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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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- 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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- Gray, L J, et al.
(författare)
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Significant variation in mortality and functional outcome after acute ischaemic stroke between western countries : Data from the tinzaparin in acute ischaemic stroke trial (TAIST)
- 2006
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 77:3, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Background: The medical care of patients with acute stroke varies considerably between countries. This could lead to measurable differences in mortality and functional outcome. Objective: To compare case mix, clinical management, and functional outcome in stroke between 11 countries. Methods: All 1484 patients from 11 countries who were enrolled into the tinzaparin in acute ischaemic stroke trial (TAIST) were included in this substudy. Information collected prospectively on demographics, risk factors, clinical features, measures of service quality (for example, admission to a stroke unit), and outcome were assessed. Outcomes were adjusted for treatment assignment, case mix, and service relative to the British Isles. Results: Differences in case mix (mostly minor) and clinical service (many of prognostic relevance) were present between the countries. Significant differences in outcome were present between the countries. When assessed by geographical region, death or dependency were lower in North America (odds ratio (OR) adjusted for treatment group only = 0.52 (95% confidence interval, 0.39 to 0.71) and north west Europe (OR = 0.54 (0.37 to 0.78)) relative to the British Isles, similar reductions were found when adjustments were made for 11 case mix variables and five service quality measures. Similarly, case fatality rates were lower in North America (OR = 0.44 (0.30 to 0.66)) and Scandinavia (OR = 0.50 (0.33 to 0.74)) relative to the British Isles, whether crude or adjusted for case mix and service quality. Conclusions: Both functional outcome and case fatality vary considerably between countries, even when adjusted for prognostic case mix variables and measures of good stroke care. Differing health care systems and the management of patients with acute stroke may contribute to these findings.
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- Jyväsjärvi, J., et al.
(författare)
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Climate-induced warming imposes a threat to north European spring ecosystems
- 2015
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Ingår i: Global Change Biology. - : Blackwell Publishing. - 1354-1013 .- 1365-2486. ; 21:12, s. 4561-4569
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Tidskriftsartikel (refereegranskat)abstract
- Interest in climate change effects on groundwater has increased dramatically during the last decade. The mechanisms of climate-related groundwater depletion have been thoroughly reviewed, but the influence of global warming on groundwater-dependent ecosystems (GDEs) remains poorly known. Here we report long-term water temperature trends in 66 northern European cold-water springs. A vast majority of the springs (82%) exhibited a significant increase in water temperature during 1968-2012. Mean spring water temperatures were closely related to regional air temperature and global radiative forcing of the corresponding year. Based on three alternative climate scenarios representing low (RCP2.6), intermediate (RCP6) and high-emission scenarios (RCP8.5), we estimate that increase in mean spring water temperature in the region is likely to range from 0.67 °C (RCP2.6) to 5.94 °C (RCP8.5) by 2086. According to the worst-case scenario, water temperature of these originally cold-water ecosystems (regional mean in the late 1970s: 4.7 °C) may exceed 12 °C by the end of this century. We used bryophyte and macroinvertebrate species data from Finnish springs and spring-fed streams to assess ecological impacts of the predicted warming. An increase in spring water temperature by several degrees will likely have substantial biodiversity impacts, causing regional extinction of native, cold-stenothermal spring specialists, whereas species diversity of headwater generalists is likely to increase. Even a slight (by 1 °C) increase in water temperature may eliminate endemic spring species, thus altering bryophyte and macroinvertebrate assemblages of spring-fed streams. Climate change-induced warming of northern regions may thus alter species composition of the spring biota and cause regional homogenization of biodiversity in headwater ecosystems.
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- Sprigg, N., et al.
