| 1. |
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| 2. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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Tidskriftsartikel (refereegranskat)abstract
- Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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| 3. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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| 4. |
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| 5. |
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| 6. |
- 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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| 7. |
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| 8. |
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| 9. |
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| 11. |
- Thomas, H. J.D., et al.
(författare)
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Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome
- 2019
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 28:2, s. 78-95
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The Authors Global Ecology and Biogeography Published by John Wiley & Sons Ltd Aim: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. Location: Tundra biome. Time period: Data collected between 1964 and 2016. Major taxa studied: 295 tundra vascular plant species. Methods: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. Results: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. Main conclusions: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra ecosystem change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insight into ecological prediction and modelling.
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| 12. |
- 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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| 13. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 14. |
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| 15. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 16. |
- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 17. |
- Björkman, Anne, 1981, et al.
(författare)
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Plant functional trait change across a warming tundra biome
- 2018
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 562:7725, s. 57-62
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Tidskriftsartikel (refereegranskat)abstract
- The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature–trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.
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| 18. |
- Marenholz, I, et al.
(författare)
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Meta-analysis identifies seven susceptibility loci involved in the atopic march
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 8804-
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Tidskriftsartikel (refereegranskat)abstract
- Eczema often precedes the development of asthma in a disease course called the ‘atopic march’. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.
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| 19. |
- Ng, Bobby G, et al.
(författare)
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ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
- 2016
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794.
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Tidskriftsartikel (refereegranskat)abstract
- Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over one hundred genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate (DLO) required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date thirteen mutations in eighteen patients from fourteen families have been described with varying degrees of clinical severity. We identified and characterized thirty-nine previously unreported cases of ALG1-CDG from thirty-two families and add twenty-six new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all twenty-seven patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder. This article is protected by copyright. All rights reserved.
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| 20. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 21. |
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| 22. |
- Herrick, A. L., et al.
(författare)
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Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study
- 2018
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 77:4, s. 563-570
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). Methods The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). Results 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. Conclusions Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. Trial registration number NCT02339441. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
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| 23. |
- Bien, Stephanie A., et al.
(författare)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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Ingår i: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 24. |
- Goodwin, G. M., et al.
(författare)
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Evidence-based guidelines for treating bipolar disorder : Revised third edition recommendations from the British Association for Psychopharmacology
- 2016
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Ingår i: Journal of Psychopharmacology. - : SAGE PUBLICATIONS LTD. - 0269-8811 .- 1461-7285. ; 30:6, s. 495-553
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Forskningsöversikt (refereegranskat)abstract
- The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.
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| 25. |
- Lyons, PA, et al.
(författare)
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Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 5120-
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.
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| 26. |
- Rayner, C, et al.
(författare)
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A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders
- 2019
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Ingår i: Translational psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1, s. 150-
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Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (rg ≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h2SNP) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h2SNP could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
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| 27. |
- Lambert-Niclot, S., et al.
(författare)
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Antiretroviral resistance at virological failure in the NEAT 001/ANRS 143 trial: Raltegravir plus darunavir/ritonavir or tenofovir/emtricitabine plus darunavir/ritonavir as first-line ART
- 2016
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 1460-2091 .- 0305-7453. ; 71:4, s. 1056-1062
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe the pattern of drug resistance at virological failure in the NEAT001/ANRS143 trial (first-line treatment with ritonavir-boosted darunavir plus either tenofovir/emtricitabine or raltegravir). Methods: Genotypic testing was performed at baseline for reverse transcriptase (RT) and protease genes and for RT, protease and integrase (IN) genes for patients with a confirmed viral load (VL) >50 copies/mL or any single VL >500 copies/mL during or after week 32. Results: A resistance test was obtained for 110/805 (13.7%) randomized participants qualifying for resistance analysis (61/401 of participants in the raltegravir arm and 49/404 of participants in the tenofovir/emtricitabine arm). No resistance-associated mutation (RAM) was observed in the tenofovir/emtricitabine plus darunavir/ritonavir arm, and all further analyses were limited to the raltegravir plus darunavir arm. In this group, 15/55 (27.3%) participants had viruses with IN RAMs (12 N155H alone, 1 N155H + Q148R, 1 F121Y and 1 Y143C), 2/53 (3.8%) with nucleotide analogue RT inhibitor RAMs (K65R, M41L) and 1/57 (1.8%) with primary protease RAM (L76V). The frequency of IN mutations at failure was significantly associated with baseline VL: 7.1% for a VL of TREND = 0.007). Of note, 4/15 participants with IN RAM had a VL <200 copies/mL at time of testing. Conclusions: In the NEAT001/ANRS143 trial, there was no RAM at virological failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen, contrasting with a rate of 29.5% (mostly IN mutations) in the raltegravir plus darunavir/ritonavir NRTI-sparing regimen. The cumulative risk of IN RAM after 96 weeks of follow-up in participants initiating ART with raltegravir plus darunavir/ritonavir was 3.9%.
