| 1. |
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| 2. |
- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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| 3. |
- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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| 4. |
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| 5. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 6. |
- Escartin, C., et al.
(författare)
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Reactive astrocyte nomenclature, definitions, and future directions
- 2021
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 24, s. 312-325
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Tidskriftsartikel (refereegranskat)abstract
- Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions. Good-bad binary classifications fail to describe reactive astrocytes in CNS disorders. Here, 81 researchers reach consensus on widespread misconceptions and provide definitions and recommendations for future research on reactive astrocytes.
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| 7. |
- Williamson, Alice, et al.
(författare)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Tidskriftsartikel (refereegranskat)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 8. |
- Cordoni, G., et al.
(författare)
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Gaia and Hubble Unveil the Kinematics of Stellar Populations in the Type II Globular Clusters ? Centauri and M22
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 898:2
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Tidskriftsartikel (refereegranskat)abstract
- The origin of multiple stellar populations in globular clusters (GCs) is one of the greatest mysteries of modern stellar astrophysics. N-body simulations suggest that the present-day dynamics of GC stars can constrain the events that occurred at high redshift and led to the formation of multiple populations. Here, we combine multiband photometry from the Hubble Space Telescope (HST) and ground-based facilities with HST and Gaia Data Release 2 proper motions to investigate the spatial distributions and the motions in the plane of the sky of multiple populations in the Type II GCs NGC 5139 (? Centauri) and NGC 6656 (M22). We first analyzed stellar populations with different metallicities. Fe-poor and Fe-rich stars in M22 share similar spatial distributions and rotation patterns and exhibit similar isotropic motions. Similarly, the two main populations with different iron abundance in ? Centauri share similar ellipticities and rotation patterns. When different radial regions are analyzed, we find that the rotation amplitude decreases from the center toward the external regions. Fe-poor and Fe-rich stars of ? Centauri are radially anisotropic in the central region and show similar degrees of anisotropy. We also investigate the stellar populations with different light-element abundances and find that their N-rich stars exhibit higher ellipticity than N-poor stars. In ? Centauri both stellar groups are radially anisotropic. Interestingly, N-rich, Fe-rich stars exhibit different rotation patterns than N-poor stars with similar metallicities. The stellar populations with different nitrogen of M22 exhibit similar rotation patterns and isotropic motions. We discuss these findings in the context of the formation of multiple populations.
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| 9. |
- Dalton, April S., et al.
(författare)
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Deglaciation of the north American ice sheet complex in calendar years based on a comprehensive database of chronological data: NADI-1
- 2023
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Ingår i: QUATERNARY SCIENCE REVIEWS. - 0277-3791 .- 1873-457X. ; 321
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Tidskriftsartikel (refereegranskat)abstract
- The most recent deglaciation of the North American Ice Sheet Complex (NAISC: comprising the Innuitian, Cordilleran, and Laurentide ice sheets) offers a broad perspective from which to analyze the timing and rate of ice retreat, deglacial sea-level rise, and abrupt climate change events. Previous efforts to portray the retreat of the NAISC have been focused largely on minimum-limiting radiocarbon ages and ice margin location(s) tied to deglacial landforms that were not, for the most part, chronologically constrained. Here, we present the first version of North American Deglaciation Isochrones (NADI-1) spanning 25 to 1 ka in calendar years before present. Key new features of this work are (i) the incorporation of cosmogenic nuclide data, which offer a direct constraint on the timing of ice recession; (ii) presentation of all data and time-steps in calendar years; (iii) optimal, minimum, and maximum ice extents for each time-step that are designed to capture uncertainties in the ice margin position, and; (iv) extensive documentation and justification for the placement of each ice margin. Our data compilation includes 2229 measurements of Be-10, 459 measurements of Al-26 and 35 measurements of Cl-36 from a variety of settings, including boulders, bedrock surfaces, cobbles, pebbles, and sediments. We also updated a previous radiocarbon dataset (n = 4947), assembled luminescence ages (n = 397) and gathered uranium-series data (n = 2). After scrutiny of the geochronological