A Chemical Analog of Curcumin as an Improved Inhibitor of Amyloid Abeta Oligomerization

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin

Designing for high expectations: Balancing ambiguity and thorough specification in the design of a wayfinding tool for firefighters

Ambiguity has been identified as a useful tool for designing ubicomp systems. In the design of safety critical systems, however, the expectations for a system are particularly high, and goals of the technology are rigidly defined. In this context is not clear if open ended systems can still be used as a tool for design. In this paper we present a detailed account of the design process of an indoor wayfinding support tool for firefighters, in which ambiguity played a central role in driving the construction of the system. Based on an ongoing work covering more than a year of close collaboration with a heterogeneous team of project partners, we present some implications of using ambiguity for designing ubiquitous computing solutions in a domain that traditionally requires more formal specifications for the construction of technology

Ethnographisch fundierte evolutionäre Produktfindung: Die Entwicklung des Community Brokers

The paper describes the iterative and inter-disciplinary development of a search tool based on an ethnographic field study on learning processes in SME in the German software branch