| 1. |
- Lekva, Tove, et al.
(author)
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Epithelial Splicing Regulator Protein 1 and Alternative Splicing in Somatotroph Adenomas
- 2013
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 154:9, s. 3331-3343
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Journal article (peer-reviewed)abstract
- Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously hypothesized that epithelial mesenchymal transition (EMT) may play a central role in the progression of these adenomas and that epithelial splicing regulator 1 (ESRP1) may function prominently as a master regulator of the EMT process in pituitary adenomas causing acromegaly. To further elucidate the role of ESRP1 in somatotroph adenomas and in EMT progression, we used RNA sequencing (RNAseq) to sequence somatotroph adenomas characterized by high and low ESRP1 levels. Transcripts identified by RNAseq were analyzed in 65 somatotroph adenomas and in GH-producing pituitary rat cells with a specific knockdown of Esrp1. The clinical importance of the transcripts was further investigated by correlating mRNA expression levels with clinical indices of disease activity and treatment response. Many of the transcripts and isoforms identified by RNAseq and verified by quantitative PCR were involved in vesicle transport and calcium signaling and were associated with clinical outcomes. Silencing Esrp1 in GH3 cells resulted in changes of gene expression overlapping the data observed in human somatotroph adenomas and revealed a decreased granulation pattern and attenuated GH release. We observed an alternative splicing pattern for F-box and leucine-rich repeat protein 20, depending on the ESPR1 levels and on changes in circulating IGF-I levels after somatostatin analog treatment. Our study indicates that ESRP1 in somatotroph adenomas regulates transcripts that may be essential in the EMT progression and in the response to somatostatin analog treatment.
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| 2. |
- Munch, Marie W., et al.
(author)
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Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial
- 2021
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In: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
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Journal article (peer-reviewed)abstract
- Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID-19 and severe hypoxemia? Findings In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days. This multicenter randomized clinical trial compares the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and >= 1 serious adverse reactions at 28 days). RESULTS Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
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| 3. |
- Björkman, Anne, 1981, et al.
(author)
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Plant functional trait change across a warming tundra biome
- 2018
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 562:7725, s. 57-62
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Journal article (peer-reviewed)abstract
- The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature–trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.
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| 4. |
- Egan-Wyer, Carys Jane, et al.
(author)
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Ease or excitement? Exploring how concept stores contribute to a retail portfolio
- 2021
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In: International Journal of Retail and Distribution Management. - 0959-0552. ; 49:7, s. 1025-1044
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Journal article (peer-reviewed)abstract
- Purpose: The study aims to explore how concept stores (theoretically) differ from other experience-based retail formats, and hence, how they (practically) contribute to a diversified retail store portfolio. Design/methodology/approach: Case study based on semi-structured, qualitative interviews with seven IKEA retail managers, three industry experts and 26 customers of IKEA concept stores in London and Stockholm. Findings: The concept store represents a conceptual departure from other experiential store formats. It is neither fully experiential in the sense that it is not only about marketing communications nor is it sales or profit-focused. Its aim is to be an accessible touchpoint that reduces friction on a diversified customer journey with its value to the retail portfolio being that it attracts new and latent customers, mitigates existing inhibiting factors and drives them to other touchpoints. Research limitations/implications: Ideas about the different characteristics of new store formats and their potential to shape the customer experience are extended. New formats reflect innovation in retailing and are part of a retail portfolio which generates different customer expectations and determinants from traditional store formats which provide the customers' existing reference point. Practical implications: The contributions of new formats should be evaluated in light of other existing formats in the portfolio and not isolated. This is particularly true when considering format cannibalisation and the potentially extended customer journey that arises when customers use traditional format stores and new concept format stores simultaneously. Originality/value: Previous research, using sales metrics and market-based results as performance determinants, suggests negative outcomes for format diversification. Our study suggests that the contributions of the concept store format should be viewed from an overall customer journey perspective and the “performance” of different format based touchpoints are not best captured through traditional sales evaluation methods.
