Membrane inserted APP fragments containing the βA4 sequence of Alzheimer's disease do not aggregate

AbstractPreviously we have shown that the COOH-terminal fragment (A4CT) of the Alzheimer amyloid protein precursor (APP), which at the NH2-terminus carries the sequence of the amyloid βA4 protein, forms highly insoluble aggregates [EMBO J. (1988) 7, 949–957]. Here we report that aggregation is prevented if A4CT is expressed in vitro with a signal sequence at the NH2-terminus (SPA4CT) under conditions which allow membrane insertion. Aggregates from SPA4CT are obtained after removal of membranes by chloroform/methanol extraction or heating

Neither essence nor accident: Situated knowledge and its importance for the community broker

The paper describes the design of the Community Broker as a case study for the development of a tool attempting to support individual web-search strategies by using the community-based nature of a great deal of information exchange and learning. Community experiences affect the understanding, validation and organization of individual knowledge. Communities affecting the representation of knowledge frame the every-day decisions individuals have to take in spite of incomplete, insecure knowledge and the vagueness of communicating in natural languages. As for the often distributed, fragmented and heterogeneous nature of knowledge and related problems of information search in the internet - some of which are described in the paper - technical tools can support information search, when the influence of community-based identities upon knowledge representation and -identification is used as a source of additional information instead of being ignored

The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer’s disease: a post-mortem autoradiographic study.

Earlier post-mortem histological and autoradiographic studies have indicated a reduction of cell numbers in the locus coeruleus (LC) and a corresponding decrease in norepinephrine transporter (NET) in brains obtained from Alzheimer's disease (AD) patients as compared to age-matched healthy controls. In order to test the hypothesis that the regional decrease of NET is a disease specific biomarker in AD and as such, it can be used in PET imaging studies for diagnostic considerations, regional differences in the density of NET in various anatomical structures were measured in whole hemisphere human brain slices obtained from AD patients and age-matched control subjects in a series of autoradiographic experiments using the novel selective PET radioligand for NET (S,S)-[F-18]FMeNER-D-2. (S,S)-[F-18]FMeNER-D-2 appears to be a useful imaging biomarker for quantifying the density of NET in various brain structures, including the LC and the thalamus wherein the highest densities are found in physiological conditions. In AD significant decreases of NET densities can be demonstrated with the radioligand in both structures as compared to age-matched controls. The decreases in AD correlate with the progress of the disease as indicated by Braak grades. As the size of the LC is below the spatial resolution of the PET scanners, but the size of the thalamus can be detected with appropriate spatial accuracy in advanced scanners, the present findings confirm our earlier observations with PET that the in vivo imaging of NET with (S,S)-[F-18]FMeNER-D-2 in the thalamus is viable. Nevertheless, further studies are warranted to assess the usefulness of such an imaging approach for the early detection of changes in thalamic NET densities as a disease-specific biomarker and the possible use of (S,S)-[F-18]FMeNER-D-2 as a molecular imaging biomarker in AD. (c) 2010 Elsevier Ltd. All rights reserved

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

Practice-relevant security research? On the role of anticipations in practice-oriented collaborative research

