| 1. |
- Berndt, Sonja I., et al.
(författare)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Tidskriftsartikel (refereegranskat)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 2. |
- McQuillan, Ruth, et al.
(författare)
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Evidence of Inbreeding Depression on Human Height
- 2012
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:7, s. e1002655-
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Tidskriftsartikel (refereegranskat)abstract
- Stature is a classical and highly heritable complex trait, with 80%–90% of variation explained by genetic factors. In recent years, genome-wide association studies (GWAS) have successfully identified many common additive variants influencing human height; however, little attention has been given to the potential role of recessive genetic effects. Here, we investigated genome-wide recessive effects by an analysis of inbreeding depression on adult height in over 35,000 people from 21 different population samples. We found a highly significant inverse association between height and genome-wide homozygosity, equivalent to a height reduction of up to 3 cm in the offspring of first cousins compared with the offspring of unrelated individuals, an effect which remained after controlling for the effects of socio-economic status, an important confounder (χ2 = 83.89, df = 1; p = 5.2×10−20). There was, however, a high degree of heterogeneity among populations: whereas the direction of the effect was consistent across most population samples, the effect size differed significantly among populations. It is likely that this reflects true biological heterogeneity: whether or not an effect can be observed will depend on both the variance in homozygosity in the population and the chance inheritance of individual recessive genotypes. These results predict that multiple, rare, recessive variants influence human height. Although this exploratory work focuses on height alone, the methodology developed is generally applicable to heritable quantitative traits (QT), paving the way for an investigation into inbreeding effects, and therefore genetic architecture, on a range of QT of biomedical importance.
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| 3. |
- Alvarsson, Jonathan, et al.
(författare)
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Benchmarking Study of Parameter Variation When Using Signature Fingerprints Together with Support Vector Machines
- 2014
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:11, s. 3211-3217
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Tidskriftsartikel (refereegranskat)abstract
- QSAR modeling using molecular signatures and support vector machines with a radial basis function is increasingly used for virtual screening in the drug discovery field. This method has three free parameters: C, ?, and signature height. C is a penalty parameter that limits overfitting, ? controls the width of the radial basis function kernel, and the signature height determines how much of the molecule is described by each atom signature. Determination of optimal values for these parameters is time-consuming. Good default values could therefore save considerable computational cost. The goal of this project was to investigate whether such default values could be found by using seven public QSAR data sets spanning a wide range of end points and using both a bit version and a count version of the molecular signatures. On the basis of the experiments performed, we recommend a parameter set of heights 0 to 2 for the count version of the signature fingerprints and heights 0 to 3 for the bit version. These are in combination with a support vector machine using C in the range of 1 to 100 and gamma in the range of 0.001 to 0.1. When data sets are small or longer run times are not a problem, then there is reason to consider the addition of height 3 to the count fingerprint and a wider grid search. However, marked improvements should not be expected.
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| 4. |
- Alvarsson, Jonathan, et al.
(författare)
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Ligand-Based Target Prediction with Signature Fingerprints
- 2014
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 54:10, s. 2647-2653
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Tidskriftsartikel (refereegranskat)abstract
- When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology. This can be done by looking at known target binding profiles of similar compounds using chemical similarity searching. The purpose of this study was to construct and evaluate the performance of chemical fingerprints based on the molecular signature descriptor for performing target binding predictions. For the comparison we used the area under the receiver operating characteristics curve (AUC) complemented with net reclassification improvement (NRI). We created two open source signature fingerprints, a bit and a count version, and evaluated their performance compared to a set of established fingerprints with regards to predictions of binding targets using Tanimoto-based similarity searching on publicly available data sets extracted from ChEMBL. The results showed that the count version of the signature fingerprint performed on par with well-established fingerprints such as ECFP. The count version outperformed the bit version slightly; however, the count version is more complex and takes more computing time and memory to run so its usage should probably be evaluated on a case-by-case basis. The NRI based tests complemented the AUC based ones and showed signs of higher power.
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| 5. |
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| 6. |
- Berglund, Björn, 1979-, et al.