(författare)
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Early Recovery and Functional Outcome are Related with Causal Stroke Subtype : Data from the Tinzaparin in Acute Ischemic Stroke Trial
- 2007
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Ingår i: Journal of Stroke & Cerebrovascular Diseases. - : Elsevier BV. - 1052-3057 .- 1532-8511. ; 16:4, s. 180-184
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Baseline severity and causal subtype are predictors of outcome in ischemic stroke. We used data from the Tinzaparin in Acute Ischemic Stroke Trial (TAIST) to further assess the relationship among stroke subtype, early recovery, and outcome. Methods: Patients with ischemic stroke (<48 hours ictus) and enrolled into TAIST were included. Severity was measured prospectively as the Scandinavian Neurological Stroke Scale (SNSS) at days 0, 4, 7, and 10. Causal subtype as large artery atherosclerosis (LAA), cardioembolism (CE), or small vessel occlusion (SVO) was assigned after standard investigations. The rate of recovery was calculated as the change in SNSS at each time point. Functional outcome was assessed using the modified Rankin Scale (mRS) and Barthel Index at day 90. Results: Analyses were performed on the 1190 patients in TAIST who met criteria for LAA, CE, and SVO. The largest change in SNSS score occurred between baseline and day 4 and was greatest in SVO (median improvement 4 U), compared with LAA (median improvement 2 U) and CE (median improvement 2 U) (P < .0001). If no improvement in SNSS had occurred by day 4, irrespective of subgroup, then early recovery (median SNSS improvement by day 10: 2) and functional outcome (mRS 4) tended to be limited, patients who recovered early tended to continue to improve (median SNSS improvement by day 10: 11) and had a better outcome at day 90 (median, mRS 2). Conclusions: Recovery is related to causal subtype. In all subtypes most recovery occurred by day 4, and was predictive of longer-term functional outcome. © 2007 National Stroke Association.
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- Sprigg, N., et al.
(författare)
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Stroke severity, early recovery and outcome are each related with clinical classification of stroke : Data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST)
- 2007
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Ingår i: Journal of the Neurological Sciences. - : Elsevier BV. - 0022-510X .- 1878-5883. ; 254:1-2, s. 54-59
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Baseline severity and clinical stroke syndrome (Oxford Community Stroke Project, OCSP) classification are predictors of outcome in stroke. We used data from the 'Tinzaparin in Acute Ischaemic Stroke Trial' (TAIST) to assess the relationship between stroke severity, early recovery, outcome and OCSP syndrome. Methods: TAIST was a randomised controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Severity was measured as the Scandinavian Neurological Stroke Scale (SNSS) at baseline and days 4, 7 and 10, and baseline OCSP clinical classification recorded: total anterior circulation infarct (TACI), partial anterior circulation infarct (PACI), lacunar infarct (LACI) and posterior circulation infarction (POCI). Recovery was calculated as change in SNSS from baseline at day 4 and 10. The relationship between stroke syndrome and SNSS at days 4 and 10, and outcome (modified Rankin Scale at 90 days) were assessed. Results: Stroke severity was significantly different between TACI (most severe) and LACI (mildest) at all four time points (p < 0.001), with no difference between PACI and POCI. The largest change in SNSS score occurred between baseline and day 4, improvement was least in TACI (median 2 units), compared to other groups (median 3 units) (p < 0.001). If SNSS did not improve by day 4, then early recovery and late functional outcome tended to be limited irrespective of clinical syndrome (SNSS, baseline: 31, day 10: 32, mRS, day 90: 4), patients who recovered early tended to continue to improve and had better functional outcome irrespective of syndrome (SNSS, baseline: 35, day 10: 50, mRS, day 90: 2). Conclusions: Although functional outcome is related to baseline clinical syndrome (best with LACI, worst with TACI), patients who improve early have a more favourable functional outcome, irrespective of their OCSP syndrome. Hence, patients with a TACI syndrome may still achieve a reasonable outcome if early recovery occurs. © 2007 Elsevier B.V. All rights reserved.
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- Marttila, H., et al.
(författare)
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Nordic hydrological frontier in the 21st century
- 2022
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Ingår i: Hydrology Research. - : IWA Publishing. - 1998-9563 .- 2224-7955 .- 0029-1277. ; 53:5, s. 700-715
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Tidskriftsartikel (refereegranskat)abstract
- The 21st century has brought new challenges and opportunities and has also increased demands on the Nordic hydrological community. Our hydrological science focus and approaches need rethinking and adaptation to the changing requirements of society in response to climate change and human interventions, in search of more comprehensive and cross-disciplinary solutions. This commentary highlights new possibilities and suggests vital steps forward for the scientific discipline within Nordic hydrological research. By providing a common direction, we hope to increase awareness, accelerate progress in the hydrological community, and emphasize the importance of hydrological knowledge for serving other fields of science and society at large. We hope that our vision and the opportunities we identify will raise awareness of the scientific discipline and assist in the long-term development of the Nordic hydrological frontier in the 21st century.
