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- Moreno-Pescador, Guillermo, et al.
(author)
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Curvature- and Phase-Induced Protein Sorting Quantified in Transfected Cell-Derived Giant Vesicles
- 2019
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In: ACS Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 13:6, s. 6689-6701
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Journal article (peer-reviewed)abstract
- Eukaryotic cells possess a dynamic network of membranes that vary in lipid composition. To perform numerous biological functions, cells modulate their shape and the lateral organization of proteins associated with membranes. The modulation is generally facilitated by physical cues that recruit proteins to specific regions of the membrane. Analyzing these cues is difficult due to the complexity of the membrane conformations that exist in cells. Here, we examine how different types of membrane proteins respond to changes in curvature and to lipid phases found in the plasma membrane. By using giant plasma membrane vesicles derived from transfected cells, the proteins were positioned in the correct orientation and the analysis was performed in plasma membranes with a biological composition. Nanoscale membrane curvatures were generated by extracting nanotubes from these vesicles with an optical trap. The viral membrane protein neuraminidase was not sensitive to curvature, but it did exhibit strong partitioning (coefficient of K = 0.16) disordered membrane regions. In contrast, the membrane repair protein annexin 5 showed a preference for nanotubes with a density up to 10-15 times higher than that on the more flat vesicle membrane. The investigation of nanoscale effects in isolated plasma membranes provides a quantitative platform for studying peripheral and integral membrane proteins in their natural environment.
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- Bak, Nina Friis, et al.
(author)
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High-dose vitamin D3 supplementation decreases the number of colonic CD103+ dendritic cells in healthy subjects.
- 2018
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In: European journal of nutrition. - : Springer Science and Business Media LLC. - 1436-6215 .- 1436-6207. ; 57:7, s. 2607-2619
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Journal article (peer-reviewed)abstract
- Vitamin D may induce tolerance in the intestinal immune system and has been shown to regulate the phenotype of tolerogenic intestinal dendritic cells (DCs) in vitro. It is unknown whether vitamin D supplementation affects human intestinal DCs in vivo, and we aimed to investigate the tolerability and effect on intestinal CD103+DCs of high-dose vitamin D3 treatment in healthy subjects.Ten healthy subjects received a total of 480,000IU oral vitamin D3 over 15days and colonic biopsies were obtained before and after intervention by endoscopy. Lamina propria mononuclear cells (LPMCs) were isolated from the biopsies, stained with DC surface markers and analysed with flow cytometry. Snap-frozen biopsies were analysed with qPCR for DC and regulatory T cell-related genes.No hypercalcemia or other adverse events occurred in the test subjects. Vitamin D decreased the number of CD103+ DCs among LPMCs (p=0.006). Furthermore, vitamin D induced mRNA expression of TGF-β (p=0.048), TNF-α (p=0.006) and PD-L1 (p=0.02) and tended to induce IL-10 expression (p=0.06). Multivariate factor analysis discriminated between pre- and post-vitamin D supplementation with a combined increased qPCR expression of PD1, PD-L1, TGF-β, IL-10, CD80, CD86, FOXP3, NFATc2 and cathelicidin.High-dose vitamin D supplementation is well tolerated by healthy subjects and has a direct effect on the CD103+ DCs, local cytokine and surface marker mRNA expression in the colonic mucosa, suggestive of a shift towards a more tolerogenic milieu.
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- Birkeland, Kare I., et al.
(author)
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Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic) : A Multinational Observational Analysis
- 2017
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In: The Lancet Diabetes and Endocrinology. - New York : Elsevier. - 2213-8587 .- 2213-8595. ; 5:9, s. 709-717
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Journal article (peer-reviewed)abstract
- Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.
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- Cameron, Adrian J., et al.