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| 5. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Manipulation with Andreev states in spin active mesoscopic Josephson junctions
- 2008
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In: Physical Review B - Condensed Matter and Materials Physics. - 2469-9950 .- 2469-9969. ; 77:18
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Journal article (peer-reviewed)abstract
- We investigate manipulation with Andreev bound states in Josephson quantum point contacts with magnetic scattering. The Rabi oscillations in the two-level Andreev subsystems are excited by resonant driving the direction of magnetic moment of the scatterer and by modulating the superconducting phase difference across the contact. The Andreev level dynamics is manifested by the temporal oscillation of the Josephson current, which is accompanied, in the case of magnetic manipulation, also by the oscillation of the Andreev states spin polarization. The interlevel transitions obey a selection rule that forbids manipulations in a certain region of external parameters and results from specific properties of Andreev bound states in magnetic contacts: 4pi periodicity with respect to the superconducting phase and strong spontaneous spin polarization.
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| 6. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Nonadiabatic Josephson dynamics in junctions with in-gap quasiparticles
- 2010
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In: Low Temperature Physics. - : AIP Publishing. - 1063-777X .- 1090-6517. ; 36:10/11, s. 925-932 [1154-1162]-932
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Journal article (peer-reviewed)abstract
- Conventional models of Josephson junction dynamics rely on the absence of low-energy quasiparticle states due to a large superconducting gap. With this assumption the quasiparticle degrees of freedom become «frozen out» and the phase difference becomes the only free variable, acting as a fictitious particle in a local in time Josephson potential related to the adiabatic and nondissipative supercurrent across the junction. In this article we develop a general framework to incorporate the effects of low-energy quasiparticles interacting nonadiabatically with the phase degree of freedom. Such quasiparticle states exist generically in constriction type junctions with high transparency channels or resonant states, as well as in junctions of unconventional superconductors. Furthermore, recent experiments have revealed the existence of spurious low-energy in-gap states in tunnel junctions of conventional superconductors — a system for which the adiabatic assumption typically is assumed to hold. We show that the resonant interaction with such low-energy states rather than the Josephson potential defines nonlinear Josephson dynamics at small amplitudes.
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| 7. |
- Michelsen, Jens Harro, 1981
(author)
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Quantum dynamics of spin active and d-wave Josephson junctions
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Conventional tunnel Josephson junctions form the basic building blocks of superconducting electronics. Their operation is based on comparatively simple dynamics where the superconducting phases across the junctions is the only dynamical degree of freedom. The goal of the project on which this thesis is based, is to understand the physics and develop a consistent theoretical description of the quantum dynamics of unconventional Josephson structures: spin active junctions, junctions containing low energy quasiparticles, and junctions composed of $d$-wave superconductors. Spin active Josephson junctions involve the additional degree of freedom of quasiparticle spin. Here we theoretically investigate the spin-structure of the current carrying interface bound states - Andreev Bound States (ABS), and induced ground state spin polarization of a short (shorter than the superconducting coherence length) nanowire junction containing a localized magnetic moment. We show that temporal variation of the superconducting phase difference and magnetic moment induce rotations in spin polarized and unpolarized subspaces respectively, which is manifested by temporal oscillation of the Josephson current.The interlevel transitions obey a selection rule that forbids manipulations in a certain region ofexternal parameters and results from specific properties of Andreev bound states in magnetic contacts where, in a certain regime of phase bias and strength of magnetic scatterer, ABS belong to different eigenstates of the combined charge and parity inversion symmetry operator.A general framework is developed to include low energy quasiparticle states into the dynamics of Josephson junctions. Such states exist in e.g. constriction type junctions with high transparency channels or resonant states, as well as in junctions of unconventional superconductors. The existence of such states prevent the separation of energy scales which in conventional tunnel junctions freezes out the quasiparticle degrees of freedom. We show that the resonant interaction with such low energy states rather than the Josephson potential defines the nonlinear Josephson dynamics at small amplitudes.The framework is applied to high temperature Josephson junctions, whose unconventional order parameter admits ABS with energies in the middle of the superconducting gap - Mid Gap States (MGS). In addition to the non-linear dynamics induced by the MGS, we identify a reentrance effect in the transition between thermal activation and macroscopic quantum tunneling associated with the MGS, and connect this phenomenon to experimental observations.
