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| 2. |
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| 3. |
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| 4. |
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| 5. |
- Arking, D. E., et al.
(författare)
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Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization
- 2014
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 46:8, s. 826-836
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼ 8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD. © 2014 Nature America, Inc.
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| 6. |
- van de Vegte, Yordi, et al.
(författare)
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Genetic insights into resting heart rate and its role in cardiovascular disease
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke. Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
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| 7. |
- Grieser, M., et al.
(författare)
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Storage ring at HIE-ISOLDE
- 2012
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Ingår i: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6401 .- 1951-6355. ; 207:1, s. 1-117
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Tidskriftsartikel (refereegranskat)abstract
- We propose to install a storage ring at an ISOL-type radioactive beam facility for the first time. Specifically, we intend to setup the heavy-ion, low-energy ring TSR at the HIE-ISOLDE facility in CERN, Geneva. Such a facility will provide a capability for experiments with stored secondary beams that is unique in the world. The envisaged physics programme is rich and varied, spanning from investigations of nuclear ground-state properties and reaction studies of astrophysical relevance, to investigations with highly-charged ions and pure isomeric beams. The TSR might also be employed for removal of isobaric contaminants from stored ion beams and for systematic studies within the neutrino beam programme. In addition to experiments performed using beams recirculating within the ring, cooled beams can also be extracted and exploited by external spectrometers for high-precision measurements. The existing TSR, which is presently in operation at the Max-Planck Institute for Nuclear Physics in Heidelberg, is well-suited and can be employed for this purpose. The physics cases as well as technical details of the existing ring facility and of the beam and infrastructure requirements at HIE-ISOLDE are discussed in the present technical design report.
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| 8. |
- Grieser, M., et al.
(författare)
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Storage ring at HIE-ISOLDE Technical design report
- 2012
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Ingår i: The European Physical Journal Special Topics. - : Springer Science and Business Media LLC. - 1951-6355 .- 1951-6401. ; 207:1, s. 1-117
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Forskningsöversikt (refereegranskat)abstract
- We propose to install a storage ring at an ISOL-type radioactive beam facility for the first time. Specifically, we intend to setup the heavy-ion, low-energy ring TSR at the HIE-ISOLDE facility in CERN, Geneva. Such a facility will provide a capability for experiments with stored secondary beams that is unique in the world. The envisaged physics programme is rich and varied, spanning from investigations of nuclear ground-state properties and reaction studies of astrophysical relevance, to investigations with highly-charged ions and pure isomeric beams. The TSR might also be employed for removal of isobaric contaminants from stored ion beams and for systematic studies within the neutrino beam programme. In addition to experiments performed using beams recirculating within the ring, cooled beams can also be extracted and exploited by external spectrometers for high-precision measurements. The existing TSR, which is presently in operation at the Max-Planck Institute for Nuclear Physics in Heidelberg, is well-suited and can be employed for this purpose. The physics cases as well as technical details of the existing ring facility and of the beam and infrastructure requirements at HIE-ISOLDE are discussed in the present technical design report.
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| 9. |
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| 10. |
- Ntalla, Ioanna, et al.
(författare)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 11. |
- Snigirev, O., et al.
(författare)
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Superconducting Quantum Interference Filters as RF amplifiers
- 2007
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Ingår i: IEEE Transactions on Applied Superconductivity. - 1558-2515 .- 1051-8223. ; 17:2, s. 718-721
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Tidskriftsartikel (refereegranskat)abstract
- The superconducting Quantum Interference Filter (SQIF) is a new type of superconducting device which has been recently proposed for highly sensitive magnetometers for absolute magnetic field measurements. It benefits of very high voltage-to-field response, which is, in contrast conventional dc SQUIDs, not periodical. The SQIF can also be used as a radiofrequency amplifier in a similar way as the dc SQUID that can operate in a gigahertz frequency range. We designed a series type of SQIF amplifier that is compatible to conventional YBa2Cu3O7 (YBCO)technology on bicrystal substrates. We present analytical, numericaland scale modeling as well as first electrical measurementsresults at frequencies up to 10 GHz. The SQIF array consists of 50 loops with randomly distributed areas from 0.5 to 1.5 times of 3x30 m2. We also compared it to the regular array of conventional SQUIDs with the same loop areas. We have additional dc contacts to each 5-th SQUIDs and the SQIFs for control and comparison. Devices are fabricated using Josephson junctions with 3 m width formed in YBCO over 24/24 and 12/12 degrees grain boundaries in yttrium-stabilized zirconia (YSZ) bicrystal substrates.
