| 1. |
- Lind, Lars, et al.
(author)
-
Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)
- 2021
-
In: eLife. - : eLife Sciences Publications Ltd. - 2050-084X. ; 10
-
Journal article (peer-reviewed)abstract
- From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
- Gustavsson, Larisa, et al.
(author)
-
Resistance to Neonectria ditissima in apple : insights from metabolomics and lipidomics analyses
- 2023
-
In: Xxxi international horticultural congress (ihc2022). - : International Society for Horticultural Science. - 9789462613614 ; , s. 329-335, s. 329-336
-
Conference paper (peer-reviewed)abstract
- European canker, caused by the necrotrophic fungus Neonectria ditissima, is the most serious disease in apple production in Sweden. The disease is favored by a relatively cool and rainy climate. The canker damages have a significant economic impact due to reduced bearing surface and increased orchard management costs. The possibilities for chemical and biological control are very limited. Therefore, directed breeding for new resistant cultivars is urgently needed. Knowledge of inheritance of canker resistance and understanding of molecular mechanisms involved in resistant and susceptible responses to fungal attacks would facilitate breeding. In this study, we evaluated the tempo-spatial differences in plant-pathogen interactions in a set of partially resistant and susceptible cultivars by conducting metabolomic and lipidomic analyses. The major trends in metabolomics and lipidomic profiles were common among cultivars, irrespective of the degree of susceptibility. Several metabolites and lipids varied with time point and cultivar under N. ditissima infection. Putative key metabolites such as suberic acid and jasmonic acid were upregulated in all cultivars upon infection. Additionally, several lipids exhibited changes 30 to 45 days post-inoculation. Thus, the approach used seems to have resulted in a rich data set to be further analyzed in light of ongoing QTL-mapping efforts.
|
|
| 5. |
- Bing, Zhao, 1990, et al.
(author)
-
Unconventional Charge–Spin Conversion in Weyl-Semimetal WTe2
- 2020
-
In: Advanced Materials. - : Wiley. - 0935-9648 .- 1521-4095. ; 32:38
-
Journal article (peer-reviewed)abstract
- An outstanding feature of topological quantum materials is their novel spin topology in the electronic band structures with an expected large charge-to-spin conversion efficiency. Here, a charge-current-induced spin polarization in the type-II Weyl semimetal candidate WTe2 and efficient spin injection and detection in a graphene channel up to room temperature are reported. Contrary to the conventional spin Hall and Rashba–Edelstein effects, the measurements indicate an unconventional charge-to-spin conversion in WTe2, which is primarily forbidden by the crystal symmetry of the system. Such a large spin polarization can be possible in WTe2 due to a reduced crystal symmetry combined with its large spin Berry curvature, spin–orbit interaction with a novel spin-texture of the Fermi states. A robust and practical method is demonstrated for electrical creation and detection of such a spin polarization using both charge-to-spin conversion and its inverse phenomenon and utilized it for efficient spin injection and detection in the graphene channel up to room temperature. These findings open opportunities for utilizing topological Weyl materials as nonmagnetic spin sources in all-electrical van der Waals spintronic circuits and for low-power and high-performance nonvolatile spintronic technologies.
|
|
| 6. |
- Diamanti, Riccardo, et al.
(author)
-
Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase
- 2022
-
In: FEBS Letters. - : John Wiley & Sons. - 0014-5793 .- 1873-3468. ; 596:12, s. 1600-1610
-
Journal article (peer-reviewed)abstract
- R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme.
|
|
| 7. |
- Green, Alanna C., et al.
(author)
-
Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells
- 2023
-
In: Nature Metabolism. - : Springer Nature. - 2522-5812. ; 5:4, s. 642-659
-
Journal article (peer-reviewed)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.
|
|
| 8. |
- Hubert, Madlen, et al.
(author)
-
Lipid accumulation controls the balance between surface connection and scission of caveolae.
- 2020
-
In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 9
-
Journal article (peer-reviewed)abstract
- Caveolae are bulb-shaped invaginations of the plasma membrane (PM) that undergo scission and fusion at the cell surface and are enriched in specific lipids. However, the influence of lipid composition on caveolae surface stability is not well described or understood. Accordingly, we inserted specific lipids into the cell PM via membrane fusion and studied their acute effects on caveolae dynamics. We demonstrate that sphingomyelin stabilizes caveolae to the cell surface, whereas cholesterol and glycosphingolipids drive caveolae scission from the PM. Although all three lipids accumulated specifically in caveolae, cholesterol and sphingomyelin were actively sequestered, whereas glycosphingolipids diffused freely. The ATPase EHD2 restricts lipid diffusion and counteracts lipid-induced scission. We propose that specific lipid accumulation in caveolae generates an intrinsically unstable domain prone to scission if not restrained by EHD2 at the caveolae neck. This work provides a mechanistic link between caveolae and their ability to sense the PM lipid composition.
|
|
| 9. |
- Johansson, Emil, et al.
