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- Morris, John A, et al.
(author)
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An atlas of genetic influences on osteoporosis in humans and mice.
- 2019
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 51, s. 258-266
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Journal article (peer-reviewed)abstract
- Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR)=58, P=1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P<0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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- Gardner, Emma, et al.
(author)
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Field boundary features can stabilise bee populations and the pollination of mass-flowering crops in rotational systems
- 2021
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In: Journal of Applied Ecology. - : Wiley. - 0021-8901 .- 1365-2664. ; 58:10, s. 2287-2304
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Journal article (peer-reviewed)abstract
- Pollinators experience large spatiotemporal fluctuations in resource availability when mass-flowering crops are rotated with resource-poor cereal crops. Yet, few studies have considered the effect this has on pollinator population stability, nor how this might be mitigated to maintain consistent crop pollination services. We assess the potential of boundary features (standard narrow 1 m grassy margins, hedgerows and wide 4 m agri-environment margins) to support and stabilise pollinator populations and pollination service in agricultural landscapes under crop rotation. Assuming a 6-year rotation, we use a process-based pollinator model to predict yearly pollinator population size and in-crop visitation rates to oilseed rape and field bean across 117 study landscapes in England with varying amounts of boundary features. We model both ground-nesting bumblebees and solitary bees and compare the predictions including and excluding boundary features from the landscapes. Ground-nesting bumblebee populations, whose longer-lifetime colonies benefit from continuity of resources, were larger and more stable (relative to the no-features scenario) in landscapes with more boundary features. Ground-nesting solitary bee populations were also larger but not significantly more stable, except with the introduction of wide permanent agri-environment margins, due to their shorter lifetimes and shorter foraging/dispersal ranges. Crop visitation by ground-nesting bumblebees was greater and more stable in landscapes with more boundary features, partly due to increased colony growth prior to crop flowering. Time averaged crop visitation by ground-nesting solitary bees was slightly lower, due to females dividing their foraging time between boundary features and the crop. However, despite this, the minimum pollination service delivered was higher, due to the more stable delivery. Synthesis and applications. Field boundary features have an important role in stabilising pollinator populations and pollination service in rotational systems, although maintenance of larger semi-natural habitat patches may be more effective for stabilising less mobile solitary bee populations. We recommend using combinations of boundary features, accounting for pollinator range when spacing features/rotating crops, and synchronising boundary feature management with crop rotation to maximise their stabilising benefits.
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- Gardner, Emma, et al.
(author)
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Reliably predicting pollinator abundance : Challenges of calibrating process-based ecological models
- 2020
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In: Methods in Ecology and Evolution. - 2041-210X. ; 11:12, s. 1673-1689
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Journal article (peer-reviewed)abstract
- Pollination is a key ecosystem service for global agriculture but evidence of pollinator population declines is growing. Reliable spatial modelling of pollinator abundance is essential if we are to identify areas at risk of pollination service deficit and effectively target resources to support pollinator populations. Many models exist which predict pollinator abundance but few have been calibrated against observational data from multiple habitats to ensure their predictions are accurate. We selected the most advanced process-based pollinator abundance model available and calibrated it for bumblebees and solitary bees using survey data collected at 239 sites across Great Britain. We compared three versions of the model: one parameterised using estimates based on expert opinion, one where the parameters are calibrated using a purely data-driven approach and one where we allow the expert opinion estimates to inform the calibration process. All three model versions showed significant agreement with the survey data, demonstrating this model's potential to reliably map pollinator abundance. However, there were significant differences between the nesting/floral attractiveness scores obtained by the two calibration methods and from the original expert opinion scores. Our results highlight a key universal challenge of calibrating spatially explicit, process-based ecological models. Notably, the desire to reliably represent complex ecological processes in finely mapped landscapes necessarily generates a large number of parameters, which are challenging to calibrate with ecological and geographical data that are often noisy, biased, asynchronous and sometimes inaccurate. Purely data-driven calibration can therefore result in unrealistic parameter values, despite appearing to improve model-data agreement over initial expert opinion estimates. We therefore advocate a combined approach where data-driven calibration and expert opinion are integrated into an iterative Delphi-like process, which simultaneously combines model calibration and credibility assessment. This may provide the best opportunity to obtain realistic parameter estimates and reliable model predictions for ecological systems with expert knowledge gaps and patchy ecological data.
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- Lepag, M, et al.