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| 13. |
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| 14. |
- Denwood, G., et al.
(författare)
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Glucose stimulates somatostatin secretion in pancreatic delta-cells by cAMP-dependent intracellular Ca-2+ release
- 2019
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Ingår i: Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 151:9, s. 1094-1115
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Tidskriftsartikel (refereegranskat)abstract
- Somatostatin secretion from pancreatic islet delta-cells is stimulated by elevated glucose levels, but the underlying mechanisms have only partially been elucidated. Here we show that glucose-induced somatostatin secretion (GISS) involves both membrane potential-dependent and -independent pathways. Although glucose-induced electrical activity triggers somatostatin release, the sugar also stimulates GISS via a cAMP-dependent stimulation of CICR and exocytosis of somatostatin. The latter effect is more quantitatively important and in mouse islets depolarized by 70 mM extracellular K+, increasing glucose from 1 mM to 20 mM produced an similar to 3.5-fold stimulation of somatostatin secretion, an effect that was mimicked by the application of the adenylyl cyclase activator forskolin. Inhibiting cAMP-dependent pathways with PKI or ESI-05, which inhibit PKA and exchange protein directly activated by cAMP 2 (Epac2), respectively, reduced glucose/forskolin-induced somatostatin secretion. Ryanodine produced a similar effect that was not additive to that of the PKA or Epac2 inhibitors. Intracellular application of cAMP produced a concentration-dependent stimulation of somatostatin exocytosis and elevation of cytoplasmic Ca2+ ([Ca2+](i)). Both effects were inhibited by ESI-05 and thapsigargin (an inhibitor of SERCA). By contrast, inhibition of PKA suppressed delta-cell exocytosis without affecting [Ca2+](i) . Simultaneous recordings of electrical activity and [Ca2+](i) in delta-cells expressing the genetically encoded Ca2+ indicator GCaMP3 revealed that the majority of glucose-induced [Ca2+](i) spikes did not correlate with delta-cell electrical activity but instead reflected Cat' release from the ER. These spontaneous [Ca2+](i) spikes are resistant to PKI but sensitive to ESI-05 or thapsigargin. We propose that cAMP links an increase in plasma glucose to stimulation of somatostatin secretion by promoting CICR, thus evoking exocytosis of somatostatin-containing secretory vesicles in the delta-cell.
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| 15. |
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| 16. |
- Fomichev, A. S., et al.
(författare)
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Long range plan with radioactive beams at Dubna
- 2010
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Ingår i: 3rd International Conference on Current Problems in Nuclear Physics and Atomic Energy, NPAE 2010; Kyiv; Ukraine; 7 June 2010 through 12 June 2010. ; , s. 64-69
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Konferensbidrag (refereegranskat)abstract
- A program for upgrade of existing radioactive ion beams facilities at Flerov Laboratory of Nuclear Reactions, JINR Dubna is presented. A project of a new in-flight fragment separator ACCULINNA-2 is proposed. It is expected the new instrument will be more universal and powerful than the existing nowadays. The beam intensity should be increased by factor 10-15, its optical quality greatly improved and the range of the accessible secondary radioactive beams broadened up to Z∼20. Main ion-optical characteristics, operating principles and a tentative plan for the project realization are included. An extensive research program based on local experiments made so far and international proposals for these equipments is discussed.
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| 17. |
- Fomichev, A. S., et al.
(författare)
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Status of the ACCULINNA-2 project at FLNR
- 2012
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Ingår i: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 337:1, s. Art. no. 012025-
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Konferensbidrag (refereegranskat)abstract
- The project of a new and more powerful in-flight fragment separator ACCULINNA-2 at U-400M cyclotron in FLNR, JINR planned to build in addition to the existing separator ACCULINNA is presented. The new separator will provide high intensity RIBs in the lowest energy range (5÷50 MeV/nucleon) which is attainable for in-flight separators. The possibilities for the astrophysics studies at the proposed device are presented. ACCULINNA-2 separator is planned to be constructed in the years 2010-2015. The current status of the project is reported.
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| 18. |
- Fomichev, A. S., et al.
(författare)
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The Suggested New Fragment Separator ACCULINNA-2
- 2010
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Ingår i: Acta Physica Polonica, Series B.. - 1509-5770 .- 0587-4254. ; 41:2, s. 475-480
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Tidskriftsartikel (refereegranskat)abstract
- We present new project of fragment separator ACCULINNA-2 that is being planned to be constructed in Flerov Laboratory of Nuclear Reaction, JINR. The ACCULINNA-2 facility is not, intended to compete with the, new large in-flight RIB facilities. It, should complement the existing/constructed facilities in certain fields. Namely, ACCULINNA-2 should provide high intensity RIBs in the lowest energy range attainable for in-flight separators.
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| 19. |
- Goryashko, Vitaliy O., et al.
(författare)
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The sharpness-induced mode stopping and spectrum rarefication in waveguides with periodically corrugated walls
- 2013
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Ingår i: Waves in Random and Complex Media. - : Informa UK Limited. - 1745-5030 .- 1745-5049. ; 23:2, s. 89-113
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Tidskriftsartikel (refereegranskat)abstract
- Starting from the rigorous excitation equation, the propagation of waves through a 2D waveguide with the periodically corrugated finite-length insert is examined in detail. The corrugation profile is chosen to obey the property that its amplitude is small as compared to the waveguide width, whereas the sharpness of the asperities is arbitrarily large. With the aid of the method of mode separation, which was developed earlier for inhomogeneous-in-bulk waveguide systems [Waves Random Media 2000; 10: 395], the corrugated segment of the waveguide is shown to serve as the effective scattering barrier whose width is coincident with the length of the insert and the average height is controlled by the sharpness of boundary asperities. Due to this barrier, the mode spectrum of the waveguide can be substantially rarefied and adjusted so as to reduce the number of extended modes to the value arbitrarily less than that in the absence of corrugation (up to zero), without changing considerably the waveguide average width.
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| 20. |
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| 21. |
- Haythorne, E., et al.
(författare)
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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic beta-cells
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes is a global health problem caused primarily by the inability of pancreatic beta-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of beta-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic beta V59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 beta-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in beta-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of beta-cells in diabetes.
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| 22. |
- Kageyama, Masa, et al.
(författare)
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The PMIP4 contribution to CMIP6-Part 1 : Overview and over-arching analysis plan
- 2018
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 11:3, s. 1033-1057
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Tidskriftsartikel (refereegranskat)abstract
- This paper is the first of a series of four GMD papers on the PMIP4-CMIP6 experiments. Part 2 (OttoBliesner et al., 2017) gives details about the two PMIP4-CMIP6 interglacial experiments, Part 3 (Jungclaus et al., 2017) about the last millennium experiment, and Part 4 (Kageyama et al., 2017) about the Last Glacial Maximum experiment. The mid-Pliocene Warm Period experiment is part of the Pliocene Model Intercomparison Project (PlioMIP) Phase 2, detailed in Haywood et al. (2016). The goal of the Paleoclimate Modelling Intercomparison Project (PMIP) is to understand the response of the climate system to different climate forcings for documented climatic states very different from the present and historical climates. Through comparison with observations of the environmental impact of these climate changes, or with climate reconstructions based on physical, chemical, or biological records, PMIP also addresses the issue of how well state-of-the-art numerical models simulate climate change. Climate models are usually developed using the present and historical climates as references, but climate projections show that future climates will lie well outside these conditions. Palaeoclimates very different from these reference states therefore provide stringent tests for state-of-the-art models and a way to assess whether their sensitivity to forcings is compatible with palaeoclimatic evidence. Simulations of five different periods have been designed to address the objectives of the sixth phase of the Coupled Model Intercomparison Project (CMIP6): the millennium prior to the industrial epoch (CMIP6 name: past1000); the mid-Holocene, 6000 years ago (midHolocene); the Last Glacial Maximum, 21 000 years ago (lgm); the Last Interglacial, 127 000 years ago (lig127k); and the mid-Pliocene Warm Period, 3.2 million years ago (midPliocene-eoi400). These climatic periods are well documented by palaeoclimatic and palaeoenvironmental records, with climate and environmental changes relevant for the study and projection of future climate changes. This paper describes the motivation for the choice of these periods and the design of the numerical experiments and database requests, with a focus on their novel features compared to the experiments performed in previous phases of PMIP and CMIP. It also outlines the analysis plan that takes advantage of the comparisons of the results across periods and across CMIP6 in collaboration with other MIPs.
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| 23. |
- Kageyama, Masa, et al.
(författare)
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The PMIP4 contribution to CMIP6-Part 4 : Scientific objectives and experimental design of the PMIP4-CMIP6 Last Glacial Maximum experiments and PMIP4 sensitivity experiments
- 2017
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 10:11, s. 4035-4055
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Tidskriftsartikel (refereegranskat)abstract
- The Last Glacial Maximum (LGM, 21 000 years ago) is one of the suite of paleoclimate simulations included in the current phase of the Coupled Model Intercomparison Project (CMIP6). It is an interval when insolation was similar to the present, but global ice volume was at a maximum, eustatic sea level was at or close to a minimum, greenhouse gas concentrations were lower, atmospheric aerosol loadings were higher than today, and vegetation and land-surface characteristics were different from today. The LGM has been a focus for the Paleoclimate Modelling Intercomparison Project (PMIP) since its inception, and thus many of the problems that might be associated with simulating such a radically different climate are well documented. The LGM state provides an ideal case study for evaluating climate model performance because the changes in forcing and temperature between the LGM and pre-industrial are of the same order of magnitude as those projected for the end of the 21st century. Thus, the CMIP6 LGM experiment could provide additional information that can be used to constrain estimates of climate sensitivity. The design of the Tier 1 LGM experiment (lgm) includes an assessment of uncertainties in boundary conditions, in particular through the use of different reconstructions of the ice sheets and of the change in dust forcing. Additional (Tier 2) sensitivity experiments have been designed to quantify feedbacks associated with land-surface changes and aerosol loadings, and to isolate the role of individual forcings. Model analysis and evaluation will capitalize on the relative abundance of paleoenvironmental observations and quantitative climate reconstructions already available for the LGM.
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| 24. |
- Klyucherev, Timofey O., et al.
(författare)
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Advances in the development of new biomarkers for Alzheimer's disease
- 2022
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Ingår i: Translational Neurodegeneration. - : Springer Nature. - 2047-9158. ; 11:1
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Forskningsöversikt (refereegranskat)abstract
- Alzheimer's disease (AD) is a complex, heterogeneous, progressive disease and is the most common type of neurodegenerative dementia. The prevalence of AD is expected to increase as the population ages, placing an additional burden on national healthcare systems. There is a large need for new diagnostic tests that can detect AD at an early stage with high specificity at relatively low cost. The development of modern analytical diagnostic tools has made it possible to determine several biomarkers of AD with high specificity, including pathogenic proteins, markers of synaptic dysfunction, and markers of inflammation in the blood. There is a considerable potential in using microRNA (miRNA) as markers of AD, and diagnostic studies based on miRNA panels suggest that AD could potentially be determined with high accuracy for individual patients. Studies of the retina with improved methods of visualization of the fundus are also showing promising results for the potential diagnosis of the disease. This review focuses on the recent developments of blood, plasma, and ocular biomarkers for the diagnosis of AD.
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| 25. |
- Krupko, S. A., et al.
(författare)
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Fragment separator ACCULINNA-2
- 2010
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Ingår i: AIP Conference Proceedings. - : AIP. - 1551-7616 .- 0094-243X. - 9780735407688 ; 1224, s. 516-521
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 26. |
- Mach, Henryk, et al.
(författare)
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Ultrafast-timing lifetime measurements in Ru-94 and Pd-96 : Breakdown of the seniority scheme in N=50 isotones
- 2017
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Ingår i: PHYSICAL REVIEW C. - : American Physical Society. - 2469-9985. ; 95:1
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Tidskriftsartikel (refereegranskat)abstract
- The advanced time-delayed gamma gamma(t) method has been applied to determine half-lives of low-lying states in the N = 50 isotones Ru-94 and Pd-96. The inferred experimental E2 strengths for the 4(+) -> 2(+) transitions in the two nuclei show a dramatic deviation with respect to the shell model predictions in the (f(5/2), p, g(9/2)) proton hole space in Sn-100. The anomalous behavior can be ascribed to a breakdown of the seniority quantum number in the pi g(9/2)(n) configuration due to particle-hole excitations across the N = Z = 50 shell as confirmed by large-scale shell model calculations.
