| 1. |
- Åberg, Anna, et al.
(författare)
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A Repetitive DNA Element Regulates Expression of the Helicobacter pylori Sialic Acid Binding Adhesin by a Rheostat-like Mechanism
- 2014
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- During persistent infection, optimal expression of bacterial factors is required to match the ever-changing host environment. The gastric pathogen Helicobacter pylori has a large set of simple sequence repeats (SSR), which constitute contingency loci. Through a slipped strand mispairing mechanism, the SSRs generate heterogeneous populations that facilitate adaptation. Here, we present a model that explains, in molecular terms, how an intergenically located T-tract, via slipped strand mispairing, operates with a rheostat-like function, to fine-tune activity of the promoter that drives expression of the sialic acid binding adhesin, SabA. Using T-tract variants, in an isogenic strain background, we show that the length of the T-tract generates multiphasic output from the sabA promoter. Consequently, this alters the H. pylori binding to sialyl-Lewis x receptors on gastric mucosa. Fragment length analysis of post-infection isolated clones shows that the T-tract length is a highly variable feature in H. pylori. This mirrors the host-pathogen interplay, where the bacterium generates a set of clones from which the best-fit phenotypes are selected in the host. In silico and functional in vitro analyzes revealed that the length of the T-tract affects the local DNA structure and thereby binding of the RNA polymerase, through shifting of the axial alignment between the core promoter and UP-like elements. We identified additional genes in H. pylori, with T- or A-tracts positioned similar to that of sabA, and show that variations in the tract length likewise acted as rheostats to modulate cognate promoter output. Thus, we propose that this generally applicable mechanism, mediated by promoter-proximal SSRs, provides an alternative mechanism for transcriptional regulation in bacteria, such as H. pylori, which possesses a limited repertoire of classical trans-acting regulatory factors.
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| 2. |
- Åberg, Anna, et al.
(författare)
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Helicobacter pylori adapts to chronic infection and gastric disease via ph-responsive baba-mediated adherence
- 2017
-
Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 21:3, s. 376-389
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Tidskriftsartikel (refereegranskat)abstract
- The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen and that bio-selection and changes in BabA binding properties through mutation and recombination with babA-related genes are selected by differences among individuals and by changes in gastric acidity over time. These processes generate diverse H. pylori subpopulations, in which BabA's adaptive evolution contributes to H. pylori persistence and overt gastric disease.
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| 3. |
- Aspholm-Hurtig, Marina, et al.
(författare)
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Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
- 2004
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5683, s. 519-22
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Tidskriftsartikel (refereegranskat)abstract
- Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.
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| 4. |
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| 5. |
- Bugaytsova, Jeanna, et al.
(författare)
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pH regulated H. pylori adherence : implications for persistent infection and disease
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori’s BabA adhesin binds strongly to gastric mucosal ABH/Leb glycans on the stomach epithelium and overlying mucus, materials continuously shed into the acidic gastric lumen. Here we report that this binding is acid labile, acid inactivation is fully reversible; and acid lability profiles vary with BabA sequence and correlate with disease patterns. Isogenic H. pylori strains from the gastric antrum and more acidic corpus were identified that differed in acid lability of receptor binding and in sequence near BabA’s carbohydrate binding domain. We propose that reversible acid inactivation of receptor binding helps H. pylori avoid clearance by mucosal shedding, and that strain differences in acid lability affect tissue tropism and the spectrum of associated gastric diseases.
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| 6. |
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| 7. |
- Lekmeechai, Sujinna, et al.
(författare)
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Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst
- 2018
-
Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Outer membrane vesicles (OMVs) play an important role in the persistence of Helicobacter pylori infection. Helicobacter OMVs carry a plethora of virulence factors, including catalase (KatA), an antioxidant enzyme that counteracts the host respiratory burst. We found KatA to be enriched and surface-associated in OMVs compared to bacterial cells. This conferred OMV-dependent KatA activity resulting in neutralization of H2O2 and NaClO, and rescue of surrounding bacteria from oxidative damage. The antioxidant activity of OMVs was abolished by deletion of KatA. In conclusion, enrichment of antioxidative KatA in OMVs is highly important for efficient immune evasion.
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| 8. |
- Moonens, Kristof, et al.
(författare)
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Structural Insights into Polymorphic ABO Glycan Binding by Helicobacter pylori
- 2016
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Ingår i: Cell Host and Microbe. - : Elsevier BV. - 1931-3128 .- 1934-6069. ; 19:1, s. 55-66
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Tidskriftsartikel (refereegranskat)abstract
- The Helicobacter pylori adhesin BabA binds mucosal ABO/Le b blood group (bg) carbohydrates. BabA facilitates bacterial attachment to gastric surfaces, increasing strain virulence and forming a recognized risk factor for peptic ulcers and gastric cancer. High sequence variation causes BabA functional diversity, but the underlying structural-molecular determinants are unknown. We generated X-ray structures of representative BabA isoforms that reveal a polymorphic, three-pronged Le(b) binding site. Two diversity loops, DL1 and DL2, provide adaptive control to binding affinity, notably ABO versus O bg preference. H. pylori strains can switch bg preference with single DL1 amino acid substitutions, and can coexpress functionally divergent BabA isoforms. The anchor point for receptor binding is the embrace of an ABO fucose residue by a disulfide-clasped loop, which is inactivated by reduction. Treatment with the redox-active pharmaceutic N-acetylcysteine lowers gastric mucosal neutrophil infiltration in H. pylori-infected Le(b)-expressing mice, providing perspectives on possible H. pylori eradication therapies.
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| 9. |
- Ohno, Tomoyuki, et al.
(författare)
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Effects of BabA expression during H. pylori infection of Mongolian gerbils
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Objective: Helicobacter pylori outer membrane proteins, such as the BabA adhesin are associated with severe pathological outcome. However, the in vivo role of the BabA adhesin during long-term infection is not clear. Design and Setting: Mongolian gerbils were inoculated with the H. pylori TN2GF4 and were necropsied at 1, 3, 6, and 18 months. Main outcome measures: Bacterial clones recovered from the infected gerbils were evaluated by immunoblot for BabA expression, radioimmunoassay for Leb-binding, and bacterial binding to gastric tissue. H1 antigen expression and the increase in sialylation levels were monitored by immunohistochemistry. Results: BabA expression increased, then progressively decreased, and was completely absent by 6 months post-infection. Loss of BabA expression was caused by nucleotide changes/deletions within the babA gene that resulted in a truncated BabA. Infection with a BabA-expressing H. pylori caused severe mucosal injury, whereas infection with a BabA non-expressing strain caused only mild inflammation. In response to the infection, changes in the epithelial glycosylation pattern were observed, similar to responses observed in humans and monkeys. Conclusion: Down-regulation of BabA is probably a result of adaptation to the host response during long-term H. pylori infection. BabA expression is most likely not essential for colonisation, but for the obtained gerbil host response, which confirms the role of BabA adhesin as a virulence factor and its impact in the induction of a severe inflammatory response. The changes in glycosylation of gastric mucosa demonstrate the relevance of the Mongolian gerbil as a model for H. pylori infection and host responses.
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| 10. |
- Ohno, Tomoyuki, et al.
(författare)
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Effects of blood group antigen-binding adhesin expression during Helicobacter pylori infection of Mongolian gerbils
- 2011
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 203:5, s. 726-735
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori outer membrane proteins, such as the blood group antigen-binding adhesin (BabA), are associated with severe pathological outcomes. However, the in vivo role of BabA during long-term infection is not clear. In this study, Mongolian gerbils were infected with H. pylori and necropsied continuously during 18 months. Bacterial clones were recovered and analyzed for BabA expression, Leb-binding activity, and adhesion to gastric mucosa. BabA expression was completely absent by 6 months post-infection. Loss of BabA expression was attributable to nucleotide changes within the babA gene that resulted in a truncated BabA. In response to the infection, changes in the epithelial glycosylation pattern were observed that were similar to responses observed in humans and monkeys. Furthermore, infections with BabA-expressing and BabA-nonexpressing H. pylori showed no differences in colonization, but infection with the BabA-expressing strain exhibited histological changes and increased inflammatory cell infiltration. This suggests that BabA expression contributes to severe mucosal injury.
