| 1. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 2. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 3. |
- Heid, Iris M, et al.
(författare)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
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Tidskriftsartikel (refereegranskat)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 4. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 5. |
- Speliotes, Elizabeth K., et al.
(författare)
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 6. |
- Wang, Li-San, et al.
(författare)
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Rarity of the Alzheimer Disease-Protective APP A673T Variant in the United States.
- 2015
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 72:2
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Tidskriftsartikel (refereegranskat)abstract
- Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States.
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| 7. |
- Žliobaitė, Indrė, et al.
(författare)
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The NOW Database of Fossil Mammals
- 2023
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Ingår i: Evolution of Cenozoic Land Mammal Faunas and Ecosystems: 25 years of the NOW database of fossil mammals. - : Springer. ; , s. 33-42
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Bokkapitel (refereegranskat)abstract
- NOW (New and Old Worlds) is a global database of fossil mammal occurrences, currently containing around 68,000 locality-species entries. The database spans the last 66 million years, with its primary focus on the last 23 million years. Whereas the database contains records from all continents, the main focus and coverage of the database historically has been on Eurasia. The database includes primarily, but not exclusively, terrestrial mammals. It covers a large part of the currently known mammalian fossil record, focusing on classical and actively researched fossil localities. The database is managed in collaboration with an international advisory board of experts. Rather than a static archive, it emphasizes the continuous integration of new knowledge of the community, data curation, and consistency of scientific interpretations. The database records species occurrences at localities worldwide, as well as ecological characteristics of fossil species, geological contexts of localities and more. The NOW database is primarily used for two purposes: (1) queries about occurrences of particular taxa, their characteristics and properties of localities in the spirit of an encyclopedia; and (2) large scale research and quantitative analyses of evolutionary processes, patterns, reconstructing past environments, as well as interpreting evolutionary contexts. The data are fully open, no logging in or community membership is necessary for using the data for any purpose.
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| 8. |
- Adams, Jimi, et al.
(författare)
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Peer Network Processes in Adolescents' Health Lifestyles
- 2022
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Ingår i: Journal of health and social behavior. - : SAGE Publications. - 0022-1465 .- 2150-6000. ; 63:1, s. 125-141
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Tidskriftsartikel (refereegranskat)abstract
- Combining theories of health lifestyles-interrelated health behaviors arising from group-based identities-with those of network and behavior change, we investigated network characteristics of health lifestyles and the role of influence and selection processes underlying these characteristics. We examined these questions in two high schools using longitudinal, complete friendship network data from the National Longitudinal Study of Adolescent to Adult Health. Latent class analyses characterized each school's predominant health lifestyles using several health behavior domains. School-specific stochastic actor-based models evaluated the bidirectional relationship between friendship networks and health lifestyles. Predominant lifestyles remained stable within schools over time, even as individuals transitioned between lifestyles. Friends displayed greater similarity in health lifestyles than nonfriend dyads. Similarities resulted primarily from teens' selection of friends with similar lifestyles but also from teens influencing their peers' lifestyles. This study demonstrates the salience of health lifestyles for adolescent development and friendship networks.
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| 9. |
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| 10. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:8, s. 868-U202
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P = 1.22 x 10(-14)), 18q21.33 (BCL2, P = 7.76 x 10(-11)), 11p15.5 (C11orf21, P = 2.15 x 10(-10)), 4q25 (LEF1, P = 4.24 x 10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P = 2.50 x 10(-9)), 9p21.3 (CDKN2B-AS1, P = 1.27 x 10(-8)), 18q21.32 (PMAIP1, P = 2.51 x 10(-8)), 15q15.1 (BMF, P = 2.71 x 10(-10)) and 2p22.2 (QPCT, P = 1.68 x 10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P = 2.08 x 10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P = 5.40 x 10(-8)) and 5p15.33 (TERT, P = 1.92 x 10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.
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| 11. |
- Cerhan, James R., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:11, s. 1233-1238
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 x 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 x 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 x 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 x 10(-13) and 3.63 x 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
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| 12. |
- Folberth, Christian, et al.
