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- Bauer, K, et al.
(författare)
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Perforin deficiency attenuates collagen-induced arthritis
- 2005
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 7:4, s. 877-884
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Tidskriftsartikel (refereegranskat)abstract
- Collagen-induced arthritis ( CIA), an approved animal model for rheumatoid arthritis, is thought to be a T cell-dependent disease. There is evidence that CD8(+) T cells are a major subset controlling the pathogenesis of CIA. They probably contribute to certain features of disease, namely tissue destruction and synovial hyperplasia. In this study we examined the role of perforin (pfp), a key molecule of the cytotoxic death pathway that is expressed mainly in CD8(+) T cells, for the pathogenesis of CIA. We generated DBA/1J mice suffering from mutations of the pfp molecule, DBA/1J-pfp(-/-), and studied their susceptibility to arthritis. As a result, pfp-deficient mice showed a reduced incidence (DBA/1J-pfp(+/+), 64%; DBA/1J-pfp(-/-), 54%), a slightly delayed onset ( onset of disease: DBA/1J-pfp(+/+), 53 +/- 3.6; DBA/1J-pfp(-/-), 59 +/- 4.9 ( mean SEM), and milder form of the disease ( maximum disease score: DBA/1J-pfp(+/+), 7.3 +/- 1.1; DBA/1J-pfp(-/-), 3.4 +/- 1.4 ( mean SEM); P < 0.05). Concomitantly, peripheral T cell proliferation in response to the specific antigen bovine collagen II was increased in pfp(-/-) mice compared with pfp(+/+) mice, arguing for an impaired killing of autoreactive T cells caused by pfp deficiency. Thus, pfp-mediated cytotoxicity is involved in the initiation of tissue damage in arthritis, but pfp-independent cytotoxic death pathways might also contribute to CIA.
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- Benson, Tyler W, et al.
(författare)
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Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms.
- 2023
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Ingår i: bioRxiv : the preprint server for biology.
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.KEY POINTS: Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
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- Fischer, Hubertus, et al.
(författare)
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Palaeoclimate constraints on the impact of 2 °C anthropogenic warming and beyond
- 2018
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Ingår i: Nature Geoscience. - : Springer Science and Business Media LLC. - 1752-0894 .- 1752-0908. ; 11:7, s. 474-485
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 3.5 million years, there have been several intervals when climate conditions were warmer than during the pre-industrial Holocene. Although past intervals of warming were forced differently than future anthropogenic change, such periods can provide insights into potential future climate impacts and ecosystem feedbacks, especially over centennial-to-millennial timescales that are often not covered by climate model simulations. Our observation-based synthesis of the understanding of past intervals with temperatures within the range of projected future warming suggests that there is a low risk of runaway greenhouse gas feedbacks for global warming of no more than 2 °C. However, substantial regional environmental impacts can occur. A global average warming of 1–2 °C with strong polar amplification has, in the past, been accompanied by significant shifts in climate zones and the spatial distribution of land and ocean ecosystems. Sustained warming at this level has also led to substantial reductions of the Greenland and Antarctic ice sheets, with sea-level increases of at least several metres on millennial timescales. Comparison of palaeo observations with climate model results suggests that, due to the lack of certain feedback processes, model-based climate projections may underestimate long-term warming in response to future radiative forcing by as much as a factor of two, and thus may also underestimate centennial-to-millennial-scale sea-level rise.
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- Hogan, Kelly A., et al.
(författare)
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Glacial sedimentation, fluxes and erosion rates associated with ice retreat in Petermann Fjord and Nares Strait, north-west Greenland
- 2020
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Ingår i: The Cryosphere. - : Copernicus GmbH. - 1994-0416 .- 1994-0424. ; 14:1, s. 261-286
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Tidskriftsartikel (refereegranskat)abstract
- Petermann Fjord is a deep ( > 1000 m) fjord that incises the coastline of north-west Greenland and was carved by an expanded Petermann Glacier, one of the six largest outlet glaciers draining the modern Greenland Ice Sheet (GrIS). Between 5 and 70 m of unconsolidated glacigenic material infills in the fjord and adjacent Nares Strait, deposited as the Petermann and Nares Strait ice streams retreated through the area after the Last Glacial Maximum. We have investigated the deglacial deposits using seismic stratigraphic techniques and have correlated our results with high-resolution bathymetric data and core lithofacies. We identify six seismoacoustic facies in more than 3500 line kilometres of subbottom and seismic-reflection profiles throughout the fjord, Hall Basin and Kennedy Channel. Seismo-acoustic facies relate to bedrock or till surfaces (Facies I), subglacial deposition (Facies II), deposition from meltwater plumes and icebergs in quiescent glacimarine conditions (Facies III, IV), deposition at grounded ice margins during stillstands in retreat (grounding-zone wedges; Facies V) and the redeposition of material downslope (Facies IV). These sediment units represent the total volume of glacial sediment delivered to the mapped marine environment during retreat. We calculate a glacial sediment flux for the former Petermann ice stream as 1080-1420 m(3) a(-1) per metre of ice stream width and an average deglacial erosion rate for the basin of 0.29-0.34 mm a(-1). Our deglacial erosion rates are consistent with results from Antarctic Peninsula fjord systems but are several times lower than values for other modern GrIS catchments. This difference is attributed to fact that large volumes of surface water do not access the bed in the Petermann system, and we conclude that glacial erosion is limited to areas overridden by streaming ice in this large outlet glacier setting. Erosion rates are also presented for two phases of ice retreat and confirm that there is significant variation in rates over a glacial-deglacial transition. Our new glacial sediment fluxes and erosion rates show that the Petermann ice stream was approximately as efficient as the palaeo-Jakobshavn Isbra at eroding, transporting and delivering sediment to its margin during early deglaciation.
