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- Fresard, Laure, et al.
(författare)
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Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts
- 2019
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Ingår i: Nature Medicine. - : NATURE PUBLISHING GROUP. - 1078-8956 .- 1546-170X. ; 25:6, s. 911-919
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Tidskriftsartikel (refereegranskat)abstract
- It is estimated that 350 million individuals worldwide suffer from rare diseases, which are predominantly caused by mutation in a single gene(1). The current molecular diagnostic rate is estimated at 50%, with whole-exome sequencing (WES) among the most successful approaches(2-5). For patients in whom WES is uninformative, RNA sequencing (RNA-seq) has shown diagnostic utility in specific tissues and diseases(6-8). This includes muscle biopsies from patients with undiagnosed rare muscle disorders(6,9), and cultured fibroblasts from patients with mitochondrial disorders(7). However, for many individuals, biopsies are not performed for clinical care, and tissues are difficult to access. We sought to assess the utility of RNA-seq from blood as a diagnostic tool for rare diseases of different pathophysiologies. We generated whole-blood RNA-seq from 94 individuals with undiagnosed rare diseases spanning 16 diverse disease categories. We developed a robust approach to compare data from these individuals with large sets of RNA-seq data for controls (n = 1,594 unrelated controls and n = 49 family members) and demonstrated the impacts of expression, splicing, gene and variant filtering strategies on disease gene identification. Across our cohort, we observed that RNA-seq yields a 7.5% diagnostic rate, and an additional 16.7% with improved candidate gene resolution.
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- Geach, J.E., et al.
(författare)
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The SCUBA-2 Cosmology Legacy Survey: 850 μm maps, catalogues and number counts
- 2017
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 465:2, s. 1789-1806
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Tidskriftsartikel (refereegranskat)abstract
- We present a catalogue of similar to 3000 submillimetre sources detected (>= 3.5 sigma) at 850 mu m over similar to 5 deg(2) surveyed as part of the James Clerk Maxwell Telescope (JCMT) SCUBA-2 Cosmology Legacy Survey (S2CLS). This is the largest survey of its kind at 850 mu m, increasing the sample size of 850 mu m selected submillimetre galaxies by an order of magnitude. The wide 850 mu m survey component of S2CLS covers the extragalactic fields: UKIDSS-UDS, COSMOS, Akari-NEP, Extended Groth Strip, Lockman Hole North, SSA22 and GOODS-North. The average 1s depth of S2CLS is 1.2 mJy beam(-1), approaching the SCUBA-2 850 mu m confusion limit, which we determine to be sigma(c) approximate to 0.8 mJy beam(-1). We measure the 850 mu m number counts, reducing the Poisson errors on the differential counts to approximately 4 per cent at S-850 approximate to 3 mJy. With several independent fields, we investigate field-to-field variance, finding that the number counts on 0.5 degrees-1 degrees scales are generally within 50 per cent of the S2CLS mean for S-850 > 3 mJy, with scatter consistent with the Poisson and estimated cosmic variance uncertainties, although there is a marginal (2 sigma) density enhancement in GOODS-North. The observed counts are in reasonable agreement with recent phenomenological and semi-analytic models, although determining the shape of the faint-end slope (S-850 < 3 mJy) remains a key test. The large solid angle of S2CLS allows us to measure the bright-end counts: at S-850 > 10 mJy there are approximately 10 sources per square degree, and we detect the distinctive up-turn in the number counts indicative of the detection of local sources of 850 mu m emission
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- Geach, J.E., et al.
(författare)
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The SCUBA-2 Cosmology Legacy Survey: blank-field number counts of 450-mu m-selected galaxies and their contribution to the cosmic infrared background
- 2013
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 432:1, s. 53-61
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Tidskriftsartikel (refereegranskat)abstract
- The first deep blank-field 450 mu m map (1 sigma approximate to 1.3 mJy) from the Submillimetre Common-User Bolometer Array-2 SCUBA-2 Cosmology Legacy Survey (S2CLS), conducted with the James Clerk Maxwell Telescope (JCMT) is presented. Our map covers 140 arcmin(2) of the Cosmological Evolution Survey field, in the footprint of the Hubble Space Telescope (HST) Cosmic Assembly Near-Infrared Deep Extragalactic Legacy Survey. Using 60 submillimetre galaxies detected at >= 3.75s, we evaluate the number counts of 450-mu m-selected galaxies with flux densities S-450 > 5 mJy. The 8 arcsec JCMT beam and high sensitivity of SCUBA-2 now make it possible to directly resolve a larger fraction of the cosmic infrared background (CIB, peaking at. similar to 200 mu m) into the individual galaxies responsible for its emission than has previously been possible at this wavelength. At S450 > 5 mJy, we resolve (7.4 +/- 0.7) x 10(-2) MJy sr(-1) of the CIB at 450 mu m (equivalent to 16 +/- 7 per cent of the absolute brightness measured by the Cosmic Background Explorer at this wavelength) into point sources. A further similar to 40 per cent of the CIB can be recovered through a statistical stack of 24 mu m emitters in this field, indicating that the majority (approximate to 60 per cent) of the CIB at 450 mu m is emitted by galaxies with S450 > 2 mJy. The average redshift of 450 mu m emitters identified with an optical/near-infrared counterpart is estimated to be = 1.3, implying that the galaxies in the sample are in the ultraluminous class (LIR approximate to 1.1 x 1012 L approximate to). If the galaxies contributing to the statistical stack lie at similar redshifts, then the majority of the CIB at 450 mu m is emitted by galaxies in the luminous infrared galaxy (LIRG) class with LIR > 3.6 x 1011 L-circle dot.
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- Tiegs, Scott D., et al.
(författare)
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Global patterns and drivers of ecosystem functioning in rivers and riparian zones
- 2019
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Ingår i: Science Advances. - Washington : American Association of Advancement in Science. - 2375-2548. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth's biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented "next-generation biomonitoring" by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
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- Melvin, Audrey, et al.
(författare)
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GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement.
- 2020
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 105:5, s. 1427-1434
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Tidskriftsartikel (refereegranskat)abstract
- GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15.To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels.We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001.GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.
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