Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

A new family of dual binding site acetylcholinesterase (AChE) inhibitors has been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), AChE-induced and self-induced β-amyloid (Aβ) aggregation and β-secretase (BACE-1), and to cross the blood-brain barrier. The new heterodimers consist of a unit of racemic or enantiopure huprine Y or X and a donepezil-related 5,6-dimethoxy-2-[(4-piperidinyl)methyl]indane moiety as the active site and peripheral site to mid-gorge-interacting moieties, respectively, connected through a short oligomethylene linker. Molecular dynamics simulations and kinetics studies support the dual site binding to AChE. The new heterodimers are potent inhibitors of human AChE and moderately potent inhibitors of human BChE, AChE-induced and self-induced Aβ aggregation, and BACE-1, and are predicted to be able to enter the central nervous system (CNS), thus constituting promising multitarget anti-Alzheimer drug candidates with the potential to modify the natural course of this disease.

No abstract

SummaryMolecular diagnosis of von Willebrand Disease (VWD) is particularly complex. The autosomal von Willebrand factor gene (VWF) is large and highly polymorphic, and there is a highly homologous (>96%) partial pseudogene in chromosome 22. Because of these difficulties, application of molecular study of VWD to the clinical routine has been considerably delayed. Recent advances in sequencing technology and bioinformatics could convert direct sequencing of the complete VWF into a routine diagnostic tool for VWD, which is especially desirable in types 1 and 3. This study describes a highly optimized procedure in which all the coding and intronic flanking regions of VWF are amplified under identical thermocycling parameters in a ready-to-use PCR plate format. The entire sequencing procedure, from blood extraction to mutation identification, can be done within 24 hours, resulting in a simple, versatile, cost-effective strategy with little hands-on time requirements. To validate the method, we performed full-length VWF sequencing of 21 index cases including seven of each VWD type. A total of 30 VWF genetic variations were identified. Twelve of these sequence variations are new, including four missense, one nonsense, one insertion, the first insertion-deletion described in VWF, and 5 potential splice site mutations. To our knowledge, this is the fastest and most efficient protocol designed to date for complete sequencing of the VWF coding region in the molecular diagnosis of VWD.

One of the great societal challenges that we face today concerns the move to more sustainable patterns of energy consumption, reflecting the need to balance both individual consumer choice and societal demands. In order for this 'energy turnaround' to take place, however, reducing residential energy consumption must go beyond using energy-efficient devices: More sustainable behaviour and lifestyles are essential parts of future 'energy aware' living. Addressing this issue from an HCI perspective, this paper presents the results of a 3-year research project dealing with the co-design and appropriation of a Home Energy Management System (HEMS) that has been rolled out in a living lab setting with seven households for a period of 18 months. Our HEMS is inspired by feedback systems in Sustainable Interaction Design and allows the monitoring of energy consumption in real-time. In contrast to existing research mainly focusing on how technology can persuade people to consume less energy ('what technology does to people'), our study focuses on the appropriation of energy feedback systems ('what people do with technology') and how newly developed practices can become a resource for future technology design. Therefore, we deliberately followed an open research design. In keeping with this approach, our study uncovers various responses, practices and obstacles of HEMS use. We show that HEMS use is characterized by a number of different features. Recognizing the distinctive patterns of technology use in the different households and the evolutionary character of that use within the households, we conclude with a discussion of these patterns in relation to existing research and their meaning for the design of future HEMSs. RESEARCH HIGHLIGHTS • We developed an own Home Energy Management System (HEMS). • We rolled out our HEMS system in a living lab setting to seven households over a period of 18 months. • Our System provides feedback through TV, PC, smartphone and tablet-based interfaces. • This allowed us to explore 'what people do with HEMS in daily life'. • We identify and discuss nine meaningful categories of appropriating HEMS. • Based on our results, we discuss potentials for the design of future HEMSs.