Repurposing bromocriptine for Aβ metabolism in Alzheimer’s disease (REBRAnD) study : randomised placebo-controlled double-blind comparative trial and open-label extension trial to investigate the safety and efficacy of bromocriptine in Alzheimer’s disease with presenilin 1 (PSEN1) mutations

Introduction Alzheimer’s disease (AD) is one of the most common causes of dementia. Pathogenic variants in the presenilin 1 (PSEN1) gene are the most frequent cause of early-onset AD. Medications for patients with AD bearing PSEN1 mutation (PSEN1-AD) are limited to symptomatic therapies and no established radical treatments are available. Induced pluripotent stem cell (iPSC)-based drug repurposing identified bromocriptine as a therapeutic candidate for PSEN1-AD. In this study, we used an enrichment strategy with iPSCs to select the study population, and we will investigate the safety and efficacy of an orally administered dose of bromocriptine in patients with PSEN1-AD. Methods and analysis This is a multicentre, randomised, placebo-controlled trial. AD patients with PSEN1 mutations and a Mini Mental State Examination-Japanese score of ≤25 will be randomly assigned, at a 2:1 ratio, to the trial drug or placebo group (≥4 patients in TW-012R and ≥2 patients in placebo). This clinical trial consists of a screening period, double-blind phase (9 months) and extension phase (3 months). The double-blind phase for evaluating the efficacy and safety is composed of the low-dose maintenance period (10 mg/day), high-dose maintenance period (22.5 mg/day) and tapering period of the trial drug. Additionally, there is an open-labelled active drug extension period for evaluating long-term safety. Primary outcomes are safety and efficacy in cognitive and psychological function. Also, exploratory investigations for the efficacy of bromocriptine by neurological scores and biomarkers will be conducted. Ethics and dissemination The proposed trial is conducted according to the Declaration of Helsinki, and was approved by the Institutional Review Board (K070). The study results are expected to be disseminated at international or national conferences and published in international journals following the peer-review process

Productivity of the Soybean Seeds Stored for Various Periods

The growth characters and productivity of the soybean plants that developed from seeds stored for various periods at 5°C and 40% relative humidity, but having 80% or higher germinability were examined in comparison with those of newly harvested seeds (new seeds). The seedlings at one month after sowing from the very old seeds (stored for 10 years and 7 months) showed morphological characters significantly different from those from the new seeds, but not those from the moderately old seeds (stored for 2 years and 7 months) or the old seeds (stored for 7 years and 7 months). In the plants from the old seeds, the mean emergence date, flowering date, maturing date, length of the main stem, yield components, seed yield, and inspection-grade or protein content of seed were not significantly different from those in the plants from the new seeds. On the other hand, in the plants from the very old seeds, the mean emergence date, length of main stem, yield components and seed yield were significantly different from those in the plants from the new seeds. We concluded that the seeds of soybean stored for 2 years and 7 months, or 7 years and 7 months having a germinability of higher than 80% are practically useful, and show normal growth characters and productivity. However, it should be noted that the seed storage for over 10 years had inferior grain yield

Plutonium management in the medium term

For many years various countries with access to commercial reprocessing services have been routinely recycling plutonium as UO2/PuO 2 mixed oxide (MOX) fuel in light water reactors (LWRs). This LWR MOX recycle strategy is still widely regarded as an interim step leading to the eventual establishment of sustainable fast reactor fuel cycles. The OECD/NEA Working Party on the Physics of Plutonium Fuels and Innovative Fuel Cycles (WPPR) has recently completed a review of the technical options for plutonium management in what it refers to as the "medium terra." For the purpose of the review, the WPPR considers the medium term to cover the period from now up to the point at which fast reactor fuel cycles are established on a commercial scale. The review identified a number of different designs of innovative plutonium fuel assemblies intended to be used in current LWR cores, in LWRs with significantly different moderation properties, as well as in high-temperature gas reactors. The full review report describes these various options and highlights their respective advantages and disadvantages. This paper briefly summarizes the main findings of the review

Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach

On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative <b>1</b> and triazole derivative <b>2</b> with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, <b>31f</b> exhibited excellent potency for MMP-13 (IC₅₀ = 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition