| 1. |
- Austin, Thomas R., et al.
(författare)
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A plasma protein-based risk score to predict hip fractures
- 2024
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Ingår i: NATURE AGING. - 2662-8465. ; 4, s. 1064-1075
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Tidskriftsartikel (refereegranskat)abstract
- As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Tr & oslash;ndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined. The authors developed a proteomic risk score that improved the prediction of hip fractures in three validation cohorts analyzed by two different proteomic platforms. This risk score constitutes a new tool to stratify patients by hip fracture risk.
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| 2. |
- Carroll, Christopher, et al.
(författare)
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Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
- 2024
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Ingår i: Cancer Research Communications. - 2767-9764. ; 4:3, s. 691-705
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer. Significance: In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.
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| 3. |
- Guo, Meiyuan, et al.
(författare)
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Using Iron L-Edge and Nitrogen K-Edge X-ray Absorption Spectroscopy to Improve the Understanding of the Electronic Structure of Iron Carbene Complexes
- 2024
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Ingår i: Inorganic Chemistry. - 0020-1669. ; 63:27, s. 12457-12468
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Tidskriftsartikel (refereegranskat)abstract
- Iron-centered N-heterocyclic carbene compounds have attracted much attention in recent years due to their long-lived excited states with charge transfer (CT) character. Understanding the orbital interactions between the metal and ligand orbitals is of great importance for the rational tuning of the transition metal compound properties, e.g., for future photovoltaic and photocatalytic applications. Here, we investigate a series of iron-centered N-heterocyclic carbene complexes with +2, + 3, and +4 oxidation states of the central iron ion using iron L-edge and nitrogen K-edge X-ray absorption spectroscopy (XAS). The experimental Fe L-edge XAS data were simulated and interpreted through restricted-active space (RAS) and multiplet calculations. The experimental N K-edge XAS is simulated and compared with time-dependent density functional theory (TDDFT) calculations. Through the combination of the complementary Fe L-edge and N K-edge XAS, direct probing of the complex interplay of the metal and ligand character orbitals was possible. The σ-donating and π-accepting capabilities of different ligands are compared, evaluated, and discussed. The results show how X-ray spectroscopy, together with advanced modeling, can be a powerful tool for understanding the complex interplay of metal and ligand.
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| 4. |
- Håård, Andreas, et al.
(författare)
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Tågtrafik i ”överjordshastighet”
- 2023
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Ingår i: Bygg och Teknik. - 0281-658X .- 2002-8350. ; :1, s. 24-28
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Just nu planeras byggandet av nya stambanor i Sverige som ska möjliggöra tågtrafik i ännu högre hastighet (250–320 km/h) än de befintliga (200 km/h). Den högre hastigheten medför flera tekniska utmaningar för anläggningens utformning. Ett exempel inom geoteknikområdet är risken för det så kallade höghastighetsfenomenet, som kan orsaka mycket stora tåg- och markvibrationer. Ett nyligen avslutat examensarbete på avdelningen för Jord- och bergmekanik vid KTH, i samarbete med Trafikverket och Norges Geotekniska Institut (NGI), har undersökt potentialen i att använda det av NGI utvecklade beräkningsverktyget VibTrain för att analysera detta fenomen [1].
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| 5. |
- Johansson, Emma, et al.
(författare)
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Participatory future visions of collaborative agroecological farmer-pastoralist systems in Tanzania
- 2023
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Ingår i: Agroecology and Sustainable Food Systems. - : Informa UK Limited. - 2168-3565 .- 2168-3573. ; 47:4, s. 548-578
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Tidskriftsartikel (refereegranskat)abstract
- Agroecology is increasingly promoted as a way to create just and sustainable farm- and food systems. Although there are multiple initiatives to scale up agroecology, current socio-political structures often hinder its potential to transform food systems. This study uses participatory approaches to create paintings that envision agroecological futures in the context of increased farmer-pastoralist collaborations in Tanzania, how they would function, and what political action is needed to support such futures. The visions are based on focus group discussions with agroecological farmers and pastoralists, and a multi-stakeholder workshop with farmer and pastoralist representatives, innovative food system actors, and researchers. We find that the envisioned transformation of the food system would lead to positive effects on farmers’ and pastoralists’ income, autonomy, long-term planning, and producers’ and consumers’ health. We conclude that new policies and financial support systems are needed to enable the expansion of agroecological farming and food systems, by increasing the availability of organic markets, supporting domestic botanicals production, and by creating more inclusive and just food value chains.