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| 28. |
- Liang, Liming, et al.
(författare)
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An epigenome-wide association study of total serum immunoglobulin E concentration
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 520:7549, s. 670-U188
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin E (IgE) is a central mediator of allergic (atopic) inflammation. Therapies directed against IgE can alleviate hay fever' and allergic asthma'''. Genetic association studies have not yet identified novel therapeutic targets or pathways underlying IgE regulation'. We therefore surveyed epigenetic associations between serum IgE concentrations and methylation at loci concentrated in CpG islands genome wide in 95 nuclear pedigrees, using DNA from peripheral blood leukocytes. We validated positive results in additional families and in subjects from the general population. Here we show replicated associations with a meta-analysis false discovery rate less than 10-4 between IgE and low methylation at 36 loci. Genes annotated to these loci encode known eosinophil products, and also implicate phospholipid inflammatory mediators, specific transcription factors and mitochondrial proteins. We confirmed that methylation at these loci differed significantly in isolated eosinophils from subjects with and without asthma and high IgE levels. The top three loci accounted for 13% of IgE variation in the primary subject panel, explaining the tenfold higher variance found compared with that derived from large single-nucleotide polymorphism genome-wide association studies'''. This study identifies novel therapeutic targets and biomarkers for patient stratification for allergic diseases.
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| 29. |
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| 30. |
- Björkman, Anne, 1981, et al.
(författare)
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Tundra Trait Team: A database of plant traits spanning the tundra biome
- 2018
-
Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 27:12, s. 1402-1411
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The Authors Global Ecology and Biogeography Published by John Wiley & Sons Ltd Motivation: The Tundra Trait Team (TTT) database includes field-based measurements of key traits related to plant form and function at multiple sites across the tundra biome. This dataset can be used to address theoretical questions about plant strategy and trade-offs, trait–environment relationships and environmental filtering, and trait variation across spatial scales, to validate satellite data, and to inform Earth system model parameters. Main types of variable contained: The database contains 91,970 measurements of 18 plant traits. The most frequently measured traits (>1,000 observations each) include plant height, leaf area, specific leaf area, leaf fresh and dry mass, leaf dry matter content, leaf nitrogen, carbon and phosphorus content, leaf C:N and N:P, seed mass, and stem specific density. Spatial location and grain: Measurements were collected in tundra habitats in both the Northern and Southern Hemispheres, including Arctic sites in Alaska, Canada, Greenland, Fennoscandia and Siberia, alpine sites in the European Alps, Colorado Rockies, Caucasus, Ural Mountains, Pyrenees, Australian Alps, and Central Otago Mountains (New Zealand), and sub-Antarctic Marion Island. More than 99% of observations are georeferenced. Time period and grain: All data were collected between 1964 and 2018. A small number of sites have repeated trait measurements at two or more time periods. Major taxa and level of measurement: Trait measurements were made on 978 terrestrial vascular plant species growing in tundra habitats. Most observations are on individuals (86%), while the remainder represent plot or site means or maximums per species. Software format: csv file and GitHub repository with data cleaning scripts in R; contribution to TRY plant trait database (www.try-db.org) to be included in the next version release.
