| 1. |
- Laurie, Steven, et al.
(författare)
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The RD-Connect Genome-Phenome Analysis Platform : Accelerating diagnosis, research, and gene discovery for rare diseases
- 2022
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 43:6, s. 717-733
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Tidskriftsartikel (refereegranskat)abstract
- Rare disease patients are more likely to receive a rapid molecular diagnosis nowadays thanks to the wide adoption of next-generation sequencing. However, many cases remain undiagnosed even after exome or genome analysis, because the methods used missed the molecular cause in a known gene, or a novel causative gene could not be identified and/or confirmed. To address these challenges, the RD-Connect Genome-Phenome Analysis Platform (GPAP) facilitates the collation, discovery, sharing, and analysis of standardized genome-phenome data within a collaborative environment. Authorized clinicians and researchers submit pseudonymised phenotypic profiles encoded using the Human Phenotype Ontology, and raw genomic data which is processed through a standardized pipeline. After an optional embargo period, the data are shared with other platform users, with the objective that similar cases in the system and queries from peers may help diagnose the case. Additionally, the platform enables bidirectional discovery of similar cases in other databases from the Matchmaker Exchange network. To facilitate genome-phenome analysis and interpretation by clinical researchers, the RD-Connect GPAP provides a powerful user-friendly interface and leverages tens of information sources. As a result, the resource has already helped diagnose hundreds of rare disease patients and discover new disease causing genes.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Allentoft, Morten E., et al.
(författare)
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Population genomics of post-glacial western Eurasia
- 2024
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
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Tidskriftsartikel (refereegranskat)abstract
- Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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| 4. |
- Beer, Tomasz M, et al.
(författare)
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Enzalutamide in metastatic prostate cancer before chemotherapy
- 2014
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 371:5, s. 33-424
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy.METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival.RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment.CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
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| 5. |
- Catalan, Nuria, et al.
(författare)
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The relevance of environment vs. composition on dissolved organic matter degradation in freshwaters
- 2021
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Ingår i: Limnology and Oceanography. - : John Wiley & Sons. - 0024-3590 .- 1939-5590. ; 66:2, s. 306-320
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Tidskriftsartikel (refereegranskat)abstract
- Dissolved organic matter (DOM) composition exerts a direct control on its degradation and subsequent persistence in aquatic ecosystems. Yet, under certain conditions, the degradation patterns of DOM cannot be solely explained by its composition, highlighting the relevance of environmental conditions for DOM degradation. Here, we experimentally assessed the relative influence of composition vs. environment on DOM degradation by performing degradation bioassays using three contrasting DOM sources inoculated with a standardized bacterial inoculum under five distinct environments. The DOM degradation kinetics modeled using reactivity continuum models showed that composition was more important than environment in determining the bulk DOM decay patterns. Changes in DOM composition resulted from the interaction between DOM source and environment. The role of environment was stronger on shaping the bacterial community composition, but the intrinsic nature of the DOM source exerted stronger control on the DOM degradation function.
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| 6. |
- Fumoto, Takayuki, et al.
(författare)
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Measurement of Moisture Content and Volume Change Distribution Inside Cement Paste Specimens Using X-Ray CT Imaging
- 2020
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Ingår i: 15th International Conference on Durability of Building Materials and Components, DBMC 2020 : DBMC 2020 - DBMC 2020. - : CIMNE. - 9788412110180 ; , s. 1511-1518
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Konferensbidrag (refereegranskat)abstract
- The purpose of this study was to clarify the internal change of concrete structures during drying. Therefore, we used X-ray CT to investigate water content and volume changes inside cement paste specimens during drying. Changes in the CT image intensities and measurements on the images indicated water content and volume changes, including local changes detected with digital volume correlation. Next steps will be to understand the link between volume changes and the local water content.
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| 7. |
- González-Jiménez, José M., et al.