dataset, we consider >90% of data to be reliable or likely reliable. Key findings include (i) a highly asynchronous maximum glacial extent in North America, occurring as early as 27 ka to as late as 17 ka, within and between ice sheets. In most marine realms, extension of the ice margin to the continental shelf break at 25 ka is somewhat speculative because it is based on undated and spatially scattered ice stream and geomorphic evidence; (ii) detachment of the Laurentide and Cordilleran ice sheets took place gradually via southerly and northerly 'unzipping' of the ice masses, starting at 17.5 ka and ending around 14 ka; (iii) the final deglaciation of Hudson Bay began at 8.5 ka, with the collapse completed by 8 ka. The maximum extent of ice during the last glaciation occurred at 22 ka and covered 15,470,000 km(2). All North American ice sheets merged at 22 ka for the first time in the Quaternary. The highly asynchronous Last Glacial Maximum in North America means that our isochrones (starting at 25 ka) capture ice advance across some areas, which is based on limited evidence and is therefore somewhat speculative. In the Supplementary Data, the complete NADI-1 chronology is available in PDF, GIF and shapefile format, together with additional visualizations and spreadsheets of geochronological data. The NADI-1 shapefiles are also available at https://doi.org/10.5281/zenodo.8161764.
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| 10. |
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| 11. |
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| 12. |
- Rae, Dale E., et al.
(författare)
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Sleep and BMI in South African urban and rural, high and low-income preschool children
- 2021
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Ingår i: BMC Public Health. - : Springer Science and Business Media LLC. - 1471-2458. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The extent to which income setting or rural and urban environments modify the association between sleep and obesity in young children is unclear. The aims of this cross-sectional observational study were to (i) describe and compare sleep in South African preschool children from rural low-income (RL), urban low-income (UL) and urban high-income (UH) settings; and (ii) test for associations between sleep parameters and body mass index (BMI).Methods: Participants were preschoolers (5.2 ± 0.7y, 49.5% boys) from RL (n = 111), UL (n = 65) and UH (n = 22) settings. Height and weight were measured. Sleep, sedentary behaviour and physical activity were assessed using accelerometery.Results: UL children had higher BMI z-scores (median: 0.39; interquartile range: − 0.27, 0.99) than the UH (− 0.38; − 0.88, 0.11) and RL (− 0.08; − 0.83, 0.53) children (p = 0.001). The UL children had later bedtimes (p < 0.001) and wake-up times (p < 0.001) and shorter 24 h (p < 0.001) and nocturnal (p < 0.001) sleep durations than the RL and UH children. After adjusting for age, sex, setting, SB and PA, for every hour less sleep obtained (24 h and nocturnal), children were 2.28 (95% CI: 1.28–4.35) and 2.22 (95% CI: 1.27–3.85) more likely, respectively, to belong to a higher BMI z-score quartile.Conclusions: Shorter sleep is associated with a higher BMI z-score in South African preschoolers, despite high levels of PA, with UL children appearing to be particularly vulnerable.
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| 13. |
- Cordoni, G., et al.
(författare)
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Exploring the Galaxy's halo and very metal-weak thick disc with SkyMapper and Gaia DR2
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 503:2, s. 2539-2561
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Tidskriftsartikel (refereegranskat)abstract
- In this work, we combine spectroscopic information from the SkyMapper survey for Extremely Metal-Poor stars and astrometry from Gaia DR2 to investigate the kinematics of a sample of 475 stars with a metallicity range of -6.5 <= [Fe/H] <= -2.05 dex. Exploiting the action map, we identify 16 and 40 stars dynamically consistent with the Gaia Sausage and Gaia Sequoia accretion events, respectively. The most metal poor of these candidates have metallicities of [Fe/H] = - 3.31 and - 3.74, respectively, helping to define the low-metallicity tail of the progenitors involved in the accretion events. We also find, consistent with other studies, that similar to 21 per cent of the sample have orbits that remain confined to within 3 kpc of the Galactic plane, that is, |Z(max)| <= 3 kpc. Of particular interest is a subsample (similar to 11 per cent of the total) of low |Z(max)| stars with low eccentricities and prograde motions. The lowest metallicity of these stars has [Fe/H] = -4.30 and the subsample is best interpreted as the very low-metallicity tail of the metal-weak thick disc population. The low |Z(max)|, low eccentricity stars with retrograde orbits are likely accreted, while the low |Z(max)|, high eccentricity pro- and retrograde stars are plausibly associated with the Gaia Sausage system. We find that a small fraction of our sample (similar to 4 per cent of the total) is likely escaping from the Galaxy, and postulate that these stars have gained energy from gravitational interactions that occur when infalling dwarf galaxies are tidally disrupted.