(author)
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Dose resolution optimization of polymer gel dosimeters using different monomers
- 2001
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In: Physics in Medicine and Biology. - : IOP Publishing. - 1361-6560 .- 0031-9155. ; 46:10, s. 2665-2680
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Journal article (peer-reviewed)abstract
- Polymer gel dosimeters of different formulations were manufactured from different monomers of acrylamide, acrylic acid, methacrylic acid, 1-vinyl-2-pyrrolidinone, 2-hydroxyethyl methacrylate and 2-hydroxyethyl acrylate. Gelatin and agarose were used as the gelling agents and N,N'-methylene-bis-acrylamide was used as a co-monomer in each polymer gel dosimeter. The T2 dependence of each dosimeter was analysed using a model of fast exchange of magnetization. The influence of the half-dose and the apparent T2 of the polymer-proton pool on the dose resolution (Dpdelta) were examined. Comparisons are made with the commonly employed R2-dose sensitivity. Differences exist suggesting that experiments reported in the literature using what were thought to be more optimal dosimeters may not actually be so. Based on Dpdelta of each formulation, conclusions are drawn on the optimal formulation required for a specific range of absorbed doses. In addition, information about the extent of polymerization of the monomers used along with some characteristics of the polymer network formed are reported. The influence of the concentration of monomers and gelling agent was subsequently evaluated using a model of fast exchange of magnetization. Based on these calculations, further improvement in Dpdelta can be expected.
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- Lundberg, Pernilla, et al.
(author)
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Greater bone formation of Y2 knockout mice is associated with increased osteoprogenitor numbers and altered Y1 receptor expression.
- 2007
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 282:26, s. 19082-19091
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Journal article (peer-reviewed)abstract
- Germ line or hypothalamus-specific deletion of Y2 receptors in mice results in a doubling of trabecular bone volume. However, the specific mechanism by which deletion of Y2 receptors increases bone mass has not yet been identified. Here we show that cultured adherent bone marrow stromal cells from Y2(-/-) mice also demonstrate increased mineralization in vitro. Isolation of two populations of progenitor cell types, an immature mesenchymal stem cell population and a more highly differentiated population of progenitor cells, revealed a greater number of the progenitor cells within the bone of Y2(-/-) mice. Analysis of Y receptor transcripts in cultured stromal cells from wild-type mice revealed high levels of Y1 but not Y2, Y4, Y5, or y6 receptor mRNA. Interestingly, germ line Y2 receptor deletion causes Y1 receptor down-regulation in stromal cells and bone tissue possibly due to the lack of feedback inhibition of NPY release and subsequent overstimulation of Y1 receptors. Furthermore, deletion of Y1 receptors resulted in increased bone mineral density in mice. Together, these findings indicate that the greater number of mesenchymal progenitors and the altered Y1 receptor expression within bone cells in the absence of Y2 receptors are a likely mechanism for the greater bone mineralization in vivo and in vitro, opening up potential new treatment avenues for osteoporosis.
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| 10. |
- Maaß, Tobias, et al.
(author)
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Heterogeneity of Collagen VI Microfibrils: Structural Analysis of Non-collagenous Regions.
- 2016
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In: Journal of Biological Chemistry. - 1083-351X. ; 291:10, s. 5247-5258
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Journal article (peer-reviewed)abstract
- Collagen VI, a collagen with uncharacteristically large N- and C-terminal non-collagenous regions, forms a distinct microfibrillar network in most connective tissues. It was long considered to consist of three genetically distinct α chains (α1, α2 and α3). Intracellularly heterotrimeric molecules associate to form dimers and tetramers, which are then secreted and assembled to microfibrils. The identification of three novel long collagen VI α chains α4, α5, and α6 led to the question if and how these may substitute for the long α3 chain in collagen VI assembly. Here we studied structural features of the novel long chains, and analyzed the assembly of these into tetramers and microfibrils. N- and C-terminal globular regions of collagen VI were recombinantly expressed and studied by SAXS. Ab initio models of the N-terminal globular regions of the α4, α5 and α6 chains showed a C-shaped structure similar to that found for the α3 chain. Single particle EM nanostructure of the N-terminal globular region of the α4 chain confirmed the C-shaped structure revealed by SAXS. Immuno EM of collagen VI extracted from tissue revealed that like the α3 chain the novel long chains assemble to homotetramers that are incorporated into mixed microfibrils. Moreover, SAXS models of the C-terminal globular regions of the α1, α2, α4, and α6 chains were generated. Interestingly, the α1, α2 and α4 C-terminal globular regions dimerize. These self-interactions may play a role in tetramer formation.
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