(författare)
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Precious metals in magmatic Fe-Ni-Cu sulfides from the Potosí chromitite deposit, eastern Cuba
- 2020
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Ingår i: Ore Geology Reviews. - : Elsevier. - 0169-1368 .- 1872-7360. ; 118
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Tidskriftsartikel (refereegranskat)abstract
- The Moa-Baracoa ophiolite in eastern Cuba is one of the few known ophiolites that display sulfide mineralization attributable to a magmatic origin in association with podiform-chromite ores hosted in the mantle-crust transition. These sulfide ores chiefly consist of Fe-Ni-Cu sulfides, namely pyrrhotite, pentlandite, chalcopyrite and cubanite partly altered to valleriite. The sulfide mineralization is located along the contact between the podiform-like chromite ores and intruding pegmatitic gabroic dykes. The detailed mineralogical study of the sulfide mineralization coupled with the first ever laser ablation ICP-MS analysis reveals that this sulfide mineralization show contents of the precious metals (Os, Ir, Ru, Pt, Re, Au, Ag) and other (semi)-metals (Co, Ni, Cu, Se, Te, Bi, Pb, As Sb) comparable to those sulfides from the magmatic sulfide deposits associated with mafic complexes hosted in the continental crust. The results obtained from this study confirm that Fe-Ni-Cu sulfides at Potosí are magmatic in origin, and very likely derived from the solidification of droplets of sulfide melt segregated by immiscibility from the intruding mafic melts once they interacted with the pre-existing chromitite at the mantle-crust transition zone of the ophiolite. The immiscibility of sulfide melt was achieved as a result of a progressive increase of fS2, very likely triggered by a set of circumstances, including the progressive fractionation of the intruding mafic melt leading to increase of aSiO2 and accumulation of volatiles as well as the crystallization of oxides. Two main generations of pentlandite were observed. One generation is primary in origin and it was locally exsolved along with pyrrhotite from monosulfide solid solution (MSS) during low-temperature cooling. The second type of pentlandite resulted from the reaction of MSS with coexisting droplets of Cu-and Ni-rich sulfide melt. LA-ICP-MS analysis reveals that most precious metals (Ru, Os, Ir, Re, Au, Ag) were concentrated along with the base-metal sulfides (BMS), although their distribution among the different BMS (pyrrhotite, pentlandite, chalcopyrite and cubanite) does not strictly follow the expected distribution according to the known melt-solid and solid-solid partition coefficients. Unlike the other analyzed PGEs, Pt was not preferentially concentrated in BMS but as discrete micrometer-sized sperrylite grains. The crystallization of sperrylite took place before and contemporaneous to sulfide segregation, and Pt-As nanoparticles probably played an important role in the Pt uptake as nucleation seeds for the formation of micron-sized sperrylite grains. These observations highlight the open-system nature of the ore forming system as well as the important role of arsenic in concentrating PGE in high-temperature silicate and sulfide melts.
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| 8. |
- Hernández-Alvarez, María Isabel, et al.
(författare)
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Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease
- 2019
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Ingår i: Cell. - : Cell Press. - 0092-8674 .- 1097-4172. ; 177:4, s. 881-895.e17
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.
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| 9. |
- Iglesias, Maria Jesus, et al.
(författare)
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Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Venous thromboembolism (VTE) is a common, multi-causal disease with potentially serious short- and long-term complications. In clinical practice, there is a need for improved plasma biomarker-based tools for VTE diagnosis and risk prediction. Here we show, using proteomics profiling to screen plasma from patients with suspected acute VTE, and several case-control studies for VTE, how Complement Factor H Related 5 protein (CFHR5), a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker. In plasma, higher CFHR5 levels are associated with increased thrombin generation potential and recombinant CFHR5 enhanced platelet activation in vitro. GWAS analysis of ~52,000 participants identifies six loci associated with CFHR5 plasma levels, but Mendelian randomization do not demonstrate causality between CFHR5 and VTE. Our results indicate an important role for the regulation of the alternative pathway of complement activation in VTE and that CFHR5 represents a potential diagnostic and/or risk predictive plasma biomarker.
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| 10. |
- Julià, Mireia, et al.
(författare)
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Employment and Labor Market Results of the SOPHIE Project : Concepts, Analyses, and Policies
- 2017
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Ingår i: International Journal of Health Services. - : SAGE Publications. - 0020-7314 .- 1541-4469. ; 47:1, s. 18-39
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Tidskriftsartikel (refereegranskat)abstract
- This article reports evidence gained by the SOPHIE Project regarding employment and labor market-related policies. In the first step, quality of employment and of precarious and informal employment in Europe were conceptualized and defined. Based on these definitions, we analyzed changes in the prevalence and population distribution of key health-affecting characteristics of employment and work between times of economic prosperity and economic crisis in Europe and investigated their impact on health outcomes. Additionally, we examined the effects of several employment and labor market-related policies on factors affecting health equity, including a specific analysis concerning work-related gender equity policies and case studies in different European countries. Our findings show that there is a need to standardize definitions and indicators of (the quality of) employment conditions and improve information systems. This is challenging given the important differences between and within European countries. In our results, low quality of employment and precarious employment is associated with poor mental health. In order to protect the well-being of workers and reduce work-related health inequalities, policies leading to precarious working and employment conditions need to be suspended. Instead, efforts should be made to improve the security and quality of employment for all workers.
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