(författare)
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Parameterization-induced uncertainties and impacts of crop management harmonization in a global gridded crop model ensemble
- 2019
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 14:9
-
Tidskriftsartikel (refereegranskat)abstract
- Global gridded crop models (GGCMs) combine agronomic or plant growth models with gridded spatial input data to estimate spatially explicit crop yields and agricultural externalities at the global scale. Differences in GGCM outputs arise from the use of different biophysical models, setups, and input data. GGCM ensembles are frequently employed to bracket uncertainties in impact studies without investigating the causes of divergence in outputs. This study explores differences in maize yield estimates from five GGCMs based on the public domain field-scale model Environmental Policy Integrated Climate (EPIC) that participate in the AgMIP Global Gridded Crop Model Intercomparison initiative. Albeit using the same crop model, the GGCMs differ in model version, input data, management assumptions, parameterization, and selection of subroutines affecting crop yield estimates via cultivar distributions, soil attributes, and hydrology among others. The analyses reveal inter-annual yield variability and absolute yield levels in the EPIC-based GGCMs to be highly sensitive to soil parameterization and crop management. All GGCMs show an intermediate performance in reproducing reported yields with a higher skill if a static soil profile is assumed or sufficient plant nutrients are supplied. An in-depth comparison of setup domains for two EPIC-based GGCMs shows that GGCM performance and plant stress responses depend substantially on soil parameters and soil process parameterization, i.e. hydrology and nutrient turnover, indicating that these often neglected domains deserve more scrutiny. For agricultural impact assessments, employing a GGCM ensemble with its widely varying assumptions in setups appears the best solution for coping with uncertainties from lack of comprehensive global data on crop management, cultivar distributions and coefficients for agro-environmental processes. However, the underlying assumptions require systematic specifications to cover representative agricultural systems and environmental conditions. Furthermore, the interlinkage of parameter sensitivity from various domains such as soil parameters, nutrient turnover coefficients, and cultivar specifications highlights that global sensitivity analyses and calibration need to be performed in an integrated manner to avoid bias resulting from disregarded core model domains. Finally, relating evaluations of the EPIC-based GGCMs to a wider ensemble based on individual core models shows that structural differences outweigh in general differences in configurations of GGCMs based on the same model, and that the ensemble mean gains higher skill from the inclusion of structurally different GGCMs. Although the members of the wider ensemble herein do not consider crop-soil-management interactions, their sensitivity to nutrient supply indicates that findings for the EPIC-based sub-ensemble will likely become relevant for other GGCMs with the progressing inclusion of such processes.
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| 13. |
- Hobbins, John C., et al.
(författare)
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Antibiotic prophylaxis before amniocentesis
- 2011
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Ingår i: Prenatal Diagnosis. - : Wiley. - 1097-0223 .- 0197-3851. ; 31:12, s. 1213-1214
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 14. |
- Kanoni, Stavroula, et al.
(författare)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 15. |
- Kinser, Taliesin J, et al.
(författare)
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Endosperm-based incompatibilities in hybrid monkeyflowers
- 2021
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Ingår i: The Plant Cell. - : Oxford University Press. - 1040-4651 .- 1532-298X. ; 33:7, s. 2235-2257
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Tidskriftsartikel (refereegranskat)abstract
- Endosperm is an angiosperm innovation central to their reproduction whose development, and thus seed viability, is controlled by genomic imprinting, where expression from certain genes is parent-specific. Unsuccessful imprinting has been linked to failed inter-specific and inter-ploidy hybridization. Despite their importance in plant speciation, the underlying mechanisms behind these endosperm-based barriers remain poorly understood. Here, we describe one such barrier between diploid Mimulus guttatus and tetraploid Mimulus luteus. The two parents differ in endosperm DNA methylation, expression dynamics, and imprinted genes. Hybrid seeds suffer from underdeveloped endosperm, reducing viability, or arrested endosperm and seed abortion when M. guttatus or M. luteus is seed parent, respectively, and transgressive methylation and expression patterns emerge. The two inherited M. luteus subgenomes, genetically distinct but epigenetically similar, are expressionally dominant over the M. guttatus genome in hybrid embryos and especially their endosperm, where paternal imprints are perturbed. In aborted seeds, de novo methylation is inhibited, potentially owing to incompatible paternal instructions of imbalanced dosage from M. guttatus imprints. We suggest that diverged epigenetic/regulatory landscapes between parental genomes induce epigenetic repatterning and global shifts in expression, which, in endosperm, may uniquely facilitate incompatible interactions between divergent imprinting schemes, potentially driving rapid barriers.
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| 16. |
- Lazarus, Jeffrey V., et al.
(författare)
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A multinational Delphi consensus to end the COVID-19 public health threat
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687.
