| 1. |
- Arber, C., et al.
(författare)
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Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta
- 2020
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:11, s. 2919-2931
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Tidskriftsartikel (refereegranskat)abstract
- Familial Alzheimer’s disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD. © 2019, Springer Nature Limited.
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| 2. |
- Arber, T. D., et al.
(författare)
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Large Larmor Radius Stability of the Z-pinch
- 1994
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 72, s. 2399-
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Tidskriftsartikel (refereegranskat)abstract
- The linear m=0 stability of the z pinch in the collisionless, large ion Larmor radius regime is examined using the Vlasov fluid model. The results reveal a strong equilibrium dependence. The uniform current density equilibrium shows a reduction in growth rate when the average ion Larmor radius is about one-fifth of the pinch radius. However, finite Larmor radius effects cannot in themselves produce a stabilized z pinch.
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| 3. |
- Arber, T. D., et al.
(författare)
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Linear Stability of the High Temperature, Dense Z-pinch
- 1995
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 74, s. 2698-
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Tidskriftsartikel (refereegranskat)abstract
- Results are presented on the linear stability of the collisionless m=1 mode in a dense Z pinch. It is shown that a reduction in growth rate by a factor of about 10 (when compared to the zero Larmor radius result) is possible by initializing the Z pinch with a sufficiently low line density. With the completion of this work we conclude that linear, large Larmor radius effects cannot stabilize the high temperature, dense Z pinch. Such pinches will always exhibit linear m=0 or m=1 instabilities with growth times comparable to the radial Alfvén transit time.
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| 4. |
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| 5. |
- Coppins, M., et al.
(författare)
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Recent progress on large Larmor radius theory
- 1997
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Ingår i: Fourth International Conference on Dense Z-pinches, Vancouver, Canada, 28-31 May 1997. - : ASCE. ; , s. 585-
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Konferensbidrag (refereegranskat)abstract
- An overview of theoretical work on large Larmor radius stability of the z-pinch is presented, highlighting two recent innovations. Firstly, finite electron temperature has been included for the linear m=0 instability. Compared to the usual cold electron case, growth rates are increased and are closer to those of ideal MHD. Secondly, a 2-D hybrid code has been written to study the non-linear development of the m=0 instability. First results provide no evidence of instability saturation.
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| 6. |
- Garcia-Reitboeck, P., et al.
(författare)
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Human Induced Pluripotent Stem Cell-Derived Microglia-Like Cells Harboring TREM2 Missense Mutations Show Specific Deficits in Phagocytosis
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 24:9, s. 2300-2311
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Tidskriftsartikel (refereegranskat)abstract
- Dysfunction of microglia, the brain's immune cells, is linked to neurodegeneration. Homozygous missense mutations in TREM2 cause Nasu-Hakola disease (NHD), an early-onset dementia. To study the consequences of these TREM2 variants, we generated induced pluripotent stem cell-derived microglia-like cells (iPSC-MGLCs) from patients with NHD caused by homozygous T66M or W50C missense mutations. iPSC-MGLCs expressed microglial markers and secreted higher levels of TREM2 than primary macrophages. TREM2 expression and secretion were reduced in variant lines. LPS-mediated cytokine secretion was comparable between control and TREM2 variant iPSC-MGLCs, whereas survival was markedly reduced in cells harboring missense mutations when compared with controls. Furthermore, TREM2 missense mutations caused a marked impairment in the phagocytosis of apoptotic bodies, but not in Escherichia coli or zymosan substrates. Coupled with changes in apoptotic cell-induced cytokine release and migration, these data identify specific deficits in the ability of iPSC-MGLCs harboring TREM2 missense mutations to respond to specific pathogenic signals.
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| 7. |
- Haines, M. G., et al.
(författare)
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Fiber Z-pinch Experiments and Calculations in the Finite Larmor Radius Regime
- 1996
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Ingår i: Laser and particle beams (Print). - 0263-0346 .- 1469-803X. ; 14, s. 261-271
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Tidskriftsartikel (refereegranskat)abstract
- The dense Z-pinch project at Imperial College is aimed at achieving radiative collapse to high density in a hydrogen plasma, and also to study plasmas close to controlled fusion conditions. To this end, the MAGPIE generator (2.4 MV, 1.25, and 200 ns) has been built and tested, and is now giving preliminary experimental data at 60% of full voltage for carbon and CD2 fibers. These discharges are characterized by an initial radial expansion followed by the occurrence of m = 0 structures with transient X-ray emission from bright spots. Late in the discharge a disruption can occur, accompanied by hard X-ray emission from the anode due to an energetic electron beam and, in the case of CD2 fibers, a neutron burst. Concomitant theoretical studies have solved the linear stability problem for a Z-pinch with large ion Larmor radii, showing that a reduction in growth rate of m = 0 and m = 1 modes to about 20% of the magnetohydrodynamic (MHD) value can occur for a parabolic density profile when the Larmor radius is optimally 20% of the pinch radius. Two dimensional MHD simulations of Z-pinches in two extremes of focussed short-pulse laserplasma interactions and of galactic jets reveal a nonlinear stabilizing effect in the presence of sheared flow. One-dimensional simulations show that at low line density the lower hybrid drift instability can lead to coronal radial expansion of a Z-pinch plasma.
