| 1. |
- Wallensten, Anders, et al.
(author)
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Surveillance of influenza A virus in migratory waterfowl in northern Europe
- 2007
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In: Emerging Infectious Diseases. - 1080-6040 .- 1080-6059. - 1080-6040 ; 13:3, s. 404-411
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Journal article (peer-reviewed)abstract
- We conducted large-scale, systematic sampling of influenza type A virus in migratory waterfowl (mostly mallards [Anas platyrhynchos]) at Ottenby Bird Observatory, southeast Sweden. As with previous studies, we found a higher prevalence in fall than spring, and among juveniles compared with adults. However, in contrast to other studies, we found that prevalence in spring was sometimes high (mean 4.0%, highest 9.5%). This finding raises the possibility that ducks are capable of perpetuating influenza A virus of different subtypes and subtype combinations throughout the year and from 1 year to the next. Isolation of the H5 and H7 subtypes was common, which suggests risk for transmission to sensitive domestic animals such as poultry. We argue that wild bird screening can function as a sentinel system, and we give an example of how it could have been used to forecast a remote and deadly outbreak of influenza A in poultry.
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| 2. |
- Cappai, Roberto, et al.
(author)
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The amyloid precursor protein(APP)of Alzheimer's disease and its paralog APLP2 modulate the Cu/Zn-NO-catalyzed degradation of glypican-1 heparan sulfate In vivo.
- 2005
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In: Journal of Biological Chemistry. - 1083-351X. ; 280:14, s. 13913-13920
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Journal article (peer-reviewed)abstract
- Processing of the recycling proteoglycan glypican-1 involves the release of its heparan sulfate chains by copper ion- and nitric oxide-catalyzed ascorbate-triggered autodegradation. The Alzheimer disease amyloid precursor protein (APP) and its paralogue, the amyloid precursor-like protein 2 (APLP2), contain copper ion-, zinc ion-, and heparan sulfate-binding domains. We have investigated the possibility that APP and APLP2 regulate glypican-1 processing during endocytosis and recycling. By using cell-free biochemical experiments, confocal laser immunofluorescence microscopy, and flow cytometry of tissues and cells from wild-type and knock-out mice, we find that (a) APP and glypican-1 colocalize in perinuclear compartments of neuroblastoma cells, (b) ascorbate-triggered nitric oxidecatalyzed glypican-1 autodegradation is zinc ion-dependent in the same cells, (c) in cell-free experiments, APP but not APLP2 stimulates glypican-1 autodegradation in the presence of both Cu(II) and Zn(II) ions, whereas the Cu(I) form of APP and the Cu(II) and Cu(I) forms of APLP2 inhibit autodegradation, (d) in primary cortical neurons from APP or APLP2 knock-out mice, there is an increased nitric oxide-catalyzed degradation of heparan sulfate compared with brain tissue and neurons from wild-type mice, and (e) in growth-quiescent fibroblasts from APLP2 knock-out mice, but not from APP knock-out mice, there is also an increased heparan sulfate degradation. We propose that the rate of autoprocessing of glypican-1 is modulated by APP and APLP2 in neurons and by APLP2 in fibroblasts. These observation identify a functional relationship between the heparan sulfate and copper ion binding activities of APP/APLP2 in their modulation of the nitroxyl anion-catalyzed heparan sulfate degradation in glypican-1.
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| 3. |
- Cheng, Fang, et al.
(author)
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Potentiation of naphthoxyloside cytotoxicity on human tumor cells by difluoromethylornithine and spermine-NONOate.
