| 1. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 2. |
- Haase, Dagmar, et al.
(författare)
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Greening cities - To be socially inclusive? About the alleged paradox of society and ecology in cities
- 2017
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Ingår i: Habitat International. - : Elsevier BV. - 0197-3975 .- 1873-5428. ; 64, s. 41-48
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Tidskriftsartikel (refereegranskat)abstract
- Greening cities, namely installing new parks, rooftop gardens or planting trees along the streets, undoubtedly contributes to an increase in wellbeing and enhances the attractiveness of open spaces in cities. At the same time, we observe an increasing use of greening strategies as ingredients of urban renewal, upgrading and urban revitalization as primarily market-driven endeavours targeting middle class and higher income groups sometimes at the expense of less privileged residents. This paper reflects on the current debate of the social effects of greening using selected examples. We discuss what tradeoffs between social and ecological developments in cities mean for the future debate on greening cities and a socially balanced and inclusive way of developing our cities for various groups of urban dwellers. We conclude that current and future functions and features of greening cities have to be discussed more critically including a greater awareness of social impacts.
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| 3. |
- Hordoir, Robinson, et al.
(författare)
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Nemo-Nordic 1.0 : a NEMO-based ocean model for the Baltic and North seas - research and operational applications
- 2019
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 12:1, s. 363-386
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Tidskriftsartikel (refereegranskat)abstract
- We present Nemo-Nordic, a Baltic and North Sea model based on the NEMO ocean engine. Surrounded by highly industrialized countries, the Baltic and North seas and their assets associated with shipping, fishing and tourism are vulnerable to anthropogenic pressure and climate change. Ocean models providing reliable forecasts and enabling climatic studies are important tools for the shipping infrastructure and to get a better understanding of the effects of climate change on the marine ecosystems. Nemo-Nordic is intended to be a tool for both short-term and long-term simulations and to be used for ocean forecasting as well as process and climatic studies. Here, the scientific and technical choices within Nemo-Nordic are introduced, and the reasons behind the design of the model and its domain and the inclusion of the two seas are explained. The model's ability to represent barotropic and baroclinic dynamics, as well as the vertical structure of the water column, is presented. Biases are shown and discussed. The short-term capabilities of the model are presented, especially its capabilities to represent sea level on an hourly timescale with a high degree of accuracy. We also show that the model can represent longer timescales, with a focus on the major Baltic inflows and the variability in deep-water salinity in the Baltic Sea.
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