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| 31. |
- Connor, T. M., et al.
(författare)
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Mutations in mitochondrial DNA causing tubulointerstitial kidney disease
- 2017
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:3
-
Tidskriftsartikel (refereegranskat)abstract
- Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A> T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNA(Phe), tRNA(Leu1) and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNA Phe (m.616T> C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNA(Phe)
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| 32. |
- Ng, Bobby G., et al.
(författare)
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DPAGT1 deficiency with encephalopathy (DPAGT1-CDG) : Clinical and genetic description of 11 new patients
- 2018
-
Ingår i: JIMD Reports. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 2192-8312 .- 2192-8304. ; 44, s. 85-92
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Bokkapitel (refereegranskat)abstract
- Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.
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| 33. |
- Wedemeyer, S., et al.
(författare)
-
SSALMON - The Solar Simulations for the Atacama Large Millimeter Observatory Network
- 2015
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Ingår i: Advances in Space Research. - : Elsevier BV. - 1879-1948 .- 0273-1177. ; 56:12, s. 2679-2692
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Tidskriftsartikel (refereegranskat)abstract
- The Solar Simulations for the Atacama Large Millimeter Observatory Network (SSALMON) was initiated in 2014 in connection with two ALMA development studies. The Atacama Large Millimeter/submillimeter Array (ALMA) is a powerful new tool, which can also observe the Sun at high spatial, temporal, and spectral resolution. The international SSALMONetwork aims at co-ordinating the further development of solar observing modes for ALMA and at promoting scientific opportunities for solar physics with particular focus on numerical simulations, which can provide important constraints for the observing modes and can aid the interpretation of future observations. The radiation detected by ALMA originates mostly in the solar chromosphere - a complex and dynamic layer between the photosphere and corona, which plays an important role in the transport of energy and matter and the heating of the outer layers of the solar atmosphere. Potential targets include active regions, prominences, quiet Sun regions, flares. Here, we give a brief overview over the network and potential science cases for future solar observations with ALMA.
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| 34. |
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| 35. |
- Itzhaki, Ruth F., et al.
(författare)
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Microbes and Alzheimer's Disease
- 2016
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 51:4, s. 979-984
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD [1–4]. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood [7]. The first observations of HSV1 in AD brain were reported almost three decades ago [8]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease [9, 10]. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic
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| 36. |
- Itzhaki, Ruth F., et al.
(författare)
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Microbes and Alzheimer's disease
- 2017
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Ingår i: Handbook of infection and Alzheimer's disease. - : IOS Press. - 9781614997054 - 9781614997061 ; , s. 3-8
-
Bokkapitel (refereegranskat)
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| 37. |
- Koivula, Robert W., et al.
(författare)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
-
Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 38. |
- Wedemeyer, S., et al.
(författare)
-
Solar Science with the Atacama Large Millimeter/Submillimeter Array-A New View of Our Sun
- 2016
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Ingår i: Space Science Reviews. - : Springer Science and Business Media LLC. - 0038-6308 .- 1572-9672. ; 200:1-4, s. 1-73
-
Forskningsöversikt (refereegranskat)abstract
- The Atacama Large Millimeter/submillimeter Array (ALMA) is a new powerful tool for observing the Sun at high spatial, temporal, and spectral resolution. These capabilities can address a broad range of fundamental scientific questions in solar physics. The radiation observed by ALMA originates mostly from the chromosphere-a complex and dynamic region between the photosphere and corona, which plays a crucial role in the transport of energy and matter and, ultimately, the heating of the outer layers of the solar atmosphere. Based on first solar test observations, strategies for regular solar campaigns are currently being developed. State-of-the-art numerical simulations of the solar atmosphere and modeling of instrumental effects can help constrain and optimize future observing modes for ALMA. Here we present a short technical description of ALMA and an overview of past efforts and future possibilities for solar observations at submillimeter and millimeter wavelengths. In addition, selected numerical simulations and observations at other wavelengths demonstrate ALMA's scientific potential for studying the Sun for a large range of science cases.