- 2009
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In: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 273, s. 148-154
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Journal article (peer-reviewed)abstract
- Here we demonstrate a synergistic and tumor selective cytotoxic effect by combined treatment with naphthoxylosides, polyamine synthesis inhibitor, and polyamine based nitric oxide (NO) donor, using in vitro human tumor models. We have earlier reported that heparan sulfate priming naphthoxyloside, 2-(6-hydroxynaphthyl)-O-beta-d-xylopyranoside, which inhibits growth of human tumor cells in vitro and in vivo models, undergoes NO dependent cleavage and accumulates in the nuclei of tumor cells. Polyamine depletion using alpha-difluoromethylornithine (DFMO) increases both the number of NO sensitive sites in heparan sulfate and uptake of the polyamine based NO donor, spermineNONOate, thereby enhancing formation of growth-inhibitory NO induced heparan sulfate products with specific cytotoxic effect on tumor cells. We also show that peracetylation of xylosides doubles the antiproliferative effect towards human cancer cells by making these compounds more permeable to the cells.
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| 4. |
- Dahl, Anna, 1975-
(author)
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Body mass index, cognitive ability, and dementia : prospective associations and methodological issues in late life
- 2009
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Doctoral thesis (other academic/artistic)abstract
- The aims of the present study were to investigate the association between overweight and cognitive ability and dementia, and to evaluate the usefulness of self-reported body mass index (BMI) in late life and various data sources commonly used in epidemiological studies to identify persons with dementia. Data were drawn from three population-based studies: the Swedish Adoption/Twin Study of Aging (SATSA), Aging in Women and Men: A Longitudinal Study of Gender Differences in Health Behaviour and Health among Elderly (the Gender Study), and the Finnish Lieto Study. In Study I, the agreement between self-reported and measured BMI over time was evaluated among 774 men and women, ages 40 to 88 years at baseline (mean age 63.9) participating in both the questionnaire phase and in-person testing of SATSA. Latent growth curve (LGC) modeling showed a small but significant increase between self-reported and measured BMI (0.02 kg/m2/y) over time, which would probably not affect the results if self-reported BMI were used as a continuous variable in longitudinal research. In Study II, the agreement between dementia diagnoses from various sources and dementia diagnoses set at a consensus conference was evaluated. Among the 498 elderly people ages 70 to 81 at baseline (mean age 74.5) enrolled in the Gender Study, 87 were diagnosed with dementia during an eight-year period. Review of medical records and nurse evaluations yielded the highest sensitivity (0.83 and 0.80, respectively) and a high specificity (0.98 and 0.96), indicating that these sources might be good proxies of dementia, while data extraction from the Swedish Inpatient Discharge Registry underestimated the prevalence of dementia (sensitivity 0.26). In Study III, the association between being overweight in midlife and cognitive ability in late life was examined in SATSA. The 781 participants ages 25 to 63 at baseline (mean age 41.6) in 1963 or 1973 self-reported their height and weight. From 1986 until 2002, they were assessed five times using a cognitive test battery. LGC models showed that people with higher midlife BMI scores had significantly lower cognitive ability and a significantly steeper decline than their thinner counterparts, an association that persisted when those who developed dementia during the study period were excluded from the analysis. This finding indicates that being overweight might affect cognitive ability independently of dementia. In Study IV, the association between BMI and dementia risk in older persons was described among 605 persons without dementia and ages 65 to 92 at baseline (mean age 70.8) in the Lieto Study. Among these, 86 persons were diagnosed with dementia during eight years of follow-up. Cox regression analyses indicated that for each unit increase in BMI score, the risk of dementia decreased 8% (hazard ratio = 0.92, 95% confidence interval = 0.87–0.97) and the association remained significant when individuals who developed dementia during the first four years of follow-up were excluded from the analyses. This result suggests that low BMI scores are present almost a decade before clinical dementia onset.
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| 5. |
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| 6. |
- Fransson, Lars-Åke, et al.
(author)
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Novel aspects of vitamin C: how important is glypican-1 recycling?
- 2007
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In: Trends in Molecular Medicine. - : Elsevier BV. - 1471-4914. ; 13:4, s. 143-149
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Research review (peer-reviewed)abstract
- The reduced form of vitamin C, ascorbic acid, is well known for its function as an antioxidant and as a protective agent against scurvy. However, many recent studies indicate other functions for vitamin C in mammalian cells. Novel findings provide possible explanations for observed beneficial effects of a high intake of vitamin C on cell growth, gene transcription, host resistance to infection, uptake of polyamines and clearance of misfolded proteins. Vitamin C exerts its effects indirectly via hypoxia-inducible factor, nitric oxide synthase and the heparan sulfate proteoglycan glypican-1, which is deglycanated in a vitamin C- and copper-dependent reaction.