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| 11. |
- Olofsson, Annelie, et al.
(författare)
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Biochemical and functional characterization of Helicobacter pylori vesicles
- 2010
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 77:6, s. 1539-1555
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori can cause peptic ulcer disease and/or gastric cancer. Adhesion of bacteria to the stomach mucosa is an important contributor to the vigor of infection and resulting virulence. H. pylori adheres primarily via binding of BabA adhesins to ABO/Lewis b (Leb) blood group antigens and the binding of SabA adhesins to sialyl-Lewis x/a (sLex/a) antigens. Similar to most Gram-negative bacteria, H. pylori continuously buds off vesicles and vesicles derived from pathogenic bacteria often include virulence-associated factors. Here we biochemically characterized highly purified H. pylori vesicles. Major protein and phospholipid components associated with the vesicles were identified with mass spectroscopy and NMR. A subset of virulence factors present was confirmed by immunoblots. Additional functional and biochemical analysis focused on the vesicle BabA and SabA adhesins and their respective interactions to human gastric epithelium. Vesicles exhibit heterogeneity in their protein composition, which were specifically studied in respect to the BabA adhesin. We also demonstrate that the oncoprotein, CagA, is associated with the surface of H. pylori vesicles. Thus, we have explored mechanisms for intimate H. pylori vesicle-host interactions and found that the vesicles carry effector-promoting properties that are important to disease development.
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| 12. |
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| 13. |
- Skoog, Emma C, 1983, et al.
(författare)
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BabA dependent binding of Helicobacter pylori to human gastric mucins cause aggregation that inhibits proliferation and is regulated via ArsS
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Mucins in the gastric mucus layer carry a range of glycan structures, which vary between individuals, can have antimicrobial effect or act as ligands for Helicobacter pylori. Mucins from various individuals and disease states modulate H. pylori proliferation and adhesin gene expression differently. Here we investigate the relationship between adhesin mediated binding, aggregation, proliferation and adhesin gene expression using human gastric mucins and synthetic adhesin ligand conjugates. By combining measurements of optical density, bacterial metabolic activity and live/dead stains, we could distinguish bacterial aggregation from viability changes, enabling elucidation of mechanisms behind the anti-prolific effects that mucins can have. Binding of H. pylori to Leb-glycoconjugates inhibited the proliferation of the bacteria in a BabA dependent manner, similarly to the effect of mucins carrying Leb. Furthermore, deletion of arsS lead to a decrease in binding to Leb-glycoconjugates and Leb-decorated mucins, accompanied by decreased aggregation and absence of anti-prolific effect of mucins and Leb-glycoconjugates. Inhibition of proliferation caused by adhesin dependent binding to mucins, and the subsequent aggregation suggests a new role of mucins in the host defense against H. pylori. This aggregating trait of mucins may be useful to incorporate into the design of adhesin inhibitors and other disease intervention molecules.
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| 14. |
- Vallström, Anna, 1979-
(författare)
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Helicobacter pylori : molecular mechanisms for variable adherence properties
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- More than half of all people worldwide are infected with H. pylori. The infection always cause a gastric inflammation that may develop into peptic ulcer disease or gastric cancer. Attachment proteins, adhesins, mediate specific adherence of H. pylori to receptor structures on the human gastric mucosa. The best-characterized H. pylori adhesin-receptor interactions are the BabA adhesin and the binding to the fucosylated blood group antigens ABO/Lewis b (Leb) and the SabA adhesin and its binding to the inflammation associated sialyl-Lewis x antigen. During H. pylori infection the availability of receptor structures on the human gastric mucosa changes as a consequence of the host inflammatory and immune responses. Consequently the bacterial population need to adjust its adherence properties to stay colonized. This thesis describes mechanisms that generate H. pylori populations with variable adherence properties and mechanisms for adjustment of adhesin expression levels.In H. pylori strains devoid of Leb-binding, we found bacterial cells with Leb-binding. Isolation of such H. pylori clones demonstrated that the change in receptor binding phenotype was obtained via the mechanisms of homologous recombination and slipped strand mispairing (SSM). Disease presentation in relation to BabA expression was studied in H. pylori infected Mongolian gerbils. We showed that BabA was not essential for colonization but caused severe injury to the gastric mucosa and was turned off during long-term infection by nucleotide changes within the babA gene. Gerbils infected with BabA-weak-expressing strains maintained BabA expressing clones for a longer period than gerbils that were infected with BabA-high-expressing strains. Studies of the gerbil gastric mucosal glycosylation showed that gerbils respond in a similar way as humans and Rhesus monkeys which support gerbils to be a model suitable for studying H. pylori infection and disease outcome in relation to adherence.We studied the SSM mechanism of SabA phase variation and the cognate shift in sLex-binding phenotype and we show sLex-binding activity to be growth phase dependent. H. pylori vesicles were characterized for the major phosholipid and protein components. Virulence factors e.g., VacA, and CagA were identified and both the BabA and the SabA adhesins was shown to be located on the vesicle surface and to mediate specific binding to their cognate receptors present on the human gastric mucosa. H. pylori generate bacterial cells with different receptor binding phenotypes via the mechanisms of homologous recombination, SSM and nucleotide changes. These mechanisms will probably contribute to bacterial fitness by the generation of quasi species populations where some of the clones will be better adapted to the environmental chances during persistent infection.
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| 15. |
- Åberg, Anna, et al.
(författare)
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Molecular insights into the fine-tuning of pH-dependent ArsR-mediated regulation of the SabA adhesin in Helicobacter pylori
- 2024
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 52:10, s. 5572-5595
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation to variations in pH is crucial for the ability of Helicobacter pylori to persist in the human stomach. The acid responsive two-component system ArsRS, constitutes the global regulon that responds to acidic conditions, but molecular details of how transcription is affected by the ArsR response regulator remains poorly understood. Using a combination of DNA-binding studies, in vitro transcription assays, and H. pylori mutants, we demonstrate that phosphorylated ArsR (ArsR-P) forms an active protein complex that binds DNA with high specificity in order to affect transcription. Our data showed that DNA topology is key for DNA binding. We found that AT-rich DNA sequences direct ArsR-P to specific sites and that DNA-bending proteins are important for the effect of ArsR-P on transcription regulation. The repression of sabA transcription is mediated by ArsR-P with the support of Hup and is affected by simple sequence repeats located upstream of the sabA promoter. Here stochastic events clearly contribute to the fine-tuning of pH-dependent gene regulation. Our results reveal important molecular aspects for how ArsR-P acts to repress transcription in response to acidic conditions. Such transcriptional control likely mediates shifts in bacterial positioning in the gastric mucus layer.
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| 16. |
- Åberg, Anna, et al.
(författare)
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The Helicobacter pylori sialic acid binding adhesin SabA is regulated via a network of two-component systems
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The acid-responsive signaling system ArsRS plays a key role in regulating factors important for survival in acidic conditions during infection of the human stomach by Helicobacter pylori. In addition, ArsRS was suggested to control the disease-associated attachment protein SabA, however, mechanistic data is still lacking. We show that the repressing effect of the ArsRS system on SabA expression occurs both at acidic and neutral conditions and is mediated at the transcriptional level. Purified His6-ArsR binds PsabA DNA at several sites, with varying affinity and independent of phosphorylation status and H. pylori strains showed unique cognate PsabA sequences to tweak the ArsR binding ability, resulting in strain-dependent repression of SabA expression. By site-directed mutagenesis we reveal key amino acids for the binding activity of ArsR. Finally, we show that that ArsR binds to A/T-rich DNA as dimers or larger multimers, suggesting that ArsR has affinity for DNA structures rather than to a specific promoter DNA sequence. SabA expression is further influenced by the FlgRS and CrdRS two-component systems, illustrating a complicated crosstalk among regulatory networks in H. pylori.
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| 17. |
- Öhman, Carina, et al.
