| 1. |
- Ellinor, Patrick T., et al.
(författare)
-
Meta-analysis identifies six new susceptibility loci for atrial fibrillation
- 2012
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:6, s. 88-670
-
Tidskriftsartikel (refereegranskat)abstract
- Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death(1). We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 x 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.
|
|
| 2. |
- von der Lieth, Claus-Wilhelm, et al.
(författare)
-
EUROCarbDB : an open-access platform for glycoinformatics
- 2011
-
Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 21:4, s. 493-502
-
Tidskriftsartikel (refereegranskat)abstract
- The EUROCarbDB project is a design study for a technical framework, which provides sophisticated, freely accessible, open-source informatics tools and databases to support glycobiology and glycomic research. EUROCarbDB is a relational database containing glycan structures, their biological context and, when available, primary and interpreted analytical data from high-performance liquid chromatography, mass spectrometry and nuclear magnetic resonance experiments. Database content can be accessed via a web-based user interface. The database is complemented by a suite of glycoinformatics tools, specifically designed to assist the elucidation and submission of glycan structure and experimental data when used in conjunction with contemporary carbohydrate research workflows. All software tools and source code are licensed under the terms of the Lesser General Public License, and publicly contributed structures and data are freely accessible. The public test version of the web interface to the EUROCarbDB can be found at http://www.ebi.ac.uk/eurocarb.
|
|
| 3. |
- Almeida, Joao, et al.
(författare)
-
Molecular understanding of sulphuric acid-amine particle nucleation in the atmosphere
- 2013
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 502:7471, s. 359-
-
Tidskriftsartikel (refereegranskat)abstract
- Nucleation of aerosol particles from trace atmospheric vapours is thought to provide up to half of global cloud condensation nuclei(1). Aerosols can cause a net cooling of climate by scattering sunlight and by leading to smaller but more numerous cloud droplets, which makes clouds brighter and extends their lifetimes(2). Atmospheric aerosols derived from human activities are thought to have compensated for a large fraction of the warming caused by greenhouse gases(2). However, despite its importance for climate, atmospheric nucleation is poorly understood. Recently, it has been shown that sulphuric acid and ammonia cannot explain particle formation rates observed in the lower atmosphere(3). It is thought that amines may enhance nucleation(4-16), but until now there has been no direct evidence for amine ternary nucleation under atmospheric conditions. Here we use the CLOUD (Cosmics Leaving OUtdoor Droplets) chamber at CERN and find that dimethylamine above three parts per trillion by volume can enhance particle formation rates more than 1,000-fold compared with ammonia, sufficient to account for the particle formation rates observed in the atmosphere. Molecular analysis of the clusters reveals that the faster nucleation is explained by a base-stabilization mechanism involving acid-amine pairs, which strongly decrease evaporation. The ion-induced contribution is generally small, reflecting the high stability of sulphuric acid-dimethylamine clusters and indicating that galactic cosmic rays exert only a small influence on their formation, except at low overall formation rates. Our experimental measurements are well reproduced by a dynamical model based on quantum chemical calculations of binding energies of molecular clusters, without any fitted parameters. These results show that, in regions of the atmosphere near amine sources, both amines and sulphur dioxide should be considered when assessing the impact of anthropogenic activities on particle formation.
|
|
| 4. |
- Donahue, Neil M., et al.
(författare)
-
How do organic vapors contribute to new-particle formation?
- 2013
-
Ingår i: Faraday discussions. - : Royal Society of Chemistry. - 1359-6640 .- 1364-5498. ; 165, s. 91-104
-
Tidskriftsartikel (refereegranskat)abstract
- Highly oxidised organic vapors can effectively stabilize sulphuric acid in heteronuclear clusters and drive new-particle formation. We present quantum chemical calculations of cluster stability, showing that multifunctional species can stabilize sulphuric acid and also present additional polar functional groups for subsequent cluster growth. We also model the multi-generation oxidation of vapors associated with secondary organic aerosol formation using a two-dimensional volatility basis set. The steady-state saturation ratios and absolute concentrations of extremely low volatility products are sufficient to drive new-particle formation with sulphuric acid at atmospherically relevant rates.
|
|
| 5. |
- Franke, Barbara, et al.
