| 1. |
- Wilman, H. R., et al.
(författare)
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Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 71:3, s. 594-602
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart disease. We identified 3 genetic variants that are linked to an increased risk of developing higher liver iron content. We show that the same genetic variants are linked to higher risk of many diseases, but they may also be associated with some health advantages. Finally, we use genetic variants associated with waist-to-hip ratio as a tool to show that central obesity is causally associated with increased liver iron content.
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| 2. |
- Chagas, Vinicius S., et al.
(författare)
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RTNduals an R/Bioconductor package for analysis of co-regulation and inference of dual regulons
- 2019
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 35:24, s. 5357-5358
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Transcription factors (TFs) are key regulators of gene expression, and can activate or repress multiple target genes, forming regulatory units, or regulons. Understanding downstream effects of these regulators includes evaluating how TFs cooperate or compete within regulatory networks. Here we present RTNduals, an R/Bioconductor package that implements a general method for analyzing pairs of regulons. RESULTS: RTNduals identifies a dual regulon when the number of targets shared between a pair of regulators is statistically significant. The package extends the RTN (Reconstruction of Transcriptional Networks) package, and uses RTN transcriptional networks to identify significant co-regulatory associations between regulons. The Supplementary Information reports two case studies for TFs using the METABRIC and TCGA breast cancer cohorts. AVAILABILITY AND IMPLEMENTATION: RTNduals is written in the R language, and is available from the Bioconductor project at http://bioconductor.org/packages/RTNduals/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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| 3. |
- Gallagher, S. J., et al.
(författare)
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The enigma of rare Quaternary oolites in the Indian and Pacific Oceans : A result of global oceanographic physicochemical conditions or a sampling bias?
- 2018
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Ingår i: Quaternary Science Reviews. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0277-3791 .- 1873-457X. ; 200, s. 114-122
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Tidskriftsartikel (refereegranskat)abstract
- Marine ooids are iconic indicators of shallow seawater carbonate saturation state, and their formation has traditionally been ascribed to physicochemical processes. The Indo-Pacific stands out as a region devoid of oolites, particularly during the Quaternary: the "ooid enigma". Here we present results from recent coring by the International Ocean Discovery Program (IODP Expedition 356) off west Australia that shows that ooid horizons are common in Pleistocene strata up to 730,000 years old. Extensive "ooid factories" were created due to the presence of long-lived tidally influenced flat topped tropical platforms suitable for intermittent ooid accretion over hundreds to thousands of years during highstands and times of lower sea level. This work suggests marine ooids may actually be more common in Indo-Pacific than previously reported. Past global ocean alkalinity was elevated during Pleistocene glacial periods and continental climate was generally more arid in the Indo-Pacific region compared to interglacials and the Holocene. Therefore, increased aridity associated with higher alkalinity conditions during the glacials facilitated ooid precipitation on adjacent tropical carbonate platforms particularly offshore from arid Australia. This confluence of factors suggests that more "ooid factories" may be encountered by further coring Indo-Pacific regions with Pleistocene flat long-lived carbonate shelves. However, Indo-Pacific Quaternary ooid occurrences outside Australia are rare, suggesting that the Northwest Shelf may be a unique archive of this non-skeletal precipitate. Further investigations into the petrography and geochemistry of pre-Holocene ooid occurrences will provide insights into their origin and the relative role of biotic, physicochemical and other factors in their formation. (C) 2018 Elsevier Ltd. All rights reserved.
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| 4. |
- Kotthoff, U., et al.