(författare)
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Phase variation and expression mechanisms of the sialic acid binding adhesin SabA in Helicobacter pylori
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial attachment to host epithelial surfaces by means of bacterial adhesion proteins is a key event in colonization. Phase variation is a mechanism used by bacteria that mediates frequent and reversible gains and losses in expression of proteins. In the inflamed stomach, H. pylori adherence to sialyl Lewis antigens (sLex) is mediated by the sialic acid binding adhesin (SabA). Instability in sLex-binding was previously reported and here we show that this is caused by the high frequency of ON/OFF switching in SabA expression. Our data shows that SabA phase variation is due to slippages in the number of CT repeat sequences in the 5’ end of the sabA gene (i.e. slipped strand mispairing). The sabA operon was defined and the sabA transcriptional start site was determined. Changes in the number of thymine bases present in a mononucleotide stretch upstream of the sabA gene and in close proximity to a -35-like promoter element did not affect the ON/OFF phase variation. Instead, we show that changes in intrinsic DNA properties are likely to influence SabA expression. The effect of growth phase on sLex-binding properties and SabA expression was also analyzed. SabA expression and sLex-binding increased as H. pylori entered late logarithmic phase. Our data show the ability of H. pylori to cycle between an adherent and non-adherent phenotype by phase variation mechanisms and adjustment of receptor binding activity. These data increase our understanding of how H. pylori adjust adherence properties during persistent infection.
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| 18. |
- Arnqvist, Anna
(författare)
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Roles of the BabA and the SabA adhesins in gastroduodenal diseases
- 2016
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Ingår i: Helicobacter pylori research. - Tokyo : Springer. - 9784431559368 - 9784431559344 ; , s. 143-164
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Bokkapitel (refereegranskat)abstract
- Adhesion is an important prerequisite for colonization and it is the initial step in infections with pathogenic bacteria. Adherence to host epithelial surfaces is the result of bacterial surface proteins, called adhesins, and their specific interaction with cognate protein- or glycoconjugate receptors on the host cells. Often, the bacteria have a set of complementary adhesins that are specific for different host receptors. Alternative mechanism has been suggested to mediate H. pylori adhesion, and this chapter will focus on the two well-characterized adhesins BabA and SabA. In the healthy gastric mucosa, the Lewis b antigen (Leb) is present in the gastric epithelial lining of blood group O (H-antigen), B, and A individuals. H. pylori binding to ABO/Leb is mediated by the blood group antigen-binding BabA adhesin. As the inflammation develops, Leb is downregulated and the levels of sialylated antigens increase. Sialyl-Lewis x/a antigens (sLex/a) are specifically recognized by the H. pylori sialic acid-binding adhesin SabA. Even though bacterial adherence per se cannot cause disease, adherence is considered as a crucial step in pathogenesis since it is needed for bacterial delivery of effector molecules into the host cell. The presence of receptors and host-immune responses are two factors that differently affect adhesion. To achieve long-term colonization, H. pylori must regulate the expression of a cognate adhesin to fit the available receptors. Adhesion to the gastric epithelial cells promotes gain of nutrients, but too tight adhesion may be intimidating because of the risk of clearance by the bacteria for life-threatening immune responses. Thus, expression levels of the adhesins must be fine-tuned in accord to host receptor expression levels. This chapter will also discuss H. pylori adhesion in relation to severe gastric diseases.
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| 19. |
- Arnqvist, Anna, et al.
(författare)
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Sigma S-dependent growth-phase induction of the csgBA promoter in Escherichia coli can be achieved in vivo by sigma 70 in the absence of the nucleoid-associated protein H-NS.
- 1994
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Ingår i: Molecular Microbiology. - 0950-382X .- 1365-2958. ; 13:6, s. 1021-32
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Tidskriftsartikel (refereegranskat)abstract
- The stationary-phase-specific sigma factor sigma S (RpoS/KatF) is required for Escherichia coli to induce expression of fibronectin-binding curli organelles upon reaching stationary phase. We show that the csgA gene which encodes the curlin subunit protein belongs to a dicistronic operon, csgBA. The transcriptional start site of csgBA was determined and an AT-rich up-stream activating sequence (UAS) required for transcriptional activation was identified. The pcsgBA promoter is not specific for sigma S since the same promoter sequence can be used by E sigma 70 in vivo in a strain lacking nucleoid-associated protein H-NS and sigma S. Transcription remained growth-phase induced and dependent upon the UAS in such a double mutant. Furthermore, we demonstrate that an additional operon, hdeAB, which is also dependent upon sigma S for transcription, can be transcribed by E sigma 70 in vivo in the absence of H-NS by utilizing the phdeAB promoter. Two other genes known to be under the control of sigma S for expression, bolA and katE, remained transcriptionally silent in the absence of H-NS. It is suggested that a subset of E. coli promoters can be recognized by both E sigma S and E sigma 70 in vivo but H-NS interacting with these sequences prevents formation of successful transcription-initiation complexes with E sigma 70.
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| 20. |
- Arnqvist, Anna, et al.
(författare)
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The Crl protein activates cryptic genes for curli formation and fibronectin binding in Escherichia coli HB101.
- 1992
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Ingår i: Molecular Microbiology. - 0950-382X .- 1365-2958. ; 6:17, s. 2443-52
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Tidskriftsartikel (refereegranskat)abstract
- Curli are thin, coiled, temperature-regulated fibres on fibronectin-binding Escherichia coli. The subunit protein of curli was highly homologous at its amino terminus to SEF-17, the subunit protein of thin, aggregative fimbriae of Salmonella enteritidis 27655 strain 3b, suggesting that these fibres form a novel class of surface organelles on enterobacteria. E. coli HB101 is non-curliated and unable to bind soluble, iodinated fibronectin. The phenotypically cryptic curlin subunit gene, csgA, in HB101 is transcriptionally activated by expressing the cytoplasmic Crl on a multicopy plasmid. Transcriptional activation of csgA by Crl was observed after growth at 26 degrees C but not at 37 degrees C, even though crl transcription was not thermoregulated. A deletion of the 39 carboxy-terminal residues abolished Crl activity, whereas a deletion of 10 residues at the C-terminus did not, implying that a region between residue 93 and 122 in the 132-amino-acid-residue large Crl protein is required for activating curli expression in E. coli HB101. crl is a normal housekeeping gene in E. coli and it is suggested that its gene product may either be a DNA-binding protein affecting chromatin structure as has been suggested for histone-like protein H1 or interact with specific regulatory protein(s) controlling transcription of genes required for curli formation and fibronectin binding.
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| 21. |
- Arnqvist, Hans, et al.
(författare)
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Vitamin D status in longstanding type 1 diabetes and controls. Association with upper extremity impairments
- 2023
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Ingår i: Upsala Journal of Medical Sciences. - : UPSALA MED SOC. - 0300-9734 .- 2000-1967. ; 128:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with type 1 diabetes have a high prevalence of upper extremity impairments (UEIs), such as frozen shoulder, carpal tunnel syndrome, and trigger finger. The UEIs are strongly associated with activity limitations and impaired quality of life. The etiology of the UEI is not clear. Vitamin D deficiency has been considered to play a role in the pathogenesis of type 1 diabetes and in the development of macro- and microvascular complications in diabetes. Aim: To characterize vitamin D status in a large population of patients with type 1 diabetes, if vitamin D deficiency is associated with metabolic factors and possible association with UEI. Material and methods: Patients who diagnosed before 35 years of age, whose diabetes duration >20 years, and who are not older than 65 years were invited to participate in this cross-sectional case-control, multicenter study. Controls matched for age and sex were obtained from the national population registry. Fasting blood samples were collected and stored at -80 degrees C until analyzed regarding 25-hydroxy-vitamin D (25(OH)D3) by a liquid chromatographic-mass spectrometric method (LC-MS/MS). Results: Vitamin D levels varied with season as expected in the northern hemisphere. The association between 25(OH)D3 and clinical variables was analyzed in a univariate general linear model, which indicated no difference in 25(OH)D3 in men with and without diabetes but higher values in women with diabetes. About 30% of both patients and controls had vitamin D deficiency (=50 nmol/L). Analyzed by binary logistic regression UEIs was not associated with 25(OH)D3 levels. In both patients and controls, 25(OH)D3 was correlated to apolipoprotein A1 (r = 0.153; 0.220, P < 0.001). Conclusion: In patients with type 1 diabetes and a duration of 20 years or more, vitamin D level is not lower than in nondiabetic controls and is not associated with UEIs.
