| 1. |
- Kaufmann, M., et al.
(författare)
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Identification of early neurodegenerative pathways in progressive multiple sclerosis
- 2022
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Ingår i: Nature Neuroscience. - : Springer Nature. - 1097-6256 .- 1546-1726. ; 25:7, s. 944-955
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Tidskriftsartikel (refereegranskat)abstract
- Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand–receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.
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| 2. |
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| 3. |
- Cheung, Mark C. M., et al.
(författare)
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Probing the Physics of the Solar Atmosphere with the Multi-slit Solar Explorer (MUSE). II. Flares and Eruptions
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- Current state-of-the-art spectrographs cannot resolve the fundamental spatial (subarcseconds) and temporal (less than a few tens of seconds) scales of the coronal dynamics of solar flares and eruptive phenomena. The highest-resolution coronal data to date are based on imaging, which is blind to many of the processes that drive coronal energetics and dynamics. As shown by the Interface Region Imaging Spectrograph for the low solar atmosphere, we need high-resolution spectroscopic measurements with simultaneous imaging to understand the dominant processes. In this paper: (1) we introduce the Multi-slit Solar Explorer (MUSE), a spaceborne observatory to fill this observational gap by providing high-cadence (<20 s), subarcsecond-resolution spectroscopic rasters over an active region size of the solar transition region and corona; (2) using advanced numerical models, we demonstrate the unique diagnostic capabilities of MUSE for exploring solar coronal dynamics and for constraining and discriminating models of solar flares and eruptions; (3) we discuss the key contributions MUSE would make in addressing the science objectives of the Next Generation Solar Physics Mission (NGSPM), and how MUSE, the high-throughput Extreme Ultraviolet Solar Telescope, and the Daniel K Inouye Solar Telescope (and other ground-based observatories) can operate as a distributed implementation of the NGSPM. This is a companion paper to De Pontieu et al., which focuses on investigating coronal heating with MUSE.
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| 4. |
- De Pontieu, Bart, et al.
(författare)
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Probing the Physics of the Solar Atmosphere with the Multi-slit Solar Explorer (MUSE). I. Coronal Heating
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- The Multi-slit Solar Explorer (MUSE) is a proposed mission composed of a multislit extreme ultraviolet (EUV) spectrograph (in three spectral bands around 171 Å, 284 Å, and 108 Å) and an EUV context imager (in two passbands around 195 Å and 304 Å). MUSE will provide unprecedented spectral and imaging diagnostics of the solar corona at high spatial (≤05) and temporal resolution (down to ∼0.5 s for sit-and-stare observations), thanks to its innovative multislit design. By obtaining spectra in four bright EUV lines (Fe ix 171 Å, Fe xv 284 Å, Fe xix–Fe xxi 108 Å) covering a wide range of transition regions and coronal temperatures along 37 slits simultaneously, MUSE will, for the first time, "freeze" (at a cadence as short as 10 s) with a spectroscopic raster the evolution of the dynamic coronal plasma over a wide range of scales: from the spatial scales on which energy is released (≤05) to the large-scale (∼170'' × 170'') atmospheric response. We use numerical modeling to showcase how MUSE will constrain the properties of the solar atmosphere on spatiotemporal scales (≤05, ≤20 s) and the large field of view on which state-of-the-art models of the physical processes that drive coronal heating, flares, and coronal mass ejections (CMEs) make distinguishing and testable predictions. We describe the synergy between MUSE, the single-slit, high-resolution Solar-C EUVST spectrograph, and ground-based observatories (DKIST and others), and the critical role MUSE plays because of the multiscale nature of the physical processes involved. In this first paper, we focus on coronal heating mechanisms. An accompanying paper focuses on flares and CMEs.
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| 5. |
- Greer, M., et al.
(författare)
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Assessing treatment outcomes in CLAD: The Hannover-extracorporeal photopheresis model
- 2023
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Ingår i: Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 42:2, s. 209-217
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a leading cause of graft loss in lung transplantation. Despite this, convincing treatment data is lacking, and protocols vary widely between centers. CLAD phenotypes exist, but phenotype transitioning has increased the challenge of designing clinically relevant studies. Extracorporeal photopheresis (ECP) has long been a suggested salvage treat-ment, but efficacy appears unpredictable. This study describes our experiences with photopheresis, using novel temporal phenotyping to illustrate the clinical course. METHODS: Retrospective analysis of patients completing >= 3 months of ECP for CLAD between 2007 and 2022 was performed. A latent class analysis employing a mixed-effects model was performed, deriving patient subgroups based on spirometry trajectory over the 12 months prior to photopheresis until graft loss or 4 years post photopheresis initiation. The resulting temporal phenotypes were com-pared in terms of treatment response and survival outcomes. Linear discriminatory analysis was used to assess phenotype predictability, relying solely on data available at photopheresis initiation. RESULTS: Data from 5,169 outpatient attendances in 373 patients was used to construct the model. Five trajectories were identified, with uniform spirometry changes evident following 6 months of photophe-resis. Outcomes were poorest in Fulminant patients (N = 25, 7%) with median survival of 1 year. In the remainder, poorer lung function at initiation led to poorer outcomes. The analysis revealed important confounders, affecting both decision-making and outcome interpretation. CONCLUSIONS: Temporal phenotyping provided novel insights into ECP treatment response in CLAD, particularly the importance of timely intervention. Limitations in % Baseline values in guiding treat-ment decisions warrant further analysis. Photopheresis may have a more uniform effect than previously thought. Predicting survival at ECP initiation appears feasible. J Heart Lung Transplant 2023;42:209-217 (c) 2022 International Society for Heart and Lung Transplantation. All rights reserved.
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