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| 8. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Quantum Phase Dynamics in High-Tc Josephson Junctions
- 2008
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In: 25th International Conference on Low Temperature Physics.
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Conference paper (other academic/artistic)abstract
- We study quantum phase fluctuations in planar junctions between high-Tc superconductors for a range of relative orientations of the a-b crystal axes. Specifically, attention is directed towards the fermionic subspace of low energy Andreev bound states (MGS). This subspace, being responsible for most of the Josephson current, strongly couples to the phase degree of freedom. At the same time, low frequency phase fluctuations introduce intrinsic dynamics in this subspace. For a given quasiclassical trajectory there may exist two bound state levels. Change in the occupations of these levels due to the phase fluctuations would lead to a strong dynamical modulation of the Josephson current. In this article it is found that transitions between pairs of MGS induced by the phase fluctuations are forbidden due to specific symmetry properties of the MGS, and the macroscopic quantum Hamiltonian remains essentially adiabatic within the assumption of a specular interface.
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| 9. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Quantum phase dynamics of high-Tc Josephson junctions
- 2009
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 150, s. 052159-
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Conference paper (peer-reviewed)abstract
- We study quantum phase fluctuations in planar junctions between high-Tc superconductors for a range of relative orientations of the a-b crystal axes. Specifically, attention is directed towards the fermionic subspace of low energy Andreev bound states, midgap states (MGS). This subspace, being responsible for most of the Josephson current, strongly couples to the phase degree of freedom. Low frequency phase fluctuations may introduce intrinsic dynamics in this subspace, which would lead to a strong dynamical modulation of the Josephson current, and thus affect the phase quantum dynamics. In this article it is found that transitions between pairs of MGS induced by the phase fluctuations are forbidden due to specific symmetry properties of the MGS, and the macroscopic quantum Hamiltonian remains essentially adiabatic within the assumption of a specular interface.
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| 10. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Reentrance Effect in Macroscopic Quantum Tunneling and Nonadiabatic Josephson Dynamics in d-Wave Junctions
- 2010
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In: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 105:12, s. 127001-
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Journal article (peer-reviewed)abstract
- We develop a theoretical description of nonadiabatic Josephson dynamics in superconducting junctions containing low energy quasiparticles. Within this approach we investigate the effects of midgap states in junctions of unconventional d-wave superconductors. We identify a reentrance effect in the transition between thermal activation and macroscopic quantum tunneling, and connect this phenomenon to the experimental observations in Phys. Rev. Lett. 94, 087003 (2005). It is also shown that nonlinear Josephson dynamics can be defined by resonant interaction with midgap states reminiscent of nonlinear optical phenomena in media of two-level atoms.
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| 11. |
- Michelsen, Jens Harro, 1981, et al.
(author)
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Reentrance of macroscopic quantum tunneling in cuprate superconductors
- 2010
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In: Advances in Science and Technology. ; 75, s. 155-
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Conference paper (peer-reviewed)abstract
- We present a theoretical analysis of the transition from thermal activation (TA) regime to the macroscopic quantum tunneling (MQT) regime of the decay from a metastable persistent current state in grain boundary junctions of cuprate superconductors. This transition is conventionally characterized by a single crossover temperature determined by the potential profile and dissipative mechanisms. It is shown that due to the existence of low energy bound states (mid-gap states) for various relative orientations of the crystal axes, there exists a window of parameters where one finds, with lowering temperature, an inverse crossover from MQT to TA, followed by a subsequent reentrance of MQT. It is shown that these predictions are in reasonable agreement with recent experiments.
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