| 1. |
- Aad, G., et al.
(författare)
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- 2012
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swepub:Mat__t (refereegranskat)
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| 2. |
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| 3. |
- 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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| 4. |
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| 5. |
- Wang, G.Q., et al.
(författare)
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Inward particle transport at high collisionality in the EAST tokamak
- 2013
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Ingår i: Physics of Plasmas. - : AIP Publishing. - 1089-7674 .- 1070-664X. ; 20:10, s. 102310-
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Tidskriftsartikel (refereegranskat)abstract
- We have simulated two discharges in the tokamak EAST at ASIPP, Hefei. Particular focus has been put on the particle transport since EAST has a peaked density profile with only edge fuelling. The turbulent particle pinch has not been assumed to be strong in such strongly collisional plasmas as that in EAST. However, as it turned out, there is an increase in the particle pinch for high collisionality in our model. This was verified by turning collisions on and off in the simulations. Overall good agreement was found.
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| 6. |
- Wuolikainen, Anna, et al.
(författare)
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Studies of the human cerebrospinal fluid metabolome reveal alterations associated with amyotrophic lateral sclerosis and subtypes of the disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: The composition of the metabolome in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis is unknown. Previous studies of single metabolites have shown conflicting results.Methods: Using GC-TOFMS and multivariate statistical modeling, we studied the metabolome signature of ~120 compounds in the cerebrospinal fluid of ALS patients stratified according to hereditary disposition and clinical subtypes of the disease.Findings: Sporadic ALS has a heterogeneous metabolite signature in the CSF, in some patients being almost identical to controls. Familial ALS without SOD1 gene mutation is less heterogeneous than sporadic ALS. The metabolome of the CSF of the 17 ALS patients with a SOD1 gene mutation appeared as a separate homogeneous group. Analysis of single metabolites revealed that glutamate, pyroglutamate and glutamine were all reduced, in particular in patients with a familial disposition.Interpretation: There are significant differences in the metabolite profile and composition among patients with familial ALS, sporadic ALS and patients carrying a mutation in the SOD1 gene suggesting that the neurodegenerative process in different subtypes of ALS may be different. Patients with a genetic predisposition to ALS have a more distinct signature than patients with a sporadic disease.
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| 7. |
- Wuolo, Annika, et al.
(författare)
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Trees with a Denser Crown have Lower Water Consumption than Trees with a Sparser Crown
- 2023
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Ingår i: JOJ Horticulture & Arboriculture. - : Juniper Publishers. - 2641-8215. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Trees have many positive effects on the urban environment, but they are also exposed to several stress factors. Water deficit is one of these. Irrigation, structural soils or selecting drought tolerant species are different ways to meet this problem. Another way might be choosing individuals that could reduce water loss due to microclimate differences within the crown. The objective of this study is to address whether different crown densities in single trees may influence the water consumption during days with high atmospheric demand. Two pairs of similar Tilia cordata Mill. ‘Green spire’ with different crown densities, one dense and one sparse, were planted in containers and placed on scales at a paved yard in Alnarp, Sweden, during July and August 2009. Daily weight loss was continuously logged, and measurements of stomatal conductance and stem water potential were performed twice a day. Stomatal conductance was approximately 66% higher (3 mm s-1) in the sparse tree of pair S7:D46 and approximately 20% higher (1 mm s-1) in the sparse tree of pair S52:D21. The dense trees and sparse tree S52 used on average 10.2-10.9 kg water day-1 (1.2-1.4 mm day-1). Sparse tree S7 used on average 13.8 kg water day-1 (2.1 mm day-1). This difference might be caused by different microclimates in the crowns of the sparse and dense trees. Other factors were kept as similar as possible within each pair. The difference in water use was, however, more pronounced in one of the pairs. This could be caused by the different ability for water uptake and transport in the two pairs. The pair with the largest difference in water use had the strongest growth. We conclude that crown density affects water use of a tree in an urban environment; sparse linden trees consume more water than dense.
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| 8. |
- Wuopio, Jonas, et al.
(författare)
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Cathepsin B and S as markers for cardiovascular risk and all-cause mortality in patients with stable coronary heart disease during 10 years : a CLARICOR trial sub-study.
- 2018
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 278, s. 97-102
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: The lysosomal cysteine proteases cathepsin B and S have been implicated in the atherosclerotic process. The present paper investigates the association between serum levels of cathepsin B and S and cardiovascular events and mortality in patients with stable coronary heart disease.METHODS: The CLARICOR trial is a randomised, placebo-controlled trial investigating the effect of clarithromycin versus placebo in patients with stable coronary heart disease. The outcome was time to either a cardiovascular event or all-cause mortality. The placebo group was used as discovery sample and the clarithromycin group as replication sample: n = 1998, n = 1979; mean age (years) 65, 65; 31%, 30% women; follow-up for 10 years; number of composite outcomes n = 1204, n = 1220; respectively. We used a pre-defined multivariable Cox regression model adjusting for inflammation, established cardiovascular risk factors, kidney function, and use of cardiovascular drugs.RESULTS: Cathepsin B was associated with an increased risk of the composite outcome in both samples after multivariable adjustment (discovery: multivariable ratio (HR) per standard deviation increase 1.12, 95% confidence interval (CI) 1.05-1.19, p < 0.001, replication; HR 1.14, 95% CI 1.07-1.21, p < 0.001). There was no significant association between cathepsin S and the composite outcome in either the discovery or replication sample after multivariable adjustment (p>0.45). Secondary analyses suggest that cathepsin B was predominantly associated with mortality rather than specific cardiovascular events.CONCLUSIONS: Cathepsin B, but not serum cathepsin S, was associated with an increased risk of cardiovascular events in patients with stable coronary heart disease. The clinical implications of our findings remain to be established.
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| 9. |
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| 10. |
- Wuopio, Jonas, et al.
(författare)
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Estimated salt intake and risk of atrial fibrillation in a prospective community-based cohort
- 2021
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 289:5, s. 700-708
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Hypertension predisposes to atrial fibrillation (AF) – a major risk factor for ischaemic stroke. Since a high dietary salt consumption is associated with hypertension, we investigated the association between urinary sodium excretion as a marker for dietary sodium intake and risk of new-onset AF in community-dwelling adults. Method: The UK Biobank includes 40- to 69-year-old British residents recruited 2006–2010. Participants were divided into sex-specific quintiles according to 24-hour sodium excretion estimated based on spot samples with the Kawasaki equation. We excluded participants with AF at baseline. Cox regression adjusted for cardiovascular risk factors was used to assess associations with risk of AF, using the third quintile as reference. Results: A total of 257 545 women and 215 535 men were included. During up to 10 years' follow-up, 2221 women and 3751 men were diagnosed with AF. There was a tendency for an increased risk of AF in the lowest and highest quintiles of estimated daily salt intake in both women and men. In the fully adjusted model, significant associations were seen amongst men in the lowest and highest quintiles of sodium excretion (hazard ratio, HRQv1, 1.20; 95% CI, 1.08–1.32, P < 0.001, and HRQv5 1.15, 95% CI, 1.03–1.27, P = 0.011). Conclusion: We found evidence for a U-shaped association between estimated daily salt intake and AF risk amongst men. A suggestive J-shaped association in women was not statistically confirmed, but analyses were likely underpowered. Our results suggest that above a certain physiological minimum level progressively higher salt intake is associated with increasing risk of AF.
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