| 1. |
- Freitag, Daniel F., et al.
(författare)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Tidskriftsartikel (refereegranskat)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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| 2. |
- Adewumi, Oluseun, et al.
(författare)
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
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Tidskriftsartikel (refereegranskat)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
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| 3. |
- Bellenguez, Celine, et al.
(författare)
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Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:3, s. 141-328
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Tidskriftsartikel (refereegranskat)abstract
- Genetic factors have been implicated in stroke risk, but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) for ischemic stroke and its subtypes in 3,548 affected individuals and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 affected individuals and 6,281 controls. We replicated previous associations for cardioembolic stroke near PITX2 and ZFHX3 and for large vessel stroke at a 9p21 locus. We identified a new association for large vessel stroke within HDAC9 (encoding histone deacetylase 9) on chromosome 7p21.1 (including further replication in an additional 735 affected individuals and 28,583 controls) (rs11984041; combined P = 1.87 x 10(-11); odds ratio (OR) = 1.42, 95% confidence interval (CI) = 1.28-1.57). All four loci exhibited evidence for heterogeneity of effect across the stroke subtypes, with some and possibly all affecting risk for only one subtype. This suggests distinct genetic architectures for different stroke subtypes.
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| 4. |
- Dong, Lan-Feng, et al.
(författare)
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Suppression of Tumor Growth In vivo by the Mitocan alpha-tocopheryl Succinate Requires Respiratory Complex II
- 2009
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Ingår i: CLINICAL CANCER RESEARCH. - 1078-0432. ; 15:5, s. 1593-1600
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Vitamin E analogues are potent novel anticancer drugs. The purpose of this study was to elucidate the cellular target by which these agents, represented by alpha-tocopoheryl succinate (alpha-TOS), suppress tumors in vivo, with the focus on the mitochondrial complex II (CII). Experimental Design: Chinese hamster lung fibroblasts with functional, dysfunctional, and reconstituted CII were transformed using H-Ras. The cells were then used to form xenografts in immunocompromized mice, and response of the cells and the tumors to alpha-TOS was studied. Results: The CII-functional and CII-reconstituted cells, unlike their CII-dysfunctional counterparts, responded to alpha-TOS by reactive oxygen species generation and apoptosis execution. Tumors derived from these cell lines reciprocated their responses to alpha-TOS. Thus, growth of CII-functional and CII-reconstituted tumors was strongly suppressed by the agent, and this was accompanied by high level of apoptosis induction in the tumor cells. On the other hand, alpha-TOS did not inhibit the CII-dysfuntional tumors. Conclusions: We document in this report a novel paradigm, according to which the mitochondrial CII, which rarely mutates in human neoplasias, is a plausible target for anticancer drugs from the group of vitamin E analogues, providing support for their testing in clinical trials.
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| 5. |
- Haig, David W., et al.
(författare)
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Early Triassic (early Olenekian) life in the interior of East Gondwana : mixed marine-terrestrial biota from the Kockatea Shale, Western Australia
- 2015
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Ingår i: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182 .- 1872-616X. ; 417, s. 511-533
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Tidskriftsartikel (refereegranskat)abstract
- A new terrestrial marine assemblage from the lower beds of a thin outcrop section of the Kockatea Shale in the northern Perth Basin, Western Australia, contains a range of fossil groups, most of which are rare or poorly known from the Lower Triassic of the region. To date, the collection includes spinose acritarchs, organic-cemented agglutinated foraminifera, lingulids, minute bivalves and gastropods, ammonoids, spinicaudatans, insects, austriocaridid crustaceans, actinopterygians, a temnospondyl-like mandible, plant remains, and spores and pollen. Of these groups, the insects, crustaceans and macroplant remains are recorded for the first time from this unit. Palynomorphs permit correlation to nearby sections where conodonts indicate an early Olenekian (Smithian) age. The locality likely represents the margin of an Early Triassic shallow interior sea with variable estuarine-like water conditions, at the southwestern end of an elongate embayment within the East Gondwana interior rift sag system preserved along the Western Australian margin. Monospecific spinose acritarch assemblages intertwined with amorphous organic matter may represent phytoplankton blooms that accumulated as mats, and suggest potentially eutrophic surface waters. The assemblage represents a mixure of marine and terrestrial taxa, suggesting variations in water conditions or that fresh/brackish-water and terrestrial organisms were transported from adjacent biotopes. Some of the lower dark shaly beds are dominated by spinicaudatans, likely indicating periods when the depositional water body was ephemeral, isolated, or subjected to other difficult environmental conditions. The biota of the Kockatea Shale is insufficiently known to estimate biotic diversity and relationships of individual taxa to their Permian progenitors and Triassic successors, but provides a glimpse into a coastal-zone from the interior of eastern Gondwana. Specialist collecting is needed to clarify the taxonomy of many groups, and comparisons to other Lower Triassic sites are required to provide insights into the pattern of biotic decline and recovery at the end-Permian crisis. (C) 2014 Elsevier B.V. All rights reserved.
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| 6. |
- Peyrot, Daniel, et al.
