| 1. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 3. |
- Michel, M., et al.
(författare)
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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
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Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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| 5. |
- Marttila, S, et al.
(författare)
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Methylation status of VTRNA2-1/nc886 is stable across populations, monozygotic twin pairs and in majority of tissues
- 2022
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Ingår i: Epigenomics. - : Future Medicine Ltd. - 1750-192X .- 1750-1911. ; 14:18, s. 1105-1124
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Tidskriftsartikel (refereegranskat)abstract
- Aims & methods: The aim of this study was to characterize the methylation level of a polymorphically imprinted gene, VTRNA2-1/ nc886, in human populations and somatic tissues.48 datasets, consisting of more than 30 tissues and >30,000 individuals, were used. Results: nc886 methylation status is associated with twin status and ethnic background, but the variation between populations is limited. Monozygotic twin pairs present concordant methylation, whereas ∼30% of dizygotic twin pairs present discordant methylation in the nc886 locus. The methylation levels of nc886 are uniform across somatic tissues, except in cerebellum and skeletal muscle. Conclusion: The nc886 imprint may be established in the oocyte, and, after implantation, the methylation status is stable, excluding a few specific tissues.
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| 7. |
- 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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| 8. |
- Brodelius, M, et al.
(författare)
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Immunolocalization of the saposin-like insert of plant aspartic proteinases exhibiting saposin C activity. Expression in young flower tissues and in barley seeds
- 2005
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Ingår i: Physiologia Plantarum. - : Wiley. - 0031-9317 .- 1399-3054. ; 125:4, s. 405-418
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Tidskriftsartikel (refereegranskat)abstract
- The plant- specific insert ( PSI) of cypro11 gene- encoding cyprosin, an aspartic proteinase from Cynara cardunculus, has been cloned by polymerase chain reaction ( PCR) into a bacterial expression vector. A rearranged form of this PSI in which the N- and C- terminal sequences were permutated to make it more similar to the structural arrangement observed in saposins was also cloned and expressed in the same system. The biological activities of the two purified recombinant proteins were compared to those of human saposins B and C. The proteins showed similar activity to saposin C, i. e. capacity to activate human glucosylceramidase. At a concentration of 5 mu M, wild- type PSI, saposin C, and rearranged PSI activated human glucosylceramidase two-, three-, and five- fold, respectively. The K-m for 4- methylumbelliferyl beta-glucopyranoside was around 7 mM in the presence of any of the three activators ( 5 mM). The neurotropic activity using NS20Y cells and lipid- binding properties of the plant recombinant proteins were tested. The two plant proteins showed lipid- binding properties similar to those of saposins but did not have any effect on neurite outgrowth. Immunolocalization of PSI showed its expression in protective tissues in flower meristem - protodermis, in C. cardunculus and embryonic root cap and coleorhiza in mature barley grains - as well as husk, pericarp, and the aleurone layer. Possible biological functions suggested for the plant homologue to saposins besides the general activation of enzymes involved in lipid metabolism would be involvement in plant defence.
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| 10. |
- Henrik Ullsten, N., et al.
(författare)
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Extruded high quality materials from wheat gluten
- 2010
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Ingår i: Polymers from Renewable Resources. - : SAGE Publications. - 2041-2479 .- 2045-1377. ; 1:4, s. 173-186
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we report that the addition of ammonium hydroxide (NH4OH)significantly enhance the properties of extruded WG-based materials. The grainystructure disappeared and the extrudate became more uniform and glossy. Thebarrier properties improved and the oxygen permeability at dry conditions was aslow as that for a number of petroleum-based plastics (poly(ethylene terephthalateand polyamide 66). The protein structure in this material was extensivelyaggregated, which improved the strength and stiffness; there was a ca 4-foldincrease in maximum stress compared to that of the NH4OH-free samples. Theprotein solubility decreased to almost zero. Even a severe sonication treatmentin sodium dodecyl sulphate (SDS) did not increase the solubility. The only typeof protein that it was possible to extract was the 'thermo-resistant' w-gliadinslacking disulfide-bonds. Our result provides new opportunities to develop a WGbasedfilm extrudate for potential use as e.g. a renewable barrier layer in foodand non-food laminate packagings.
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| 17. |
- Cao, Hao
(författare)
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Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
- 2016
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Ingår i: Basic & Clinical Pharmacology & Toxicology. - : Wiley. - 1742-7835 .- 1742-7843.
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Tidskriftsartikel (refereegranskat)abstract
- Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed toDEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects fromDEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP mayhave detrimental effects on metabolic functions.
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| 19. |
- Gustafsson, Nina M. S., et al.
(författare)
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Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-gamma H2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
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| 20. |
- Heneen, Waheeb K., et al.