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| 14. |
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| 15. |
- Dlamini, Siphiwe N., et al.
(författare)
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Targeted proteomics of appendicular skeletal muscle mass and handgrip strength in black South Africans : a cross-sectional study
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Although appendicular skeletal muscle mass (ASM) and handgrip strength (HGS) are key components of sarcopenia, their underlying biological mechanisms remain poorly understood. We aimed to investigate associations of circulating biomarkers with ASM and HGS in middle-aged black South Africans. This study consisted of 934 black South Africans (469 men and 465 women, aged 41–72 years) from the Middle-aged Soweto cohort. Linear regression models were used to examine relationships between 182 biomarkers (measured with proximity extension assay) and dual-energy X-ray absorptiometry-measured ASM and dynamometer-measured HGS. Age, height, sex, smoking, alcohol, food insecurity, physical activity, visceral adipose tissue, HIV and menopausal status were included as confounders. Regression models showing sex-interactions were stratified by sex. The Benjamini–Hochberg false discovery rate (FDR) was used to control for multiple testing, and FDR-adjusted P values were reported. In the total sample, 10 biomarkers were associated with higher ASM and 29 with lower ASM (P < 0.05). Out of these 39 biomarkers, 8 were also associated with lower HGS (P < 0.05). MMP-7 was associated with lower HGS only (P = 0.011) in the total sample. Sex-interactions (P < 0.05) were identified for 52 biomarkers for ASM, and 6 for HGS. For men, LEP, MEPE and SCF were associated with higher ASM (P < 0.001, = 0.004, = 0.006, respectively), and MEPE and SCF were also associated with higher HGS (P = 0.001, 0.012, respectively). Also in men, 37 biomarkers were associated with lower ASM (P < 0.05), with none of these being associated with lower HGS. Furthermore, DLK-1 and MYOGLOBIN were associated with higher HGS only (P = 0.004, 0.006, respectively), while GAL-9 was associated with lower HGS only (P = 0.005), among men. For women, LEP, CD163, IL6, TNF-R1 and TNF-R2 were associated with higher ASM (P < 0.001, = 0.014, = 0.027, = 0.014, = 0.048, respectively), while IGFBP-2, CTRC and RAGE were associated with lower ASM (P = 0.043, 0.001, 0.014, respectively). No biomarker was associated with HGS in women. In conclusion, most biomarkers were associated with ASM and not HGS, and the associations of biomarkers with ASM and HGS displayed sex-specificity in middle-aged black South Africans. Proteomic studies should examine ASM and HGS individually. Future research should also consider sexual dimorphism in the pathophysiology of sarcopenia for development of sex-specific treatment and diagnostic methods.
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| 16. |
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| 17. |
- Gamble, LD, et al.
(författare)
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A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of ODC1, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype MYCN-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased ODC1 expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the ODC1 promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in MYCN-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the ODC1 G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.
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| 18. |
- Goedecke, Julia H., et al.
