Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Nanostructured gold films exhibiting almost complete absorption of light at visible wavelengths

Nanostructured metal surfaces have been known to exhibit properties that deviate from that of the bulk material. By simply modifying the texture of a metal surface, various unique optical properties can be observed. In this paper, we present a simple two step electrochemical process combining electrodeposition and anodization to generate black gold surfaces. This process is simple, versatile and up-scalable for the production of large surfaces. The black gold films have remarkable optical behavior as they absorb more than 93% of incident light over the entire visible spectrum and also exhibit no specular reflectance. A careful analysis by scanning electron microscopy reveals that these unique optical properties are due to their randomly rough surface, as they consist in a forest of dendritic microstructures with a nanoscale roughness. This new type of black films can be fabricated to a large variety of substrates, turning them to super absorbers with potential applications in photovoltaic solar cells or highly sensitive detectors and so on.

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Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS)

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.     

Synthesis, Autoorganization and Reactivity of Amphiphilic Derivatives of 1-Aminoisoindole in Water and Formamide

In this work, we present the synthesis of cationic surfactants based on 1-aminoisoindole. The physico-chemical properties were studied by conductometry, tensiometry, dynamic light scattering and transmission electron microscopy in water and in formamide. The reactivity of these novel surfactants has been studied at concentrations below and above critical aggregation concentrations (CAC) and it was found that reactions can proceed in structured media without the addition of other catalysts.     

Understanding Interactive Legends: a Comparative Evaluation with Standard Widgets

Interactive information visualization systems rely on widgets to allow users to interact with the data and modify the representation. We define interactive legends as a class of controls combining the visual representation of static legends and interaction mechanisms of widgets. As interactive legends start to appear in popular websites, we categorize their designs for common data types and evaluate their effectiveness compare to standard widgets. Results suggest that 1) interactive legends can lead to faster perception of the mapping between data values and visual encodings and 2) interaction time is affected differently depending on the data type. Additionally, our study indicates superiority both in terms of perception and interaction of ordinal controls over numerical ones. Numerical techniques are mostly used in today's systems. By providing solutions to allowing users to modify ranges interactively, we believe that interactive legends make it possible to increase the use of ordinal techniques for visual exploration.     

On the relationship between snow grain morphology and in-situ near infrared calibrated reflectance photographs

Seasonal and permanent snow cover a significant portion of our planet, and its impact on climate is significant. Through specific thermophysical properties, snow controls radiative and turbulent fluxes between the ground and the atmosphere, but many aspects of the energy balance are poorly understood due to lingering uncertainties regarding snow properties, such as grain size in particular. Rapid and accurate measurement method has yet to be developed given the reality of field and laboratory logistical constraints, and the sensitivity of snow to any sort of manipulation.In this paper, we investigate the relationship between snow grain morphology parameters measured from visible (traditional) snow grain photography and optical diameter estimated from Near-InfraRed (NIR) reflectance photographs of snow walls. A total of 51 snowpits were analyzed during our International Polar Year field campaign across a 1000 km South-to-North transect over Eastern Canada. We compared the NIR measurements with the theoretical snow albedo model of Kokhanovsky and Zege (2004). Results show the large difference between the snow specific surface area (SSA) of snow grains derived from snow albedo model and the geometrical (visual) diameter. From three different snow grain classes which can be distinguished from traditional photography, linkages can be made with shape factors required in the optical model in order to retrieve optical grain size from NIR photography.     

Interpersonal victimization patterns and psychopathology among Latino women: Results from the SALAS study.

