| 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. |
- Johansson, Ronnie, et al.
(författare)
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On the Definition and Scope of Information Fusion as a Field of Research
- 2022
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Ingår i: ISIF Perspectives on Information Fusion. - : International Society of Information Fusion (ISIF). - 2831-4824 .- 2831-4832. ; 5:1, s. 3-12
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Tidskriftsartikel (refereegranskat)abstract
- A definition of information fusion (IF) as a field of research can benefit researchers within the field, who may use such a definition when motivating their own work and evaluating the contributions of others. Moreover, it can enable researchers and practitioners outside the field to more easily relate their own work to the field and more easily understand the scope of IF techniques and methods. Based on strengths and weaknesses of existing definitions, a definition is proposed that is argued to effectively fulfill the requirements that can be put on a definition of IF as a field of research. Although the proposed definition aims to be precise, it does not fully capture the richness and versatility of the IF field. To address that limitation, we highlight some topics to explore the scope of IF, covering the systems perspective of IF and its relation to ma-chine learning, optimization, robot behavior, opinion aggregation, and databases.
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| 3. |
- Ranjbar, Parivash, et al.
(författare)
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Vibrotactile guidance for trips with autonomous vehicles for persons with blindness, deafblindness, and deafness
- 2022
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Ingår i: Transportation Research Interdisciplinary Perspectives. - : Elsevier BV. - 2590-1982. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Autonomous vehicles are becoming a reality with great potential. However, persons with blindness, deafblindness, and deafness, who usually receive information and guidance from the driver, could miss information when travelling in an autonomous car. In this case study, 15 people with hearing and vision impairments explore and compare trips with and without vibrotactile guidance (using Ready-Ride or Ready-Move) in a simulated autonomous vehicle in real traffic (using a Wizard-of-Oz method). The study investigated if vibrotactile aid could enable persons with blindness, deafblindness, and deafness to use autonomous vehicles. Different phases of a trip (before, during, and after) were analysed. The study shows that people with functional impairments such as blindness, deafblindness, and deafness can perform trips independently if given information adapted to their needs through auditory, tactile, or visual information channels. It would be difficult for the target groups to travel without any additional communication aid, such as a vibrotactile guidance aid for all phases of the trip, especially for those with blindness. In all rides with the simulated autonomous car (Wizard-of-Oz set up) without vibrotactile guidance, the driver or assistant (in at least one phase of the trip) had to intervene for the research participants with blindness to complete the trip and continue the study. The study also highlights the usability of the vibrotactile guidance aid and identifies areas in need of improvement.
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