(författare)
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Waist circumference thresholds predicting incident dysglycaemia and type 2 diabetes in Black African men and women
- 2022
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Ingår i: Diabetes, obesity and metabolism. - : John Wiley & Sons. - 1462-8902 .- 1463-1326. ; 24:5, s. 918-927
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the waist circumference (WC) thresholds for the prediction of incident dysglycaemia and type 2 diabetes (T2D) in Black South African (SA) men and women and to compare these to the advocated International Diabetes Federation (IDF) Europid thresholds.Materials and Methods: In this prospective study, Black SA men (n = 502) and women (n = 527) from the Middle-aged Sowetan Cohort study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up until 2017 to 2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycaemia and T2D.Results: In men, the optimal WC threshold was 96.8 cm for both dysglycaemia and T2D (sensitivity: 56% and 70%; specificity: 74% and 70%, respectively), and had higher specificity (P < 0.001) than the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycaemia was 91.8 cm (sensitivity 86%, specificity 37%) and for T2D it was 95.8 cm (sensitivity 85%, specificity 45%), which had lower sensitivity, but higher specificity to predict incident dysglycaemia and T2D than the IDF threshold of 80 cm (sensitivity: 97% and 100%; specificity: 12% and 11%, respectively)).Conclusions: We show for the first time using prospective cohort data from Africa that the IDF Europid WC thresholds are not appropriate for an African population, and show that African-specific WC thresholds perform better than the IDF Europid thresholds to predict incident dysglycaemia and T2D.
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| 19. |
- Howard, Steven J., et al.
(författare)
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Challenging socioeconomic status : A cross-cultural comparison of early executive function
- 2020
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Ingår i: Developmental Science. - : John Wiley & Sons. - 1363-755X .- 1467-7687. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- The widely and internationally replicated socioeconomic status (SES) gradient of executive function (EF) implies that intervention approaches may do well to extrapolate conditions and practices from contexts that generate better child outcomes (in this case, higher SES circumstances) and translate these to contexts with comparatively poorer outcomes (often low-SES populations). Yet, can the reverse also be true? Using data from equivalent assessments of 1,092 pre-schoolers' EFs in South Africa and Australia, we evaluated: the SES gradient of EF within each sample; and whether this SES gradient extended cross-culturally. The oft-found EF-SES gradients were replicated in both samples. However, contrary to the inferences of EF-SES associations found nationally, the most highly disadvantaged South African subsample outperformed middle- and high-SES Australian pre-schoolers on two of three EFs. This suggests the possibility of EF-protective and -promotive practices within low- and middle-income countries that may aid understandings of the nature and promotion of EFs.
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| 20. |
- Kalantar-Zadeh, Kamyar, et al.
(författare)
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Nomenclature in nephrology : preserving renal and nephro in the glossary of kidney health and disease
- 2021
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Ingår i: JN. Journal of Nephrology. - : SPRINGER HEIDELBERG. - 1121-8428 .- 1724-6059. ; 34:3, s. 639-648
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Tidskriftsartikel (refereegranskat)abstract
- A recently published nomenclature by a "Kidney Disease Improving Global Outcomes" (KDIGO) Consensus Conference suggested that the word "kidney" should be used in medical writings instead of "renal" or "nephro" when referring to kidney disease and kidney health. Whereas the decade-old move to use "kidney" more frequently should be supported when communicating with the public-at-large, such as the World Kidney Day, or in English speaking countries in communications with patients, care-partners, and non-medical persons, our point of view is that "renal" or "nephro" should not be removed from scientific and technical writings. Instead, the terms can coexist and be used in their relevant contexts. Cardiologists use "heart" and "cardio" as appropriate such as "heart failure" and "cardiac care units" and have not replaced "cardiovascular" with "heartvessel", for instance. Likewise, in nephrology, we consider that "chronic kidney disease" and "continuous renal replacement therapy" should coexist. We suggest that in scientific writings and technical communications, the words "renal" and "nephro" and their derivatives are more appropriate and should be freely used without any pressure by medical journals to compel patients, care-partners, healthcare providers, researchers and other stakeholders to change their selected words and terminologies. We call to embrace the terms "kidney", "renal" and "nephro" as they are used in different contexts and ask that scientific and medical journals not impose terminology restrictions for kidney disease and kidney health. The choice should be at the discretion of the authors, in the different contexts including in scientific journals.
