| 1. |
- Åberg, Anna, et al.
(author)
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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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In: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 52:10, s. 5572-5595
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Journal article (peer-reviewed)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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| 2. |
- Arnqvist, Hans, et al.
(author)
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Vitamin D status in longstanding type 1 diabetes and controls. Association with upper extremity impairments
- 2023
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In: Upsala Journal of Medical Sciences. - : UPSALA MED SOC. - 0300-9734 .- 2000-1967. ; 128:1
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Journal article (peer-reviewed)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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| 3. |
- Gutefeldt, Kerstin, 1972-, et al.
(author)
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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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In: Journal of Diabetes Research. - : Hindawi Publishing Corporation. - 2314-6745 .- 2314-6753. ; 2020
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Journal article (peer-reviewed)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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| 4. |
- Gutefeldt, Kerstin, 1972-, et al.
(author)
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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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In: Disability and Rehabilitation. - : Taylor & Francis. - 0963-8288 .- 1464-5165. ; 43:18, s. 2578-2584
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Journal article (peer-reviewed)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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| 5. |
- Janzon, Erik
(author)
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Local Effects On Icing Forecasts for Wind Power In Cold Climate
- 2022
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Licentiate thesis (other academic/artistic)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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| 6. |
- Janzon, Erik
(author)
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Local Effects On Icing Forecasts for Wind Power In Cold Climate
- 2022
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Doctoral thesis (other academic/artistic)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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| 7. |
- Janzon, Erik, et al.
(author)
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Modelling the flow response to surface heterogeneity during a semi-idealized diurnal cycle
- 2023
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In: Journal of Applied Meteorology and Climatology. - : American Meteorological Society. - 1558-8424 .- 1558-8432. ; 62:4, s. 511-527
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Journal article (peer-reviewed)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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| 8. |
- Janzon, Erik, et al.
(author)
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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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In: Energies. - : MDPI. - 1996-1073. ; 13:16
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Journal article (peer-reviewed)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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| 9. |
- Nadeem, Aftab, et al.
(author)
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Phosphatidic acid-mediated binding and mammalian cell internalization of the Vibrio cholerae cytotoxin MakA
- 2021
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In: PLoS Pathogens. - : Public Library of Science. - 1553-7366 .- 1553-7374. ; 17:3
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Journal article (peer-reviewed)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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| 10. |
- Sharafutdinov, Irshad, et al.
(author)
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Campylobacter jejuni surface-bound protease HtrA, but not the secreted protease nor protease in shed membrane vesicles, disrupts epithelial cell-to-cell junctions
- 2024
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In: Cells. - : MDPI. - 2073-4409. ; 13:3
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Journal article (peer-reviewed)abstract
- Fundamental functions of the intestinal epithelium include the digestion of food, absorption of nutrients, and its ability to act as the first barrier against intruding microbes. Campylobacter jejuni is a major zoonotic pathogen accounting for a substantial portion of bacterial foodborne illnesses. The germ colonizes the intestines of birds and is mainly transmitted to humans through the consumption of contaminated poultry meat. In the human gastrointestinal tract, the bacterium triggers campylobacteriosis that can progress to serious secondary disorders, including reactive arthritis, inflammatory bowel disease and Guillain–Barré syndrome. We recently discovered that C. jejuni serine protease HtrA disrupts intestinal epithelial barrier functions via cleavage of the tight and adherens junction components occludin, claudin-8 and E-cadherin. However, it is unknown whether epithelial damage is mediated by the secreted soluble enzyme, by HtrA contained in shed outer-membrane vesicles (OMVs) or by another mechanism that has yet to be identified. In the present study, we investigated whether soluble recombinant HtrA and/or purified OMVs induce junctional damage to polarized intestinal epithelial cells compared to live C. jejuni bacteria. By using electron and confocal immunofluorescence microscopy, we show that HtrA-expressing C. jejuni bacteria trigger efficient junctional cell damage, but not soluble purified HtrA or HtrA-containing OMVs, not even at high concentrations far exceeding physiological levels. Instead, we found that only bacteria with active protein biosynthesis effectively cleave junctional proteins, which is followed by paracellular transmigration of C. jejuni through the epithelial cell layer. These findings shed new light on the pathogenic activities of HtrA and virulence strategies of C. jejuni.
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