(författare)
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Challenges for developing a system for biogas as vehicle fuel : lessons from Linkoping, Sweden
- 2011
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Biofuels are being employed in nearly all the EU member states to fulfill the targets set up by the European Directive 2003/30/EC to have a 5.75% share of renewable energy in their transport sector by 2010. In Sweden ethanol is the leading biofuel, while biogas mainly depend on local initiatives with the city of Linköping as a case in point. Our purpose with this article is to analyze the development of biogas in Linköping within a framework of technological transition theory. To this we add a set of concepts from large technical systems-literature to address and re-analyze two earlier studies on the biogas development in Linköping to achieve a deeper understanding of this success story. We argue that the establishment of a development trajectory for biogas depended on the ability of the involved actors to establish and nurture their social network, to create learning processes and stimulate the articulation of expectations and visions. It was also important that these three factors were allowed to influence each other for the system to gain a momentum of its own. Furthermore, the biogas development in Linköping is found to be interesting in that the triggers for the development came from a variety of levels and angles. Initially, the rising fuel prices after the oil crises in the 1970’s resulted in an increased interest in renewable fuels in general. Second, an anticipated national pipeline for natural gas planned through Linköping was considered a huge potential for methane exports. A part from these external energy incentives, the local trigger was the bad urban air quality caused by the public transport authority’s bus fleet. The breakthrough came when it was discovered that by-product biogas from the wastewater treatment facility could be used as a fuel for transport. When the plans for the national pipeline were rejected, a fruitful co-operation between the municipally owned production facility and the public transport authority was set up to meet the constructed demand from public transport. This cooperative pair-arrangement was the starting point for the biogas niche trajectory as other actors subsequently were enrolled to increase the size and agency of the network. Nowadays, biogas and other renewable fuels play a significant role in the supply of transport fuels for Linköping. In 2009, a total of 9.5% of all transport fuels used in Linköping were from renewable sources, i.e. biogas (4.6%), ethanol and biodiesel. This puts the city well ahead of the European target of 5.75% renewable fuels by 2010.
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| 7. |
- Buchholt, Kristina, et al.
(författare)
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Growth and characterization of epitaxial Ti3GeC2 thin films on 4H-SiC(0001)
- 2012
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Ingår i: Journal of Crystal Growth. - : Elsevier. - 0022-0248 .- 1873-5002. ; 343:1, s. 133-137
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Tidskriftsartikel (refereegranskat)abstract
- Epitaxial Ti3GeC2 thin films were deposited on 4 degrees off-cut 4H-SiC(0001) using magnetron sputtering from high purity Ti, C, and Ge targets. Scanning electron microscopy and helium ion microscopy show that the Ti3GeC2 films grow by lateral step-flow with {11 (2) over bar0} faceting on the SiC surface. Using elastic recoil detection analysis, atomic force microscopy, and X-Ray diffraction the films were found to be substoichiometric in Ge with the presence of small Ge particles at the surface of the film.
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| 8. |
- Buchholt, Kristina, et al.
(författare)
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Ohmic contact properties of magnetron sputtered Ti3SiC2 on n- and p-type 4H-silicon carbide
- 2011
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 98:4, s. 042108-
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Tidskriftsartikel (refereegranskat)abstract
- Epitaxial Ti3SiC2 (0001) thin film contacts were grown on doped 4H-SiC (0001) using magnetron sputtering in an ultra high vacuum system. The specific contact resistance was investigated using linear transmission line measurements. Rapid thermal annealing at 950 degrees C for 1 min of as-deposited films yielded ohmic contacts to n-type SiC with contact resistances in the order of 10(-4) Omega cm(2). Transmission electron microscopy shows that the interface between Ti3SiC2 and n-type SiC is atomically sharp with evidence of interfacial ordering after annealing. (c) 2011 American Institute of Physics.
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| 9. |
- Carlsson, Lars, et al.
(författare)
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Model building in Bioclipse Decision Support applied to open datasets
- 2012
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Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 211:Suppl., s. S62-
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Tidskriftsartikel (refereegranskat)abstract
- Bioclipse Decision Support (DS) is a system capable of building predictive models of any collection of SAR data, and making them available in a simple user interface based on Bioclipse (www.bioclipse.net).The method is fast and uses Faulon Signatures as chemical descriptors together with a Support Vector Machine algorithm for QSAR model building. A key feature is the capability to visualize and interpret results by highlighting the substructures which contributed most to the prediction. This, together with very fast predictions, allows for editing chemical structures with instantly updated results.We here present the results from applying Bioclipse Decision Support to several open QSAR data sets, including endpoints from OpenTox and PubChem. The results show how to extract data from the sources and to build models which can be integrated with user specific models.
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| 10. |
- Egeblad, Louise, et al.
(författare)
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Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1
- 2010
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 277:23, s. 4920-30
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Tidskriftsartikel (refereegranskat)abstract
- Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway.
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