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| 22. |
- Arnqvist, Johan, 1985-
(författare)
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Mean Wind and Turbulence Conditions in the Boundary Layer above Forests
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As wind turbines have grown, new installation areas become possible. Placing wind turbines in forested landscapes introduce uncertainties to the wind resource estimation. Even though close-to-canopy processes have been studied intensively during the last thirty years, the focus has mostly been on exchange processes and the height span of the studies has been below the rotor of a modern wind turbine.This thesis contains analysis of new measurements from a 138 m high tower in a forested landscape. The previous knowledge of near-canopy processes is extended to the region above the roughness sublayer. It is shown that above the roughness sublayer, the surface layer behaves as over low vegetation, and Monin-Obukhov similarity is shown to hold for several variables. However, in stable stratification, effects that could be linked to the boundary layer depth are shown to be present in the measurements. These include wind turning with height, the behaviour of the turbulence length scale and the curvature of the wind profile.Two new analytical models are presented in the thesis. One is a flux-profile expression in the roughness sublayer, which allows for analytical integration of the wind gradient. The model suggests that the roughness-sublayer effect depends on stratification and that the aerodynamic roughness length changes with stability. A decrease of roughness length in stable stratification is confirmed with a new method to determine the roughness length using measurements from the 138 m tower.The other model determines the spectral tensor in stable stratification using analytical solution to the rapid distortion equations for stratified shear flow, with homogeneous stratification and shear. By using a formulation for the integration time of the distortions of an isotropic spectrum, a model is derived which provides the cross spectra of velocity and temperature at any two given points in space.Finally the existence of waves in the wind over forests is investigated and it is concluded that the Kelvin-Helmholtz instability can create waves which are coherent in time and exist over the entire height span of wind turbine rotors. Linear wave theory is shown to be able to explain certain features of the waves.
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| 23. |
- Aspholm, Marina, et al.
(författare)
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Helicobacter pylori adhesion to carbohydrates
- 2006
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Ingår i: Methods in Enzymology. - 0076-6879 .- 1557-7988. ; 417, s. 293-339
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of bacterial pathogens to host tissues contributes to colonization and virulence and typically involves specific interactions between bacterial proteins called adhesins and cognate oligosaccharide (glycan) or protein motifs in the host that are used as receptors. A given pathogen may have multiple adhesins, each specific for a different set of receptors and, potentially, with different roles in infection and disease. This chapter provides strategies for identifying and analyzing host glycan receptors and the bacterial adhesins that exploit them as receptors, with particular reference to adherence of the gastric pathogen Helicobacter pylori.
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| 24. |
- Aspholm, Marina, et al.
(författare)
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SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans.
- 2006
-
Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of Helicobacter pylori to inflamed gastric mucosa is dependent on the sialic acid-binding adhesin (SabA) and cognate sialylated/fucosylated glycans on the host cell surface. By in situ hybridization, H. pylori bacteria were observed in close association with erythrocytes in capillaries and post-capillary venules of the lamina propria of gastric mucosa in both infected humans and Rhesus monkeys. In vivo adherence of H. pylori to erythrocytes may require molecular mechanisms similar to the sialic acid-dependent in vitro agglutination of erythrocytes (i.e., sialic acid-dependent hemagglutination). In this context, the SabA adhesin was identified as the sialic acid-dependent hemagglutinin based on sialidase-sensitive hemagglutination, binding assays with sialylated glycoconjugates, and analysis of a series of isogenic sabA deletion mutants. The topographic presentation of binding sites for SabA on the erythrocyte membrane was mapped to gangliosides with extended core chains. However, receptor mapping revealed that the NeuAcalpha2-3Gal-disaccharide constitutes the minimal sialylated binding epitope required for SabA binding. Furthermore, clinical isolates demonstrated polymorphism in sialyl binding and complementation analysis of sabA mutants demonstrated that polymorphism in sialyl binding is an inherent property of the SabA protein itself. Gastric inflammation is associated with periodic changes in the composition of mucosal sialylation patterns. We suggest that dynamic adaptation in sialyl-binding properties during persistent infection specializes H. pylori both for individual variation in mucosal glycosylation and tropism for local areas of inflamed and/or dysplastic tissue.
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| 25. |
- Bachrach-Lindström, Margaretha, 1957-, et al.
(författare)
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Assessment of nutritional status using biochemical and anthropometric variables in a nutritional intervention study of women with hip fracture
- 2001
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Ingår i: Clinical Nutrition. - : Elsevier BV. - 0261-5614 .- 1532-1983. ; 20:3, s. 217-223
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: The aim of this study of women with hip fracture was to describe nutritional status with biochemical markers and anthropometric variables, and to evaluate the effect of nutritional intervention with the intention of increasing protein and energy intake.Methods: The first consecutive 44 women were included, and used as controls. The next 44 were matched for age, fracture and mental state. Anthropometric variables, IGF-I, hormones and serum albumin were collected 4–6 days (baseline), 1 and 3 months after surgery. Twenty-four women filled out a 7-day food record.Results: At baseline, one fourth had BMI <20 kg/m2and subnormal triceps skinfold thickness. Baseline serum albumin, IGF-I and growth hormone levels were low, probably as an acute response to trauma. Women with BMI <20 kg/m2had lower IGF-I levels compared to those with higher BMI. At 3 months, one-third of both groups were protein and energy malnourished. The intervention group obtained higher daily energy percentage from fat but none of the groups reached their calculated energy need.Conclusions: Using biochemical markers in the acute postoperative situation to assess nutritional status is not recommended. The intervention had no impact on anthropometric or biochemical variables.
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| 26. |
- Basmarke-Wehelie, Rahma, et al.
(författare)
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The complement regulator CD46 is bactericidal to Helicobacter pylori and blocks urease activity
- 2011
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Ingår i: Gastroenterology. - Baltimore : Elsevier BV. - 0016-5085 .- 1528-0012. ; 141:3, s. 918-928
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: CD46 is a C3b/C4b binding complement regulator and a receptor for several human pathogens. We examined the interaction between CD46 and Helicobacter pylori (a bacterium that colonizes the human gastric mucosa and causes gastritis), peptic ulcers, and cancer.METHODS: Using gastric epithelial cells, we analyzed a set of H pylori strains and mutants for their ability to interact with CD46 and/or influence CD46 expression. Bacterial interaction with full-length CD46 and small CD46 peptides was evaluated by flow cytometry, fluorescence microscopy, enzyme-linked immunosorbent assay, and bacterial survival analyses.RESULTS: H pylori infection caused shedding of CD46 into the extracellular environment. A soluble form of CD46 bound to H pylori and inhibited growth, in a dose- and time-dependent manner, by interacting with urease and alkyl hydroperoxide reductase, which are essential bacterial pathogenicity-associated factors. Binding of CD46 or CD46-derived synthetic peptides blocked the urease activity and ability of bacteria to survive in acidic environments. Oral administration of one CD46 peptide eradicated H pylori from infected mice.CONCLUSIONS: CD46 is an antimicrobial agent that can eradicate H pylori. CD46 peptides might be developed to treat H pylori infection.