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- 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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18. |
- 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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- Tylewicz, Szymon, et al.
(författare)
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Photoperiodic control of seasonal growth is mediated by ABA acting on cell-cell communication
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 360:6385, s. 212-214
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Tidskriftsartikel (refereegranskat)abstract
- In temperate and boreal ecosystems, seasonal cycles of growth and dormancy allow perennial plants to adapt to winter conditions. We show, in hybrid aspen trees, that photoperiodic regulation of dormancy is mechanistically distinct from autumnal growth cessation. Dormancy sets in when symplastic intercellular communication through plasmodesmata is blocked by a process dependent on the phytohormone abscisic acid. The communication blockage prevents growth-promoting signals from accessing the meristem. Thus, precocious growth is disallowed during dormancy. The dormant period, which supports robust survival of the aspen tree in winter, is due to loss of access to growth-promoting signals.
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21. |
- Willforss, J, et al.
(författare)
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Interactive proteogenomic exploration of response to Fusarium head blight in oat varieties with different resistance
- 2020
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Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 218, s. 103688-103688
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Tidskriftsartikel (refereegranskat)abstract
- Fusarium species are cereal pathogens that cause the Fusarium Head Blight (FHB) disease. FHB can reduce yield, cause mycotoxin accumulation in the grain and reduce germination efficiency of the harvested seeds. Understanding the biochemical interactions between the host plants and the pathogen is crucial for controlling the disease and for the development of cultivars with improved tolerance to FHB. Here, we studied morphological and proteomic differences between the susceptible oat variety Belinda and the more resistant variety Argamak using variety-specific transcriptome assemblies as references. Measurements of deoxynivalenol toxin levels confirmed the partial resistance in Argamak and the susceptibility in Belinda. To jointly investigate the proteomics- and sequence data, we developed an RShiny-based interface for interactive exploration of the dataset using univariate and multivariate statistics. When applying this interface to the dataset, quantitative protein differences between Belinda and Argamak were detected, and eighteen peptides were found uniquely in Argamak during infection, among them several lipoxygenases. Such proteins can be developed as markers for Fusarium resistance breeding. In conclusion, this study provides the first proteogenomic insight on molecular Fusarium-oat interactions at both morphological and molecular levels and the data are openly available through an interactive interface for further inspection. SIGNIFICANCE: Fusarium head blight causes widespread damage to crops, and chronic and acute toxicity to human and livestock due to the accumulation of toxins during infection. In the present study, two oat varieties with differing resistance were challenged with Fusarium to understand the disease better, and studied both at morphological and molecular levels, identifying proteins which could play a role in the defense mechanism. Furthermore, a proteogenomics approach allows joint profiling of expression and sequence level differences to identify potentially functionally differing mutations. Here such analysis is made openly available through an interactive interface which allows other scientists to draw further findings from the data. This study may both serve as a basis for understanding oat disease response and developing breeding markers for Fusarium resistant oat and future proteogenomic studies using the interactive approach described.
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- Bin Ashraf, Faisal, et al.
(författare)
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Changes in short term river flow regulation and hydropeaking in Nordic rivers
- 2018
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying short-term changes in river flow is important in understanding the environmental impacts of hydropower generation. Energy markets can change rapidly and energy demand fluctuates at sub-daily scales, which may cause corresponding changes in regulated river flow (hydropeaking). Due to increasing use of renewable energy, in future hydropower will play a greater role as a load balancing power source. This may increase current hydropeaking levels in Nordic river systems, creating challenges in maintaining a healthy ecological status. This study examined driving forces for hydropeaking in Nordic rivers using extensive datasets from 150 sites with hourly time step river discharge data. It also investigated the influence of increased wind power production on hydropeaking. The data revealed that hydropeaking is at high levels in the Nordic rivers and have seen an increase over the last decade and especially over the past few years. These results indicate that increased building for renewable energy may increase hydropeaking in Nordic rivers.
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- 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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- 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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- Green, Alanna C., et al.
(författare)
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Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
- 2023
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Ingår i: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase–cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a ‘folate trap’. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
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- Gustafsson, Dan J, et al.
