From the global simulation, we reproduce the solar wind‐magnetosphere‐ionosphere (S‐M‐I) interaction under the northward interplanetary magnetic field (IMF) with negative By. Reconnection structures, ...the plasma sheet, and lobes are formed in magnetospheric convection, while lobe/round‐merging/reciprocal/nightside cells appear in the ionosphere. Associated with the S‐M interaction, northern open field is generated at the evening open‐closed (O/C) boundary, due to successive cusp and interchange reconnections (in round‐merging cell) or by Dungey‐type reconnection (in nightside cell). Corresponding interchange and Dungey‐type reconnections occur at the southern null. Dungey‐type reconnection at the same time generates southern open field on the outer‐most magnetopause. Open field injected into the northern polar cap/void/lobe constructs the open field part of the round‐merging and nightside cells. After open‐field convection in the lobe, reclosures occur by again successive cusp and interchange reconnections on the dayside separator, or separator reconnection on the nightside separator. Former closed field line proceeds toward the evening O/C boundary through the dayside closed‐field convection in the round‐merging cell, while latter closed field line through the nightside closed‐field convection in the nightside cell. Shear that causes the large‐scale sun‐aligned arc is generated by the process of injecting open magnetic field into the void and the conjugate of process of connecting return flux from the plasma sheet to the nightside cell in counter hemisphere.
Key Points
Under the northward IMF, the S‐M interaction has in front and off‐front components exciting the round‐merging cell and the nightside cell
In the nightside cell, closed flux is formed at nightside separator and transported along the nightside cell to the flank where reopened
The HCA is explained by shear structure presented in this paper, without adopting evening‐morning symmetrical convection as in the DLR
Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a ...remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D, and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.
The theta aurora is reproduced by global simulation. First, we construct a solution for the stationary northward interplanetary magnetic field (IMF) forming the separatrices, the separators, the ...nulls, and the stemlines. From the drawing of last‐closed field lines, the overall structure under this condition is summarized as the northern lobe is generated by a separatrix emanating from the southern null. In this paper, all variations are antisymmetric in the southern hemisphere. Afterward, the IMF By is switched to reproduce the theta aurora. The ionospheric theta aurora is reproduced as closed magnetic field regions. The polar cap is divided to old and new parts, by the theta bar. In the magnetosphere, two dayside nulls occur corresponding to the new IMF and two nulls corresponding to the old IMF retreat tailward. The four nulls form a structure connected by four separators, constructing the magnetospheric topology corresponding to the theta aurora. In this topology, old and new nulls in the southern hemisphere generate old and new lobes in the northern hemisphere. Each lobe is projected onto northern old and new polar caps. The origin of the theta bar is the stagnating closed magnetic field region that occurs between old and new lobes. Separator reconnection occurs between the old lobe in the southern and the new lobe in the northern hemispheres, reducing southern old polar caps. This is the cause of the movement of the theta bar. The theta aurora is the phenomenon that demonstrates the existence of the null‐separator structure.
Key Points
The theta aurora is an image of the magnetospheric null‐separator structure projected to the virtual mirror in the ionosphere
Northern new and old lobes are respectively generated from new dayside and old retreating nulls in the southern hemisphere
The theta bar is the projection of stagnating closed magnetic field regions accumulating at the interface between old and new lobes
Edoxaban (the free base of DU-176b) is an oral, direct factor (F)Xa inhibitor in clinical development for the prevention and treatment of thromboembolic events.
The aim of the present study was to ...evaluate the efficacy and safety of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing total knee arthroplasty (TKA).
This was a randomized, double-blind, placebo-controlled, multicenter study conducted in Japan. A total of 523 Japanese patients were assigned to receive edoxaban 5, 15, 30 or 60 mg once daily or placebo for 11-14 days. A placebo control was used as neither low-molecular-weight heparin (LMWH) nor fondaparinux had been approved for thromboprophylaxis at the time of the study in Japan. The primary efficacy outcome was the incidence of VTE (lower-extremity deep vein thrombosis, symptomatic pulmonary embolism or symptomatic deep vein thrombosis). The primary safety outcome was the incidence of major and clinically relevant non-major bleeding.