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Tidskriftsartikel (refereegranskat)abstract
- Despite notable scientific and medical advances, broader political, socioeconomic and behavioural factors continue to undercut the response to the COVID-19 pandemic1,2. Here we convened, as part of this Delphi study, a diverse, multidisciplinary panel of 386 academic, health, non-governmental organization, government and other experts in COVID-19 response from 112 countries and territories to recommend specific actions to end this persistent global threat to public health. The panel developed a set of 41 consensus statements and 57 recommendations to governments, health systems, industry and other key stakeholders across six domains: communication; health systems; vaccination; prevention; treatment and care; and inequities. In the wake of nearly three years of fragmented global and national responses, it is instructive to note that three of the highest-ranked recommendations call for the adoption of whole-of-society and whole-of-government approaches1, while maintaining proven prevention measures using a vaccines-plus approach2 that employs a range of public health and financial support measures to complement vaccination. Other recommendations with at least 99% combined agreement advise governments and other stakeholders to improve communication, rebuild public trust and engage communities3 in the management of pandemic responses. The findings of the study, which have been further endorsed by 184 organizations globally, include points of unanimous agreement, as well as six recommendations with >5% disagreement, that provide health and social policy actions to address inadequacies in the pandemic response and help to bring this public health threat to an end.
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| 17. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
-
Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 18. |
- Müller, Christoph, et al.
(författare)
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Global gridded crop model evaluation : Benchmarking, skills, deficiencies and implications
- 2017
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 10:4, s. 1403-1422
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Tidskriftsartikel (refereegranskat)abstract
- Crop models are increasingly used to simulate crop yields at the global scale, but so far there is no general framework on how to assess model performance. Here we evaluate the simulation results of 14 global gridded crop modeling groups that have contributed historic crop yield simulations for maize, wheat, rice and soybean to the Global Gridded Crop Model Intercomparison (GGCMI) of the Agricultural Model Intercomparison and Improvement Project (AgMIP). Simulation results are compared to reference data at global, national and grid cell scales and we evaluate model performance with respect to time series correlation, spatial correlation and mean bias. We find that global gridded crop models (GGCMs) show mixed skill in reproducing time series correlations or spatial patterns at the different spatial scales. Generally, maize, wheat and soybean simulations of many GGCMs are capable of reproducing larger parts of observed temporal variability (time series correlation coefficients (r) of up to 0.888 for maize, 0.673 for wheat and 0.643 for soybean at the global scale) but rice yield variability cannot be well reproduced by most models. Yield variability can be well reproduced for most major producing countries by many GGCMs and for all countries by at least some. A comparison with gridded yield data and a statistical analysis of the effects of weather variability on yield variability shows that the ensemble of GGCMs can explain more of the yield variability than an ensemble of regression models for maize and soybean, but not for wheat and rice. We identify future research needs in global gridded crop modeling and for all individual crop modeling groups. In the absence of a purely observation-based benchmark for model evaluation, we propose that the best performing crop model per crop and region establishes the benchmark for all others, and modelers are encouraged to investigate how crop model performance can be increased. We make our evaluation system accessible to all crop modelers so that other modeling groups can also test their model performance against the reference data and the GGCMI benchmark.
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| 19. |
- Müller, Christoph, et al.
(författare)
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The Global Gridded Crop Model Intercomparison phase 1 simulation dataset
- 2019
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Ingår i: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- The Global Gridded Crop Model Intercomparison (GGCMI) phase 1 dataset of the Agricultural Model Intercomparison and Improvement Project (AgMIP) provides an unprecedentedly large dataset of crop model simulations covering the global ice-free land surface. The dataset consists of annual data fields at a spatial resolution of 0.5 arc-degree longitude and latitude. Fourteen crop modeling groups provided output for up to 11 historical input datasets spanning 1901 to 2012, and for up to three different management harmonization levels. Each group submitted data for up to 15 different crops and for up to 14 output variables. All simulations were conducted for purely rainfed and near-perfectly irrigated conditions on all land areas irrespective of whether the crop or irrigation system is currently used there. With the publication of the GGCMI phase 1 dataset we aim to promote further analyses and understanding of crop model performance, potential relationships between productivity and environmental impacts, and insights on how to further improve global gridded crop model frameworks. We describe dataset characteristics and individual model setup narratives.
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| 20. |
- Nduva, George M., et al.
