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- Ali Doosti, Baharan, 1991, et al.
(författare)
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Membrane Tubulation in Lipid Vesicles Triggered by the Local Application of Calcium Ions
- 2017
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Ingår i: Langmuir. - : American Chemical Society (ACS). - 1520-5827 .- 0743-7463. ; 33:41, s. 11010-11017
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Tidskriftsartikel (refereegranskat)abstract
- Experimental and theoretical studies on ion-lipid interactions predict that binding of calcium ions to cell membranes leads to macroscopic mechanical effects and membrane remodeling. Herein, we provide experimental evidence that a point source of Ca2+ acting upon a negatively charged membrane generates spontaneous curvature and triggers the formation of tubular protrusions that point away from the ion source. This behavior is rationalized by strong binding of the divalent cations to the surface of the charged bilayer, which effectively neutralizes the surface charge density of outer leaflet of the bilayer. The mismatch in the surface charge density of the two leaflets leads to nonzero spontaneous curvature. We probe this mismatch through the use of molecular dynamics simulations and validate that calcium ion binding to a lipid membrane is sufficient to generate inward spontaneous curvature, bending the membrane. Additionally, we demonstrate that the formed tubular protrusions can be translated along the vesicle surface in a controlled manner by repositioning the site of localized Ca2+ exposure. The findings demonstrate lipid membrane remodeling in response to local chemical gradients and offer potential insights into the cell membrane behavior under conditions of varying calcium ion concentrations.
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- Brander, Søren, et al.
(författare)
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Biochemical evidence of both copper chelation and oxygenase activity at the histidine brace
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322 .- 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Lytic polysaccharide monooxygenase (LPMO) and copper binding protein CopC share a similar mononuclear copper site. This site is defined by an N-terminal histidine and a second internal histidine side chain in a configuration called the histidine brace. To understand better the determinants of reactivity, the biochemical and structural properties of a well-described cellulose-specific LPMO from Thermoascus aurantiacus (TaAA9A) is compared with that of CopC from Pseudomonas fluorescens (PfCopC) and with the LPMO-like protein Bim1 from Cryptococcus neoformans. PfCopC is not reduced by ascorbate but is a very strong Cu(II) chelator due to residues that interacts with the N-terminus. This first biochemical characterization of Bim1 shows that it is not redox active, but very sensitive to H2O2, which accelerates the release of Cu ions from the protein. TaAA9A oxidizes ascorbate at a rate similar to free copper but through a mechanism that produce fewer reactive oxygen species. These three biologically relevant examples emphasize the diversity in how the proteinaceous environment control reactivity of Cu with O2.
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- Delfin, Carl, et al.
(författare)
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A Federated Database for Obesity Research : An IMI-SOPHIA Study
- 2024
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Ingår i: Life. - 0024-3019. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is considered by many as a lifestyle choice rather than a chronic progressive disease. The Innovative Medicines Initiative (IMI) SOPHIA (Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy) project is part of a momentum shift aiming to provide better tools for the stratification of people with obesity according to disease risk and treatment response. One of the challenges to achieving these goals is that many clinical cohorts are siloed, limiting the potential of combined data for biomarker discovery. In SOPHIA, we have addressed this challenge by setting up a federated database building on open-source DataSHIELD technology. The database currently federates 16 cohorts that are accessible via a central gateway. The database is multi-modal, including research studies, clinical trials, and routine health data, and is accessed using the R statistical programming environment where statistical and machine learning analyses can be performed at a distance without any disclosure of patient-level data. We demonstrate the use of the database by providing a proof-of-concept analysis, performing a federated linear model of BMI and systolic blood pressure, pooling all data from 16 studies virtually without any analyst seeing individual patient-level data. This analysis provided similar point estimates compared to a meta-analysis of the 16 individual studies. Our approach provides a benchmark for reproducible, safe federated analyses across multiple study types provided by multiple stakeholders.
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- Mattsson, Lars-Åke, 1945, et al.
(författare)
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Ultra-low-dose estradiol and norethisterone acetate: bleeding patterns and other outcomes over 52 weeks of therapy.