Collaborative research between scientists from public research institutions with actors from civil society, such as practitioners, entrepreneurs, or domain-specific experts, has become ubiquitous in design-oriented research due to several reasons. On the one hand, applied-oriented research methodologies postulate the need for cooperation with practitioners during the evaluation of innovative artifacts in order to address stakeholder-relevant problems. On the other hand, as a precondition for funding of research proposals, both German and European funding policy demands on the involvement of entrepreneurs, end users or domain experts, to foster technical innovations with a sustainable potential for change in specific social domains. Even though it pervades several areas of applied science disciplines, there is a fundamental lack of empirical knowledge to both inform and guide researchers on how the claim of cooperation can be concretely operationalized in research. How cooperative research processes constitute over time, and how early research phases of applied technology research can be managed adequately (phases such as problem definition and analysis, the exploration of alternative technical solutions in context of technical and practical feasibility), are not addressed by rather abstract research methodologies. Such recommendations would be very valuable to guide researchers in understanding, researching, and managing joint research projects. In this dissertation an explorative study is presented that looks deeply into the collaboration work of a three years joint research project focused on developing an innovative navigation tool for reconnaissance missions of firefighters using ad-hoc deployable sensor-networks. The “Landmarke” project was one out of seven joint research projects of the so called “technology networks” of the Civil Security research programme, funded by the federal ministry of education and research of Germany between 2008 and 2011. The empirical interrogation of 60 hours of audio and video recordings provide access to the inner workings of project work among actors from a wide-range of professional backgrounds, such as scientists from several research institutions, firefighting practitioners and members of a firefighting training center; as well as entrepreneurs from different companies. This study identifies by the case of Landmarke the role of anticipations in design-oriented research practice. Anticipations have an epistemological value in informing decisions in collaborative design and evaluation of technical artifacts. The epistemological value of anticipations is grounded in how well anticipations are informed by experience, and how anticipations are justified by intersubjective transparent assessments. In the case of Landmarke, the reflections around firefighting practices to identify problems, and the introduction of technical artifacts to address navigation problems were closely intertwined. Collaborative reflections on navigation practice justified technical designs to support navigation. Collaborative evaluations of artefacts allowed firefighting practitioners to reflect navigation tactics on possible problems. This not only helped in moving forward the project, but also helped industry partners, scientists, and firefighters identifying the potential of the Landmarke technology as a promising tool way beyond supporting navigation.Verbundkooperationen zwischen Wissenschaftlern öffentlicher Forschungseinrichtungen mit Akteuren der Zivilgesellschaft, wie Praktikern, Unternehmern oder Domänen-spezifischen Experten sind in der gestaltungsorientierten Forschung nahezu allgegenwärtig geworden. Einerseits postulieren Forschungsmethodologien den Bedarf zur Kooperation bei der Evaluation von innovativen Artefakten, um Bedürfnissen relevanter Anspruchsgruppen Rechnung zu tragen. Andererseits ist die Bereitschaft zur Verbundkooperation zur Förderbedingung in der europäischen und deutschen Förderpolitik erhoben worden, um praxistaugliche Technikinnovationen mit Potenzial für Wandel in spezifischen gesellschaftlichen Domänen zu fördern. Trotz des hohen Stellenwerts von Forschungskooperationen dieser Art ist ein grundsätzlicher Mangel an empirischen Studien festzustellen. Wie sich kooperative Forschungsprozesse im Verlauf der Projektarbeit konstituieren, und wie Forschungsphasen der frühen der Technikentwicklung geeignet moderiert werden können, dazu fehlen jenseits abstrakter Grundsätze (z.B. zur Evaluation von technischen Artefakten im Forschungsprozess), die in Forschungs¬methodologien postuliert werden, konkretere Handreichungen für die Forschungs¬praxis. Solche Empfehlungen können wertvoll sein, um Forschern im Verständnis, bei der Erforschung und im Management von Verbundforschungsprojekten Handreichungen zu geben. In dieser Dissertation wird eine explorative Studie vorgestellt, die Kooperationsarbeit in einem dreijährigen Verbundprojekt genauer untersucht, das auf die Entwicklung eines innovativen Navigationswerkzeugs für Erkundungseinsätze von Feuerwehrleuten unter Verwendung von ad hoc ausbringbaren Sensornetzwerken fokussiert gewesen ist. Das „Landmarke“-Projekt war ein von sieben Verbundforschungsprojekten, das vom deutschen Ministerium für Bildung und Forschung zwischen 2008 bis 2011 gefördert wurde. Die empirische Untersuchung von 60 Stunden Audio- und Videomaterials bietet Zugang zu inneren Abläufen von Verbundarbeit, an denen Akteure unterschiedlicher beruflicher Hintergründe beteiligt gewesen sind, wie Wissenschaftler verschiedener Forschungseinrichtungen, Praktiker und Ausbilder der Feuerwehr und Vertreter mehrerer Unternehmen. Die Studie weist auf die Bedeutung von sog. Antizipationen für den gestaltungsorientierten Forschungsprozess hin, die einen erkenntnistheoretischen Wert bei Entscheidungen zur Gestaltung technischer Artefakte haben, wenn technische Artefakte am Nutzen für eine spezifische Praxis bewertet und verfeinert entwickelt werden. Der erkenntnistheoretische Wert von Antizipationen beruhte darauf, wie gut Antizipationen auf Erfahrungswerten basiert haben und inwiefern Antizipationen durch intersubjektive transparente Bewertungen gerechtfertigt waren. Im Fall von Landmarke waren die Überlegungen zu Brandbekämpfungspraktiken zur Identifizierung von Problemen und die Einführung technischer Artefakte zur Behebung von Navigationsproblemen eng miteinander verknüpft. Gemeinsame Überlegungen der beteiligten Akteure zur Navigationspraxis rechtfertigten technische Entwürfe zur Unterstützung der Navigation. Durch gemeinsame Evaluationen von Artefakten konnten Feuerwehrleute die Navigationstaktiken zu möglichen Problemen reflektieren. Dies trug nicht nur dazu bei, das Projekt hinsichtlich einer technischen Weiterentwicklung voranzutreiben, sondern ermöglichte den Beteiligten, das Potenzial der Landmarke-Technologie als vielversprechendes Werkzeug zu identifizieren, das weit über den ursprünglichen Zweck „Unterstützung der Navigation von Feuerwehrleuten“ hinausging

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