(författare)
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Temporal trends and transmission dynamics of pre-treatment HIV-1 drug resistance within and between risk groups in Kenya, 1986–2020
- 2024
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Ingår i: Journal of Antimicrobial Chemotherapy. - 0305-7453. ; 79:2, s. 287-296
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Tidskriftsartikel (refereegranskat)abstract
- Background: Evidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) among risk groups is limited in Africa. We assessed the prevalence, trends and transmission dynamics of pre-treatment HIVDR within and between MSM, people who inject drugs (PWID), female sex workers (FSWs), heterosexuals (HETs) and perinatally infected children in Kenya. Methods: HIV-1 partial pol sequences from antiretroviral-naive individuals collected from multiple sources between 1986 and 2020 were used. Pre-treatment reverse transcriptase inhibitor (RTI), PI and integrase inhibitor (INSTI) mutations were assessed using the Stanford HIVDR database. Phylogenetic methods were used to determine and date transmission clusters. Results: Of 3567 sequences analysed, 550 (15.4%, 95% CI: 14.2–16.6) had at least one pre-treatment HIVDR mutation, which was most prevalent amongst children (41.3%), followed by PWID (31.0%), MSM (19.9%), FSWs (15.1%) and HETs (13.9%). Overall, pre-treatment HIVDR increased consistently, from 6.9% (before 2005) to 24.2% (2016–20). Among HETs, pre-treatment HIVDR increased from 6.6% (before 2005) to 20.2% (2011–15), but dropped to 6.5% (2016–20). Additionally, 32 clusters with shared pre-treatment HIVDR mutations were identified. The majority of clusters had R0 ≥ 1.0, indicating ongoing transmissions. The largest was a K103N cluster involving 16 MSM sequences sampled between 2010 and 2017, with an estimated time to the most recent common ancestor (tMRCA) of 2005 [95% higher posterior density (HPD), 2000–08], indicating propagation over 12 years. Conclusions: Compared to HETs, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2017 may have abrogated the increase in pre-treatment RTI mutations, albeit in the HET population only. Taken together, our findings underscore the need for targeted efforts towards equitable access to ART for children and key populations in Kenya.
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| 21. |
- Reyna, Matthew A, et al.
(författare)
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Pathway and network analysis of more than 2500 whole cancer genomes
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53, TLE4, and TCF4. We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and samples containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as samples with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
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| 22. |
- Ricordi, Camillo, et al.
(författare)
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National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial : Manufacture of a Complex Cellular Product at Eight Processing Facilities
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:11, s. 3418-3428
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Tidskriftsartikel (refereegranskat)abstract
- Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.
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| 23. |
- Rivera-Cuevas, Yolanda, et al.
(författare)
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Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins
- 2021
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 17:12, s. e1010138-e1010138
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Tidskriftsartikel (refereegranskat)abstract
- Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole (PV), the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the host Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T. gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV-1 virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV-1 Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of TgGRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T. gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PV membrane (PVM). These findings provide new insight into how T. gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission.
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| 24. |
- Ruane, Alex C., et al.
(författare)
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Strong regional influence of climatic forcing datasets on global crop model ensembles
- 2021
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Ingår i: Agricultural and Forest Meteorology. - : Elsevier BV. - 0168-1923. ; 300
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Tidskriftsartikel (refereegranskat)abstract
- We present results from the Agricultural Model Intercomparison and Improvement Project (AgMIP) Global Gridded Crop Model Intercomparison (GGCMI) Phase I, which aligned 14 global gridded crop models (GGCMs) and 11 climatic forcing datasets (CFDs) in order to understand how the selection of climate data affects simulated historical crop productivity of maize, wheat, rice and soybean. Results show that CFDs demonstrate mean biases and differences in the probability of extreme events, with larger uncertainty around extreme precipitation and in regions where observational data for climate and crop systems are scarce. Countries where simulations correlate highly with reported FAO national production anomalies tend to have high correlations across most CFDs, whose influence we isolate using multi-GGCM ensembles for each CFD. Correlations compare favorably with the climate signal detected in other studies, although production in many countries is not primarily climate-limited (particularly for rice). Bias-adjusted CFDs most often were among the highest model-observation correlations, although all CFDs produced the highest correlation in at least one top-producing country. Analysis of larger multi-CFD-multi-GGCM ensembles (up to 91 members) shows benefits over the use of smaller subset of models in some regions and farming systems, although bigger is not always better. Our analysis suggests that global assessments should prioritize ensembles based on multiple crop models over multiple CFDs as long as a top-performing CFD is utilized for the focus region.
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| 25. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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