- 2015
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Ingår i: Climacteric : the journal of the International Menopause Society. - : Informa UK Limited. - 1473-0804. ; 18, s. 419-425
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Tidskriftsartikel (refereegranskat)abstract
- Background Continuous combined hormone replacement therapy (HRT) with 0.5 mg 17β-estradiol (E2) + 0.1 mg norethisterone acetate (NETA) received marketing approval based on 24-week results. The current study collected data up to 52 weeks, including consideration of bleeding, a major reason for stopping HRT. Methods This 52-week (13 lunar-month), non-interventional, prospective study involved 169 women from Norway and Sweden receiving daily oral 0.5 mg E2 + 0.1 mg NETA to treat menopausal symptoms. Incidences and cumulative rates of amenorrhea (no bleeding or spotting) and no bleeding (women could have spotting) were evaluated, together with hot flushes and quality of life. Results Overall, > 78% and > 90% of subjects were amenorrheic or had no bleeding, respectively, in each of the first 3 lunar months, while > 88% and > 96% were amenorrheic or had no bleeding, respectively, in each of lunar months 10, 11 and 12. Cumulative rates of amenorrhea and no bleeding were 67% and 83%, respectively, in lunar months 1-3, and 84% and 94%, respectively, in lunar months 10-12. The number of hot flushes declined during treatment (means at weeks 1, 12 and 52, respectively: 15.5, 5.0 and 4.1 [mild]; 19.0, 3.0 and 2.3 [moderate]; 10.8, 1.1 and 0.9 [severe]). Improvement in all four domains of the Menopause-Specific Quality of Life-Intervention questionnaire (vasomotor, psychosocial, physical and sexual) was evident by week 26. Conclusion For women receiving 0.5 mg E2 + 0.1 mg NETA, lack of bleeding-related side-effects, together with beneficial effects on hot flush symptoms and quality of life, may promote treatment continuance.
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- Otte, J, et al.
(författare)
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Formation of amyloid-like fibrils upon limited proteolysis of bovine alpha-lactalbumin
- 2005
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Ingår i: International Dairy Journal. - : Elsevier BV. - 0958-6946. ; 15:3, s. 219-229
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Tidskriftsartikel (refereegranskat)abstract
- Bovine alpha-lactalbumin (alpha-LA) (10 g L-1) was incubated with a protease from Bacillus licheniformis at pH 7.5 and 50 degreesC. The reaction was biphasic consisting of an initial hydrolysis of intact alpha-LA and formation of dimers from large hydrolysis products within 60 min followed by aggregation of dimers into aggregates of 500 kDa. The aggregates consisted primarily of fibrillar strands with a diameter of 5 nm. Formation of these strands was accompanied by a change in secondary structure towards higher beta-sheet content and strong binding of thioflavin, features shared with amyloidal fibrils. The main components in these fibrils were fragments of 8.8 and 9.8 kDa shown to occur in a monomer-dimer equilibrium. These fragments were identified and a molecular mechanism involving side-by-side assembly of dimers of these fragments into fibrils is proposed.
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- Rowat, Amy C., et al.
(författare)
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Farnesylated peptides in model membranes: a biophysical investigation
- 2004
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Ingår i: European Biophysics Journal. - : Springer Science and Business Media LLC. - 0175-7571 .- 1432-1017. ; 33:4, s. 300-9
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Tidskriftsartikel (refereegranskat)abstract
- Protein prenylation plays an important role in signal transduction, protein–protein interactions, and the localization and association of proteins with membranes. Using three different techniques, this study physically characterizes the interactions between model dimyristoylphosphatidylcholine membranes and a series of farnesylated peptides. Magic angle spinning nuclear Overhauser enhancement spectroscopy and differential scanning calorimetry reveal that both charged [Ac-Asn-Lys-Asn-Cys-(farnesyl)-OMe and Ac-Asn-Lys-Asn-Cys-(farnesyl)-NH2] and uncharged [Ac-Cys-(farnesyl)-OMe and farnesol] species partition into dimyristoylphosphatidylcholine bilayers. Calorimetry and vesicle fluctuation analysis of giant unilamellar vesicles show that the charged peptides modestly decrease the main gel–fluid phase transition and markedly increase the bending rigidity of large unilamellar vesicles. Uncharged species, on the other hand, dramatically decrease the main phase transition and modestly decrease the bending rigidity. No difference with carboxyl methylation is detected.
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