| 1. |
- Andersson, Arne, et al.
(författare)
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Amyloid Deposition in Transplanted Human Pancreatic Islets : A Conceivable Cause of Their Long-Term Failure
- 2008
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Ingår i: EXPERIMENTAL DIABETES RESEARCH. - : Hindawi Limited. - 1687-5214 .- 1687-5303. ; 2008:562985
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Tidskriftsartikel (refereegranskat)abstract
- Following the encouraging report of the Edmonton group, there was a rejuvenation of the islet transplantation field. After that, more pessimistic views spread when long-term results of the clinical outcome were published. A progressive loss of the beta-cell function meant that almost all patients were back on insulin therapy after 5 years. More than 10 years ago, we demonstrated that amyloid deposits rapidly formed in human islets and in mouse islets transgenic for human IAPP when grafted into nude mice. It is, therefore, conceivable to consider amyloid formation as one potential candidate for the long-term failure. The present paper reviews attempts in our laboratories to elucidate the dynamics of and mechanisms behind the formation of amyloid in transplanted islets with special emphasis on the impact of long-term hyperglycemia.
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| 2. |
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| 3. |
- Paulsson, Johan, 1976-, et al.
(författare)
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Intracellular amyloid-like deposits contain unprocessed pro-islet amyloid polypeptide (proIAPP) in beta cells of transgenic mice overexpressing the gene for human IAPP and transplanted human islets
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:6, s. 1237-1246
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Islet amyloid is a frequent finding in the islets of Langerhans of individuals with type 2 diabetes. The main amyloid constituent is the beta cell-derived polypeptide hormone islet amyloid polypeptide (IAPP). In general, amyloid refers to an extracellular deposit of a congophilic material, but intracellular amyloid is seen in some beta cells of transgenic mice expressing the gene for human IAPP and in human islets transplanted into nude mice. The aim of this study was to immunohistochemically characterise the intracellular amyloid. Methods: Antisera against the N- and C-terminal processing sites of proIAPP (which were therefore specific for proIAPP), the C-terminal flanking peptide and mature IAPP were used for immunoelectron microscopy. Results: Fibrillar aggregates were seen in the halo region of the secretory granules in some beta cells in human IAPP transgenic mice. These aggregates were labelled with proIAPP-specific antisera. Also, proIAPP reactivity was more widespread in the intracellular amyloid-like aggregates in beta cells of transgenic mice than in human islet transplants, in which the intracellular amyloid-like deposits were larger, but the proIAPP labelling was restricted to small spots within the amyloid deposits. Conclusions/ interpretation: We suggest that proIAPP forms the first amyloid fibrils and that this can occur already in the secretory granules of the beta cells. The proIAPP-derived fibrils can act as seed for further amyloid formation, now made up by IAPP. The observed difference between human islet transplants and human IAPP transgenic animals may reflect differences in stages of amyloid development. © Springer-Verlag 2006.
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| 4. |
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| 5. |
- Bartlett, Michael A., et al.
(författare)
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A study of humidified gas turbines for short-term realization in midsized power generation - Part I : Nonintercooled cycle analysis
- 2005
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Ingår i: Journal of engineering for gas turbines and power. - : ASME International. - 0742-4795 .- 1528-8919. ; 127:1, s. 91-99
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Tidskriftsartikel (refereegranskat)abstract
- Humidified Gas Turbine (HGT) cycles are a group of advanced gas turbine cycles that use water-air mixtures as the working media. In this article, three known HGT configurations are examined in the context of short-term realization for small to midsized power generation: the Steam Injected Gas Turbine, the Full-flow Evaporative Gas Turbine, and the Part-flow Evaporative Gas Turbine. The heat recovery characteristics and performance potential of these three cycles are assessed, with and without intercooling, and a preliminary economic analysis is carried out for the most promising cycles.
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| 6. |
- Ihse, E, et al.