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| 39. |
- Birkholzer, Jens T., et al.
(författare)
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25 years of DECOVALEX - Scientific advances and lessons learned from an international research collaboration in coupled subsurface processes
- 2019
-
Ingår i: International Journal of Rock Mechanics And Mining Sciences. - : PERGAMON-ELSEVIER SCIENCE LTD. - 1365-1609 .- 1873-4545. ; 122
-
Forskningsöversikt (refereegranskat)abstract
- This paper provides an overview of an international research collaboration for advancing the understanding and modeling of coupled thermo-hydro-mechanical-chemical (THMC) processes in geological systems. The creation of the international DECOVALEX Project, now running for over 25 years, was initially motivated by the recognition that prediction of these coupled effects is an essential part of the performance and safety assessment of geologic disposal systems for radioactive waste and spent nuclear fuel. Later it was realized that these processes also play a critical role in other subsurface engineering activities, such as storage of CO2, exploration of enhanced geothermal systems, and unconventional oil and gas production through hydraulic fracturing. Research teams from radioactive waste management organizations, national research institutes, regulatory agencies, universities, as well as industry and consulting groups have participated in the DECOVALEX Project, providing a wide range of perspectives and solutions to these complex problems. Analysis and comparative modeling of state-of-the-art field and laboratory experiments has been at the core of the collaborative work, with an increasing focus on characterizing uncertainty and blind prediction of experimental results. Over these 25 years, many of the major advances in this field of research have been made through DECOVALEX, as evidenced by three books, seven journal special issues, and a good number of seminal papers that have emerged from the DECOVALEX modeling work. Examples of specific research advances will be presented in this paper to illustrate the significant impact of DECOVALEX on the current state-of-the-art of understanding and modeling coupled THMC processes. These examples range from the modeling of large-scale in situ heater tests representing mock-ups of nuclear waste disposal tunnels, to studies of fluid flow and chemical-mechanical coupling in heterogeneous fractures, and to the numerical analysis of controlled-injection meso-scale fault slip experiments.
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| 40. |
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| 41. |
- Cattell, C., et al.
(författare)
-
Dayside response of the magnetosphere to a small shock compression : Van Allen Probes, Magnetospheric MultiScale, and GOES-13
- 2017
-
Ingår i: Geophysical Research Letters. - : AMER GEOPHYSICAL UNION. - 0094-8276 .- 1944-8007. ; 44:17, s. 8712-8720
-
Tidskriftsartikel (refereegranskat)abstract
- Observations from Magnetospheric MultiScale (similar to 8 Re) and Van Allen Probes (similar to 5 and 4 Re) show that the initial dayside response to a small interplanetary shock is a double-peaked dawnward electric field, which is distinctly different from the usual bipolar (dawnward and then duskward) signature reported for large shocks. The associated ExB flow is radially inward. The shock compressed the magnetopause to inside 8 Re, as observed by Magnetospheric MultiScale (MMS), with a speed that is comparable to the ExB flow. The magnetopause speed and the ExB speeds were significantly less than the propagation speed of the pulse from MMS to the Van Allen Probes and GOES-13, which is consistent with the MHD fast mode. There were increased fluxes of energetic electrons up to several MeV. Signatures of drift echoes and response to ULF waves also were seen. These observations demonstrate that even very weak shocks can have significant impact on the radiation belts. Plain Language Summary Very fast moving clouds of charged particles are ejected from the Sun when it is active. Shock waves often develop at the cloud front as it plows through the solar wind. When the shock hits the Earth's magnetic field, it can push the Earth's magnetic shield inside the distance where many communication and weather satellites orbit. The energy associated with the shock can also very rapidly increase the energy of electrons trapped in the Earth's magnetic field in the Van Allen Radiation belts. These electrons can damage satellites. We have used four satellites arrayed at different locations on the dayside of the Earth's magnetic field to show, for the first time, that small shocks have a different effect than the large shocks that are usually studied but that even small shocks can produce relativistic electrons.