Edoxaban produced a significant dose-related reduction in VTE: the incidence of VTE was 29.5%, 26.1%, 12.5% and 9.1% in the edoxaban 5-, 15-, 30- and 60-mg treatment groups vs. 48.3% in the placebo group. The incidence of major and clinically relevant non-major bleeding was similar across all groups without any significant differences among edoxaban doses or between edoxaban and placebo.
Edoxaban demonstrated significant dose-dependent reductions in VTE in patients undergoing TKA with a bleeding incidence similar to placebo. This trial is registered with JAPIC, JapicCTI-060283 (ja)..
The solar wind‐Jovian magnetosphere‐ionosphere interaction is studied from the global magnetohydrodynamic simulation. The calculation considers the high‐speed solar wind, Io plasma emission, ...high‐speed rotation, ionospheric ions, and precession of magnetic field, and consequently reproduces the confinement of Jovian magnetic field, distributions of O+ and H+, supply of H+ by the polar wind, the interchange instability, and the current system that maintains co‐rotation. The radial transport process of plasma generated from Io is traceable from this solution, such that the transport mechanism gradually changes from the Io torus to the distant tail. In the transport of Io plasma, the precession plus interchange instability is effective near 10–15 Rj, interchange instability is predominant around 15–20 Rj, and the centrifugal force is predominant beyond 25 Rj. The current system supplies torque from the planet to co‐rotating plasma beyond 25 Rj to compensate the rotation delay. The associated upward field‐aligned current (FAC) is connected to the main emission (ME) in the ionosphere. The polar emission (PE) position coincides with that of downward feedback current of upward FAC causing the ME. High‐speed polar wind develops in the ME and in the polar cap, while slow polar wind develops in lower latitudes. In the middle of transport, Io plasma is mixed around 15 Rj with H+ supplied from the ionosphere by the low‐speed polar wind. Afterward, mixed plasma diffuses outward. The equatorial diffuse emission occurs in the projected position of the plasma mixing process.
Key Points
Around 10–15 Rj in the equatorial plane, precession effect overwhelms interchange for the outward transport of Io plasma
Io plasma is interchange unstable around 15–20 Rj and here diffuses outward while being mixed with H+ from the ionosphere
The equatorial diffuse emission is projected with the low‐speed polar wind to the outer shell of the Io torus around 15–20 Rj in the equatorial plane
The plant embryonic cuticle is a hydrophobic barrier deposited de novo by the embryo during seed development. At germination, it protects the seedling from water loss and is, thus, critical for ...survival. Embryonic cuticle formation is controlled by a signaling pathway involving the ABNORMAL LEAF SHAPE1 subtilase and the two GASSHO receptor-like kinases. We show that a sulfated peptide, TWISTED SEED1 (TWS1), acts as a GASSHO ligand. Cuticle surveillance depends on the action of the subtilase, which, unlike the TWS1 precursor and the GASSHO receptors, is not produced in the embryo but in the neighboring endosperm. Subtilase-mediated processing of the embryo-derived TWS1 precursor releases the active peptide, triggering GASSHO-dependent cuticle reinforcement in the embryo. Thus, a bidirectional molecular dialogue between embryo and endosperm safeguards cuticle integrity before germination.
A number of MR-derived quantitative metrics have been suggested to assess the pathophysiology of MS, but the reports about combined analyses of these metrics are scarce. Our aim was to assess the ...spatial distribution of parameters for white matter myelin and axon integrity in patients with relapsing-remitting MS by multiparametric MR imaging.
Twenty-four patients with relapsing-remitting MS and 24 age- and sex-matched controls were prospectively scanned by quantitative synthetic and 2-shell diffusion MR imaging. Synthetic MR imaging data were used to retrieve relaxometry parameters (R1 and R2 relaxation rates and proton density) and myelin volume fraction. Diffusion tensor metrics (fractional anisotropy and mean, axial, and radial diffusivity) and neurite orientation and dispersion index metrics (intracellular volume fraction, isotropic volume fraction, and orientation dispersion index) were retrieved from diffusion MR imaging data. These data were analyzed using Tract-Based Spatial Statistics.
