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- Antonov, A. N., et al.
(författare)
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The electron-ion scattering experiment ELISe at the International Facility for Antiproton and Ion Research (FAIR)-A conceptual design study
- 2011
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Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002 .- 0167-5087. ; 637:1, s. 60-76
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Tidskriftsartikel (refereegranskat)abstract
- The electron-ion scattering experiment ELISe is part of the installations envisaged at the new experimental storage ring at the International Facility for Antiproton and Ion Research (FAIR) in Darmstadt, Germany. It offers an unique opportunity to use electrons as probe in investigations of the structure of exotic nuclei. The conceptual design and the scientific challenges of ELISe are presented. (C) 2011 Elsevier B.V. All rights reserved.
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| 4. |
- Taddeo, EP, et al.
(författare)
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Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:2, s. 131-145
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Tidskriftsartikel (refereegranskat)abstract
- Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.
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| 5. |
- Diktanas, S, et al.
(författare)
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Factors associated with time to sputum culture conversion of rifampicin-resistant tuberculosis patients in Klaipeda, Lithuania in 2016-2019: a cohort study
- 2021
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Ingår i: Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace. - : PAGEPress Publications. - 1122-0643. ; 91:1
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Tidskriftsartikel (refereegranskat)abstract
- The global proportion of successful treatment outcomes of Multidrug-Resistant/Rifampicin-Resistant Tuberculosis (MDR/RR-TB) remains unacceptably low. Time to culture conversion is important in making treatment-related decisions and is used as an interim predictor of pulmonary MDR/RR-TB treatment success. No previous studies have been conducted to assess determinants of time to culture conversion for MDR/RR-TB patients in Lithuania. Secondary analysis of data of culture-positive MDR/RR-TB patients, treated in Republican Klaipeda Hospital between 1st July 2016 and 1st July 2019 was performed. Culture conversion was defined as two consecutive negative cultures on solid media submitted at least 30 days apart. Factors associated with culture conversion were estimated by crude and multivariable Cox regression accounting for competing risks. In total, 115 consecutive patients starting treatment were included in the study. Of them, the majority was male (86/115; 74.8%) with a mean age of 48 (standard deviation (SD) ±12) years and Human Immunodeficiency Virus (HIV) negative (105/115; 91.3%). Nearly two-thirds (72/115; 62.6%) had XDR (extensive drug resistance) or MDR/RR-TB with additional resistance to second-line injectables or fluoroquinolones. Of 115 culture-positive patients at baseline, 103 (89.6%) patients achieved culture conversion during 12 months of treatment. The median time to culture conversion was 1.1 months (interquartile range: 0.9-1.8). Patients aged ≥60 years compared with <40 years [adjusted hazard ration (aHR): 0.40, 95% confidence interval (CI): 0.18-0.86], smokers (aHR: 0.39, 95% CI: 0.2-0.73), patients with positive sputum smear microscopy at baseline (aHR: 0.40, 95% CI: 0.25-0.63), cavities on initial chest X-ray (aHR: 0.56, 95% CI: 0.35-0.88) and resistance to at least one fluoroquinolone drug (aHR: 0.52, 95% CI: 0.32-0.84) were slower to culture convert. In conclusion, we recommend providing additional counseling, treatment adherence interventions and scale up the use of new and repurposed TB drugs to patient groups at risk of worse interim treatment outcome: patients aged 60 and above, with resistance to fluoroquinolones, smear–positive, smokers, or with signs of extensive disease evident on initial chest radiography.
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| 6. |
- McKay, Kyla A, et al.
(författare)
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Risk of Multiple Sclerosis in People Living with HIV: An International Cohort Study.