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| 42. |
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| 43. |
- Hallgren, M, et al.
(författare)
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Anti-Social Behaviors Associated with Anabolic-Androgenic Steroid Use among Male Adolescents
- 2015
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Ingår i: European addiction research. - : S. Karger AG. - 1421-9891 .- 1022-6877. ; 21:6, s. 321-326
-
Tidskriftsartikel (refereegranskat)abstract
- Anabolic-androgenic steroids (AAS) have been linked to a range of problematic behaviors, but AAS use is still sometimes portrayed as more benign than other forms of classical drug abuse. To address this issue, we compared the prevalence of anti-social behaviors among adolescent AAS users, non-AAS illicit drug users, and drug non-users. We examined 3 waves (2004, 2008, and 2012) of self-reported cross-sectional data from a secondary school survey conducted in Stockholm, Sweden (total n = 19,773; response percentage, 79.6%). Across all survey years, the risk ratios for virtually all measured anti-social behaviors were significantly higher among AAS users compared to non-AAS illicit drug users and to drug non-users.
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| 44. |
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| 45. |
- Hudson, J. A., et al.
(författare)
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Coupled THMC modeling for safety assessment of geological disposal of radioactive wastes : The DECOVALEX project (1992-2015)
- 2017
-
Ingår i: Rock Mechanics and Engineering Volume 3: Analysis, Modeling and Design. - : CRC Press. - 9781317481942 - 9781138027619 ; , s. 3-44
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- This Chapter describes a long-term research effort (1992 to the present) on coupled THMC processes in geological systems in the context of the safe geological disposal of radioactive wastes: the DECOVALEX project (DEvelopment of COupled models and their VAlidation through EXperiments). This project is a unique international co-operative research project which was initiated in 1991, officially started in 1992, has continued through a number of phases without interruption since then and is still continuing in the time of preparing this chapter by the authors. The overall objective of this research has been the development, validation and application of numerical modeling methods and techniques for the performance and safety assessments of geological disposal of radioactive waste (GDRW) in underground repositories. The cooperation has been financed by national waste management organizations, regulatory bodies and national research institutes and individual universities in Canada, China, Czech Republic, European Commission, Finland, France, Germany, Republic of Korea, Spain, Japan, Sweden, UK and USA.Over the period of 23 years, the project has made impressive advanced researches in the field of coupled THMC (Thermo- Hydro-Mechanical-Chemical) processes in geological systems, especially in fractured crystalline and sedimentary rocks and buffer/backfill materials, through integrated numerical modeling and laboratory and field experiments. The experiments cover scales ranging from laboratory-sized samples to in situ experiments in underground research laboratories (URLs) in different host rocks in different countries. The work has resulted in an impressive number ofmajor developments, as reported in scientific publications and helped to educate and train younger generations of researchers in this field. This Chapter presents the goals, structure, contents and approaches of the project, as well as achievements and lessons learned during this long-term project, at both the fundamental and application levels.
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| 46. |
- Jankovic, Momcilo, et al.