Patients with MS showed significantly lower fractional anisotropy and myelin volume fraction and higher isotropic volume fraction in widespread white matter areas. Areas with different isotropic volume fractions were included within areas with lower fractional anisotropy. Myelin volume fraction showed no significant difference in some areas with significantly decreased fractional anisotropy in MS, including in the genu of the corpus callosum and bilateral anterior corona radiata, whereas myelin volume fraction was significantly decreased in some areas where fractional anisotropy showed no significant difference, including the bilateral posterior limb of the internal capsule, external capsule, sagittal striatum, fornix, and uncinate fasciculus.
We found differences in spatial distribution of abnormality in fractional anisotropy, isotropic volume fraction, and myelin volume fraction distribution in MS, which might be useful for characterizing white matter in patients with MS.
Synthetic FLAIR images are of lower quality than conventional FLAIR images. Here, we aimed to improve the synthetic FLAIR image quality using deep learning with pixel-by-pixel translation through ...conditional generative adversarial network training.
Forty patients with MS were prospectively included and scanned (3T) to acquire synthetic MR imaging and conventional FLAIR images. Synthetic FLAIR images were created with the SyMRI software. Acquired data were divided into 30 training and 10 test datasets. A conditional generative adversarial network was trained to generate improved FLAIR images from raw synthetic MR imaging data using conventional FLAIR images as targets. The peak signal-to-noise ratio, normalized root mean square error, and the Dice index of MS lesion maps were calculated for synthetic and deep learning FLAIR images against conventional FLAIR images, respectively. Lesion conspicuity and the existence of artifacts were visually assessed.
The peak signal-to-noise ratio and normalized root mean square error were significantly higher and lower, respectively, in generated-versus-synthetic FLAIR images in aggregate intracranial tissues and all tissue segments (all
< .001). The Dice index of lesion maps and visual lesion conspicuity were comparable between generated and synthetic FLAIR images (
= 1 and .59, respectively). Generated FLAIR images showed fewer granular artifacts (
= .003) and swelling artifacts (in all cases) than synthetic FLAIR images.
Using deep learning, we improved the synthetic FLAIR image quality by generating FLAIR images that have contrast closer to that of conventional FLAIR images and fewer granular and swelling artifacts, while preserving the lesion contrast.
Synthetic MR imaging creates multiple contrast-weighted images based on a single time-efficient quantitative scan, which has been mostly performed for 2D acquisition. We assessed the utility of 3D ...synthetic MR imaging in patients with MS by comparing its diagnostic image quality and lesion volumetry with conventional MR imaging.
Twenty-four patients with MS prospectively underwent 3D quantitative synthetic MR imaging and conventional T1-weighted, T2-weighted, FLAIR, and double inversion recovery imaging, with acquisition times of 9 minutes 3 seconds and 18 minutes 27 seconds for the synthetic MR imaging and conventional MR imaging sequences, respectively. Synthetic phase-sensitive inversion recovery images and those corresponding to conventional MR imaging contrasts were created for synthetic MR imaging. Two neuroradiologists independently assessed the image quality on a 5-point Likert scale. The numbers of cortical lesions and lesion volumes were quantified using both synthetic and conventional image sets.
The overall diagnostic image quality of synthetic T1WI and double inversion recovery images was noninferior to that of conventional images (
= .23 and .20, respectively), whereas that of synthetic T2WI and FLAIR was inferior to that of conventional images (both
s
<
.001). There were no significant differences in the number of cortical lesions (
= .17 and .53 for each rater) or segmented lesion volumes (
= .61) between the synthetic and conventional image sets.
Three-dimensional synthetic MR imaging could serve as an alternative to conventional MR imaging in evaluating MS with a reduced scan time.
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