Targeted Synthesis of Complex Spiro[3H-indole-3,2′-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2–p53 Inhibitors

Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96_MDM2. The designed molecules required the targeted synthesis of structurally complex spiro[indole-3,2′-pyrrolo[2,3-c]pyrrole]-2,4′-diones for which we developed an unprecedented intramolecular azomethine ylide cycloaddition and investigated the results by computational methods. One of the new compounds showed superior cellular potency over previously reported BI-0252. This finding is a significant step toward an inhibitor suitable to potentially mitigate hematological on-target adverse effects.     

Caffeine intake and its sources: A review of national representative studies

Aim of this review is to summarize current daily caffeine intake of children, adolescents, and adults, and trends in caffeine intake over the past decade. A literature search was conducted (1997–2015) which yielded 18 reports on nationally representative studies, describing caffeine consumption of over 275,000 children, adolescents and adults. The data revealed that mean total daily caffeine intake in children, adolescents, and adults is below caffeine intake recommendations such as those stated by Health Canada (2.5 mg/kg bw/day for children and adolescents, and 400 mg/day for adults) and the European Food Safety Authority, EFSA (3 mg/kg bw/day for children and adolescents, and 400 mg/day for adults). Total daily caffeine intake has remained stable in the last 10–15 years, and coffee, tea and soft drinks are the most important caffeine sources. Across all age groups, energy drinks contribute little to total caffeine intake. The highest potential for reducing daily caffeine intake is by limiting coffee consumption, and in some countries and age groups, by reducing tea and soft drink consumption.     

Micro molecular tagging velocimetry for analysis of gas flows in mini and micro systems

A new micro molecular tagging velocimetry (μMTV) setup has been developed to analyze velocity fields in confined internal gas flows. MTV is a little-intrusive velocimetry technique. It relies on the properties of molecular tracers which can experience relatively long lifetime luminescence once excited by a laser beam with an appropriate wavelength. The technique has been validated for acetone seeded flows of argon inside a 1 mm depth rectangular minichannel, with a multilayer design offering two optical accesses. Velocity profiles have been obtained using a specific data reduction process, with a resolution in the order of 15 μm. The experimental data are compared to theoretical velocity profiles of compressible pressure-driven flows. A good agreement is observed, except close to the walls, where the accuracy would still need to be improved. Following these first results obtained at atmospheric pressure, the influence of pressure on the luminescence intensity of acetone molecules is analyzed. The obtained data lead to a discussion of MTV applicability to rarefied flows and its possible use for a direct measurement of velocity slip at the channel walls.     

Flexible time reduction method for burn-in of high-quality products

Burn-in is an effective method to screen out early failures of electronic devices. Typically, this is achieved by operating the devices under accelerated stress conditions. This paper focuses on a burn-in concept where a random sample of devices is drawn out of the running production, put to burn-in, and investigated for early failures. This procedure is called burn-in study. In parallel, as long as the burn-in study is ongoing, all other produced devices are subjected to burn-in screening. In this article, new flexible sampling plans for burn-in studies are introduced. These are based on the progress of these studies and defined quality targets. Furthermore, these sampling plans enable fast burn-in time reductions and various time reduction strategies. From a statistical point of view, this requires to combine the proportion of early failures in a population with their lifetime distribution function. The new model is illustrated by case studies and simulations. It contributes to burn-in cost reductions, while controlling quality levels at the same time.     

Biodegradable Frequency‐Selective Magnesium Radio‐Frequency Microresonators for Transient Biomedical Implants

Bioresorbable implantable medical devices show a great potential for applications requiring medical care over well‐defined periods of time. Once their function is fulfilled, such implants naturally degrade and resorb in the body, which eliminates adverse long‐term effects or the need for a secondary surgery to extract the implanted device. Since biodegradable materials are water‐soluble, the fabrication of such transient electronic circuits and devices requires special care and needs to rely solely on dry processing steps without exposure to aqueous solutions. A further challenge is the in vivo powering of medical implants that are only constituted of biodegradable materials. This paper describes the design, fabrication, and testing of radio‐frequency biodegradable magnesium microresonators. To this end, an innovative microfabrication process with minimal exposure to aqueous media is developed to fabricate magnesium‐based, water‐soluble electronic components. It consists of a novel sequence of only three steps: one physical vapor deposition, one photolithography, and one ion beam etching step. The frequency‐selective wireless heating of different resonators is demonstrated. This represents a significant step toward their use as power receivers and microheaters in biodegradable implantable medical devices, for applications such as triggered drug release.     

In-situ resource utilisation manufacturing of optically transparent glass from lunar regolith simulant

Journal of Materials Science - International space agencies are aiming to establish permanent outposts on the lunar surface. For that purpose, new technologies and equipment are being developed...     

亚洲洗涤习惯与衣物白度的保持

荧光增白剂会在使用过程中被清洗或降解掉,其常规性更新换代促使白色织物越来越被人们所接受.由于白色织物的种类和洗涤习惯都存在着千差万别,很难定义一种最为行之有效的荧光增白剂配方,既能提供高效的增白效果,又不具有不可逆地破坏织物外观的威胁.通过预测白度在反复的洗涤和日晒过程中可能发生的变化,可以得到一种减小风险的新方法.这个模型的基础是来源于不同地区的白色织物的基本数据,光照数据和评价一切与白度相关的因素的各种工具.     

Ultralow loading Pt nanocatalysts prepared by atomic layer deposition on carbon aerogels

Using atomic layer deposition (ALD), we show that Pt nanoparticles can be deposited on the inner surfaces of carbon aerogels (CA). The resultant Pt-loaded materials exhibit high catalytic activity for the oxidation of CO even at loading levels as low as approximately 0.05 mg Pt/cm2. We observe a conversion efficiency of nearly 100% in the 150-250 degrees C temperatures range, and the total conversion rate seems to be limited only by the thermal stability of the CA support in ambient oxygen. The ALD approach described here is universal in nature, and can be applied to the design of new catalytic materials for a variety of applications, including fuel cells, hydrogen storage, pollution control, green chemistry, and liquid fuel production.     

COMT genetic variation affects fear processing: Psychophysiological evidence.

Emotional dysregulation is a core characteristic of many psychiatric diseases, including the anxiety disorders. Although heritable influences account for a significant degree of variation in risk for such disorders, relatively few candidate susceptibility factors have been identified. A coding variant in one such gene, encoding the dopamine catabolic enzyme catechol-O-methyltransferase (COMT Val158Met), has previously been associated with anxiety and with anxiety-related temperament and altered neural responses to affective stimuli in healthy individuals. In 96 healthy women recruited from a sample of 800 participants according to genotype, the authors tested for an association between the DRD2/ANKK1 Taq Ia, the COMT Val158Met, and a psychophysiological measure of emotion processing, the acoustic affective startle reflex modulation (ASRM) paradigm, and found that COMT genotype significantly affected startle reflex modulation by aversive stimuli, with Met158 homozygotes exhibiting a markedly potentiated startle reflex compared with Val158 carriers. A trait measure of anxiety (Gray's Behavioral Inhibition System; J. A. Gray & N. McNaughton, 2000) was also associated with ASRM. The functional polymorphism in the dopamine D2 receptor (DRD2/ANKK1 Taq Ia) had no effect on startle modulation. The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)