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| 7. |
- Löfgren, Kajsa, et al.
(author)
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Involvement of glypican-1 autoprocessing in scrapie infection
- 2008
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In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 28:5, s. 964-972
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Journal article (peer-reviewed)abstract
- The copper-binding cellular prion protein (PrPC) and the heparan sulphate (HS)-containing proteoglycan glypican-1 (Gpc-1) can both be attached to lipid rafts via their glycosylphosphatidylinositol anchors, and copper ions stimulate their cointernalization from the cell surface to endosomes. The prion protein controls cointernalization and delivers copper necessary for S-nitrosylation of conserved cysteines in the Gpc-1 core protein. Later, during recycling through endosomal compartments, nitric oxide can be released from the S-nitroso groups and catalyses deaminative degradation and release of the HS substituents. Here, by using confocal immunofluorescence microscopy, we show that normal PrPC and Gpc-1 colocalize inside GT1-1 cells. However, in scrapie-infected cells (ScGT1-1), Gpc-1 protein remained at the cell surface separate from the cellular prion protein. Scrapie infection stimulated Gpc-1 autoprocessing and the generated HS degradation products colocalized with intracellular aggregates of the disease-related scrapie prion protein isoform (PrPSc). Coimmunoprecipitation experiments demonstrated an association between Gpc-1 and PrPC in uninfected cells, and between HS degradation products and PrPSc in infected cells. Silencing of Gpc-1 expression or prevention of Gpc-1 autoprocessing elevated the levels of intracellular PrPSc aggregates in infected cells. These results suggest a role for Gpc-1 autoprocessing in the clearance of PrPSc from infected cells.
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| 8. |
- Mani, Katrin, et al.
(author)
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Constitutive and vitamin C-induced, NO-catalyzed release of heparan sulfate from recycling glypican-1 in late endosomes.
- 2006
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 16:12, s. 1251-1261
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Journal article (peer-reviewed)abstract
- The recycling heparan sulfate (HS)-containing proteoglycan glypican-1 (Gpc-1) is processed by nitric oxide (NO)-catalyzed deaminative cleavage of its HS chains at N-unsubstituted glucosamines. This generates anhydromannose (anMan)-containing HS degradation products that can be detected by a specific antibody. Here we have attempted to identify the intracellular compartments where these products are formed. The anMan-positive degradation products generated constitutively in human bladder carcinoma cell line (T24) or fibroblasts appeared neither in caveolin-1-associated vesicles nor in lysosomes. In Niemann-Pick C-1 (NPC-1) fibroblasts, where deaminative degradation is abrogated, formation of anMan-positive products can be restored by ascorbate. These products colocalized with Rab7, a marker for late endosomes. When NO-catalyzed degradation of HS was depressed in mouse neuroblastoma cell line (N2a) by using 3-beta[2(diethylamino) ethoxy]androst-5-en-17-one (U18666A), both ascorbate and dehydroascorbic acid restored formation of anMan-positive products that colocalized with Rab7. In T24 cells, constitutively generated anMan-positive products colocalized with both Rab7 and Rab9, whereas Gpc-1 colocalized with Rab9, a marker for transporting endosomes. Inhibition of endosomal acidification, which blocks transfer from early (Rab5) to late (Rab7) endosomes, abrogated deaminative degradation of HS. This could also be overcome by the addition of ascorbate, which induced formation of anMan-positive degradation products that colocalized with Rab7. After (35)S-sulfate labeling, similar degradation products were recovered in Rab7-positive vesicles. We conclude that NO-catalyzed degradation of HS may begin in early endosomes but is mainly taking place in late endosomes.
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| 9. |
- Mani, Katrin, et al.
(author)
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Defective NO-dependent, deaminative cleavage of glypican-1 heparan sulfate in Niemann-Pick C1 fibroblasts.
- 2006
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 16:8, s. 711-718
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Journal article (peer-reviewed)abstract
- Exit of recycling cholesterol from late endosomes is defective in Niemann-Pick C1 (NPC1) and Niemann-Pick C2 (NPC2) diseases. The traffic route of the recycling proteoglycan glypican-1 (Gpc-1) may also involve late endosomes and could thus be affected in these diseases. During recycling through intracellular compartments, the heparan sulfate (HS) side chains of Gpc-1 are deaminatively degraded by nitric oxide (NO) derived from preformed S-nitroso groups in the core protein. We have now investigated whether this NO-dependent Gpc-1 autoprocessing is active in fibroblasts from NPC1 disease. The results showed that Gpc-1 autoprocessing was defective in these cells and, furthermore, greatly depressed in normal fibroblasts treated with U18666A (3-beta-[2-(diethylamino)ethoxy]androst-5-en-17-one), a compound widely used to induce cholesterol accumulation. In both cases, autoprocessing was partially restored by treatment with ascorbate which induced NO release, resulting in deaminative cleavage of HS. However, when NO-dependent Gpc-1 autoprocessing is depressed and heparanase-catalyzed degradation of HS remains active, a truncated Gpc-1 with shorter HS chains would prevail, resulting in fewer NO-sensitive sites/proteoglycan. Therefore, addition of ascorbate to cells with depressed autoprocessing resulted in nitration of tyrosines. Nitration was diminished when heparanase was inhibited with suramin or when Gpc-1 expression was silenced by RNAi. Gpc-1 misprocessing in NPC1 cells could thus contribute to neurodegeneration mediated by reactive nitrogen species.
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| 10. |
- Mani, Katrin, et al.
(author)
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Heparan sulfate degradation products can associate with oxidized proteins and proteasomes.
- 2007
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In: Journal of Biological Chemistry. - 1083-351X. ; 282:30, s. 21934-21944
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Journal article (peer-reviewed)abstract
- The S-nitrosylated proteoglycan glypican-1 recycles via endosomes where its heparan sulfate chains are degraded into anhydromannose-containing saccharides by NO-catalyzed deaminative cleavage. Because heparan sulfate chains can be associated with intracellular protein aggregates, glypican-1 autoprocessing may be involved in the clearance of misfolded recycling proteins. Here we have arrested and then reactivated NO-catalyzed cleavage in the absence or presence of proteasome inhibitors and analyzed the products present in endosomes or co-precipitating with proteasomes using metabolic radiolabeling and immunomagnet isolation as well as by confocal immunofluorescence microscopy. Upon reactivation of deaminative cleavage in T24 carcinoma cells, [S-35] sulfate-labeled degradation products appeared in Rab7-positive vesicles and co-precipitated with a 20 S proteasome subunit. Simultaneous inhibition of proteasome activity resulted in a sustained accumulation of degradation products. We also demonstrated that the anhydromannose-containing heparan sulfate degradation products are detected by a hydrazide-based method that also identifies oxidized, i.e. carbonylated, proteins that are normally degraded in proteasomes. Upon inhibition of proteasome activity, pronounced colocalization between carbonyl-staining, anhydro-mannosecontaining degradation products, and proteasomes was observed in both T24 carcinoma and N2a neuroblastoma cells. The deaminatively generated products that co-precipitated with the proteasomal subunit contained heparan sulfate but were larger than heparan sulfate oligosaccharides and resistant to both acid and alkali. However, proteolytic degradation released heparan sulfate oligosaccharides. In Niemann-Pick C-1 fibroblasts, where deaminative degradation of heparan sulfate is defective, carbonylated proteins were abundant. Moreover, when glypican-1 expression was silenced in normal fibroblasts, the level of carbonylated proteins increased raising the possibility that deaminative heparan sulfate degradation is involved in the clearance of misfolded proteins.
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