(author)
-
Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection
- 2022
-
In: Cells. - : MDPI. - 2073-4409. ; 11:19
-
Journal article (peer-reviewed)abstract
- Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.
|
|
| 10. |
- Long, Maeve, et al.
(author)
-
DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion
- 2022
-
In: EMBO Journal. - : John Wiley & Sons. - 0261-4189 .- 1460-2075. ; 41
-
Journal article (peer-reviewed)abstract
- Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN-independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1-dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.
|
|
| 11. |
- Mansour, Mohammed S.I., et al.
(author)
-
Factors Influencing Concordance of PD-L1 Expression between Biopsies and Cytological Specimens in Non-Small Cell Lung Cancer
- 2021
-
In: Diagnostics. - : MDPI AG. - 2075-4418. ; 11:10
-
Journal article (peer-reviewed)abstract
- PD-L1 expression assessed by immunohistochemical staining is used for the selection of immunotherapy in non-small cell lung cancer (NSCLC). Appropriate validation of PD-L1 expression in cytology specimens is important as cytology is often the only diagnostic material in NSCLC. In a previous study comprising two different cohorts of paired biopsies and cytological specimens, we found a fairly good cyto-histological correlation of PD-L1 expression in one, whereas only a moderate correlation was found in the other cohort. Therefore, that cohort with additional new cases was now further investigated for the impact of preanalytical factors on PD-L1 concordance in paired biopsies and cytological specimens. A total of 100 formalin-fixed paraffin-embedded cell blocks from 19 pleural effusions (PE), 17 bronchial brushes (BB), and 64 bronchoalveolar lavage (BAL) and concurrent matched biopsies from 80 bronchial biopsies and 20 transthoracic core biopsies from NSCLC patients were stained using the PD-L1 28-8 assay. Using the cutoffs & GE;1%, & GE;5%, & GE;10%, and & GE;50% positive tumour cells, the overall agreement between histology and cytology was 77-85% (kappa 0.51-0.70) depending on the applied cutoff value. The concordance was better for BALs (kappa 0.53-0.81) and BBs (kappa 0.55-0.85) than for PEs (kappa -0.16-0.48), while no difference was seen for different types of biopsies or histological tumour type. A high number of tumour cells (> 500) in biopsies was associated with better concordance at the & GE;50% cutoff. In conclusion, the study results suggest that PEs may be less suitable for evaluation of PD-L1 due to limited cyto-histological concordance, while a high amount of tumour cells in biopsies may be favourable when regarding cyto-histological PD-L1 concordance.
|
|
| 12. |
- Vandenput, Liesbeth, 1974, et al.
(author)
-
Update of the fracture risk prediction tool FRAX : a systematic review of potential cohorts and analysis plan
- 2022
-
In: Osteoporosis International. - : Springer. - 0937-941X .- 1433-2965. ; 33:10, s. 2103-2136
-
Research review (peer-reviewed)abstract
- Summary: We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures.Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors.Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible.Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of the cohort-specific beta coefficients for each risk factor, models comprising 10-year probability of hip and major osteoporotic fracture, with or without femoral neck bone mineral density, will be computed.Conclusions: These assembled cohorts and described models will provide the framework for an updated FRAX tool enabling enhanced assessment of fracture risk (PROSPERO (CRD42021227266)).
|
|
| 13. |
- Yammine, S.G., et al.
(author)
-
Dietary fatty acids and endometrial cancer risk within the European Prospective Investigation into Cancer and Nutrition
- 2023
-
In: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1
-
Journal article (peer-reviewed)abstract
- Background: Diet may impact important risk factors for endometrial cancer such as obesity and inflammation. However, evidence on the role of specific dietary factors is limited. We investigated associations between dietary fatty acids and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods: This analysis includes 1,886 incident endometrial cancer cases and 297,432 non-cases. All participants were followed up for a mean of 8.8 years. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of endometrial cancer across quintiles of individual fatty acids estimated from various food sources quantified through food frequency questionnaires in the entire EPIC cohort. The false discovery rate (q-values) was computed to control for multiple comparisons.Results: Consumption of n-6 γ-linolenic acid was inversely associated with endometrial cancer risk (HR comparing 5th with 1st quintileQ5−Q1=0.77, 95% CI = 0.64; 0.92, ptrend=0.01, q-value = 0.15). This association was mainly driven by γ-linolenic acid derived from plant sources (HRper unit increment=0.94, 95%CI= (0.90;0.98), p = 0.01) but not from animal sources (HRper unit increment= 1.00, 95%CI = (0.92; 1.07), p = 0.92). In addition, an inverse association was found between consumption of n-3 α-linolenic acid from vegetable sources and endometrial cancer risk (HRper unit increment= 0.93, 95%CI = (0.87; 0.99), p = 0.04). No significant association was found between any other fatty acids (individual or grouped) and endometrial cancer risk.Conclusion: Our results suggest that higher consumption of γ-linolenic acid and α-linoleic acid from plant sources may be associated with lower risk of endometrial cancer.
|
|