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| 21. |
- Macías Ruiz, MDC, et al.
(författare)
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Magnesium in Kidney Function and Disease-Implications for Aging and Sex-A Narrative Review
- 2023
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 15:7
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Tidskriftsartikel (refereegranskat)abstract
- Magnesium (Mg) has a vital role in the human body, and the kidney is a key organ in the metabolism and excretion of this cation. The objective of this work is to compile the available evidence regarding the role that Mg plays in health and disease, with a special focus on the elderly population with chronic kidney disease (CKD) and the eventual sex differences. A narrative review was carried out by executing an exhaustive search in the PubMed, Scopus, and Cochrane databases. Ten studies were found in which the role of Mg and sex was evaluated in elderly patients with CKD in the last 10 years (2012–2022). The progression of CKD leads to alterations in mineral metabolism, which worsen as the disease progresses. Mg can be used as a coadjuvant in the treatment of CKD patients to improve glomerular filtration, but its use in clinical applications needs to be further characterized. In conclusion, there’s a need for well-designed prospective clinical trials to advise and standardize Mg supplementation in daily clinical practice, taking age and sex into consideration.
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| 22. |
- Mendham, Amy E., et al.
(författare)
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Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women
- 2023
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 66, s. 174-189
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes.Methods: This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210).Results: We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient –0.35; 95% CI –0.44, –0.25) and men (coefficient –0.09; 95% CI –0.15, –0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men.Conclusions/interpretation: We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.
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| 23. |
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| 24. |
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| 25. |
- Peluso, Michael J, et al.
(författare)
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Cerebrospinal fluid soluble CD30 elevation despite suppressive antiretroviral therapy in individuals living with HIV-1.
- 2020
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Ingår i: Journal of virus eradication. - 2055-6640. ; 6:1, s. 19-26
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to assess soluble CD30 (sCD30), a protein that colocalises with HIV-1 RNA and DNA in lymphoid cells and tissues, in cerebrospinal fluid (CSF) as a marker of HIV-1 infection in the central nervous system (CNS).This was a cross-sectional study using archived samples from two clinical cohorts. Soluble CD30 concentrations were measured in paired CSF and plasma from untreated viraemic individuals (n=52), individuals on suppressive antiretroviral therapy (ART) (n=33), HIV-1 controllers (n=10), participants with CSF HIV-1 'escape' (n=11) and controls without HIV-1 infection (n=16). Nonparametric tests were used to compare levels across groups and evaluate correlations with HIV-1 RNA, CSF neurofilament light chain protein (NFL) and neopterin.Compared with controls (median 30ng/mL, interquartile range [IRQ] 23-50), plasma sCD30 levels were elevated in viraemic participants (75ng/mL, 52-116; P<0.001), but not in those on suppressive ART (38ng/mL, 32-62). In contrast, CSF sCD30 levels were elevated in ART-suppressed individuals (34ng/mL, 19-46; P=0.001) and in those with CSF 'escape' (33ng/mL, 27-40; P=0.004) compared with controls (18ng/mL, 11-23), but not in untreated viraemic individuals. No association was observed between CSF sCD30 and plasma HIV-1 RNA, concurrent or nadir CD4+ T cell count, duration of infection or plasma sCD30. CSF sCD30 correlated with CSF NFL (r=0.34, P=0.001).In contrast to plasma, sCD30 levels are elevated in the CSF of individuals with HIV-1 infection who are on suppressive ART. Elevated levels of sCD30 in the CSF may be an indicator of persistent CNS HIV-1 infection, although the mechanism underlying this elevation warrants further investigation.
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| 26. |
- Sherwood, S. C., et al.