(författare)
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Long-term survivors of childhood cancer : cure and care—the Erice Statement (2006) revised after 10 years (2016)
- 2018
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Ingår i: Journal of Cancer Survivorship. - : Springer Science and Business Media LLC. - 1932-2259 .- 1932-2267. ; 12:5, s. 647-650
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: The number of persons who have successfully completed treatment for a cancer diagnosed during childhood and who have entered adulthood is increasing over time, and former patients will become aging citizens. Methods: Ten years ago, an expert panel met in Erice, Italy, to produce a set of principles concerning the cure and care of survivors of childhood and adolescent cancer. The result was the Erice Statement (Haupt et al. Eur J Cancer 43(12):1778–80, 2007) that was translated into nine languages. Ten years on, it was timely to review, and possibly revise, the Erice Statement in view of the changes in paediatric oncology and the number and results of international follow-up studies conducted during the intervening years. Results: The long-term goal of the cure and care of a child with cancer is that he/she becomes a resilient and autonomous adult with optimal health-related quality of life, accepted in society at the same level as his/her age peers. “Cure” refers to cure from the original cancer, regardless of any potential for, or presence of, remaining disabilities or side effects of treatment. The care of a child with cancer should include complete and honest information for parents and the child. Conclusions and implication for cancer survivors: Some members of the previous expert panel, as well as new invited experts, met again in Erice to review the Erice Statement, producing a revised version including update and integration of each of the ten points. In addition, a declaration has been prepared, by the Childhood Cancer International Survivors Network in Dublin on October 2016 (see Annex 1).
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| 47. |
- Jönsson, Peter, et al.
(författare)
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Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions
- 2016
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 113:20, s. 5682-5687
-
Tidskriftsartikel (refereegranskat)abstract
- The αβ T-cell coreceptor CD4 enhances immune responses more than 1 million-fold in some assays, and yet the affinity of CD4 for its ligand, peptide-major histocompatibility class II (pMHC II) on antigen-presenting cells, is so weak that it was previously unquantifiable. Here, we report that a soluble form of CD4 failed to bind detectably to pMHC II in surface plasmon resonance-based assays, establishing a new upper limit for the solution affinity at 2.5 mM. However, when presented multivalently on magnetic beads, soluble CD4 bound pMHC II-expressing B cells, confirming that it is active and allowing mapping of the native coreceptor binding site on pMHC II. Whereas binding was undetectable in solution, the affinity of the CD4/pMHC II interaction could be measured in 2D using CD4- and adhesion molecule-functionalized, supported lipid bilayers, yielding a 2D Kd of ∼5,000 molecules/μm2. This value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with only a small, 2-20% increase in the effective affinity of the TCR for pMHC II. The affinity of CD4/pMHC II therefore seems to be set at a value that increases T-cell sensitivity by enhancing phosphorylation, without compromising ligand discrimination.
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| 48. |
- Liu, Jian-li, et al.
(författare)
-
Bacterial diversity in typical abandoned multi-contaminated nonferrous metal(loid) tailings during natural attenuation
- 2019
-
Ingår i: Environmental Pollution. - : Elsevier. - 0269-7491 .- 1873-6424. ; 274, s. 98-107
-
Tidskriftsartikel (refereegranskat)abstract
- Abandoned nonferrous metal(loid) tailings sites are anthropogenic, and represent unique and extreme ecological niches for microbial communities. Tailings contain elevated and toxic content of metal(loid)s that had negative effects on local human health and regional ecosystems. Microbial communities in these typical tailings undergoing natural attenuation are often very poorly examined. The diversity and inferred functions of bacterial communities were examined at seven nonferrous metal(loid) tailings sites in Guangxi (China), which were abandoned between 3 and 31 years ago. The acidity of the tailings sites rose over 31 years of site inactivity. Desulfurivibrio, which were always coupled with sulfur/sulfide oxidation to dissimilate the reduction of nitrate/nitrite, were specific in tailings with 3 years abandonment. However, genus beneficial to plant growth (Rhizobium), and iron/sulfur-oxidizing bacteria and metal(loid)-related genera (Acidiferrobacter and Acidithiobacillus) were specific within tailings abandoned for 23 years or more. The increased abundance of acid-generating iron/sulfur-oxidizing and metal(loid)-related bacteria and specific bacterial communities during the natural attenuation could provide new insights for understanding microbial ecosystem functioning in mine tailings. OTUs related to Sulfuriferula, Bacillus, Sulfurifustis, Gaiella, and Thiobacillus genera were the main contributors differentiating the bacterial communities between the different tailing sites. Multiple correlation analyses between bacterial communities and geochemical parameters indicated that pH, TOC, TN, As, Pb, and Cu were the main drivers influencing the bacterial community structures. PICRUSt functional exploration revealed that the main functions were related to DNA repair and recombination, important functions for bacterial adaptation to cope with the multi-contamination of tailings. Such information provides new insights to guide future metagenomic studies for the identification of key functions beyond metal-transformation/resistance. As well, our results offers novel outlooks for the management of bacterial communities during natural attenuation of multi-contaminated nonferrous metal(loid) tailings sites.