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| 27. |
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| 28. |
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| 29. |
- Gideonsson, Pär, 1982-
(författare)
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Helicobacter pylori : molecular insights into regulation of adhesion properties
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Helicobacter pylori infects the human stomach and triggers an inflammatory response that damages the gastric tissue. This host-pathogen interplay has dire consequences as up to 20 % of infected individuals develop peptic ulcer disease or gastric cancer. Given that half of the world’s population is infected, the number of afflicted humans is staggering and also tells that H. pylori is extremely efficient in spreading and maintaining infection. To enable persistent infection many factors play a role, but one important feature of H. pylori is its impressive ability to adhere to the slimy gastric mucus layer and the underlying epithelial cells. This occurs mainly via the BabA and SabA proteins that bind ABO/Leb- and sLex/sLea-antigens. I have in my thesis studied how these two proteins are utilized and regulated.H. pylori transcription is in part controlled by two-component systems (TCSs) that use a sensor protein and a DNA-binding response regulator. We have studied how these systems control sabA and to some extent babA and indeed found a better map of how sabA and babA is regulated at the transcriptional level. We also found that variations in a polynucleotide T-tract located in the sabA promotor could fine-tune SabA expression/ sLex-binding. Thus we have exposed how strict regulation by TCSs combined with stochastic processes together shapes attachment in the bacterial population.As the buffering mucus layer is constantly exfoliated, placing H. pylori in bactericidal acid, we hypothesized that low pH should abrogate adhesion. SabA expression was indeed repressed in low pH, however BabA expression remained unaffected. The BabA/ Leb-binding was instead directly reversibly hampered by low pH and the degree of pH sensitivity was strain dependent and encoded in the BabA sequence. We believe that the pH dependent loss of binding is one key factor H. pylori utilizes to maintain persistent infection.BabA is divided in generalists that bind ABO antigens and specialists that only bind blood group (bg) O. We co-crystalized BabA bound to these receptors and established the structural basis for generalist vs. specialist discrimination. We furthermore found a disulfide-clasped loop (CL2) in the center of the binding domain crucial for binding. Breaking CL2 with N-Acetylcysteine (NAC) disrupted binding and H. pylori infection mice experiments revealed inflammatory reduction upon NAC-treatment.In sum, I have in my thesis dissected how H. pylori controls its adhesive abilities and how intrinsic properties in binding can be exploited for therapeutic purposes.
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| 30. |
- Gutefeldt, Kerstin, 1972-, et al.
(författare)
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Clinical Examination and Self-Reported Upper Extremity Impairments in Patients with Long-Standing Type 1 Diabetes Mellitus
- 2020
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Ingår i: Journal of Diabetes Research. - : Hindawi Publishing Corporation. - 2314-6745 .- 2314-6753. ; 2020
-
Tidskriftsartikel (refereegranskat)abstract
- Aim. The aims of the current study were (1) to determine the prevalence of upper extremity impairments (UEIs) in patients with type 1 diabetes by clinical investigation; (2) to investigate if self-reported impairments were concordant with clinical findings and if key questions could be identified; and (3) to investigate if answers to our self-reported questionnaire regarding UEIs are reliable. Methods. Patients with type 1 diabetes were invited to participate in a cross-sectional study of clinical and self-reported (12 items) UEIs in adjunction to ordinary scheduled clinical visit. Before the visit, a questionnaire on UEIs was filled in twice (test-retest) followed by clinical testing at the planned visit. Results. In total, 69 patients aged and with diabetes duration were included in the study. In the clinical examination, two-thirds (65%) of the patients showed one or more UEI, with failure to perform hand against back as the most common clinical finding (40%) followed by positive Phalen’s test (27%), Tinel’s test (26%), and Prayer’s sign (24%). UEIs observed by clinical examination were often bilateral, and multiple impairments often coexisted. Self-reported shoulder stiffness was associated with impaired shoulder mobility and with Prayer’s sign. Self-reported reduced hand strength was associated to lower grip force, Prayer’s sign, trigger finger, fibrosis string structures, and reduced thenar strength as well as reduced shoulder mobility. In addition, self-reporting previous surgery of carpal tunnel and trigger finger was associated with several clinical UEIs including shoulder, hand, and finger. The test-retest of the questionnaire showed a high agreement of 80-98% for reported shoulder, hand, and finger impairments. Conclusion. UEIs are common in type 1 diabetes. Self-reported shoulder stiffness and reduced hand strength might be used to capture patients with UEIs in need of clinical investigation and enhanced preventive and therapeutic strategies, as well as rehabilitative interventions.
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| 31. |
- Gutefeldt, Kerstin, et al.
(författare)
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Dysregulated growth hormone-insulin-like growth factor-1 axis in adult type 1 diabetes with long duration
- 2018
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Ingår i: Clinical Endocrinology. - : WILEY. - 0300-0664 .- 1365-2265. ; 89:4, s. 424-430
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Tidskriftsartikel (refereegranskat)abstract
- ContextIn type 1 diabetes (T1D), dysregulation of the GH-IGF-1 axis has been reported. Whether this is related to upper extremity impairments (UEI) is unknown. ObjectiveExamine differences in GH-IGF-1 axis between T1D on subcutaneous insulin treatment and matched controls without diabetes and possible associations between GH-IGF-1 axis and UEI. DesignCross-sectional population-based study. Patients with T1D, onset amp;lt;35years, duration 20years, amp;lt;67years old and controls were invited to answer questionnaires and take blood samples. SubjectsA total of 605 patients with T1D and 533 controls accepted to participate. OutcomesFasting levels of IGF-1, IGF-1 Z-score, IGFBP-1, IGFBP-3, C-peptide, GH and UEI. ResultsPatients with T1D had lower IGF-1 and IGFBP-3 and higher IGFBP-1 and GH than controls. The difference in IGF-1 persisted with age. Insulin dose was associated with increasing IGF-1 Z-score but even at a very high insulin dose (amp;gt;1U/kg) IGF-1 Z-score was subnormal compared to controls. IGF-1 Z-score was unaffected by glycaemic control (HbA1c) but increased with residual insulin secretion, (C-peptide 1-99 pmol/L). IGFBP-1 was associated with fasting blood glucose, negatively in controls and positively in patients with T1D probably reflecting insulin resistance and insulin deficiency, respectively. There was no association between lower IGF-1 Z-score and UEI in T1D. ConclusionIn adult T1D with fair glycaemic control, the GH-IGF-1 axis is dysregulated exhibiting GH resistance, low IGF-1 and elevated IGFBP-1. Subcutaneous insulin cannot normalize these changes while endogenous insulin secretion has marked effects on IGF-1 pointing to a role of portal insulin.
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| 32. |
- Gutefeldt, Kerstin, 1972-, et al.
(författare)
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Low health-related quality of life is strongly linked to upper extremity impairments in type 1 diabetes with a long duration
- 2021
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Ingår i: Disability and Rehabilitation. - : Taylor & Francis. - 0963-8288 .- 1464-5165. ; 43:18, s. 2578-2584
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To compare health-related quality of life (HRQOL) in type 1 diabetes and non-diabetic controls and possible links to upper extremity impairments (UEIs). Prevalence of sick-leave and causes were investigated.Materials and methods: This Swedish population-based case-control study included type 1 diabetes patients <67 years old and with a diabetes duration ≥20 years. Participants completed a postal questionnaire including Short Form 36, and questions regarding UEIs, and sick-leave.Results: In total, 773 patients, aged 50 ± 10 years (diabetes duration 35 ± 10 years), and 708 non-diabetic controls, aged 54 ± 9 years, completed the study. Patients reported significantly lower HRQOL compared with controls. The difference was greatest for general health, vitality, and bodily pain. Patients with shoulder or hand but not finger impairments scored significantly lower than asymptomatic patients. The prevalence of sick leave was higher in patients vs. controls (23% vs. 9%, p < 0.001), and nearly half cited impairments from back, muscles, or joints as the main reason.Conclusions: Health-related quality of life is lower in type 1 diabetes than controls and in patients with shoulder and hand impairments than in asymptomatic. Musculoskeletal impairments (back/muscle/joints) have impact on work ability. Identification of UEIs is important for initiating preventative-, therapeutic-, and rehabilitative interventions.Implications for rehabilitationUpper extremity impairments (UEIs) that are common in type 1 diabetes, and associated with reduced health-related quality of life, should preferably be screened for on a regular basis along with other known diabetes complications.Early identification of UEIs is important to improve health by initiating preventive as well as therapeutic multi-professional rehabilitative interventions.Sick leave is higher in type 1 diabetes than in controls. Musculoskeletal impairments, including the back, muscles, and joints, are a common cause for sick leave warranting further studies.