(författare)
-
Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1
- 2014
-
Ingår i: Open Biology. - London, United Kingdom : The Royal Society Publishing. - 2046-2441. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- MuRF1 is an E3 ubiquitin ligase central to muscle catabolism. It belongs to the TRIM protein family characterized by a tripartite fold of RING, B-box and coiled-coil (CC) motifs, followed by variable C-terminal domains. The CC motif is hypothesized to be responsible for domain organization in the fold as well as for high-order assembly into functional entities. But data on CC from this family that can clarify the structural significance of this motif are scarce. We have characterized the helical region from MuRF1 and show that, contrary to expectations, its CC domain assembles unproductively, being the B2- and COS-boxes in the fold (respectively flanking the CC) that promote a native quaternary structure. In particular, the C-terminal COS-box seemingly forms an α-hairpin that packs against the CC, influencing its dimerization. This shows that a C-terminal variable domain can be tightly integrated within the conserved TRIM fold to modulate its structure and function. Furthermore, data from transfected muscle show that in MuRF1 the COS-box mediates the in vivo targeting of sarcoskeletal structures and points to the pharmacological relevance of the COS domain for treating MuRF1-mediated muscle atrophy.
|
|
| 6. |
- Pierce, David M., et al.
(författare)
-
DT-MRI Based Computation of Collagen Fiber Deformation in Human Articular Cartilage : A Feasibility Study
- 2010
-
Ingår i: Annals of Biomedical Engineering. - : Springer Science and Business Media LLC. - 0090-6964 .- 1573-9686. ; 38:7, s. 2447-2463
-
Tidskriftsartikel (refereegranskat)abstract
- Accurate techniques for simulating the deformation of soft biological tissues are an increasingly valuable tool in many areas of biomechanical analysis and medical image computing. To model the complex morphology and response of articular cartilage, a hyperviscoelastic (dispersed) fiber-reinforced constitutive model is employed to complete two specimen-specific finite element (FE) simulations of an indentation experiment, with and without considering fiber dispersion. Ultra-high field Diffusion Tensor Magnetic Resonance Imaging (17.6 T DT-MRI) is performed on a specimen of human articular cartilage before and after indentation to similar to 20% compression. Based on this DT-MRI data, we detail a novel FE approach to determine the geometry (edge detection from first eigenvalue), the meshing (semi-automated smoothing of DTI measurement voxels), and the fiber structural input (estimated principal fiber direction and dispersion). The global and fiber fabric deformations of both the un-dispersed and dispersed fiber models provide a satisfactory match to that estimated experimentally. In both simulations, the fiber fabric in the superficial and middle zones becomes more aligned with the articular surface, although the dispersed model appears more consistent with the literature. In the future, a multi-disciplinary combination of DT-MRI and numerical simulation will allow the functional state of articular cartilage to be determined in vivo.
|
|
| 7. |
- Prank, Marje, et al.
(författare)
-
An operational model for forecasting ragweed pollen release and dispersion in Europe.
- 2013
-
Ingår i: Agricultural and Forest Meteorology. - : Elsevier BV. - 0168-1923. ; 182-183, s. 43-53
-
Tidskriftsartikel (refereegranskat)abstract
- The paper considers the possibilities of modelling the release and dispersion of the pollen of common ragweed (Ambrosia artemisiifolia L.), a highly allergenic invasive weed, which is spreading through southern and central Europe. In order to provide timely warnings for the allergy sufferers, a model was developed for forecasting ragweed pollen concentrations in the air. The development was based on the system for integrated modelling of atmospheric composition (SILAM) and concentrated on spatio-temporal modelling of ragweed flowering season and pollen release, which constitutes the emission term. Evaluation of the new model against multi-annual ragweed pollen observations demonstrated that the model reproduces well the main ragweed pollen season in the areas with major plant presence, such as the Pannonian Plain, the Lyon area in France, the Milan region in Italy, Ukraine and southern Russia. The predicted start of the season is mostly within 3 days of the observed for the majority of stations in these areas. The temporal correlation between modelled and observed concentrations exceeds 0.6 for the bulk of the stations. Model application to the seasons of 2005–2011 indicated the regions with high ragweed pollen concentrations, in particular the areas where allergenic thresholds are exceeded. It is demonstrated that, due to long-range transport of pollen, high-concentration areas are substantially more extensive than the heavily infested territories.
|
|
| 8. |
- von Castelmur, Eleonore, et al.
(författare)
-
Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase
- 2012
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Washington, DC, United States : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:34, s. 13608-13613
-
Tidskriftsartikel (refereegranskat)abstract
- Titin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn(31)-Nlinker-kinase-CRD-Ig(26)) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N- and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes.
|
|