(author)
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The influence of hip circumference on the relationship between abdominal obesity and mortality
- 2012
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In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:2, s. 484-494
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Journal article (peer-reviewed)abstract
- Background Higher waist circumference and lower hip circumference are both associated with increased cardiovascular disease (CVD) risk, despite being directly correlated. The real effects of visceral obesity may therefore be underestimated when hip circumference is not fully taken into account. We hypothesized that adding waist and hip circumference to traditional risk factors would significantly improve CVD risk prediction. Methods In a population-based survey among South Asian and African Mauritians (n = 7978), 1241 deaths occurred during 15 years of follow-up. In a model that included variables used in previous CVD risk calculations (a Framingham-type model), the association between waist circumference and mortality was examined before and after adjustment for hip circumference. The percentage with an increase in estimated 10-year cumulative mortality of > 25% and a decrease of > 20% after waist and hip circumference were added to the model was calculated. Results Waist circumference was strongly related to mortality only after adjustment for hip circumference and vice versa. Adding waist and hip circumference to a Framingham-type model increased estimated 10-year cumulative CVD mortality by > 25% for 23.7% of those who died and 15.7% of those censored. Cumulative mortality decreased by > 20% for 4.5% of those who died and 14.8% of those censored. Conclusions The effect of central obesity on mortality risk is seriously underestimated without adjustment for hip circumference. Adding waist and hip circumference to a Framingham-type model for CVD mortality substantially increased predictive power. Both may be important inclusions in CVD risk prediction models.
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| 11. |
- Persson, Frederik, et al.
(author)
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Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy : A multinational observational study
- 2018
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In: Diabetes, obesity and metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 20:2, s. 344-351
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Journal article (peer-reviewed)abstract
- Aims To compare the sodium-glucose-cotransporter-2 (SGLT-2) inhibitor dapagliflozin with dipeptidyl peptidase-4 (DPP-4) inhibitors with regard to risk associations with major adverse cardiovascular (CV) events (MACE; non-fatal myocardial infarction, non-fatal stroke or cardiovascular mortality), hospitalization for heart failure (HHF), atrial fibrillation and severe hypoglycaemia in patients with type 2 diabetes (T2D) in a real-world setting.Methods All patients with T2D prescribed glucose-lowering drugs (GLDs) during 2012 to 2015 were identified in nationwide registries in Denmark, Norway and Sweden. Patients were divided into two groups: new users of dapagliflozin and new users of DPP-4 inhibitors, matched 1:3 by propensity score, calculated by patient characteristics, comorbidities and drug treatment. Cox survival models were used to estimate hazard ratio (HR) per country separately, and a weighted average was calculated.Results After matching, a total of 40908 patients with T2D were identified as new users of dapagliflozin (n=10227) or a DPP-4 inhibitor (n=30681). The groups were well balanced at baseline; their mean age was 61years and 23% had CV disease. The mean follow-up time was 0.95years, with a total of 38760 patient-years. Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95% confidence interval [CI] 0.67-0.94), 0.62 (95% CI 0.50-0.77), and 0.59 (95% CI 0.49-0.72), respectively. Numerically lower, but non-significant HRs were observed for myocardial infarction (0.91 [95% CI 0.72-1.16]), stroke (0.79 [95% CI 0.61-1.03]) and CV mortality (0.76 [95% CI 0.53-1.08]) Neutral associations with atrial fibrillation and severe hypoglycaemia were observed.Conclusions Dapagliflozin was associated with lower risks of CV events and all-cause mortality compared with DPP-4 inhibitors in a real-world clinical setting and a broad T2D population.
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| 12. |
- Sollie, Ove, et al.
(author)
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Protein intake in the early recovery period after exhaustive exercise improves performance the following day.