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| 33. |
- Gutefeldt, Kerstin, et al.
(författare)
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Upper extremity impairments in type 1 diabetes with long duration : common problems with great impact on daily life
- 2019
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Ingår i: Disability and Rehabilitation. - : Taylor & Francis. - 0963-8288 .- 1464-5165. ; 41:6, s. 633-640
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To investigate the prevalence, activity limitations and potential risk factors of upper extremity impairments in type 1 diabetes in comparison to controls.METHODS: In a cross-sectional population-based study in the southeast of Sweden, patients with type 1 diabetes <35 years at onset, duration ≥20 years, <67 years old and matched controls were invited to answer a questionnaire on upper extremity impairments and activity limitations and to take blood samples.RESULTS: Seven hundred and seventy-three patients (ages 50 ± 10 years, diabetes duration 35 ± 10 years) and 708 controls (ages 54 ± 9 years) were included. Shoulder pain and stiffness, hand paraesthesia and finger impairments were common in patients with a prevalence of 28-48%, which was 2-4-folds higher than in controls. Compared to controls, the patients had more bilateral impairments, often had coexistence of several upper extremity impairments, and in the presence of impairments, reported more pronounced activity limitations. Female gender (1.72 (1.066-2.272), p = 0.014), longer duration (1.046 (1.015-1.077), p = 0.003), higher body mass index (1.08 (1.017-1.147), p = 0.013) and HbA1c (1.029 (1.008-1.05), p = 0.007) were associated with upper extremity impairments.CONCLUSIONS: Compared to controls, patients with type 1 diabetes have a high prevalence of upper extremity impairments, often bilateral, which are strongly associated with activity limitations. Recognising these in clinical practise is crucial, and improved preventative, therapeutic and rehabilitative interventions are needed. Implications for rehabilitation Upper extremity impairments affecting the shoulder, hand and fingers are common in patients with type 1 diabetes, the prevalence being 2-4-fold higher compared to non-diabetic persons. Patients with diabetes type 1 with upper extremity impairments have more pronounced limitations in daily activities compared to controls with similar impairments. Recognising upper extremity impairments and activity limitations are important and improved preventive, therapeutic and rehabilitation methods are needed.
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| 34. |
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| 35. |
- Hammar, M, et al.
(författare)
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Expression of two csg operons is required for production of fibronectin- and congo red-binding curli polymers in Escherichia coli K-12.
- 1995
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Ingår i: Molecular Microbiology. - : Wiley. - 0950-382X .- 1365-2958. ; 18:4, s. 661-70
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Tidskriftsartikel (refereegranskat)abstract
- Two divergently transcribed operons in Escherichia coli required for the expression of fibronectin- and Congo red-binding curli polymers were identified and characterized by transposon mutagenesis, sequencing and transcriptional analyses, as well as for their ability to produce the curli subunit protein. The csgBA operon encodes CsgA, the major subunit protein of the fibre, and CsgB, a protein with sequence homology to CsgA. A non-polar csgB mutant is unaffected in its production of CsgA, but the subunit protein is not assembled into insoluble fibre polymers. A third open reading frame, orfC, positioned downstream of csgA may affect some functional property of curli since an insertion in this putative gene abolishes the autoagglutinating ability typical of curliated cells without affecting the production of the fibre. The promoter for the oppositely transcribed csgDEFG operon was identified by primer extension and shown, like the csgBA promoter, to be dependent upon the alternate stationary phase-specific sigma factor sigma s in wild-type cells, but not in mutants lacking the nucleoid associated protein H-NS. Insertions in csgD abolish completely trancription from the csgBA promoter. Therefore, any regulatory effect on the csgBA promoter might be secondary to events controlling the csgDEFG promoter and/or activation of CsgD. Insertions in csgE, csgF and csgG abolish curli formation but allow CsgA expression suggesting that one or more of these gene products are involved in secretion/assembly of the CsgA subunit protein. No amino acid sequence homologies were found between the CsgE, CsgF and CsgG proteins and secretion/assembly proteins for other known bacterial fibres, suggesting that the formation of curli follows a novel pathway.
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| 36. |
- Hedman, Christina, 1964-, et al.
(författare)
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The IGF-system is not affected by a twofold change in protein intake in patients with type 1 diabetes
- 2005
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Ingår i: Growth Hormone & IGF Research. - : Elsevier BV. - 1096-6374 .- 1532-2238. ; 15:4, s. 304-310
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Tidskriftsartikel (refereegranskat)abstract
- Objective In type 1 diabetes the circulating IGF-system is altered with low IGF-I and changes in levels of IGF-binding proteins (IGFBPs) which may be of importance for the development of diabetes complications. Our aim was to study if IGF-I, as supported by experimental data in animals, can be affected by dietary protein intake.Design and methods Twelve patients with type 1 diabetes, age 37.5 ± 10.0 years (mean ± SD), diabetes duration 20.1 ± 9.3 years and HbA1c 6.3 ± 0.6% were allocated to isocaloric diets with either low normal protein content (LNP), (10 E%; 0.9 g protein/kg body weight) or high normal protein content (HNP) (20 E%; 1.8 g protein/kg body weight) in an open randomised cross-over study. Each diet was taken for 10 days with a wash-out period of 11 days in between. Circulating levels of total and free IGF-I and -II, IGFBP-1, -2 and -3 and GH-binding protein (GHBP) as well as ghrelin were measured with validated in-house immunoassays.Results At day 10, urinary urea excretion was 320 ± 75 mmol/24 h during LNP diet compared with 654 ± 159 mmol/24 h during HNP diet (p < 0.001). There were no changes in body weight or glycaemic control between the diets. Fasting levels of total IGF-I were 121 ± 33 μg/L after LNP and 117 ± 28 μg/L after HNP diet (ns) and the corresponding concentrations of IGFBP-1 were 142(141) and 132(157) μg/L [median (IQR)] (ns). There were no differences in plasma concentrations of total IGF-II, free IGF-I and -II, IGFBP-3, GHBP and ghrelin, whereas a small difference was found for IGFBP-2 (302 ± 97 vs. 263 ± 66 μg/L; LNP vs. HNP; p < 0.04).Conclusions A twofold change of the dietary protein intake does not influence the altered circulating IGF-system in type 1 diabetes. In order to affect the IGF-system other interventions must be used.
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| 37. |
- Henricsson, Marianne, et al.
(författare)
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The incidence of retinopathy 10 years after diagnosis in young adult people with diabetes: results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS).
- 2003
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 26:2, s. 349-354
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE—To estimate the prevalence and severity of diabetic retinopathy (DR) 10 years after diagnosis in a nationwide population-based cohort study of young adult diabetic patients in Sweden. RESEARCH DESIGN AND METHODS—The Diabetes Incidence Study in Sweden (DISS) aims to register all incident cases of diabetes aged 15–34 years in Sweden. In 1987–1988, 806 cases were reported, and 627 (78%) of them were followed up with regard to retinopathy 8–10 years later. The assessment was based on retinal photographs in most cases (86%). RESULTS—Ten years after diagnosis, retinopathy was found in 247 patients (39%). The retinopathy was mild in 206 (33%), whereas 30 (4.8%) patients had moderate nonproliferative DR (NPDR) and 11 (1.8%) had proliferative DR (PDR). Patients with retinopathy had worse glycemic control during the years than patients without (HbA1c 8.1 ± 1.5% and 6.8 ± 1.2%, respectively; P < 0.001). In a Cox regression analysis, time to retinopathy was related to high HbA1c (P < 0.001) and high BMI (P = 0.001). Patients with type 2 diabetes had an increased prevalence of severe retinopathy (NPDR or PDR) compared with those with type 1 diabetes (14 of 93 [15%] versus no or mild 24 of 471 [5%], respectively; P < 0.001). CONCLUSIONS—Despite modern diabetes management, 39% of young adult diabetic patients developed retinopathy within the first 10 years of the disease. Nevertheless, compared with the prevalence of retinopathy (63%), after a similar duration of diabetes before the Diabetes Control and Complications Trial, this prevalence was clearly lower. Current treatment aimed to achieve strict glycemic control has reduced the risk for developing retinopathy.