- 2023
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Ingår i: Annals of neurology. - 1531-8249. ; 95:3, s. 487-94
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Tidskriftsartikel (refereegranskat)abstract
- There has been interest in a possible negative association between HIV and multiple sclerosis (MS). We aimed to compare the risk of MS in a cohort of individuals living with HIV to that in the general population.Population-based health data were accessed for 2 cohorts of HIV-positive persons from Sweden and British Columbia, Canada. Incident MS was identified using MS registries or a validated algorithm applied to administrative data. Individuals with HIV were followed from 1year after the first clinical evidence of HIV or the first date of complete administrative health data (Canada= April 1, 1992 and Sweden=January 1, 2001) until the earliest of incident MS, emigration, death, or study end (Canada=March 31, 2020 and Sweden=December 31, 2018). The observed MS incidence rate in the HIV-positive cohort was compared to the expected age-, sex-, calendar year-, income-specific, and region of birth-specific rates in a randomly selected sample of >20% of each general population. The standardized incidence ratio (SIR) for MS following the first antiretroviral therapy exposure ("ART-exposed") was also calculated.The combined Sweden-Canada cohort included 29,163 (75% men) HIV-positive persons. During 242,248 person-years of follow-up, 14 incident MS cases were observed in the HIV-positive cohort, whereas 26.19 cases were expected. The SIR for MS in the HIV-positive population was 0.53 (95% confidence interval [CI]=0.32-0.90). The SIR for MS following the first ART exposure was 0.55 (95% CI=0.31-0.96).This international population-based study demonstrated a lower risk of MS among HIV-positive individuals, and HIV-positive ART-exposed individuals. These findings provide support for further exploration into the relationship among HIV, ART, and MS. ANN NEUROL 2023.
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| 7. |
- Robson-Doucette, Christine A., et al.
(författare)
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beta-Cell Uncoupling Protein 2 Regulates Reactive Oxygen Species Production, Which Influences Both Insulin and Glucagon Secretion
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 60:11, s. 2710-2719
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-The role of uncoupling protein 2 (UCP2) in pancreatic beta-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the beta-cell, beta-cell-specific UCP2 knockout mice (UCP2BKO) were generated and characterized. RESEARCH DESIGN AND METHODS-UCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels. RESULTS-UCP2BKO beta-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater alpha-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions. CONCLUSIONS-Using a novel beta-cell-specific UCP2K0 mouse model, we have shed light on UCP2 function in primary beta-cells. UCP2 does not behave as a classical metabolic uncoupler in the beta-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, beta-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in alpha-cell morphology and glucagon secretion. Diabetes 60:2710-2719, 2011
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| 9. |
- Wikström, Jakob D., et al.
(författare)
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A novel high throughput assay for islet respiration reveals uncoupling of rodent and human islets
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:5, s. e33023-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR) may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. Methodology/Principal Findings: The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. Conclusions/Significance: The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.
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| 10. |
- Wikström, Jakob D., et al.
(författare)
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Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure
- 2014
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 33:5, s. 418-436
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Tidskriftsartikel (refereegranskat)abstract
- Adrenergic stimulation of brown adipocytes (BA) induces mitochondrial uncoupling, thereby increasing energy expenditure by shifting nutrient oxidation towards thermogenesis. Here we describe that mitochondrial dynamics is a physiological regulator of adrenergically-induced changes in energy expenditure. The sympathetic neurotransmitter Norepinephrine (NE) induced complete and rapid mitochondrial fragmentation in BA, characterized by Drp1 phosphorylation and Opa1 cleavage. Mechanistically, NE-mediated Drp1 phosphorylation was dependent on Protein Kinase-A (PKA) activity, whereas Opa1 cleavage required mitochondrial depolarization mediated by FFAs released as a result of lipolysis. This change in mitochondrial architecture was observed both in primary cultures and brown adipose tissue from cold-exposed mice. Mitochondrial uncoupling induced by NE in brown adipocytes was reduced by inhibition of mitochondrial fission through transient Drp1 DN overexpression. Furthermore, forced mitochondrial fragmentation in BA through Mfn2 knock down increased the capacity of exogenous FFAs to increase energy expenditure. These results suggest that, in addition to its ability to stimulate lipolysis, NE induces energy expenditure in BA by promoting mitochondrial fragmentation. Together these data reveal that adrenergically-induced changes to mitochondrial dynamics are required for BA thermogenic activation and for the control of energy expenditure.
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