[Correction Notice: An erratum for this article was reported in Vol 3(1) of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2010-26899-001). There were citation errors in the last sentence of the first column of text on page 9, and a reference was omitted from the reference list. The sentence should have read: “This result is consistent with other work that has found support for the anxious and dissociative reaction associated with trauma among Latinos and how it may relate to “ataque de nervios” (Hinton, Chong, Pollack, Barlow, & McNally, 2008; Lewis-Fernandez et al., 2002; Schechter et al., 2000; Tolin, Robinson, Gaztambide, Horowitz, & Blank, 2007).] [Correction Notice: An erratum for this article was reported in of Psychological Trauma: Theory, Research, Practice, and Policy (see record 2010-26899-001). In the original article there were citation errors in the last sentence of the first column of text on page 9, and a reference was omitted from the reference list. The sentence should have read: “This result is consistent with other work that has found support for the anxious and dissociative reaction associated with trauma among Latinos and how it may relate to “ataque de nervios” (Hinton, Chong, Pollack, Barlow, & McNally, 2008; Lewis-Fernandez et al., 2002; Schechter et al., 2000; Tolin, Robinson, Gaztambide, Horowitz, & Blank, 2007).] Research on the victimization of Latino women and the subsequent psychological impact has been limited by focusing on individual forms of victimization, primarily partner violence or sexual assault. Another deficiency includes mainly using convenience and/or geographically restricted samples, which impacts the generalizability of the results. To overcome these research limitations, the Sexual Assault Among Latinas (SALAS) study aimed to evaluate the broader scope of victimization among Latino women. The study surveyed a national sample of 2,000 Latino women using random digit dial methodology. Women were asked about various forms of victimization in childhood and adulthood including physical assaults, sexual assaults, stalking, threats, and witnessed violence, as well as psychological symptomatology including depression, anxiety, anger, and dissociation. This analysis found that victimized women were more likely to experience some form of polyvictimization and/or revictimization throughout their lives, with only 36% of victimized women experiencing one form of victimization in childhood or adulthood alone. Furthermore, multiple victimization experiences significantly increased the proportion of women who experienced psychological distress symptoms in the clinical range. For almost all evaluated symptoms, the multiple forms of victimization or varying victimization patterns significantly predicted clinical levels of psychological distress over any specific form or single incident of victimization. The results suggest that victimized Latino women experience multiple forms of victimization and that the evaluation of a broader spectrum of victimization better accounts for pathological symptomatology. Clinical implications for Latino women and future research directions are discussed. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

“Area Without Numbers”: Using Touchscreen Dynamic Geometry to Reason About Shape

Abstract

In this article, we report on two lessons aimed at introducing junior high school students to the idea of shearing in a touchscreen dynamic geometry environment. By using shearing, we hoped to shift students’ attention away from a formula-driven, computational conception of area toward a more geometric one. We found that the students were able to solve several problems involving the comparison of polygons based on verbal and diagrammatic explanations. We describe the features of the touchscreen dynamic geometry technology that supported their learning, as well as the specific role that the teacher played in modeling students’ reasoning about area.     

Risk in Transport Investments

We discuss how the standard Cost-Benefit Analysis should be modified in order to take risk (and uncertainty) into account. We propose different approaches used in finance (Value at Risk, Conditional Value at Risk, Downside Risk Measures, and Efficiency Ratio) as useful tools to model the impact of risk in project evaluation. After introducing the concepts, we show how they could be used in CBA and provide some simple examples to illustrate how such concepts can be applied to evaluate the desirability of a new project infrastructure.     

On the use of masking models for image and audio watermarking

In most watermarking systems, masking models, inherited from data compression algorithms, are used to preserve fidelity by controlling the perceived distortion resulting from adding the watermark to the original signal. So far, little attention has been paid to the consequences of using such models on a key design parameter: the robustness of the watermark to intentional attacks. The goal of this paper is to demonstrate that by considering fidelity alone, key information on the location and strength of the watermark may become available to an attacker; the latter can exploit such knowledge to build an effective mask attack. First, defining a theoretical framework in which analytical expressions for masking and watermarking are laid, a relation between the decrease of the detection statistic and the introduced perceptual distortion is found for the mask attack. The latter is compared to the Wiener filter attack. Then, considering masking models widely used in watermarking, experiments on both simulated and real data (audio and images) demonstrate how knowledge on the mask enables to greatly reduce the detection statistic, even for small perceptual distortion costs. The critical tradeoff between robustness and distortion is further discussed, and conclusions on the use of masking models in watermarking drawn.