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| 38. |
- Ilver, D, et al.
(författare)
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Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging
- 1998
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 279:5349, s. 373-377
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Tidskriftsartikel (refereegranskat)abstract
- The bacterium Helicobacter pylori is the causative agent for peptic ulcer disease. Bacterial adherence to the human gastric epithelial lining is mediated by the fucosylated Lewis b (Leb) histo-blood group antigen. The Leb-binding adhesin, BabA, was purified by receptor activity-directed affinity tagging. The bacterial Leb-binding phenotype was associated with the presence of the cag pathogenicity island among clinical isolates of H. pylori. A vaccine strategy based on the BabA adhesin might serve as a means to target the virulent type I strains of H. pylori.
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| 39. |
- Janzon, Erik, et al.
(författare)
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Impacts of land cover heterogeneity on wind turbine icing
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Atmospheric icing affecting wind turbines is a challenge for energy companies operating in cold climate regions. In addition, low level super cooled clouds that cause rime ice in these areas are often subject to surface-atmosphere interactions. In numerical weather prediction (NWP) models, the detailed characteristics of the surface boundary--including the presence of snow cover and the patchiness, or heterogeneity, of land cover--are unknown and must be parameterized. This study examines the sensitivity of ice accretion to the land surface, with respect to changing the heterogeneity length scale ($L_{f}$) of roughness elements and the presence of snow. This is tested using large eddy simulation (LES) integrated over a semi-idealized partial diurnal cycle in combination with an offline ice accretion model for both an early- and late-season case. The ice accretion is found to be most sensitive to the heterogeneity length scale when snow is present in the bare patches, although an opposite icing response with respect to $L_{f}$ is found for different solar insolation. The ice accretion response to $L_{f}$ is shown to be mostly due to changes in the content of liquid water and cloud ice when snow is at the surface.
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| 40. |
- Janzon, Erik
(författare)
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Local Effects On Icing Forecasts for Wind Power In Cold Climate
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis will examine the local effects of land cover on icing forecasts. In Paper I, a single column model was used to test the sensitivity of icing forecasts to land cover fraction. Here, the ice accretion forecast was found to be highly sensitive to the wind magnitude response to the surface roughness. Diabatic effects related to the surface albedo played a secondary role, significant in cases with strong solar irradiance. Paper II examined the impact of 2-dimensional patterns of land cover heterogeneity on the effective surface roughness and blending height using large eddy simulation over a diurnal cycle of solar irradiance. The blending height--or the elevation at which the atmospheric response to the underlying land cover becomes horizontally homogeneous--has been proposed as a guide for coupling numerical weather models to surface parameterizations. In stable conditions, when the atmospheric boundary layer height was shallow, the blending height over surfaces with large heterogeneity length scale was found to be much lower than that of analytical models from previous studies. A new formula for a dynamic blending height was proposed taking this effect into account. The effective surface roughness was found to decrease with increasing land cover heterogeneity. The wind power response from an idealized wind turbine with 80-meter hub height to the effective surface roughness was shown, with a positive response in wind power with increasing land cover heterogeneity. The wind power response was smaller and less systematic with wind turbines extending above the blending height, further highlighting the utility of an accurate formulation for this variable.
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| 41. |
- Janzon, Erik
(författare)
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Local Effects On Icing Forecasts for Wind Power In Cold Climate
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Understanding the risk of atmospheric icing on wind turbines is crucial for the operation of wind farms in cold climate regions. Processes leading to atmospheric icing in the planetary boundary layer are subject to interactions with the land surface--the details of which are largely unknown in current numerical weather prediction models and must be parameterized. This thesis examines the impact of the representation of land surface cover in these models on meteorological variables related to wind turbine icing. First, a sensitivity analysis is conducted using a single-column model to test the relative impacts of the vegetation fraction on ice accretion at the elevation of a modern commercial wind turbine. The impact of the representation of surface roughness due to the vegetation fraction and parameterization of processes related to the forest canopy is found to have the largest impact on icing in the simulations. This effect is combined with an important secondary role due to the albedo of the surface, which impacts the evolution of the icing event under early season solar insolation. Next, large eddy simulations (LES) are conducted to test the impact of the land cover heterogeneity length scale on wind profiles during a semi-idealized diurnal cycle in dry, subarctic conditions. The effective surface roughness is found to decrease as a function of the land cover heterogeneity length scale and the blending height is found to be limited by the height of the atmospheric boundary layer. Using the findings of this study in combination with previous work in the literature, a dynamic blending height model is presented as a possible coupling strategy for surface parameterizations. Following the results of the aforementioned study, LES simulations of different heterogeneity length scales are used to validate an analytical model that is used to simulate mean wind profiles and wind stress over arbitrary patterns of surface roughness. Lastly, semi-idealized LES simulations of supercooled low-level clouds are used to test the sensitivity of meteorological variables related to wind turbine icing to land cover heterogeneity length scales. Here, the presence of snow cover in bare patches has a significant effect on the icing prediction. The results of this thesis show that the representation of the surface can have a significant impact on wind turbine icing forecasts and that these findings will be helpful in identifying uncertainties in these predictions.
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| 42. |
- Janzon, Erik, et al.
(författare)
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Modelling the effects of surface heterogeneity on the internal boundary layer during a diurnal cycle
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- To characterize the effects of subgrid surface heterogeneity, the blending height concept has been developed as a coupling strategy for surface parameterization schemes used in numerical weather prediction (NWP) models. Previous modelling studies have tested this concept using stationary conditions with one-dimensional strips of surface roughness. Here, Large Eddy Simulations (LES) are used to examine the response of the blending height and effective surface roughness to two-dimensional chessboard patterns of alternating high and low vegetation given a diurnal cycle of solar irradiance. In each experiment, the length scale of the roughness elements is increased while the total domain fraction of each vegetation type is kept constant. The effective surface roughness was found to decrease with increasing length scale of surface cover heterogeneity, which is shown to have a significant impact on estimated wind turbine power calculated from logarithmic wind profiles. In stable conditions, the blending height in cases with large heterogeneity length scales was found to exist well above the surface layer. As the behavior of the blending height has implications for coupled models, a simple model for the blending height as a function of heterogeneity length scale is introduced.
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| 43. |
- Janzon, Erik, et al.
(författare)
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Modelling the flow response to surface heterogeneity during a semi-idealized diurnal cycle
- 2023
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Ingår i: Journal of Applied Meteorology and Climatology. - : American Meteorological Society. - 1558-8424 .- 1558-8432. ; 62:4, s. 511-527
-
Tidskriftsartikel (refereegranskat)abstract
- To characterize the effects of subgrid surface heterogeneity, the blending height concept has been developed as a coupling strategy for surface parameterization schemes used in numerical weather prediction (NWP) models. Previous modelling studies have tested this concept using stationary conditions with one-dimensional strips of surface roughness. Here, Large Eddy Simulations (LES) are used to examine the response of the blending height and effective surface roughness to \reva{tiled land cover heterogeneity, or a two-dimensional chessboard pattern }of alternating high and low vegetation given a diurnal cycle of solar irradiance \revg{in subarctic conditions}. In each experiment, the length scale of the roughness elements is increased while the total domain fraction of each vegetation type is kept constant. The effective surface roughness was found to decrease with increasing length scale of surface cover heterogeneity, which is shown to have a significant impact on estimated wind turbine power calculated from logarithmic wind profiles. In stable conditions, the blending height in cases with large heterogeneity length scales was found to exist well above the surface layer. As the behavior of the blending height has implications for coupled models, a simple model for the blending height as a function of heterogeneity length scale is introduced.
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| 44. |
- Janzon, Erik, et al.
