| 1. |
- Kanoni, Stavroula, et al.
(författare)
-
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
-
Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
|
|
| 2. |
- Zhou, Wei, et al.
(författare)
-
Global Biobank Meta-analysis Initiative : Powering genetic discovery across human disease
- 2022
-
Ingår i: Cell Genomics. - : Elsevier. - 2666-979X. ; 2:10
-
Tidskriftsartikel (refereegranskat)abstract
- Biobanks facilitate genome-wide association studies (GWASs), which have mapped genomic loci across a range of human diseases and traits. However, most biobanks are primarily composed of individuals of European ancestry. We introduce the Global Biobank Meta-analysis Initiative (GBMI)-a collaborative network of 23 biobanks from 4 continents representing more than 2.2 million consented individuals with genetic data linked to electronic health records. GBMI meta-analyzes summary statistics from GWASs generated using harmonized genotypes and phenotypes from member biobanks for 14 exemplar diseases and endpoints. This strategy validates that GWASs conducted in diverse biobanks can be integrated despite heterogeneity in case definitions, recruitment strategies, and baseline characteristics. This collaborative effort improves GWAS power for diseases, benefits understudied diseases, and improves risk prediction while also enabling the nomination of disease genes and drug candidates by incorporating gene and protein expression data and providing insight into the underlying biology of human diseases and traits.
|
|
| 3. |
|
|
| 4. |
- Lensink, Marc F., et al.
(författare)
-
Impact of AlphaFold on structure prediction of protein complexes: The CASP15-CAPRI experiment
- 2023
-
Ingår i: Proteins. - : WILEY. - 0887-3585 .- 1097-0134.
-
Tidskriftsartikel (refereegranskat)abstract
- We present the results for CAPRI Round 54, the 5th joint CASP-CAPRI protein assembly prediction challenge. The Round offered 37 targets, including 14 homodimers, 3 homo-trimers, 13 heterodimers including 3 antibody-antigen complexes, and 7 large assemblies. On average similar to 70 CASP and CAPRI predictor groups, including more than 20 automatics servers, submitted models for each target. A total of 21 941 models submitted by these groups and by 15 CAPRI scorer groups were evaluated using the CAPRI model quality measures and the DockQ score consolidating these measures. The prediction performance was quantified by a weighted score based on the number of models of acceptable quality or higher submitted by each group among their five best models. Results show substantial progress achieved across a significant fraction of the 60+ participating groups. High-quality models were produced for about 40% of the targets compared to 8% two years earlier. This remarkable improvement is due to the wide use of the AlphaFold2 and AlphaFold2-Multimer software and the confidence metrics they provide. Notably, expanded sampling of candidate solutions by manipulating these deep learning inference engines, enriching multiple sequence alignments, or integration of advanced modeling tools, enabled top performing groups to exceed the performance of a standard AlphaFold2-Multimer version used as a yard stick. This notwithstanding, performance remained poor for complexes with antibodies and nanobodies, where evolutionary relationships between the binding partners are lacking, and for complexes featuring conformational flexibility, clearly indicating that the prediction of protein complexes remains a challenging problem.
|
|
| 5. |
- Laisk, Triin, et al.
(författare)
-
The genetic architecture of sporadic and multiple consecutive miscarriage.
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Miscarriage is a common, complex trait affecting ~15% of clinically confirmed pregnancies. Here we present the results of large-scale genetic association analyses with 69,054 cases from five different ancestries for sporadic miscarriage, 750 cases of European ancestry for multiple (≥3) consecutive miscarriage, and up to 359,469 female controls. We identify one genome-wide significant association (rs146350366, minor allele frequency (MAF) 1.2%, P=3.2 × 10-8, odds ratio (OR)=1.4) for sporadic miscarriage in our European ancestry meta-analysis and three genome-wide significant associations for multiple consecutive miscarriage (rs7859844, MAF=6.4%, P=1.3 × 10-8, OR=1.7; rs143445068, MAF=0.8%, P=5.2 × 10-9, OR=3.4; rs183453668, MAF=0.5%, P=2.8 × 10-8, OR=3.8). We further investigate the genetic architecture of miscarriage with biobank-scale Mendelian randomization, heritability, and genetic correlation analyses. Our results show that miscarriage etiopathogenesis is partly driven by genetic variation potentially related to placental biology, and illustrate the utility of large-scale biobank data for understanding this pregnancy complication.
|
|
| 6. |
|
|
| 7. |
- Chen, Lan, et al.
(författare)
-
A modified ionization difference UV-vis method for fast quantitation of guaiacyl-type phenolic hydroxyl groups in lignin
- 2022
-
Ingår i: International Journal of Biological Macromolecules. - : Elsevier BV. - 0141-8130 .- 1879-0003. ; 201, s. 330-337
-
Tidskriftsartikel (refereegranskat)abstract
- An ionization difference UV-Vis method (Delta epsilon-spectrum method) is the most potentially simple method for fast quantitation of phenolic hydroxyl groups (ph-OH) in lignin. However, the underestimated results were calculated from the conventional Delta epsilon-spectrum method using one- or two-point wavelengths measurement. In this study, a modified Delta epsilon-spectrum method using multi-point wavelengths measurement was developed and the negative absorbance was also considered. Four main typical lignin models, e.g. vanilla alcohol, 5-5 biphenyl, stilbenoid and vanillin, were applied as the guaiacyl-type (G-type) phenolic models for the determination of ph-OH by the modified Delta epsilon-spectrum method. The 2-methoxyethanol/water/acetic acid = 8/2/0.2 (V/V/V) was used as the acidic solvent system and the 2-methoxyethanol/0.2 M NaOH solution = 1/9 (V/V) was used as the alkaline solvent system. The ph-OH contents in the spruce milled wood lignin (SMWL) and the spruce Kraft lignin (SKL) were respectively quantified by the modified Delta epsilon-spectrum method as 1.078 and 4.348 mmol/g, which were comparable to the counterparts determined by P-31 Nuclear Magnetic Resonance Spectroscopy (P-31 NMR). The results revealed that the modified Delta epsilon-spectrum method can provide more accurate and reliable results compared to the conventional method.
|
|
| 8. |
- Hou, Jianshen, et al.
(författare)
-
Rewiring carbon flux in Escherichia coli using a bifunctional molecular switch
- 2020
-
Ingår i: Metabolic Engineering. - : Elsevier BV. - 1096-7176 .- 1096-7184. ; 61, s. 47-57
-
Tidskriftsartikel (refereegranskat)abstract
- The unbalanced distribution of carbon flux in microbial cell factories can lead to inefficient production and poor cell growth. Uncoupling cell growth and chemical synthesis can therefore improve microbial cell factory efficiency. Such uncoupling, which requires precise manipulation of carbon fluxes, can be achieved by up-regulating or down-regulating the expression of enzymes of various pathways. In this study, a dynamic turn-off switch (dTFS) and a dynamic turn-on switch (dTNS) were constructed using growth phase-dependent promoters and degrons. By combining the dTFS and dTNS, a bifunctional molecular switch that could orthogonally regulate two target proteins was introduced. This bifunctional molecular switch was used to uncouple cell growth from shikimic acid and D-glucaric acid synthesis, resulting in the production of 14.33 g/L shikimic acid and the highest reported productivity of D-glucaric acid (0.0325 g/L/h) in Escherichia coli MG1655. This proved that the bifunctional molecular switch could rewire carbon fluxes by controlling target protein abundance.
|
|
| 9. |
- Keyu, Guo, et al.
(författare)
-
A Phase-Domain Model of Dual Three-Phase Segmented Powered Linear PMSM for Hardware-assisted Real-Time Simulation
- 2022
-
Ingår i: IEEE Transactions on Industry Applications. - 0093-9994 .- 1939-9367. ; 58:4, s. 4511-4521
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper, a Hardware-assisted real-time simulation phase-domain (PD) model of a dual three-phase segmented powered linear permanent magnet synchronous machine (SP-LPMSM) used in electromagnetic launch is established. The model is able to consider the end-effect, saturation effect, coupling effect and open-phase fault conditions, which are specially occurs in the segmented structure in SP-LPMSM. The unbalanced inductances and saturation effect caused by the segmented structure are investigated and a simplified look-up table for inductances is introduced. Additionally, to accurately evaluate the coupling effect, the permanent magnet (PM) flux linkage is decoupled into the product of unit PM flux linkage and coupling coefficient. In order to avoid the numerical impulse caused by the derivative in the progress of calculating back-EMF, sigmoid function is adopted to express the coupling coefficient. Meanwhile, to make the PD-model compatible with the open-circuit fault conditions, incidence matrices and current constraint matrices are introduced to unify the PD-models with different winding connection types and open circuit faults into one general form. The PD-Model realized in Field-Programmable Gate Arrays (FPGA) based hardware is validated in comparison with finite element analysis results.
|
|
| 10. |
- Li, Danqin, et al.
(författare)
-
n-Doping of photoactive layer in binary organic solar cells realizes over 18.3% efficiency
- 2022
-
Ingår i: Nano Energy. - : ELSEVIER. - 2211-2855 .- 2211-3282. ; 96
-
Tidskriftsartikel (refereegranskat)abstract
- Electronic doping of conjugated semiconductor plays a critical role in the fabrication of high efficiency organic optoelectronic devices. Here, we report an organic solar cell (OSC) by doping n-type DMBI-BDZC into one host binary bulk heterojunction (BHJ) photoactive layer comprised of a polymer donor PM6 and a nonfullerene acceptor Y6. The resulting champion device yields a significantly improved power conversion efficiency from 17.17% to 18.33% with an impressive fill factor of 80.20%. It is found that the electrically doped photoactive layer exhibits enhanced and balanced charge carrier mobilities, more effective exciton dissociation, longer carrier lifetime, and suppressed charge recombination with smaller energy loss. The dopant molecule DMBIBDZC also act as a surface morphology modifier of the photoactive layer with enhanced charge transport. This work demonstrates that manipulation of charge transport via adding a low concentration dopant into photoactive layer is a promising approach for further improvement of BHJ OSC performance.
|
|