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| 27. |
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| 28. |
- Shigeto, Makoto, et al.
(författare)
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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
- 2015
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:12, s. 4714-4728
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Tidskriftsartikel (refereegranskat)abstract
- Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the K-ATP channel blacker tolbutamide, and the L-type Ca2+ channel blacker isradipine; however, depolarization was abolished by lowering extracellular Na+. The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of NW-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by beta cells.
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| 29. |
- Tarasov, A. I., et al.
(författare)
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Monitoring real-time hormone release kinetics: Via high-content 3-D imaging of compensatory endocytosis
- 2018
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Ingår i: Lab on a Chip. - : Royal Society of Chemistry (RSC). - 1473-0197 .- 1473-0189. ; 18:18, s. 2838-2848
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Tidskriftsartikel (refereegranskat)abstract
- High-content real-time imaging of hormone secretion in tissues or cell populations is a challenging task, which is unlikely to be resolved directly, despite immense translational value. We approach this problem indirectly, using compensatory endocytosis, a process that closely follows exocytosis in the cell, as a surrogate read-out for secretion. The tissue is immobilized in an open-air perifusion chamber and imaged using a two-photon microscope. A fluorescent polar tracer, perifused through the experimental circuit, gets trapped into the cells via endocytosis, and is quantified using a feature-detection algorithm. The signal of the tracer that accumulates into the endocytotic system reliably reflects stimulated exocytosis, which is demonstrated via co-imaging of the latter using existing reporters. A high signal-to-noise ratio and compatibility with multisensor imaging affords the real-time quantification of the secretion at the tissue/population level, whereas the cumulative nature of the signal allows imprinting of the “secretory history” within each cell. The technology works for several cell types, reflects disease progression and can be used for human tissue.
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| 30. |
- van Setten, Jessica, et al.
(författare)
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PR interval genome-wide association meta-analysis identifies 50 loci associated with atrial and atrioventricular electrical activity
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genomewide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are overrepresented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of similar to 105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ionchannel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.
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| 31. |
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| 32. |
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| 33. |
- Wohlfarth, B, et al.
(författare)
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Unstable early-Holocene climatic and environmental conditions in northwestern Russia derived from a multidisciplinary study of a lake-sediment sequence from Pichozero, southeastern Russian Karelia
- 2004
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Ingår i: The Holocene. - : SAGE Publications. - 0959-6836 .- 1477-0911. ; 14:5, s. 732-746
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Tidskriftsartikel (refereegranskat)abstract
- A sediment core from Lake Pichozero (61degrees46'; N, 37degrees25'; E 118 m a.s.l.) provides information on the environmental and climatic conditions in southeastern Russian Karelia during the Lateglacial and early Holocene (12800-9300 cal. BP). The chronology of the sequence is constrained by varve counting and AMS C-14 measurement of terrestrial plant macrofossils. Multiproxy analyses (magnetic susceptibility, grain size, TOC, TN, TS, Rock Eval, pollen and macrofossils) imply that cold and dry regional climatic conditions with sparse Arctic vegetation prevailed prior to 11500 cal. BP. Coincident with the transition to the Holocene at 11500 cal. BP, air temperatures and lake productivity increased and Betula pubescens and Populus tremula started to migrate into the area, followed by Picea abies at 10750 cal. BP. Although lake productivity decreased at around 11000 cal. BP and remained low until 9600 cal. BP, pollen-based climate reconstructions imply variable climatic conditions in the region over time. Drier and colder summers prevailed from similar to11200 to 10900 cal. BP, followed by an interval of higher annual temperatures and precipitation from 10900 to 10750 cal. BP. Lower annual temperatures and drier conditions existed from 10750 to 10200 cal. BP, and higher temperatures and precipitation are inferred between 10200 and 10000 cal. BP. Finally, declining temperatures and precipitation occurred from 10000 cal. BP onwards, with a minimum at around 9600 cal. BP. These climatic shifts are temporally coincident with those recorded in North Atlantic terrestrial, marine and ice-core archives and indicate that relatively minor climate signals were transmitted further to the east.
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| 34. |
- Young, William J., et al.
(författare)
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Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The QT interval is a heritable electrocardiographic measure associated with arrhythmia risk when prolonged. Here, the authors used a series of genetic analyses to identify genetic loci, pathways, therapeutic targets, and relationships with cardiovascular disease. The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.
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