(författare)
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Reconstructing Holocene temperature and salinity variations in the western Baltic Sea region: a multi-proxy comparison from the Little Belt (IODP Expedition 347, Site M0059)
- 2017
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 14, s. 5607-5632
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Tidskriftsartikel (refereegranskat)abstract
- Sediment records recovered from the Baltic Sea during Integrated Ocean Drilling Program Expedition 347 provide a unique opportunity to study paleoenvironmental and climate change in central and northern Europe. Such studies contribute to a better understanding of how environmental parameters change in continental shelf seas and enclosed basins. Here we present a multi-proxy-based reconstruction of paleotemperature (both marine and terrestrial), paleosalinity, and paleoecosystem changes from the Little Belt (Site M0059) over the past ∼ 8000 years and evaluate the applicability of inorganic- and organic-based proxies in this particular setting. All salinity proxies (diatoms, aquatic palynomorphs, ostracods, diol index) show that lacustrine conditions occurred in the Little Belt until ∼ 7400 cal yr BP. A connection to the Kattegat at this time can thus be excluded, but a direct connection to the Baltic Proper may have existed. The transition to the brackish–marine conditions of the Littorina Sea stage (more saline and warmer) occurred within ∼ 200 years when the connection to the Kattegat became established after ∼ 7400 cal yr BP. The different salinity proxies used here generally show similar trends in relative changes in salinity, but often do not allow quantitative estimates of salinity. The reconstruction of water temperatures is associated with particularly large uncertainties and variations in absolute values by up to 8 °C for bottom waters and up to 16 °C for surface waters. Concerning the reconstruction of temperature using foraminiferal Mg / Ca ratios, contamination by authigenic coatings in the deeper intervals may have led to an overestimation of temperatures. Differences in results based on the lipid paleothermometers (long chain diol index and TEXL86) can partly be explained by the application of modern-day proxy calibrations to intervals that experienced significant changes in depositional settings: in the case of our study, the change from freshwater to marine conditions. Our study shows that particular caution has to be taken when applying and interpreting proxies in coastal environments and marginal seas, where water mass conditions can experience more rapid and larger changes than in open ocean settings. Approaches using a multitude of independent proxies may thus allow a more robust paleoenvironmental assessment.
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| 5. |
- Golla, Sandeep S V, et al.
(författare)
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Parametric Binding Images of the TSPO Ligand 18F-DPA-714.
- 2016
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 57:10, s. 1543-1547
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Tidskriftsartikel (refereegranskat)abstract
- (18)F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of (18)F-DPA-714 binding.METHODS: Ninety-minute dynamic (18)F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images.RESULTS: Plasma-input Logan analysis (r(2) = 0.99; slope, 0.88) and spectral analysis (r(2) = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r(2) = 0.83; slope, 0.95) and reference Logan analysis (r(2) = 0.88; slope, 1.01) correlated well with nonlinear regression-based estimates.CONCLUSION: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of (18)F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.
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| 6. |
- Groeneveld, Jeroen, et al.
(författare)
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Australian shelf sediments reveal shifts in Miocene Southern Hemisphere westerlies
- 2017
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- Global climate underwent a major reorganization when the Antarctic ice sheet expanded ~14 million years ago (Ma) (1). This event affected global atmospheric circulation, including the strength and position of the westerlies and the Intertropical Convergence Zone (ITCZ), and, therefore, precipitation patterns (2–5). We present new shallow-marine sediment records from the continental shelf of Australia (International Ocean Discovery Program Sites U1459 and U1464) providing the first empirical evidence linking high-latitude cooling around Antarctica to climate change in the (sub)tropics during the Miocene. We show that Western Australia was arid during most of the Middle Miocene. Southwest Australia became wetter during the Late Miocene, creating a climate gradient with the arid interior, whereas northwest Australia remained arid throughout. Precipitation and river runoff in southwest Australia gradually increased from 12 to 8 Ma, which we relate to a northward migration or intensification of the westerlies possibly due to increased sea ice in the Southern Ocean (5). Abrupt aridification indicates that the westerlies shifted back to a position south of Australia after 8 Ma. Our midlatitude Southern Hemisphere data are consistent with the inference that expansion of sea ice around Antarctica resulted in a northward movement of the westerlies. In turn, this may have pushed tropical atmospheric circulation and the ITCZ northward, shifting the main precipitation belt over large parts of Southeast Asia (4).
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