(författare)
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Fusion of oil bodies in endosperm of oat grains
- 2008
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Ingår i: Planta. - : Springer Science and Business Media LLC. - 0032-0935 .- 1432-2048. ; 228:4, s. 589-599
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Tidskriftsartikel (refereegranskat)abstract
- Few microscopical studies have been made on lipid storage in oat grains, with variable results as to the extent of lipid accumulation in the starchy endosperm. Grains of medium- and high-lipid oat (Avena sativa L.) were studied at two developmental stages and at maturity, by light microscopy using different staining methods, and by scanning and transmission electron microscopy. Discrete oil bodies occurred in the aleurone layer, scutellum and embryo. In contrast, oil bodies in the starchy endosperm often had diffuse boundaries and fused with each other and with protein vacuoles during grain development, forming a continuous oil matrix between the protein and starch components. The different microscopical methods were confirmative to each other regarding the coalescence of oil bodies, a phenomenon probably correlated with the reduced amount of oil-body associated proteins in the endosperm. This was supported experimentally by SDS-PAGE separation of oil-body proteins and immunoblotting and immunolocalization with antibodies against a 16 kD oil-body protein. Much more oil-body proteins per amount of oil occurred in the embryo and scutellum than in the endosperm. Immunolocalization of 14 and 16 kD oil-body associated proteins on sectioned grains resulted in more heavy labeling of the embryo, scutellum and aleurone layer than the rest of the endosperm. Observations on the appearance of oil bodies at an early stage of development pertain to the prevailing hypotheses of oil-body biogenesis.
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| 30. |
- Kuktaite, Ramune, et al.
(författare)
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Changes in the hierarchical protein polymer structure : Urea and temperature effects on wheat gluten films
- 2012
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Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 2:31, s. 11908-11914
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Tidskriftsartikel (refereegranskat)abstract
- Understanding bio-based protein polymer structures is important when designing new materials with desirable properties. Here the effect of urea on the wheat gluten (WG) protein structure in WG-urea films was investigated. Small-angle X-ray scattering indicated the formation of a hexagonal close-packed (HCP) hierarchical structure in the WG-urea materials. The HCP structure was influenced significantly by the urea concentration and processing conditions. The interdomain distance d I between the HCP scattering objects increased with increasing content of urea and the objects seemed to be oriented in the extrusion direction. Additionally, the effect of temperature on the HCP structure was studied and it was shown that at ≥55°C the HCP structure disappeared. Transmission electron microscopy revealed a rather denatured pattern of both HMW-glutenins and gliadins in the WG-urea films. The molecular packing of the WG protein polymer can be highly affected by an additive and the processing method used.
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| 31. |
- Kuktaite, R, et al.
(författare)
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Effect of mixing time on gluten recovered by ultracentrifugation studied by microscopy and rheological measurements
- 2005
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Ingår i: Cereal Chemistry. - 0009-0352. ; 82:4, s. 375-384
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Tidskriftsartikel (refereegranskat)abstract
- The effect of mixing time on gluten formation was studied for four commercial flour mixtures. The gluten phase was separated from dough using a nondestructive ultracentrifugation method. Small I deformation dynamic theological measurements and light and scanning electron microscopy were used. The recovered gluten was relatively pure with a small amount of starch granules embedded. The protein matrix observed by microscopy became smoother with prolonged mixing. No effect of overmixing was observed on the storage modulus (G') of gluten for any of the flours. The amount of water in gluten increased from optimum to over mixing for most of the flours. Increased water content during prolonged mixing was not related to an effect on G'. The Standard flour resulted in the highest water content of gluten, which increased considerably with mixing time. The Strong flour had the lowest G' of dough, a high G' of gluten, and no increase in gluten water content from optimum to overmixing. The Durum flour did not show gluten development and breakdown similar to the other flours. The differences in gluten protein network formation during dough mixing are genetically determined and depend on the flour type.
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| 32. |
- Kuktaite, Ramune, et al.
(författare)
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Structure and Morphology of Wheat Gluten Films : From Polymeric Protein Aggregates toward Superstructure Arrangements
- 2011
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 12:5, s. 1438-1448
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Tidskriftsartikel (refereegranskat)abstract
- Evaluation of structure and morphology of extruded wheat gluten (WG) films showed WG protein assemblies elucidated on a range of length scales from nano (4.4 angstrom and 9 to 10 angstrom, up to 70 angstrom) to micro (10 mu m). The presence of NaOH in WG films induced a tetragonal structure with unit cell parameters, a = 51.85 angstrom and c = 40.65 angstrom, whereas NH4OH resulted in a bidimensional hexagonal close-packed (HCP) structure with a lattice parameter of 70 angstrom. In the WG films with NH4OH, a highly polymerized protein pattern with intimately mixed glutenins and gliadins bounded through SH/SS interchange reactions was found. A large content of beta-sheet structures was also found in these films, and the film structure was oriented in the extrusion direction. In conclusion, this study highlights complexities of the supramolecular structures and conformations of wheat gluten polymeric proteins in biofilms not previously reported for biobased materials.
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| 41. |
- Marttila, S, et al.
(författare)
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Number of sons contributes to ageing-associated inflammation
- 2015
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 8631-
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Tidskriftsartikel (refereegranskat)abstract
- The rate of inflammation increases in elderly individuals, a phenomenon called inflammaging and is associated with degenerative diseases. However, the causes of inflammaging and the origin of the associated inflammatory mediators have remained enigmatic. We show herein that there is a positive correlation between the number of sons born and C-reactive protein concentrations in 90-year-old women. This association is influenced by HLA genetics known to regulate the immune response against HY antigens.
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