| 1. |
- Kulikowski, E, et al.
(författare)
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Apabetalone Mediated Epigenetic Modulation is Associated with Favorable Kidney Function and Alkaline Phosphatase Profile in Patients with Chronic Kidney Disease
- 2018
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Ingår i: Kidney & blood pressure research. - : S. Karger AG. - 1423-0143 .- 1420-4096. ; 43:2, s. 449-457
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background/Aims:</i></b> The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. <b><i>Methods:</i></b> A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m<sup>2</sup>, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. <b><i>Results:</i></b> Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m<sup>2</sup>) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m<sup>2</sup>) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. <b><i>Conclusion</i></b>: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.
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| 2. |
- Viviani, M., et al.
(författare)
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Transition from axi- to nonaxisymmetric dynamo modes in spherical convection models of solar-like stars
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 616
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Tidskriftsartikel (refereegranskat)abstract
- Context. Both dynamo theory and observations of stellar large-scale magnetic fields suggest a change from nearly axisymmetric configurations at solar rotation rates to nonaxisymmetric configurations for rapid rotation. Aims. We seek to understand this transition using numerical simulations. Methods. We use three-dimensional simulations of turbulent magnetohydrodynamic convection in spherical shell wedges and considered rotation rates between 1 and 31 times the solar value. Results. We find a transition from axi- to nonaxisymmetric solutions at around 1.8 times the solar rotation rate. This transition coincides with a change in the rotation profile from antisolar- to solar-like differential rotation with a faster equator and slow poles. In the solar-like rotation regime, the field configuration consists of an axisymmetric oscillatory field accompanied by an m = 1 azimuthal mode (two active longitudes), which also shows temporal variability. At slow (rapid) rotation, the axisymmetric (nonaxisymmetric) mode dominates. The axisymmetric mode produces latitudinal dynamo waves with polarity reversals, while the nonaxisymmetric mode often exhibits a slow drift in the rotating reference frame and the strength of the active longitudes changes cyclically over time between the different hemispheres. In the majority of cases we find retrograde waves, while prograde waves are more often found from observations. Most of the obtained dynamo solutions exhibit cyclic variability either caused by latitudinal or azimuthal dynamo waves. In an activity-period diagram, the cycle lengths normalized by the rotation period form two different populations as a function of rotation rate or magnetic activity level. The slowly rotating axisymmetric population lies close to what in observations is called the inactive branch, where the stars are believed to have solar-like differential rotation, while the rapidly rotating models are close to the superactive branch with a declining cycle to rotation frequency ratio and an increasing rotation rate. Conclusions. We can successfully reproduce the transition from axi- to nonaxisymmetric dynamo solutions for high rotation rates, but high-resolution simulations are required to limit the effect of rotational quenching of convection at rotation rates above 20 times the solar value.
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| 3. |
- Käpylä, Petri J., et al.
(författare)
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Effects of a subadiabatic layer on convection and dynamos in spherical wedge simulations
- 2019
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Ingår i: Geophysical and Astrophysical Fluid Dynamics. - : Informa UK Limited. - 0309-1929 .- 1029-0419. ; 113:1-2, s. 149-183
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Tidskriftsartikel (refereegranskat)abstract
- We consider the effect of a subadiabatic layer at the base of the convection zone on convection itself and the associated large-scale dynamos in spherical wedge geometry. We use a heat conduction prescription based on the Kramers opacity law which allows the depth of the convection zone to dynamically adapt to changes in the physical characteristics such as rotation rate and magnetic fields. We find that the convective heat transport is strongly concentrated towards the equatorial and polar regions in the cases without a substantial radiative layer below the convection zone. The presence of a stable layer below the convection zone significantly reduces the anisotropy of radial enthalpy transport. Furthermore, the dynamo solutions are sensitive to subtle changes in the convection zone structure. We find that the kinetic helicity changes sign in the deeper parts of the convection zone at high latitudes in all runs. This region expands progressively towards the equator in runs with a thicker stably stratified layer.
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| 4. |
- Mahindra, Anuj, et al.