(författare)
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Adenovirus 11p downregulates CD46 early in infection
- 2010
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Ingår i: Virology. - : Elsevier BV. - 0042-6822 .- 1096-0341. ; 405:2, s. 474-482
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Tidskriftsartikel (refereegranskat)abstract
- Adenovirus 11 prototype (Ad11p), belonging to species B, uses CD46 as an attachment receptor. CD46, a complement regulatory molecule, is expressed on all human nucleated cells. We show here that Ad11p virions downregulate CD46 on the surface of K562 cells as early as 5min p.i. Specific binding to CD46 by the Ad11p fiber knob was required to mediate downregulation. The complement regulatory factors CD55 and CD59 were also reduced to a significant extent as a consequence of Ad11p binding to K562 cells. In contrast, binding of Ad7p did not result in downregulation of CD46 early in infection. Thus, the presumed interaction between Ad7p and CD46 did not have the same consequences as the Ad11p-CD46 interaction, the latter virus (Ad11p) being a promising gene therapy vector candidate. These findings may lead to a better understanding of the pathogenesis of species B adenovirus infections.
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- Macassa, Gloria, et al.
(författare)
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Perceptions of Health and Wellbeing Among Employees in a Work Integration Social Enterprise in Sweden
- 2023
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Ingår i: Annals of Global Health. - : Ubiquity Press. - 2214-9996. ; 89:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Work Integration Social Enterprises (WISEs) constitute an important vehiclefor providing employment opportunities for disadvantaged groups.Objective: The goal of this qualitative case study is to explore perceptions of health andwellbeing among employees working in a WISE located in the Gävleborg region, in eastcentral Sweden.Methods: Data were gathered using 16 in-depth, semi-structured interviews with thesocial enterprise employees.Results: Findings were categorized into three main categories: the importance of financialindependence and societal benefits; team spirit and a sense of belonging; and improvedquality of life and wellbeing.Conclusion: The participants perceived that working in the WISE gave them a feeling offreedom and increased their self-esteem because of the possibility to earn an income.Also, they were satisfied with their job (e.g., with regard to work quality and flexibility)and believed that their work contributed to society. Moreover, through working in a WISE,the participants felt a sense of belonging and togetherness through interaction with coworkersand managers, and an improved quality of life for themselves and their families.
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- Sprigg, Nikola, et al.
(författare)
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elationship between outcome and baseline blood pressure and other haemodynamic measures in acute ischaemic stroke : Data from the TAIST trial
- 2006
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Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352 .- 1473-5598. ; 24:7, s. 1413-1417
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A poor outcome after stroke is associated independently with high blood pressure during the acute phase, however, relationships with other haemodynamic measures [heart rate (HR), pulse pressure (PP), rate-pressure product (RPP)] remain less clear. METHODS: The Tinzaparin in Acute Ischaemic Stroke Trial is a randomised, controlled trial assessing the safety and efficacy of tinzaparin versus aspirin in 1484 patients with acute ischaemic stroke. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and HR measurements taken immediately prior to randomization were averaged, and the mid-blood pressure (MBP), PP, mean arterial pressure (MAP), pulse pressure index, and RPP were calculated. The relationship between these haemodynamic measures and functional outcome (death or dependency, modified Rankin Scale > 2) and early recurrent stroke, were studied with adjustment for baseline prognostic factors and treatment group. Odds ratios (OR) and 95% confidence intervals (CI) refer to a change in haemodynamic measure by 10 points. RESULTS: A poor functional outcome was associated with SBP (adjusted OR, 1.11, 95% CI, 1.03-1.21), HR (adjusted OR, 1.15, 95% CI, 1.00-1.31), MBP (adjusted OR, 1.15, 95% CI, 1.03-1.29), PP (adjusted OR, 1.14, 95% CI, 1.02-1.26), MAP (adjusted OR, 1.15, 95% CI, 1.02-1.31) and RPP (adjusted OR, 1.01, 95% CI, 1.00-1.02). Early recurrent stroke was associated with SBP, DBP, MBP and MAP. CONCLUSIONS: A poor outcome is independently associated with elevations in blood pressure, HR and their derived haemodynamic variables, including PP and the RPP. Agents that modify these measures may improve functional outcome after stroke. © 2006 Lippincott Williams & Wilkins.
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