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| 49. |
- Liu, Jian-li, et al.
(författare)
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China's most typical nonferrous organic-metal facilities own specific microbial communities
- 2018
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
-
Tidskriftsartikel (refereegranskat)abstract
- The diversity and function of microorganisms have yet to be explored at non-ferrous metal mining facilities (NMMFs), which are the world's largest and potentially most toxic sources of co-existing metal(loid)s and flotation reagents (FRs). The diversity and inferred functions of different bacterial communities inhabiting two types of sites (active and abandoned) in Guangxi province (China) were investigated for the first time. Here we show that the structure and diversity of bacteria correlated with the types of mine sites, metal(loid)s, and FRs concentrations; and best correlated with the combination of pH, Cu, Pb, and Mn. Combined microbial coenobium may play a pivotal role in NMMFs microbial life. Arenimonas, specific in active mine sites and an acidophilic bacterium, carries functions able to cope with the extreme conditions, whereas Latescibacteria specific in abandoned sites can degrade organics. Such a bacterial consortium provides new insights to develop cost-effective remediation strategies of co-contaminated sites that currently remain intractable for bioremediation.
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| 50. |
- Pedersen, C. A., et al.
(författare)
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In situ observations of black carbon in snow and the corresponding spectral surface albedo reduction
- 2015
-
Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 120:4, s. 1476-1489
-
Tidskriftsartikel (refereegranskat)abstract
- Black carbon (BC) particles emitted from incomplete combustion of fossil fuel and biomass and deposited on snow and ice darken the surface and reduce the surface albedo. Even small initial surface albedo reductions may have larger adjusted effects due to snow morphology changes and changes in the sublimation and snow melt rate. Most of the literature on the effect of BC on snow surface albedo is based on numerical models, and few in situ field measurements exist to confirm this reduction. Here we present an extensive set of concurrent in situ measurements of spectral surface albedo, BC concentrations in the upper 5 cm of the snowpack, snow physical parameters (grain size and depth), and incident solar flux characteristics from the Arctic. From this data set (with median BC concentrations ranging from 5 to 137 ng BC per gram of snow) we are able to separate the BC signature on the snow albedo from the natural snow variability. Our measurements show a significant correlation between BC in snow and spectral surface albedo. Based on these measurements, parameterizations are provided, relating the snow albedo, as a function of wavelength, to the equivalent BC content in the snowpack. The term equivalent BC used here is the elemental carbon concentration inferred from the thermo-optical method adjusted for the fraction of non-BC constituents absorbing sunlight in the snow. The first parameterization is a simple equation which efficiently describes the snow albedo reduction due to the equivalent BC without including details on the snow or BC microphysics. This can be used in models when a simplified description is needed. A second parameterization, including snow grain size information, shows enhanced correspondence with the measurements. The extracted parameterizations are valid for wavelength bands 400-900 nm, constrained for BC concentrations between 1 and 400 ng g(-1), and for an optically thick snowpack. The parameterizations are purely empirical, and particular focus was on the uncertainties associated with the measurements, and how these uncertainties propagate in the parameterizations. Integrated, the first parameterization (based only on the equivalent BC) gives a broadband (400-900 nm) snow albedo reduction of 0.004 due to 10 ng equivalent BC per gram of snow, while the effect is almost 5 times larger for BC concentrations 1 order of magnitude higher. The study shows that the reconstructed albedo from the second parameterization (including information on the snow grain size) corresponds better to the radiative transfer model Snow, Ice, and Aerosol Radiation albedo than the reconstructed albedo from the first parameterization (excluding grain size information).
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