(författare)
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The greening of Western Australian landscapes: the Phanerozoic plant record
- 2019
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Ingår i: Journal of the Royal Society of Western Australia. - Perth : Royal Society of Western Australia. - 0035-922X. ; 102, s. 52-82
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Tidskriftsartikel (refereegranskat)abstract
- Western Australian terrestrial floras first appeared in the Middle Ordovician (c. 460 Ma) and developed Gondwanan affinities in the Permian. During the Mesozoic, these floras transitioned to acquire a distinctly austral character in response to further changes in the continent’s palaeolatitude and its increasing isolation from other parts of Gondwana. This synthesis of landscape evolution is based on palaeobotanical and palynological evidence mostly assembled during the last 60 years. The composition of the plant communities and the structure of vegetation changed markedly through the Phanerozoic. The Middle Ordovician –Middle Devonian was characterised by diminutive vegetation in low-diversity communities. An increase in plant size is inferred from the Devonian record, particularly from that of the Late Devonian when a significant part of the flora was arborescent. Changes in plant growth-forms accompanied a major expansion of vegetation cover to episodically or permanently flooded lowland settings and, from the latest Mississippian onwards, to dry hinterland environments. Wetter conditions during the Permian yielded waterlogged environments with complex swamp communities dominated by Glossopteris. In response to the Permian–Triassic extinction event, a transitional vegetation characterised by herbaceous lycopsids became dominant but was largely replaced by the Middle Triassic with seed ferns and shrubs or trees attributed to Dicroidium. Another floristic turnover at the Triassic–Jurassic boundary introduced precursors of Australia’s modern vegetation and other southern hemisphere regions. Most importantly, flowering plants gained ascendancy during the Late Cretaceous. Characteristics of the state’s modern vegetation, such as sclerophylly and xeromorphy, arose during the Late Cretaceous and Paleogene. The vegetation progressively developed its present-day structure and composition in response to the increasing aridity during the Neogene–Quaternary.
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| 7. |
- Weiberg, Erika, 1971-, et al.
(författare)
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Long-term trends of land use and demography in Greece : A comparative study
- 2019
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 29:5, s. 742-760
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Tidskriftsartikel (refereegranskat)abstract
- This paper offers a comparative study of land use and demographic development in northern and southern Greece from the Neolithic to the Byzantine period. Results from summed probability densities (SPD) of archaeological radiocarbon dates and settlement numbers derived from archaeological site surveys are combined with results from cluster-based analysis of published pollen core assemblages to offer an integrated view of human pressure on the Greek landscape through time. We demonstrate that SPDs offer a useful approach to outline differences between regions and a useful complement to archaeological site surveys, evaluated here especially for the onset of the Neolithic and for the Final Neolithic (FN)/Early Bronze Age (EBA) transition. Pollen analysis highlight differences in vegetation between the two sub-regions, but also several parallel changes. The comparison of land cover dynamics between two sub-regions of Greece further demonstrates the significance of the bioclimatic conditions of core locations and that apparent oppositions between regions may in fact be two sides of the same coin in terms of socio-ecological trajectories. We also assess the balance between anthropogenic and climate-related impacts on vegetation and suggest that climatic variability was as an important factor for vegetation regrowth. Finally, our evidence suggests that the impact of humans on land cover is amplified from the Late Bronze Age (LBA) onwards as more extensive herding and agricultural practices are introduced.
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| 8. |
- Woodbridge, Jessie, et al.
(författare)
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Pollen-inferred regional vegetation patterns and demographic change in Southern Anatolia through the Holocene
- 2019
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 29:5, s. 728-741
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Tidskriftsartikel (refereegranskat)abstract
- Southern Anatolia is a highly significant area within the Mediterranean, particularly in terms of understanding how agriculture moved into Europe from neighbouring regions. This study uses pollen, palaeoclimate and archaeological evidence to investigate the relationships between demography and vegetation change, and to explore how the development of agriculture varied spatially. Data from 21 fossil pollen records have been transformed into forested, parkland and open vegetation types using cluster analysis. Patterns of change have been explored using non-metric multidimensional scaling (nMDS) and through analysis of indicator groups, such as an Anthropogenic Pollen Index, and Simpson’s Diversity. Settlement data, which indicate population densities, and summed radiocarbon dates for archaeological sites have been used as a proxy for demographic change. The pollen and archaeological records confirm that farming can be detected earlier in Anatolia in comparison with many other parts of the Mediterranean. Dynamics of change in grazing indicators and the OJCV (Olea, Juglans, Castanea and Vitis) index for cultivated trees appear to match cycles of population expansion and decline. Vegetation and land use change is also influenced by other factors, such as climate change. Investigating the early impacts of anthropogenic activities (e.g. woodcutting, animal herding, the use of fire and agriculture) is key to understanding how societies have modified the environment since the mid–late Holocene, despite the capacity of ecological systems to absorb recurrent disturbances. The results of this study suggest that shifting human population dynamics played an important role in shaping land cover in central and southern Anatolia.
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| 9. |
- Wu, Ona, et al.
(författare)
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Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data
- 2019
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Ingår i: Stroke. - 1524-4628. ; 50:7, s. 1734-1741
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.
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