(författare)
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Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
- 2008
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:2, s. 253-61
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Tidskriftsartikel (refereegranskat)abstract
- Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.
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| 7. |
- Lundberg, Erik, et al.
(författare)
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Stability and fibril formation properties of human and fish transthyretin, and of the Escherichia coli transthyretin-related protein
- 2009
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Ingår i: FEBS JOURNAL. - : Wiley. - 1742-464X .- 1742-4658. ; 276:7, s. 1999-2011
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Tidskriftsartikel (refereegranskat)abstract
- Human transthyretin (hTTR) is one of several proteins known to cause amyloid disease. Conformational changes in its native structure result in aggregation of the protein, leading to insoluble amyloid fibrils. The transthyretin (TTR)-related proteins comprise a protein family of 5-hydroxyisourate hydrolases with structural similarity to TTR. In this study, we tested the amyloidogenic properties, if any, of sea bream TTR (sbTTR) and Escherichia coli transthyretin-related protein (ecTRP), which share 52% and 30% sequence identity, respectively, with hTTR. We obtained filamentous structures from all three proteins under various conditions, but, interestingly, different structures displayed different tinctorial properties. hTTR and sbTTR formed thin, curved fibrils at low pH (pH 2-3) that bound thioflavin-T (thioflavin-T-positive) but did not stain with Congo Red (CR) (CR-negative). Aggregates formed at the slightly higher pH of 4.0-5.5 had different morphology, displaying predominantly amorphous structures. CR-positive material of hTTR was found in this material, in agreement with previous results. ecTRP remained soluble at pH 2-12 at ambient temperatures. By raising of the temperature, fibril formation could be induced at neutral pH in all three proteins. Most of these temperature-induced fibrils were thicker and straighter than the in vitro fibrils seen at low pH. In other words, the temperature-induced fibrils were more similar to fibrils seen in vivo. The melting temperature of ecTRP was 66.7 degrees C. This is approximately 30 degrees C lower than the melting temperatures of sbTTR and hTTR. Information from the crystal structures was used to identify possible explanations for the reduced thermostability of ecTRP.
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| 8. |
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| 9. |
- Swartling, Fredrik J., et al.
(författare)
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Cyclic GMP-dependent protein kinase II inhibits cell proliferation, Sox9 expression and Akt phosphorylation in human glioma cell lines
- 2009
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 28:35, s. 3121-3131
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Tidskriftsartikel (refereegranskat)abstract
- Earlier we used a glioma model to identify loci in the mouse genome, which were repeatedly targeted by platelet-derived growth factor (PDGF)-containing Moloney murine leukemia viruses. The gene Prkg2, encoding cyclic guanosine monophosphate (cGMP)-dependent protein kinase II, cGKII, was tagged by retroviral insertions in two brain tumors. The insertions were both situated upstream of the kinase domain and suggested creating a truncated form of the cGKII protein. We transfected different human glioma cell lines with Prkg2 and found an overall reduction in colony formation and cell proliferation compared with controls transfected with truncated Prkg2 (lacking the kinase domain) or empty vector. All glioma cells transfected with the cGKII phosphorylate vasodilator-stimulated phosphoprotein, VASP, after cGMP analog treatment. Glioma cell lines positive for the Sox9 transcription factor showed reduced Sox9 expression when Prkg2 was stably transfected. When cGKII was activated by cGMP analog treatment, Sox9 was phosphorylated, Sox9 protein expression was suppressed and the glioma cell lines displayed loss of cell adhesion, inhibition of Akt phosphorylation and G1 arrest. Sox9 repression by siRNA was similarly shown to reduce glioma cell proliferation. Expression analysis of stem and glial lineage cell markers also suggests that cGKII induces differentiation of glioma cell lines. These findings describe an anti-proliferative role of cGKII in human glioma biology and would further explain the retroviral tagging of the cGKII gene during brain tumor formation in PDGF-induced tumors.
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