| 11. |
- Scott, Robert A., et al.
(författare)
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A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:341
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to guide development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in six genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow-up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association of those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr; rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomized controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
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| 12. |
- Solera-Rico, Alberto, et al.
(författare)
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β-Variational autoencoders and transformers for reduced-order modelling of fluid flows
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Variational autoencoder architectures have the potential to develop reduced-order models for chaotic fluid flows. We propose a method for learning compact and near-orthogonal reduced-order models using a combination of a β-variational autoencoder and a transformer, tested on numerical data from a two-dimensional viscous flow in both periodic and chaotic regimes. The β-variational autoencoder is trained to learn a compact latent representation of the flow velocity, and the transformer is trained to predict the temporal dynamics in latent-space. Using the β-variational autoencoder to learn disentangled representations in latent-space, we obtain a more interpretable flow model with features that resemble those observed in the proper orthogonal decomposition, but with a more efficient representation. Using Poincaré maps, the results show that our method can capture the underlying dynamics of the flow outperforming other prediction models. The proposed method has potential applications in other fields such as weather forecasting, structural dynamics or biomedical engineering.
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| 13. |
- Wang, Yuning, et al.
(författare)
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Towards optimal β-variational autoencoders combined with transformers for reduced-order modelling of turbulent flows
- 2024
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Ingår i: International Journal of Heat and Fluid Flow. - : Elsevier BV. - 0142-727X .- 1879-2278. ; 105
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Tidskriftsartikel (refereegranskat)abstract
- Variational autoencoders (VAEs) have shown promising potential as artificial neural networks (NN) for developing reduced-order models (ROMs) in the context of turbulent flows. In this study, we propose a method that combines β-VAEs for modal decomposition and transformer neural networks for temporal-dynamics prediction in the latent space to develop ROMs. We apply our method to an existing database of a turbulent flow around a wall-mounted square cylinder obtained by direct numerical simulation (DNS). A parametric study is performed to investigate the effects of the hyperparameters of the proposed β-VAEs and determine the optimal values. For the first time, we incorporate the consideration of the complexity of architecture into our studies, providing new insights into hyperparameter selection for β-VAEs, which remains a challenging problem for optimising model performance. Results regarding the influence of the different hyperparameters and guidelines to design these architectures are reported. Our optimal model achieves a reconstruction accuracy of 97.18% of the entire dataset using only ten modes. Subsequently, we employ the transformer models to identify latent-space temporal dynamics learned by the optimal β-VAE model and build ROMs to predict instantaneous fields. The resulting model achieves promising accuracy in temporal-dynamics predictions and yields energy reconstruction levels of 96.5% and 83% for a field 25 and 50 steps into the future, respectively, showcasing the potential of the transformer in predicting the temporal dynamics. Overall, the proposed method has potential applications in advanced flow control and fundamental studies of complex turbulent flows.
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| 14. |
- Wessel, Jennifer, et al.
(författare)
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Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.
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| 15. |
- Xiong, Shaobing, et al.
(författare)
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Direct Observation on p- to n-Type Transformation of Perovskite Surface Region during Defect Passivation Driving High Photovoltaic Efficiency
- 2021
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Ingår i: Joule. - : CELL PRESS. - 2542-4351. ; 5:2, s. 467-480
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Tidskriftsartikel (refereegranskat)abstract
- Perovskite solar cells (PSCs) suffer from significant nonradiative recombination, limiting their power conversion efficiencies. Here, for the first time, we directly observe a complete transformation of perovskite MAPbI(3) surface region energetics from p- to n-type during defect passivation caused by natural additive capsaicin, attributed to the spontaneous formation of a p-n homojunction in perovskite active layer. We demonstrate that the p-n homojunction locates at similar to 100 nm below perovskite surface. The energetics transformation and defect passivation promote charge transport in bulk perovskite layer and at perovskite/PCBM interface, suppressing both defect-assisted recombination and interface carrier recombination. As a result, an efficiency of 21.88% and a fill factor of 83.81% with excellent device stability are achieved, both values are the highest records for polycrystalline MAPbI(3) based p-i-n PSCs reported to date. The proposed new concept of synergetic defect passivation and energetic modification via additive provides a huge potential for further improvement of PSC performance.
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