(författare)
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Single Column Model Simulations of Icing Conditions in Northern Sweden : Sensitivity to Surface Model Land Use Representation
- 2020
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Ingår i: Energies. - : MDPI. - 1996-1073. ; 13:16
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Tidskriftsartikel (refereegranskat)abstract
- In-cloud ice mass accretion on wind turbines is a common challenge that is faced by energy companies operating in cold climates. On-shore wind farms in Scandinavia are often located in regions near patches of forest, the heterogeneity length scales of which are often less than the resolution of many numerical weather prediction (NWP) models. The representation of these forests-including the cloud water response to surface roughness and albedo effects that are related to them-must therefore be parameterized in NWP models used as meteorological input in ice prediction systems, resulting in an uncertainty that is poorly understood and, to the present date, not quantified. The sensitivity of ice accretion forecasts to the subgrid representation of forests is examined in this study. A single column version of the HARMONIE-AROME three-dimensional (3D) NWP model is used to determine the sensitivity of the forecast of ice accretion on wind turbines to the subgrid forest fraction. Single column simulations of a variety of icing cases at a location in northern Sweden were examined in order to investigate the impact of vegetation cover on ice accretion in varying levels of solar insolation and wind magnitudes. In mid-winter cases, the wind speed response to surface roughness was the primary driver of the vegetation effect on ice accretion. In autumn cases, the cloud water response to surface albedo effects plays a secondary role in the impact of in-cloud ice accretion, with the wind response to surface roughness remaining the primary driver for the surface vegetation impact on icing. Two different surface boundary layer (SBL) forest canopy subgrid parameterizations were tested in this study that feature different methods for calculating near-surface profiles of wind, temperature, and moisture, with the ice mass accretion again following the wind response to surface vegetation between both of these schemes.
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| 45. |
- Lindén, S. K., et al.
(författare)
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Helicobacter pylori Adhesion to the Gastric Surface
- 2010
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Ingår i: Helicobacter pylori in the 21st Century. - WALLINGFORD : CABI Publishing. - 9781845935948 ; , s. 248-268
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Bokkapitel (refereegranskat)abstract
- AbstractThis chapter discusses the adhesins and other structures that Helicobacter pylori uses to adhere to the gastric surface, as well as how these adhesins are regulated. The host structures (mucus layer and glycosphingolipids) to which H. pylori binds are described.
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| 46. |
- Littorin, Bengt, et al.
(författare)
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Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects : results from the nationwide Diabetes Incidence Study in Sweden (DISS)
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:12, s. 2847-2852
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Tidskriftsartikel (refereegranskat)abstract
- Low plasma vitamin D concentrations may promote the development of type 1 diabetes. To test this hypothesis, we measured plasma 25-hydroxyvitamin D (25OHD) in young adults with type 1 diabetes.The nationwide Diabetes Incidence Study in Sweden (DISS) covers 15- to 34-year-old people with newly diagnosed diabetes. Blood samples at diagnosis were collected during the 2-year period 1987/1988. Patients with islet antibodies (islet cell antibodies, GAD antibodies or tyrosine phosphatase-like protein antibodies) were defined as having autoimmune type 1 diabetes. Plasma 25OHD was measured in samples taken from 459 patients at the time of diagnosis, and in 138 of these subjects 8 years later. The results were compared with age- and sex-matched control subjects (n=208).At diagnosis, plasma 25OHD levels were significantly lower in patients with type 1 diabetes than in control subjects (82.5 +/- 1.3 vs 96.7 +/- 2.0 nmol/l; p < 0.0001). Eight years later, plasma 25OHD had decreased in patients (81.5 +/- 2.6 nmol/l; p=0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic women at diagnosis (77.9 +/- 1.4 vs 90.1 +/- 2.4 nmol/l; p < 0.0001) and at follow-up (77.1 +/- 2.8 nmol/l vs 87.2 +/- 4.5 nmol/l; p=0.048). 81.5 +/- 2.6 nmol/l; p=0.04). Plasma 25OHD levels were significantly lower in diabetic men than in diabetic women at diagnosis (77.9 +/- 1.4 vs 90.1 +/- 2.4 nmol/l; p < 0.0001) and at follow-up (77.1 +/- 2.8 nmol/l vs 87.2 +/- 4.5 nmol/l; p=0.048). Conclusions/interpretation The plasma 25OHD level was lower at diagnosis of autoimmune type 1 diabetes than in control subjects, and may have a role in the development of type 1 diabetes. Plasma 25OHD levels were lower in men than in women with type 1 diabetes. This difference may be relevant to the high incidence of type 1 diabetes among young adult men.
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| 47. |
- Mahdavi, Jafar, et al.
(författare)
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Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation
- 2002
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 297:5581, s. 573-578
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.
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| 48. |
- Mahdavi, Jafar, et al.
(författare)
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The blood group antigen binding activity of the Helicobacter pylori baba adhesin is regulated by local ph and redox potential
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The blood group antigen hinding adhesin, BabA, which binds to fucosylated blood group antigens, such as the Lewis b (Leb) and H1 antigens constitutes one of the best recognized adhesin-receptor interactions that mediate adherence of Helicobacter pylori to the gastric epithelium. BabA belongs to a family of H. pylori outer membrane, proteins (HOPs), a group of some 30 proteins with most similar N- and C-terminal domains.We previously identified the babA1 and babA2 genes, where babA2 was found to encode the BabA adhesin in strain CCUG17875. Here, we confirmed the identity of the BabA protein by immunoblot-analysis, followed by MALDIT-OF MS analysis, which also provided molecular weight of the BabA polypeptide and the unique peptide sequences for BabA. Surprisingly, the BabA protein was found to be expressed 50-fold higher compared to the number of calculated bacterial Leb-binding sites.Furthermore, surface scan of the bacterial membrane by freeze fracture immuno-EM technique localized the BabA by immunogold labeling to the bacterial surface in numbers similar to the predicted binding sites. To help explain the binding results, crosslinker-analyses were performed which revealed that BabA form supra-molecular complexes on the bacterial surfaces. In addition, binding to the Lewis b antigen was shown to be pH dependent and took place over a broad pH range but binding activity was reversibly lost when approaching pH 3, i.e. conditions similar to the acidic gastric juice.The binding activity of the BabA adhesin was shown to be sensitive for reducing conditions, which suggests the presence of disulfide bond(s) close to the carbohydrate-binding domain. The dynamics of BabA in Leb-binding suggest that the bacterial adhesin is regulated by local variations in pH and redox potential, such as the pH gradient in the slimy mucus lining of the epithelium, and the reduced conditions of the inflamed gastric mucosa.
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| 49. |
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| 50. |
- Nadeem, Aftab, et al.
(författare)
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Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA
- 2021
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Ingår i: PLoS Pathogens. - : Public Library of Science. - 1553-7366 .- 1553-7374. ; 17:3
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Tidskriftsartikel (refereegranskat)abstract
- Vibrio cholerae is a noninvasive intestinal pathogen extensively studied as the causative agent of the human disease cholera. Our recent work identified MakA as a potent virulence factor of V. cholerae in both Caenorhabditis elegans and zebrafish, prompting us to investigate the potential contribution of MakA to pathogenesis also in mammalian hosts. In this study, we demonstrate that the MakA protein could induce autophagy and cytotoxicity of target cells. In addition, we observed that phosphatidic acid (PA)-mediated MakA-binding to the host cell plasma membranes promoted macropinocytosis resulting in the formation of an endomembrane-rich aggregate and vacuolation in intoxicated cells that lead to induction of autophagy and dysfunction of intracellular organelles. Moreover, we functionally characterized the molecular basis of the MakA interaction with PA and identified that the N-terminal domain of MakA is required for its binding to PA and thereby for cell toxicity. Furthermore, we observed that the ΔmakA mutant outcompeted the wild-type V. cholerae strain A1552 in the adult mouse infection model. Based on the findings revealing mechanistic insights into the dynamic process of MakA-induced autophagy and cytotoxicity we discuss the potential role played by the MakA protein during late stages of cholera infection as an anti-colonization factor.
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