(författare)
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New Cancers after Autotransplantations for Multiple Myeloma
- 2015
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 21:4, s. 738-745
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Tidskriftsartikel (refereegranskat)abstract
- We describe baseline incidence and risk factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma in the United States from 1990 to 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13,387 person-years at-risk. In total, 163 new cancers were observed, for a crude incidence rate of 1.2 new cancers per 100 person-years and cumulative incidences of 2.6% (95% confidence interval [CI], 2.09 to 3.17), 4.2% (95% CI, 3.49 to 5.00), and 6.1% (95% CI, 5.08 to 7.24) at 3, 5, and 7 years, respectively. The incidence of new cancers in the autotransplantation cohort was similar to age-, race-, and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI, .81 to 1.22). However, acute myeloid leukemia and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI, 1.67 to 12.04; P = .0004), and 3.58 (99% CI, 1.82 to 6.29; P < .0001), respectively. Obesity, older age, and male gender were associated with increased risks of new cancers in multivariate analyses. This large data set provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving postautotransplantation therapies, such as maintenance.
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| 5. |
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| 6. |
- Miesch, M., et al.
(författare)
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Large-Eddy Simulations of Magnetohydrodynamic Turbulence in Heliophysics and Astrophysics
- 2015
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Ingår i: Space Science Reviews. - : Springer Netherlands. - 0038-6308 .- 1572-9672.
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Tidskriftsartikel (refereegranskat)abstract
- We live in an age in which high-performance computing is transforming the way we do science. Previously intractable problems are now becoming accessible by means of increasingly realistic numerical simulations. One of the most enduring and most challenging of these problems is turbulence. Yet, despite these advances, the extreme parameter regimes encountered in space physics and astrophysics (as in atmospheric and oceanic physics) still preclude direct numerical simulation. Numerical models must take a Large Eddy Simulation (LES) approach, explicitly computing only a fraction of the active dynamical scales. The success of such an approach hinges on how well the model can represent the subgrid-scales (SGS) that are not explicitly resolved. In addition to the parameter regime, heliophysical and astrophysical applications must also face an equally daunting challenge: magnetism. The presence of magnetic fields in a turbulent, electrically conducting fluid flow can dramatically alter the coupling between large and small scales, with potentially profound implications for LES/SGS modeling. In this review article, we summarize the state of the art in LES modeling of turbulent magnetohydrodynamic (MHD) flows. After discussing the nature of MHD turbulence and the small-scale processes that give rise to energy dissipation, plasma heating, and magnetic reconnection, we consider how these processes may best be captured within an LES/SGS framework. We then consider several specific applications in heliophysics and astrophysics, assessing triumphs, challenges, and future directions.
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| 7. |
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| 8. |
- Warnecke, J., et al.
(författare)
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Turbulent transport coefficients in spherical wedge dynamo simulations of solar-like stars
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 609
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Tidskriftsartikel (refereegranskat)abstract
- Aims. We investigate dynamo action in global compressible solar-like convective dynamos in the framework of mean-field theory. Methods. We simulate a solar-type star in a wedge-shaped spherical shell, where the interplay between convection and rotation self-consistently drives a large-scale dynamo. To analyze the dynamo mechanism we apply the test-field method for azimuthally (φ) averaged fields to determine the 27 turbulent transport coefficients of the electromotive force, of which six are related to the α tensor. This method has previously been used either in simulations in Cartesian coordinates or in the geodynamo context and is applied here for the first time to fully compressible simulations of solar-like dynamos. Results. We find that the φφ-component of the α tensor does not follow the profile expected from that of kinetic helicity. The turbulent pumping velocities significantly alter the effective mean flows acting on the magnetic field and therefore challenge the flux transport dynamo concept. All coefficients are significantly affected by dynamically important magnetic fields. Quenching as well as enhancement are being observed. This leads to a modulation of the coefficients with the activity cycle. The temporal variations are found to be comparable to the time-averaged values and seem to be responsible for a nonlinear feedback on the magnetic field generation. Furthermore, we quantify the validity of the Parker-Yoshimura rule for the equatorward propagation of the mean magnetic field in the present case.