(författare)
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An Assessment of Earth's Climate Sensitivity Using Multiple Lines of Evidence
- 2020
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Ingår i: Reviews of geophysics. - 8755-1209 .- 1944-9208. ; 58:4
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Forskningsöversikt (refereegranskat)abstract
- We assess evidence relevant to Earth's equilibrium climate sensitivity per doubling of atmospheric CO2, characterized by an effective sensitivity S. This evidence includes feedback process understanding, the historical climate record, and the paleoclimate record. An S value lower than 2 K is difficult to reconcile with any of the three lines of evidence. The amount of cooling during the Last Glacial Maximum provides strong evidence against values of S greater than 4.5 K. Other lines of evidence in combination also show that this is relatively unlikely. We use a Bayesian approach to produce a probability density function (PDF) for S given all the evidence, including tests of robustness to difficult-to-quantify uncertainties and different priors. The 66% range is 2.6-3.9 K for our Baseline calculation and remains within 2.3-4.5 K under the robustness tests; corresponding 5-95% ranges are 2.3-4.7 K, bounded by 2.0-5.7 K (although such high-confidence ranges should be regarded more cautiously). This indicates a stronger constraint on S than reported in past assessments, by lifting the low end of the range. This narrowing occurs because the three lines of evidence agree and are judged to be largely independent and because of greater confidence in understanding feedback processes and in combining evidence. We identify promising avenues for further narrowing the range in S, in particular using comprehensive models and process understanding to address limitations in the traditional forcing-feedback paradigm for interpreting past changes.
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| 27. |
- Stahl, M. G., et al.
(författare)
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Childhood growth prior to screen-detected celiac disease: prospective follow-up of an at-risk birth cohort
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 55:11, s. 1284-1290
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To determine the association between childhood growth prior to the development of celiac disease (CD) and CD autoimmunity (CDA) identified by periodic serological screening. Study design: The Diabetes Autoimmunity Study in the Young cohort includes 1979 genetically at-risk children from Denver, Colorado, with annual growth measurements from age nine months until ten years. Between 1993 and February 2019, 120 children developed CDA defined by persistent positive tissue transglutaminase autoantibodies (TGA); among these, 71 met our criteria for CD based on histopathological findings or high TGA levels. Age- and sex-specific z-scores of weight, body mass index (BMI), and height prior to seroconversion were derived using US reference charts as standards. Joint modeling of serial growth measurements was used to estimate adjusted hazard ratios (aHRs) accounting for celiac-associated human leukocyte antigens, early-life feeding practices, and socio-demographics. Results: In the first 10 years of life, there were no significant associations between the child’s current weight, BMI and height and the risk of screening-detected CDA or CD, neither was the weight nor BMI velocity associated with CDA or CD as identified by screening (all aHRs approximated 1). Increased height velocity was associated with later CD, but not CDA, development (aHR per 0.01-z score/year, 1.28; 95% confidence interval [CI] 1.18–1.38 and 1.03; 0.97–1.09, respectively). Conclusions: In the first 10 years of life, from prospectively collected serial growth measurements, we found no evidence of impaired childhood growth before CD and CDA development as identified through early and periodic screening. © 2020 Informa UK Limited, trading as Taylor & Francis Group.
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| 28. |
- Tomaz, Simone A., et al.
(författare)
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Objectively Measured Physical Activity in South African Children Attending Preschool and Grade R : Volume, Patterns, and Meeting Guidelines
- 2020
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Ingår i: Pediatric Exercise Science. - : Human Kinetics. - 0899-8493 .- 1543-2920. ; 32:3, s. 150-156
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess physical activity (PA) and determine the proportion of preschoolers meeting PA recommendations in different income settings in South Africa.Methods: Preschoolers from urban high-income (UH), urban low-income (UL), and rural low-income (RL) settings wore an ActiGraph GT3X+ accelerometer for 7 days. PA variables of interest included volume moderate- to vigorous-intensity PA (MVPA) and total PA (light- to vigorous-intensity PA), hourly PA patterns, and percentage of children meeting guidelines (180 min/d of total PA, inclusive of 60 min/d of MVPA). Between-sex differences were assessed using t tests and Mann–Whitney U tests; between-setting differences assessed using 1-way analyses of variance and Kruskal–Wallis tests.Results: For all children (n = 229, aged 5.17 [0.69] y), average MVPA was 124.4 (37.5) minutes per day and total PA was 457.0 (61.1) minutes per day; 96.9% of children met guidelines. Boys did significantly more MVPA than girls (136.7 [39.37] vs 111.5 [30.70] min/d, P < .001), and UH preschoolers were significantly less active than UL and RL preschoolers (UH 409.1 [48.4] vs UL 471.1 [55.6] and RL 461.6 [61.4], P < .001).Conclusion: In both practice and research, it is necessary to explore ways to ensure that South African preschoolers from all income settings continue to engage in and benefit from healthy volumes of PA. This is especially important as preschoolers transition to a formal school environment.