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- Schmittner, Andreas, et al.
(författare)
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Calibration of the carbon isotope composition (δ13C) of benthic foraminifera
- 2017
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Ingår i: Paleoceanography. - 0883-8305. ; 32:6, s. 512-530
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Tidskriftsartikel (refereegranskat)abstract
- The carbon isotope composition (δ13C) of seawater provides valuable insight on ocean circulation, air-sea exchange, the biological pump, and the global carbon cycle and is reflected by the δ13C of foraminifera tests. Here more than 1700 δ13C observations of the benthic foraminifera genus Cibicides from late Holocene sediments (δ13CCibnat) are compiled and compared with newly updated estimates of the natural (preindustrial) water column δ13C of dissolved inorganic carbon (δ13CDICnat) as part of the international Ocean Circulation and Carbon Cycling (OC3) project. Using selection criteria based on the spatial distance between samples, we find high correlation between δ13CCibnat and δ13CDICnat, confirming earlier work. Regression analyses indicate significant carbonate ion (-2.6 ± 0.4) × 10-3‰/(μmol kg-1) [CO3 2-] and pressure (-4.9 ± 1.7) × 10-3‰ m-1 (depth) effects, which we use to propose a new global calibration for predicting δ13CDICnat from δ13CCibnat. This calibration is shown to remove some systematic regional biases and decrease errors compared with the one-to-one relationship (δ13CDICnat = δ13CCibnat). However, these effects and the error reductions are relatively small, which suggests that most conclusions from previous studies using a one-to-one relationship remain robust. The remaining standard error of the regression is generally σ ≅ 0.25‰, with larger values found in the southeast Atlantic and Antarctic (σ ≅ 0.4‰) and for species other than Cibicides wuellerstorfi. Discussion of species effects and possible sources of the remaining errors may aid future attempts to improve the use of the benthic δ13C record.
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- Zhu, J, et al.
(författare)
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Peripheral nerve myelin modulates the effect of antidepressants on major histocompatibility complex expression on macrophages in experimental allergic neuritis
- 1995
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Ingår i: INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY. - : SAGE Publications. - 0394-6320 .- 2058-7384. ; 8:3, s. 185-198
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The effect of bovine peripheral nerve myelin (BPM) used for induction of experimental allergic neuritis (EAN) in Lewis rats, on antidepressants' modulation of interferon-gamma (IFN-γ)-induced major histocompatibility complex (MHC) class I and II antigen expression on peritoneal macrophages in EAN rats was studied. Antidepressants with different profiles concerning inhibition of the neuronal reuptake of the monoamines serotonin (5-HT) and noradrenalin (NA), respectively, in concentrations of 10−4 to 10−8 M were used. At the concentration of 1.0 U/ml IFN-γ, most antidepressants significantly enhanced both MHC class I and class II expression, except maprotiline, a selective NA reuptake inhibiting antidepressant that suppressed MHC class I expression. Zimeldine, a selective 5-HT reuptake inhibitor did not affect MHC class II expression. BPM in general had an enhancing effect on modulation of both MHC class I and class II expression by antidepressants. By itself BPM enhanced MHC class I expression, but did not affect class II expression at IFN-γ 1.0 U/ml. The modulating effect of BPM on regulation of MHC expression by antidepressants could be the result of contaminating T cells and release of IFN-γ into cultures. The modulatory effect of antidepressants on MHC expression may to some extent be exerted by the action on 5-HT and/or NA regulation, but also by direct effects of antidepressants on macrophages. They probably play a role in zimeldine-induced Guillain-Barré syndrome in some patients and in the suppression of clinical signs of EAN in Lewis rats reported for some antidepressants.
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