The Apoptosome: Emerging Insights and New Potential Targets for Drug Design

Apoptosis plays a crucial role in tissue homeostasis, development and many diseases. The relevance of Apaf1, the molecular core of apoptosome, has been underlined in mitochondria-dependent apoptosis, which according to a growing body of evidence, is involved in various pathologies where the equilibrium of life-and-death is dysregulated, such as heart attack, stroke, liver failure, cancer and autoimmune diseases. Consequently, great interest has emerged in devising therapeutic strategies for regulating the key molecules involved in the life-and-death decision. Here we review recent progress in apoptosis-based pharmacological therapies and, in particular, we point out a possible role of the apoptosome as an emerging and promising pharmacological target

Completion of JT-60SA construction and contribution to ITER

Construction of the JT-60SA tokamak was completed on schedule in March 2020. Manufacture and assembly of all the main tokamak components satisfied technical requirements, including dimensional accuracy and functional performances. Development of the plasma heating systems and diagnostics have also progressed, including the demonstration of the favourable electron cyclotron range of frequency (ECRF) transmission at multiple frequencies and the achievement of long sustainment of a high-energy intense negative ion beam. Development of all the tokamak operation control systems has been completed, together with an improved plasma equilibrium control scheme suitable for superconducting tokamaks including ITER. For preparation of the tokamak operation, plasma discharge scenarios have been established using this advanced equilibrium controller. Individual commissioning of the cryogenic system and the power supply system confirmed that these systems satisfy design requirements including operational schemes contributing directly to ITER, such as active control of heat load fluctuation of the cryoplant, which is essential for dynamic operation in superconducting tokamaks. The integrated commissioning (IC) is started by vacuum pumping of the vacuum vessel and cryostat, and then moved to cool-down of the tokamak and coil excitation tests. Transition to the super-conducting state was confirmed for all the TF, EF and CS coils. The TF coil current successfully reached 25.7 kA, which is the nominal operating current of the TF coil. For this nominal toroidal field of 2.25 T, ECRF was applied and an ECRF plasma was created. The IC was, however, suspended by an incident of over current of one of the superconducting equilibrium field coil and He leakage caused by insufficient voltage holding capability at a terminal joint of the coil. The unique importance of JT-60SA for H-mode and high-β steady-state plasma research has been confirmed using advanced integrated modellings. These experiences of assembly, IC and plasma operation of JT-60SA contribute to ITER risk mitigation and efficient implementation of ITER operation

Rivaroxaban with or without aspirin in stable cardiovascular disease

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=−4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events

Analysis of ELM stability with extended MHD models in JET, JT-60U and future JT-60SA tokamak plasmas

The stability with respect to a peelingballooning mode (PBM) was investigated numerically with extended MHD simulation codes in JET, JT-60U and future JT-60SA plasmas. The MINERVA-DI code was used to analyze the linear stability, including the effects of rotation and ion diamagnetic drift (w∗i), in JET-ILW and JT-60SA plasmas, and the JOREK code was used to simulate nonlinear dynamics with rotation, viscosity and resistivity in JT-60U plasmas. It was validated quantitatively that the ELM trigger condition in JET-ILW plasmas can be reasonably explained by taking into account both the rotation and w∗i effects in the numerical analysis. When deuterium poloidal rotation is evaluated based on neoclassical theory, an increase in the effective charge of plasma destabilizes the PBM because of an acceleration of rotation and a decrease in w∗i. The difference in the amount of ELM energy loss in JT-60U plasmas rotating in opposite directions was reproduced qualitatively with JOREK. By comparing the ELM affected areas with linear eigenfunctions, it was confirmed that the difference in the linear stability property, due not to the rotation direction but to the plasma density profile, is thought to be responsible for changing the ELM energy loss just after the ELM crash. A predictive study to determine the pedestal profiles in JT-60SA was performed by updating the EPED1 model to include the rotation and w∗i effects in the PBM stability analysis. It was shown that the plasma rotation predicted with the neoclassical toroidal viscosity degrades the pedestal performance by about 10% by destabilizing the PBM, but the pressure pedestal height will be high enough to achieve the target parameters required for the ITER-like shape inductive scenario in JT-60SA