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- Conlon, Thomas M, et al.
(författare)
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Inhibition of LTβR signalling activates WNT-induced regeneration in lung
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588:7836, s. 151-156
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Tidskriftsartikel (refereegranskat)abstract
- Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
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| 2. |
- Franzmeier, Nicolai, 1989, et al.
(författare)
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Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer's disease.
- 2024
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Ingår i: Nature communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- In Alzheimer's disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer's spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer's disease.
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| 3. |
- Malpetti, Maura, et al.
(författare)
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Neuroinflammation Parallels 18F-PI-2620 Positron Emission Tomography Patterns in Primary 4-Repeat Tauopathies
- 2024
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Ingår i: MOVEMENT DISORDERS. - 0885-3185 .- 1531-8257.
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Tidskriftsartikel (refereegranskat)abstract
- Background Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. Objective We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. Methods We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. Results In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (beta = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (beta = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. Conclusions Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions.
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| 6. |
- Ringkjøb, Hans-Kristian, et al.
(författare)
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Short-term solar and wind variability in long-term energy system models - A European case study
- 2020
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Ingår i: Energy. - : Elsevier Ltd. - 0360-5442 .- 1873-6785. ; 209
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Tidskriftsartikel (refereegranskat)abstract
- Integration of variable renewables such as solar and wind has grown at an unprecedented pace in Europe over the past two decades. As the share of solar and wind rises, it becomes increasingly important for long-term energy system models to adequately represent their short-term variability. This paper uses a long-term TIMES model of the European power and district heat sectors towards 2050 to explore how stochastic modelling of short-term solar and wind variability as well as different temporal resolutions influence the model performance. Using a stochastic model with 48 time-slices as benchmark, the results show that deterministic models with low temporal resolution give a 15–20% underestimation of annual costs, an overestimation of the contribution of variable renewables (13–15% of total electricity generation) and a lack of system flexibility. The results of the deterministic models converge towards the stochastic solution when the temporal resolution is increased, but even with 2016 time-slices, the need for flexibility is underestimated. In addition, the deterministic model with 2016 time-slices takes 30 times longer to solve than the stochastic model with 48 time-slices. Based on these findings, a stochastic approach is recommended for long-term studies of energy systems with large shares of variable renewable energy sources. © 2020 The Authors
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| 7. |
- Roemer, Sebastian N., et al.
(författare)
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Subcortical tau is linked to hypoperfusion in connected cortical regions in 4-repeat tauopathies
- 2024
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Ingår i: BRAIN. - 0006-8950 .- 1460-2156. ; 147:7, s. 2428-2439
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Tidskriftsartikel (refereegranskat)abstract
- Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies.We included 51 A beta-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres.As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion.Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity. Four-repeat tauopathies are rapidly progressive neurodegenerative diseases with mixed subcortical and cortical symptoms. Using advanced neuroimaging methods, Roemer et al. show that subcortical tau accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions.
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