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| 29. |
- Wimberger, Sandra, 1987, et al.
(författare)
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Simultaneous inhibition of DNA-PK and Pol ϴ improves integration efficiency and precision of genome editing
- 2023
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Ingår i: Nature Communications. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome editing, specifically CRISPR/Cas9 technology, has revolutionized biomedical research and offers potential cures for genetic diseases. Despite rapid progress, low efficiency of targeted DNA integration and generation of unintended mutations represent major limitations for genome editing applications caused by the interplay with DNA double-strand break repair pathways. To address this, we conduct a large-scale compound library screen to identify targets for enhancing targeted genome insertions. Our study reveals DNA-dependent protein kinase (DNA-PK) as the most effective target to improve CRISPR/Cas9-mediated insertions, confirming previous findings. We extensively characterize AZD7648, a selective DNA-PK inhibitor, and find it to significantly enhance precise gene editing. We further improve integration efficiency and precision by inhibiting DNA polymerase theta (Pol ϴ). The combined treatment, named 2iHDR, boosts templated insertions to 80% efficiency with minimal unintended insertions and deletions. Notably, 2iHDR also reduces off-target effects of Cas9, greatly enhancing the fidelity and performance of CRISPR/Cas9 gene editing. Low efficiency of target DNA integration remains a challenge in genome engineering. Here the authors perform large-scale compound library and genetic screens to identify targets that enhance gene editing: they see that combined DNA-PK and Pol ϴ inhibition with potent compounds increases editing efficiency and precision.
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| 30. |
- Yong, D., et al.
(författare)
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High-resolution spectroscopic follow-up of the most metal-poor candidates from SkyMapper DR1.1
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 507:3, s. 4102-4119
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Tidskriftsartikel (refereegranskat)abstract
- We present chemical abundances for 21 elements (from Li to Eu) in 150 metal-poor Galactic stars spanning −4.1 < [Fe/H] < −2.1. The targets were selected from the SkyMapper survey and include 90 objects with [Fe/H] ≤ −3 of which some 15 have [Fe/H] ≤ −3.5. When combining the sample with our previous studies, we find that the metallicity distribution function has a power-law slope of Δ(log N)/Δ[Fe/H] = 1.51 ± 0.01 dex per dex over the range −4 ≤ [Fe/H] ≤ −3. With only seven carbon-enhanced metal-poor stars in the sample, we again find that the selection of metal-poor stars based on SkyMapper filters is biased against highly carbon-rich stars for [Fe/H] > −3.5. Of the 20 objects for which we could measure nitrogen, 11 are nitrogen-enhanced metal-poor (NEMP) stars. Within our sample, the high NEMP fraction (55 per cent ± 21 per cent) is compatible with the upper range of predicted values (between 12 per cent and 35 per cent). The chemical abundance ratios [X/Fe] versus [Fe/H] exhibit similar trends to previous studies of metal-poor stars and Galactic chemical evolution models. We report the discovery of nine new r-I stars, four new r-II stars, one of which is the most metal-poor known, nine low-α stars with [α/Fe] ≤ 0.15 as well as one unusual star with [Zn/Fe] = +1.4 and [Sr/Fe] = +1.2 but with normal [Ba/Fe]. Finally, we combine our sample with literature data to provide the most extensive view of the early chemical enrichment of the Milky Way Galaxy.
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