| 1. |
- Estrada, Karol, et al.
(author)
-
Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
-
Journal article (peer-reviewed)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
|
|
| 2. |
- Thiele, I., et al.
(author)
-
A community-driven global reconstruction of human metabolism
- 2013
-
In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 31:5, s. 419-
-
Journal article (peer-reviewed)abstract
- Multiple models of human metabolism have been reconstructed, but each represents only a subset of our knowledge. Here we describe Recon 2, a community-driven, consensus 'metabolic reconstruction', which is the most comprehensive representation of human metabolism that is applicable to computational modeling. Compared with its predecessors, the reconstruction has improved topological and functional features, including similar to 2x more reactions and similar to 1.7x more unique metabolites. Using Recon 2 we predicted changes in metabolite biomarkers for 49 inborn errors of metabolism with 77% accuracy when compared to experimental data. Mapping metabolomic data and drug information onto Recon 2 demonstrates its potential for integrating and analyzing diverse data types. Using protein expression data, we automatically generated a compendium of 65 cell type-specific models, providing a basis for manual curation or investigation of cell-specific metabolic properties. Recon 2 will facilitate many future biomedical studies and is freely available at http://humanmetabolism.org/.
|
|
| 3. |
- Baldi, A., et al.
(author)
-
Mg/Ti multilayers : Structural and hydrogen absorption properties
- 2010
-
In: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 81:22, s. 224203-
-
Journal article (peer-reviewed)abstract
- Mg-Ti alloys have uncommon optical and hydrogen absorbing properties, originating from a "spinodal-like" microstructure with a small degree of chemical short-range order in the atomic distribution. In the present study we artificially engineer short-range order by depositing Pd-capped Mg/Ti multilayers with different periodicities. Notwithstanding the large lattice mismatch between Mg and Ti, the as-deposited metallic multilayers show good structural coherence. On exposure to H-2 gas a two-step hydrogenation process occurs with the Ti layers forming the hydride before Mg. From in situ measurements of the bilayer thickness Lambda at different hydrogen pressures, we observe large out-of-plane expansions of Mg and Ti layers on hydrogenation, indicating strong plastic deformations in the films and a consequent shortening of the coherence length. On unloading at room temperature in air, hydrogen atoms remain trapped in the Ti layers due to kinetic constraints. Such loading/unloading sequence can be explained in terms of the different thermodynamic properties of hydrogen in Mg and Ti, as shown by diffusion calculations on a model multilayered systems. Absorption isotherms measured by hydrogenography can be interpreted as a result of the elastic clamping arising from strongly bonded Mg/Pd and broken Mg/Ti interfaces.
|
|
| 4. |
- Andersson, K. G., et al.
(author)
-
Parametric improvement for the ingestion dose module of the European ARGOS and RODOS decision support systems
- 2011
-
In: Radioprotection. - : EDP Sciences. - 0033-8451 .- 1769-700X. ; 46
-
Journal article (peer-reviewed)abstract
- The European decision support systems ARGOS and RODOS rely on the ECOSYS model for prognoses of ingestion doses. ECOSYS needs an update of various parameter values to provide reliable estimates. This paper reports on some results of a Nordic initiative to derive parameter values that are specific to Nordic conditions, as well as to improve generic parameter values in ECOSYS, taking into account the host of useful measurement data accumulated since ECOSYS was created. © 2011 EDP Sciences.
|
|
| 5. |
- Azofeifa, D. E., et al.
(author)
-
Temperature-and hydrogen-induced changes in the optical properties of Pd capped V thin films
- 2012
-
In: Physica Scripta. - : IOP Publishing. - 0031-8949 .- 1402-4896. ; 86:6, s. 065702-
-
Journal article (peer-reviewed)abstract
- Optical properties of V thin films deposited on MgO substrates have been obtained from spectrophotometric measurements. The V films were coated with a thin Pd layer to protect them from oxidation and to favor absorption of atomic hydrogen. Electrical resistance was recorded while hydrogen pressure was increased slowly up to 750mbar keeping the temperature constant. Simultaneously, visible and near-infrared transmittance spectra of this Pd/V/MgO system were measured. The spectra were numerically inverted to obtain the spectral behavior of the Pd and V dielectric functions at 22 and 140 degrees C. Hydrogen concentrations were first determined from the combined effect of hydrogen content on the electrical resistance and on the optical direct transmission of the system. Then, determination of these concentrations was improved using retrieved values of the absorption coefficients of the hydrides and taking into account the structural change of V and the volumetric expansion of Pd. Good agreement is established when considering qualitative correlations between spectral features of the optimized PdHy and VHx dielectric functions and band structure calculations and densities of states for these two transition metal hydrides.
|
|
| 6. |
- Kiemeney, Lambertus A, et al.
(author)
-
A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
-
In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
-
Journal article (peer-reviewed)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
|
|
| 7. |
- Oei, Ling, et al.
(author)
-
A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus
- 2014
-
In: Journal of Medical Genetics. - : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 51:2, s. 122-131
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.AIM: To identify CNVs associated with osteoporotic bone fracture risk.METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies.RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk.CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.
|
|