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| 8. |
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| 9. |
- Mallach, A., et al.
(författare)
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Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer's disease risk variant, R47H(het), on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47H(het) iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47H(het) TREM2 variant may underlie the increased risk of Alzheimer's disease associated with this variant.
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| 10. |
- Mikus, Maria, et al.
(författare)
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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
- 2016
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Ingår i: Liver international. - : John Wiley & Sons. - 1478-3223 .- 1478-3231. ; 37:1, s. 132-140
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
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| 11. |
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| 12. |
- Russell, P. G. F., et al.
(författare)
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Linear Stability of the Collisionless, Large Larmor Radius Z-pinch
- 1997
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Ingår i: Physics of Plasmas. - : AIP Publishing. - 1070-664X .- 1089-7674. ; 4, s. 2322-
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Tidskriftsartikel (refereegranskat)abstract
- The Vlasov fluid model is used to study the m=0 and m=1 internal and free boundary modes in a collisionless, large Larmor radius Z pinch. Two methods (initial value and variational) are employed, and give good agreement. The growth rate can be reduced from its zero Larmor radius value by a factor of up to 10 for m=1, and up to 3 for m=0. Stability thresholds and the role of resonant ions are discussed.
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| 13. |
- Scheffel, Jan, 1954-, et al.
(författare)
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Kinetic Stability of the Finite Electron Temperature Z-pinch
- 1997
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Ingår i: Plasma Physics and Controlled Fusion. - 0741-3335 .- 1361-6587. ; 39:4, s. 559-568
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Tidskriftsartikel (refereegranskat)abstract
- Large Larmor radius (LLR) stability of linear m = 0 and m = 1 modes in a Z-pinch has been studied using the Vlasov-fluid model (Arber et al1994 Phys. Rev. Lett. 72 2399; 1995 Phys. Rev. Lett. 74 2698). Ions have been modelled fully kinetically through the Vlasov equation, and electrons are treated as a zero temperature, massless fluid. In the present work an improved Vlasov-fluid model is used to investigate the effect of finite electron temperature on m = 0 modes. An electron energy equation is introduced, and results for both adiabatic and isothermal dynamics are presented. It is found that finite electron temperature has a destabilizing effect in general. As a result, the Z-pinch is only weakly stabilized by LLR effects.
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| 14. |
- Scheffel, Jan, 1954-, et al.
(författare)
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Kinetic Stability of the Z-pinch
- 1993
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Ingår i: APS Plasma Physics Meeting 1-5 Nov. 1993, St. Louis, Missouri, USA.
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Konferensbidrag (refereegranskat)
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| 15. |
- Scheffel, Jan, 1954-, et al.
(författare)
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Linear Stability of the Large Larmor Radius Z-pinch
- 1994
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Ingår i: Third International Conference on Dense Z-pinches, Imperial College, London, 19-23 April 1993. - : AIP. ; , s. 75-
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Konferensbidrag (refereegranskat)abstract
- For the first time, calculations of large Larmor radius (LLR) effects on the linear stability of realistic Z-pinch equilibria have been performed. The fixed boundary m=0 instability of the pure Z-pinch (no external magnetic field) is considered (free-boundary and m=1 modes are presently under study). We use the Vlasov-Fluid model, where ions are treated fully kinetically and electrons are modelled as a cold, massless fluid. Stability is found to be remarkably sensitive to equilibrium profiles. A flat current equilibrium is increasingly stabilized (smaller growth rate) by LLR effects as the normalized average Larmor radius ε is increased to about 0.1. Complete stabilization cannot be obtained. For larger values of ε the growth rate increases to reach above the small Larmor radius value when ε~0.3. The Bennett equilibrium, however, is increasingly destabilized as ε increases.
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| 16. |
- Valent, Peter, et al.
(författare)
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Advances in the Classification and Treatment of Mastocytosis : Current Status and Outlook toward the Future.
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:6, s. 1261-1270
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Tidskriftsartikel (refereegranskat)abstract
- Mastocytosis is a term used to denote a heterogeneous group of conditions defined by the expansion and accumulation of clonal (neoplastic) tissue mast cells in various organs. The classification of the World Health Organization (WHO) divides the disease into cutaneous mastocytosis, systemic mastocytosis, and localized mast cell tumors. On the basis of histomorphologic criteria, clinical parameters, and organ involvement, systemic mastocytosis is further divided into indolent systemic mastocytosis and advanced systemic mastocytosis variants, including aggressive systemic mastocytosis and mast cell leukemia. The clinical impact and prognostic value of this classification has been confirmed in numerous studies, and its basic concept remains valid. However, refinements have recently been proposed by the consensus group, the WHO, and the European Competence Network on Mastocytosis. In addition, new treatment options are available for patients with advanced systemic mastocytosis, including allogeneic hematopoietic stem cell transplantation and multikinase inhibitors directed against KIT D816V and other key signaling molecules. Our current article provides an overview of recent advances in the field of mastocytosis, with emphasis on classification, prognostication, and emerging new treatment options in advanced systemic mastocytosis.
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| 17. |
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