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- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 3. |
- Gross, Angelina S., et al.
(författare)
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Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK
- 2019
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 294:32, s. 12020-12039
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Tidskriftsartikel (refereegranskat)abstract
- Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the de novo synthesis of lipids. However, it is unclear how de novo lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 (acc1(S/A)) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, acc1(S/A) cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by acc1(S/A). Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
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- Müller, Martina, et al.
(författare)
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Hard x-ray photoelectron spectroscopy of tunable oxide interfaces
- 2022
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Ingår i: Journal of Vacuum Science & Technology. A. Vacuum, Surfaces, and Films. - : American Vacuum Society. - 0734-2101 .- 1520-8559. ; 40:1
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Tidskriftsartikel (refereegranskat)abstract
- The tunability of the oxygen content in complex oxides and heterostructures has emerged as a key to designing their physical functionalities. Controlling the interface reactivity by redox reactions provides a powerful means to deliberately set distinct oxide phases and emerging properties. We present routes on how to control oxygen-driven redox mechanisms in ultrathin ferro(i)magnetic and ferroelectric oxide films and across oxide interfaces. We address the growth and control of metastable EuO oxide phases, the control of phase transitions of binary Fe oxides by oxygen migration, the in operando determination of NiFe2O4/SrTiO3 interface band alignments, as well as the role of interfacial oxide exchange in ferroelectric HfO 2-based capacitors-uncovered by the unique capabilities of photoelectron spectroscopy and, in particular, using hard x-rays.
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- Virkki, Vili, et al.
(författare)
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Globally widespread and increasing violations of environmental flow envelopes
- 2022
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Ingår i: Hydrology and Earth System Sciences. - : Copernicus GmbH. - 1027-5606 .- 1607-7938. ; 26:12, s. 3315-3336
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Tidskriftsartikel (refereegranskat)abstract
- Human actions and climate change have drastically altered river flows across the world, resulting in adverse effects on riverine ecosystems. Environmental flows (EFs) have emerged as a prominent tool for safeguarding the riverine ecosystems, but at the global scale, the assessment of EFs is associated with high uncertainty related to the hydrological data and EF methods employed. Here, we present a novel, in-depth global EF assessment using environmental flow envelopes (EFEs). Sub-basin-specific EFEs are determined for approximately 4400 sub-basins at a monthly time resolution, and their derivation considers the methodological uncertainties related to global-scale EF studies. In addition to a lower bound of discharge based on existing EF methods, we introduce an upper bound of discharge in the EFE. This upper bound enables areas to be identified where streamflow has substantially increased above natural levels. Further, instead of only showing whether EFs are violated over a time period, we quantify, for the first time, the frequency, severity, and trends of EFE violations during the recent historical period.Discharge was derived from global hydrological model outputs from the ISIMIP 2b ensemble. We use pre-industrial (1801–1860) quasi-natural discharge together with a suite of hydrological EF methods to estimate the EFEs. We then compare the EFEs with recent historical (1976–2005) discharge to assess the violations of the EFE. These violations most commonly manifest as insufficient streamflow during the low-flow season, with fewer violations during the intermediate-flow season, and only a few violations during the high-flow season. The EFE violations are widespread and occur in half of the sub-basins of the world during more than 5 % of the months between 1976 and 2005, which is double compared with the pre-industrial period. The trends in EFE violations have mainly been increasing, which will likely continue in the future with the projected hydroclimatic changes and increases in anthropogenic water use. Indications of increased upper extreme streamflow through EFE upper bound violations are relatively scarce and dispersed. Although local fine-tuning is necessary for practical applications, and further research on the coupling between quantitative discharge and riverine ecosystem responses at the global scale is required, the EFEs provide a quick and globally robust way of determining environmental flow allocations at the sub-basin scale to inform global research and policies on water resources management.
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