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| 9. |
- Zheng, J., et al.
(författare)
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Mendelian Randomization Analysis Reveals a Causal Influence of Circulating Sclerostin Levels on Bone Mineral Density and Fractures
- 2019
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 34:10, s. 1824-1836
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Tidskriftsartikel (refereegranskat)abstract
- In bone, sclerostin is mainly osteocyte-derived and plays an important local role in adaptive responses to mechanical loading. Whether circulating levels of sclerostin also play a functional role is currently unclear, which we aimed to examine by two-sample Mendelian randomization (MR). A genetic instrument for circulating sclerostin, derived from a genomewide association study (GWAS) meta-analysis of serum sclerostin in 10,584 European-descent individuals, was examined in relation to femoral neck bone mineral density (BMD; n = 32,744) in GEFOS and estimated bone mineral density (eBMD) by heel ultrasound (n = 426,824) and fracture risk (n = 426,795) in UK Biobank. Our GWAS identified two novel serum sclerostin loci, B4GALNT3 (standard deviation [SD]) change in sclerostin per A allele (beta = 0.20, p = 4.6 x 10(-49)) and GALNT1 (beta = 0.11 per G allele, p = 4.4 x 10(-11)). B4GALNT3 is an N-acetyl-galactosaminyltransferase, adding a terminal LacdiNAc disaccharide to target glycocoproteins, found to be predominantly expressed in kidney, whereas GALNT1 is an enzyme causing mucin-type O-linked glycosylation. Using these two single-nucleotide polymorphisms (SNPs) as genetic instruments, MR revealed an inverse causal relationship between serum sclerostin and femoral neck BMD (beta = -0.12, 95% confidence interval [CI] -0.20 to -0.05) and eBMD (beta = -0.12, 95% CI -0.14 to -0.10), and a positive relationship with fracture risk (beta = 0.11, 95% CI 0.01 to 0.21). Colocalization analysis demonstrated common genetic signals within the B4GALNT3 locus for higher sclerostin, lower eBMD, and greater B4GALNT3 expression in arterial tissue (probability >99%). Our findings suggest that higher sclerostin levels are causally related to lower BMD and greater fracture risk. Hence, strategies for reducing circulating sclerostin, for example by targeting glycosylation enzymes as suggested by our GWAS results, may prove valuable in treating osteoporosis. (c) 2019 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
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| 10. |
- Bushby, P. J., et al.
(författare)
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Large-scale dynamos in rapidly rotating plane layer convection
- 2018
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Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 612
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Tidskriftsartikel (refereegranskat)abstract
- Context. Convectively driven flows play a crucial role in the dynamo processes that are responsible for producing magnetic activity in stars and planets. It is still not fully understood why many astrophysical magnetic fields have a significant large-scale component. Aims. Our aim is to investigate the dynamo properties of compressible convection in a rapidly rotating Cartesian domain, focusing upon a parameter regime in which the underlying hydrodynamic flow is known to be unstable to a large-scale vortex instability. Methods. The governing equations of three-dimensional non-linear magnetohydrodynamics (MHD) are solved numerically. Different numerical schemes are compared and we propose a possible benchmark case for other similar codes. Results. In keeping with previous related studies, we find that convection in this parameter regime can drive a large-scale dynamo. The components of the mean horizontal magnetic field oscillate, leading to a continuous overall rotation of the mean field. Whilst the large-scale vortex instability dominates the early evolution of the system, the large-scale vortex is suppressed by the magnetic field and makes a negligible contribution to the mean electromotive force that is responsible for driving the large-scale dynamo. The cycle period of the dynamo is comparable to the ohmic decay time, with longer cycles for dynamos in convective systems that are closer to onset. In these particular simulations, large-scale dynamo action is found only when vertical magnetic field boundary conditions are adopted at the upper and lower boundaries. Strongly modulated large-scale dynamos are found at higher Rayleigh numbers, with periods of reduced activity (grand minima-like events) occurring during transient phases in which the large-scale vortex temporarily re-establishes itself, before being suppressed again by the magnetic field.
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