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- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Bellaver, B., et al.
(författare)
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Astrocyte reactivity influences amyloid-beta effects on tau pathology in preclinical Alzheimer's disease
- 2023
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Ingår i: Nature Medicine. - 1078-8956. ; 29:7
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Tidskriftsartikel (refereegranskat)abstract
- Cross-sectional and longitudinal analyses of tau pathology in preclinical Alzheimer's disease reveal that tau tangles accumulate as a function of amyloid-beta burden only in individuals positive for an astrocyte reactivity biomarker. An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-beta (A beta)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash A beta effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of A beta with tau phosphorylation in CU individuals. We found that A beta was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast(+)). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of A beta only in CU Ast(+) individuals. Our findings suggest astrocyte reactivity as an important upstream event linking A beta with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials.
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- Bezuidenhout, L, et al.
(författare)
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Validity of Hip and Ankle Worn Actigraph Accelerometers for Measuring Steps as a Function of Gait Speed during Steady State Walking and Continuous Turning
- 2021
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Ingår i: Sensors (Basel, Switzerland). - : MDPI AG. - 1424-8220. ; 21:9
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to investigate the accuracy and reliability of hip and ankle worn Actigraph GT3X+ (AG) accelerometers to measure steps as a function of gait speed. Additionally, the effect of the low frequency extension filter (LFEF) on the step accuracy was determined. Thirty healthy individuals walked straight and walked with continuous turns in different gait speeds. Number of steps were recorded with a hip and ankle worn AG, and with a Stepwatch (SW) activity monitor positioned around the right ankle, which was used as a reference for step count. The percentage agreement, interclass correlation coefficients and Bland–Altmann plots were determined between the AG and the reference SW across gait speeds for the two walking conditions. The ankle worn AG with the default filter was the most sensitive for step detection at >0.6 m/s, whilst accurate step detection for gait speeds < 0.6 m/s were only observed when applying the LFEF. The hip worn AG with the default filter showed poor accuracy (12–78%) at gait speeds < 1.0 m/s whereas the accuracy increased to >87% for gait speeds < 1.0 m/s when applying the LFEF. Ankle worn AG was the most sensitive to measure steps at a vast range of gait speeds. Our results suggest that sensor placement and filter settings need to be taken into account to provide accurate estimates of step counts.
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- Breyer, F., et al.
(författare)
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TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria
- 2021
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Ingår i: Embo Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 40:10
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Tidskriftsartikel (refereegranskat)abstract
- Tumour progression locus 2 (TPL-2) kinase mediates Toll-like receptor (TLR) activation of ERK1/2 and p38 alpha MAP kinases in myeloid cells to modulate expression of key cytokines in innate immunity. This study identified a novel MAP kinase-independent regulatory function for TPL-2 in phagosome maturation, an essential process for killing of phagocytosed microbes. TPL-2 catalytic activity was demonstrated to induce phagosome acidification and proteolysis in primary mouse and human macrophages following uptake of latex beads. Quantitative proteomics revealed that blocking TPL-2 catalytic activity significantly altered the protein composition of phagosomes, particularly reducing the abundance of V-ATPase proton pump subunits. Furthermore, TPL-2 stimulated the phosphorylation of DMXL1, a regulator of V-ATPases, to induce V-ATPase assembly and phagosome acidification. Consistent with these results, TPL-2 catalytic activity was required for phagosome acidification and the efficient killing of Staphylococcus aureus and Citrobacter rodentium following phagocytic uptake by macrophages. TPL-2 therefore controls innate immune responses of macrophages to bacteria via V-ATPase induction of phagosome maturation.
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