- 2018
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In: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 125:6, s. 1731-1742
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Journal article (peer-reviewed)abstract
- The aim of the present study was to investigate the effect of protein and carbohydrate ingestion during early recovery from exhaustive exercise on performance after 18 h recovery. Eight elite cyclists (VO2max 74.0±1.6 ml∙kg-1∙min-1) completed two exercise and diet interventions in a double-blinded, randomized, crossover design. Participants cycled first at 73% of VO2max (W73%) followed by one-min intervals at 90% of VO2max until exhaustion. During the first two hours of recovery, participants ingested either 1.2 g carbohydrate∙kg-1∙h-1 (CHO) or 0.8 g carbohydrate + 0.4 g protein∙kg-1∙h-1 (CHO+PROT). The diet during the remaining recovery period was similar for both interventions and adjusted to body weight. After an 18 h recovery, cycling performance was assessed with a 10 s sprint test, 30 min of cycling at W73%, and a cycling time trial (TT). The TT was 8.5% faster (41:53±1:51 min vs 45:26±1:32 min; p<0.03) after CHO+PROT compared to CHO. Mean power output during the sprints was 3.7% higher in CHO-PROT compared to CHO (1063±54 W vs 1026±53 W; p<0.01). Nitrogen balance in the recovery period was negative in CHO and neutral in CHO+PROT (-82.4±11.5 vs 7.0±15.4 mg∙kg-1; p<0.01).IN CONCLUSION: TT and sprint performances were improved 18 h after exhaustive cycling by CHO-PROT supplementation during the first two hours of recovery compared with isoenergetic CHO supplementation. Our results indicate that intake of carbohydrate plus protein after exhaustive endurance exercise more rapidly converts the body from a catabolic to an anabolic state than carbohydrate alone, thus speeding recovery and improving subsequent cycling performance.
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| 13. |
- Sundberg, J., et al.
(author)
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A Versatile Dinucleating Ligand Containing Sulfonamide Groups
- 2014
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In: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 53:6, s. 2873-2882
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Journal article (peer-reviewed)abstract
- Copper, iron, and gallium coordination chemistries of the new pentadentate bis-sulfonamide ligand 2,6-bis(N-2-pyridylmethylsulfonamido)-4-methylphenol (psmpH(3)) were investigated. PsmpH(3) is capable of varying degrees of deprotonation, and notably, complexes containing the fully trideprotonated ligand can be prepared in aqueous solutions using only divalent metal ions. Two of the copper(II) complexes, [Cu-2(psmp)(OH)] and [Cu-2(psmp)(OAc)(2)](-), demonstrate the anticipated 1:2 ligand/metal stoichiometry and show that the dimetallic binding site created for exogenous ligands possesses high inherent flexibility since additional one- and three-atom bridging ligands bridge the two copper(11) ions in each complex, respectively. This gives rise to a difference of 0.4 angstrom in the Cu center dot center dot center dot Cu distances. Complexes with 2:3 and 2:1 ligand/metal stoithiometries for the divalent and trivalent metal ions, respectively, were observed in [Cu-3(psmp)(2)(H2O)] and [M(psmpH)(psmpH(2))], where M = Ga-III, Fe-III. The deprotonated tridentate N-2-pyridylsulfonylmethylphenolato moieties chelate the metal ions in a meridional fashion, whereas in [Cu-3(psmp)(2)(H2O)] the rare mu(2)-N-sulfonarnido bridging coordination mode is observed. In the bis-ligand mononuclear complexes, one picolyl arm of each ligand is protonated and uncoordinated. Magnetic susceptibility measurements on the doubly and triply bridged dicopper(II) complexes indicate strong and medium strength antiferromagnetic coupling interactions, with J = 234 cm(-1) and 115 cm(-1) for [Cu-2(psmp)(OH)] and [Cu-2(psmp)(OAc)(2)](-), respectively (in H-HDvV = ... +JS(1)S(2) convention). The trinudear [Cu-3(psmp)(2)(H2O)], in which the central copper ion is linked to two flanking copper atoms by two mu(2)-N-sulfonamido bridges and two phenoxide bridges shows an overall magnetic behavior of antiferromagnetic coupling. This is corroborated computationally by broken-symmetry densityfunctional theory, which for isotropic modeling of the coupling predicts an antiferromagnetic coupling strength of J = 70.5 cm(-1).
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