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- Ruilope, LM, et al.
(författare)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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- Sugita, S., et al.
(författare)
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The geomorphology, color, and thermal properties of Ryugu: Implications for parent-body processes
- 2019
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Ingår i: Science. - : AAAS. - 0036-8075 .- 1095-9203. ; 364:6437
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Tidskriftsartikel (refereegranskat)abstract
- Asteroids fall to Earth in the form of meteorites, but these provide little information about their origins. The Japanese mission Hayabusa2 is designed to collect samples directly from the surface of an asteroid and return them to Earth for laboratory analysis. Three papers in this issue describe the Hayabusa2 team's study of the near-Earth carbonaceous asteroid 162173 Ryugu, at which the spacecraft arrived in June 2018 (see the Perspective by Wurm). Watanabeet al.measured the asteroid's mass, shape, and density, showing that it is a “rubble pile” of loose rocks, formed into a spinning-top shape during a prior period of rapid spin. They also identified suitable landing sites for sample collection. Kitazatoet al.used near-infrared spectroscopy to find ubiquitous hydrated minerals on the surface and compared Ryugu with known types of carbonaceous meteorite. Sugitaet al.describe Ryugu's geological features and surface colors and combined results from all three papers to constrain the asteroid's formation process. Ryugu probably formed by reaccumulation of rubble ejected by impact from a larger asteroid. These results provide necessary context to understand the samples collected by Hayabusa2, which are expected to arrive on Earth in December 2020.Science, this issue p.268, p.272, p.eaaw0422; see also p.230
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- Nango, E., et al.
(författare)
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A three-dimensional movie of structural changes in bacteriorhodopsin
- 2016
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 354:6319, s. 1552-1557
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Tidskriftsartikel (refereegranskat)abstract
- Bacteriorhodopsin (bR) is a light-driven proton pump and a model membrane transport protein. We used time-resolved serial femtosecond crystallography at an x-ray free electron laser to visualize conformational changes in bR from nanoseconds to milliseconds following photoactivation. An initially twisted retinal chromophore displaces a conserved tryptophan residue of transmembrane helix F on the cytoplasmic side of the protein while dislodging a key water molecule on the extracellular side. The resulting cascade of structural changes throughout the protein shows how motions are choreographed as bR transports protons uphill against a transmembrane concentration gradient.
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- Oimatsu, S., et al.
(författare)
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Drift-Bounce Resonance Between Pc5 Pulsations and Ions at Multiple Energies in the Nightside Magnetosphere : Arase and MMS Observations
- 2018
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Ingår i: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 45:15, s. 7277-7286
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Tidskriftsartikel (refereegranskat)abstract
- A Pc5 wave is observed by the Exploration of energization and Radiation in Geospace Arase satellite in the inner magnetosphere (L similar to 5.4-6.1) near postmidnight (L-magnetic local time similar to 1.8-2.5 hr) during the storm recovery phase on 27 March 2017. Its azimuthal wave number (m-number) is estimated using two independent methods with satellites and ground observations to be -8 to -15. The direct measurement of the m-number enables us to calculate the resonance energy. The flux oscillations of H+ and O+ ions at >= 56.3 keV are caused by drift resonance and those of O+ ions at <= 18.6 keV by bounce resonance. Resonances of O+ ions at multiple energies are simultaneously observed for the first time. The enhancement of the O+/H+ flux ratio at <= 18.6 keV indicates selective acceleration of O+ ions through bounce resonance. Plain Language Summary Geomagnetic pulsations are magnetic fluctuations excited by solar wind or plasma instabilities in the magnetosphere. Pc5 waves are continuous geomagnetic pulsations with a period of 150-600 s. A Pc5 wave was observed in the inner magnetosphere during a magnetic storm on 27 March 2017. It propagated westward with a wave number of 8 to 15 and resonated with charged particles, resulting in oscillations of the H+ and O+ ion fluxes at >= 56.3 keV and the O+ ion fluxes at <= 18.6 keV. Resonances of O+ ions at multiple energies are simultaneously observed for the first time. At the same time, the O+/H+ flux ratio at <= 18.6 keV enhanced corresponding to the O+ ion flux oscillations, which indicates selective acceleration of O+ ions through resonances.
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- Mead, AJ, et al.
(författare)
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Niche-mediated depletion of the normal hematopoietic stem cell reservoir by Flt3-ITD-induced myeloproliferation
- 2017
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 214:7, s. 2005-2021
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Tidskriftsartikel (refereegranskat)abstract
- Although previous studies suggested that the expression of FMS-like tyrosine kinase 3 (Flt3) initiates downstream of mouse hematopoietic stem cells (HSCs), FLT3 internal tandem duplications (FLT3 ITDs) have recently been suggested to intrinsically suppress HSCs. Herein, single-cell interrogation found Flt3 mRNA expression to be absent in the large majority of phenotypic HSCs, with a strong negative correlation between Flt3 and HSC-associated gene expression. Flt3-ITD knock-in mice showed reduced numbers of phenotypic HSCs, with an even more severe loss of long-term repopulating HSCs, likely reflecting the presence of non-HSCs within the phenotypic HSC compartment. Competitive transplantation experiments established that Flt3-ITD compromises HSCs through an extrinsically mediated mechanism of disrupting HSC-supporting bone marrow stromal cells, with reduced numbers of endothelial and mesenchymal stromal cells showing increased inflammation-associated gene expression. Tumor necrosis factor (TNF), a cell-extrinsic potent negative regulator of HSCs, was overexpressed in bone marrow niche cells from FLT3-ITD mice, and anti-TNF treatment partially rescued the HSC phenotype. These findings, which establish that Flt3-ITD–driven myeloproliferation results in cell-extrinsic suppression of the normal HSC reservoir, are of relevance for several aspects of acute myeloid leukemia biology.
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