled logit models estimated as well as an alternative dependent variable. Our attrition analysis revealed that results for cardiovascular diseases were affected by attrition, but not results from estimations on the relationship between the economic crisis and hypertension. When compared to the boom year 2007, our results point to an increased probability of Icelandic women having hypertension in the year 2012, when the Icelandic economy had recovered substantially from the economic collapse in 2008. This represents a deviation from pre-crisis trends, thus suggesting a true economic-recovery impact on hypertension.The project was funded by the Icelandic Research Fund (IRF grant number 130611-052) and The University of Iceland Eimskip Fund. The data collection was financed and carried out by the Directorate of Health Iceland (and formerly the Public Health Institute of Iceland). The authors would like to thank the Directorate for access to the data.Peer Reviewe

Soft stimulation treatment of geothermal well RV-43 to meet the growing heat demand of Reykjavik

Reykjavik is almost entirely heated by geothermal energy. Yet, recent growth of the city significantly increased the heat demand. Past experiences in Iceland's capital region showed that hydraulic stimulation of existing geothermal wells is suited to improve hydraulic performance and energy supply. However, fluid injection may also trigger felt or even damaging earthquakes, which are of concern in populated areas and pose a significant risk to stimulation operations. Consequently, soft stimulation concepts have been developed to increase geothermal well performance while minimizing environmental effects such as induced seismicity. In a demonstration project of hydraulic soft stimulation in October 2019, more than 20.000 m³ of water were injected into well RV-43 in Reykjavik in multiple stages and with different injection schemes. The hydraulic performance of the well was improved without inducing felt seismicity. An a priori seismic risk assessment was conducted and for the first time the risk was continuously updated by an adaptive traffic light system supported by a sophisticated realtime microseismic monitoring. Our results confirm that it is possible to improve the performance of geothermal wells in Reykjavik and worldwide with acceptable technical, economic, and environmental risks. Here we provide an overview of the entire stimulation project including site description, stimulation design, zonal isolation, logging, seismic risk assessment and mitigation measures, realtime seismic, hydraulic and chemical monitoring, and stimulation results and challenges

MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation

Endothelial cells in different microvascular segments of the kidney have diverse functions and exhibit differential responsiveness to disease stimuli. The responsible molecular mechanisms are largely unknown. We previously showed that during hemorrhagic shock, VCAM-1 protein was expressed primarily in extraglomerular compartments of the kidney, while E-selectin protein was highly induced in glomeruli only (van Meurs M, Wulfert FM, Knol AJ, de Haes A, Houwertjes M, Aarts LPHJ, Molema G. Shock 29: 291-299, 2008). Here, we investigated the molecular control of expression of these endothelial cell adhesion molecules in mouse models of renal inflammation. Microvascular segment-specific responses to the induction of anti-glomerular basement membrane (anti-GBM), glomerulonephritis and systemic TNF-α treatment showed that E-selectin expression was transcriptionally regulated, with high E-selectin mRNA and protein levels preferentially expressed in the glomerular compartment. In contrast, VCAM-1 mRNA expression was increased in both arterioles and glomeruli, while VCAM-1 protein expression was limited in the glomeruli. These high VCAM-1 mRNA/low VCAM-1 protein levels were accompanied by high local microRNA (miR)-126 and Egfl7 levels, as well as higher Ets1 levels compared with arteriolar expression levels. Using miR-reporter constructs, the functional activity of miR-126 in glomerular endothelial cells could be demonstrated. Moreover, in vivo knockdown of miR-126 function unleashed VCAM-1 protein expression in the glomeruli upon inflammatory challenge. These data imply that miR-126 has a major role in the segmental, heterogenic response of renal microvascular endothelial cells to systemic inflammatory stimuli. © 2012 the American Physiological Society.link_to_subscribed_fulltex

Anti-VCAM-1 and Anti-E-selectin SAINT-O-Somes for Selective Delivery of siRNA into Inflammation-Activated Primary Endothelial Cells

<p>Activated endothelial cells play a pivotal role in the pathology of inflammatory diseases and present a rational target for therapeutic intervention by endothelial specific delivery of short interfering RNAs (siRNA). This study demonstrates the potential of the recently developed new generation of liposomes based on cationic amphiphile SAINT C18 (1-methyl-4-(cis-9-dioleyl)methyl-pyridinium-chloride) for functional and selective delivery of siRNA into inflamed primary endothelial cells. To create specificity for inflamed endothelial cells, these so-called SAINT-O-Somes were harnessed with antibodies against vascular cell adhesion protein 1 (VCAM-1) or respectively E-selectin and tested in TNF-alpha activated primary endothelial cells from venous and aortic vascular beds. Both targeted SAINT-O-Sornes carrying siRNA against the endothelial gene VE-cadherin specifically downregulated its target rnRNA and protein without exerting cellular toxicity. SAINT-O-Somes formulated with siRNA formed small particles (106 nm) with a 71% siRNA encapsulation efficiency. SAINT-O-Somes were stable in the presence of serum at 37 C, protected siRNA from degradation by serum RNases, and after iv injection displayed pharmacokinetic comparable to conventional long circulating liposornes. These anti-VCAM-1 and anti-E-selectin SAINT-O-Somes are thus a novel drug delivery system that can achieve specific and effective delivery of siRNA into inflamed primary endothelial cells and have physicochemical features that comply with in vivo application demands.</p>