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| 6. |
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| 7. |
- Johansson, Maria, 1965-
(författare)
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Interkulturalitet och historia : Historieundervisningens teori och praktik i en mångkulturell värld
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The purpose of this thesis is to investigate interculturality in history as an idea and practice. Two overarching research questions are raised, each concerning the theoretical and practical levels: How can history, as a field of knowledge and teaching, be related to intercultural learning as a normative practice? What obstacles and opportunities for teaching and learning emerge when intercultural historical learning is the goal? This thesis comprises four published studies. Through a hermeneutic process, the aspects of interculturality and history are investigated as interplays between theory and empirics and between generic outcomes and specific cases. Cases from three Swedish upper secondary history classrooms provide data. They are analysed narratively, using both analytical tools based on the theories of historical consciousness and historical thinking, as well as the framework of threshold concepts. Utilising the theory of powerful knowledge, interculturality, as a normative and extrinsic goal, is brought together with history as a dynamic body of knowledge. In the thesis, I argue that interculturality in history teaching is best understood as a shift in perspectives, adopting a specific gaze on historical narratives. The identified obstacles relate to the normativity of interculturality, the methodological nationalism of history and the pedagogical risk of fragmentation and deconstruction. A major result is the potential to construct complex, multidirectional narratives centred on cultural encounters and migration processes, which combine temporal and spatial layers to open the past for intercultural connections. There also seem to be specifically productive learning situations and liminal spaces in which students acquire new subject understandings. Finally, in a systematic approach, a didactic model of intercultural historical learning is presented, constituting the final, but still provisional, hermeneutic loop of the research project.
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| 8. |
- Lindström, Sara, et al.
(författare)
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Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions
- 2023
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:6, s. 712-732
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
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| 9. |
- Parker, Victoria E. R., et al.
(författare)
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Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes
- 2023
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Ingår i: Nature Metabolism. - : NATURE PORTFOLIO. - 2522-5812. ; 5, s. 2086-2093
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Tidskriftsartikel (refereegranskat)abstract
- Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994. In a two-part randomized phase 2a trial in men and women with overweight or obesity and type 2 diabetes mellitus, cotadutide promoted greater reductions in liver glycogen and fat than placebo and liraglutide.
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| 10. |
- Stark, Andreas, et al.
(författare)
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Hybrid digital manufacturing: Capturing the value of digitalization
- 2023
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Ingår i: Journal of Operations Management. - : Wiley. - 1873-1317 .- 0272-6963. ; 69:6, s. 890-910
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Tidskriftsartikel (refereegranskat)abstract
- A chasm is growing between the advanced technologies available for improving manufacturing operations and those effectively used in practice. The vision of Industry 4.0 is to mobilize industry to seek out these possibilities for improvement and to close the gap between opportunity and reality. However, when compared with more established improvement opportunities such as lean manufacturing, the digitalization of manufacturing lacks in both paradigmatic examples and an understanding of how to achieve the benefits. This lack is a complication of concern: Without an appropriate operations strategy to capture the value of digitalization, manufacturing companies will be unable to focus on technological investments and operational changes. To address this concern, operations management academics must develop new theory through active engagement in the practice of digitalization in manufacturing. This research presents a paradigmatic example, based on engaged scholarship, focused on effectively combining novel object-interactive and conventional manufacturing syntax for benefiting from digitalization in internal operations and the wider supply chain. The contribution to literature is a novel operations strategy—hybrid digital manufacturing—for capturing the value of Industry 4.0 technologies.
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