Dissociation of tau toxicity and phosphorylation: role of GSK-3β, MARK and Cdk5 in a Drosophila model

Hyperphosphorylation of tau at multiple sites has been implicated in the formation of neurofibrillary tangles in Alzheimer’s disease; however, the relationship between toxicity and phosphorylation of tau has not been clearly elucidated. Putative tau kinases that play a role in such phosphorylation events include the proline-directed kinases glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5), as well as nonproline-directed kinases such as microtubule affinity-regulating kinase (MARK)/PAR-1; however, whether the cascade of events linking tau phosphorylation and neurodegeneration involves sequential action of kinases as opposed to parallel pathways is still a matter of controversy. Here, we employed a well-characterized Drosophila model of tauopathy to investigate the interdependence of tau kinases in regulating the phosphorylation and toxicity of tau in vivo. We found that tau mutants resistant to phosphorylation by MARK/PAR-1 were indeed less toxic than wild-type tau; however, this was not due to their resistance to phosphorylation by GSK-3β/Shaggy. On the contrary, a tau mutant resistant to phosphorylation by GSK-3β/Shaggy retained substantial toxicity and was found to have increased affinity for microtubules compared with wild-type tau. The fly homologs of Cdk5/p35 did not have major effects on tau toxicity or phosphorylation in this model. These data suggest that, in addition to tau phosphorylation, microtubule binding plays a crucial role in the regulation of tau toxicity when misexpressed. These data have important implications for the understanding and interpretation of animal models of tauopathy

\u3ci\u3eAmicus Curiae\u3c/i\u3e Brief of the Hon. Judith Fitzgerald (Bankruptcy Judge, Ret.), and Law Professors Pamela Foohey, George Kuney, Robert Lawless, Jonathan Lipson, Bruce A. Markell, Nancy Rapoport, Richard Squire, Ray Warner and Jack Williams, In Support of the Petitioner

Professor Pamela Foohey filed an amicus brief with a group of law professors and a former bankruptcy judge in MOAC Mall Holdings LLC v. Transform Holdco LLC

The pre-concept design of the DEMO tritium, matter injection and vacuum systems

In the Pre-Concept Design Phase of EU-DEMO, the work package TFV (Tritium – Matter Injection – Vacuum) has developed a tritium self-sufficient three-loop fuel cycle architecture. Driven by the need to reduce the tritium inventory in the systems to an absolute minimum, this requires the continual recirculation of gases in loops without storage, avoiding hold-ups of tritium in each process stage by giving preference to continuous over batch technologies, and immediate use of tritium extracted from tritium breeding blankets. In order to achieve this goal, a number of novel concepts and technologies had to be found and their principal feasibility to be shown. This paper starts from a functional analysis of the fuel cycle and introduces the results of a technology survey and ranking exercise which provided the prime technology candidates for all system blocks. The main boundary conditions for the TFV systems are described based on which the fuel cycle architecture was developed and the required operational windows of all subsystems were defined. To validate this, various R&D lines were established, selected results of which are reported, together with the key technology developments. Finally, an outlook towards the Concept Design Phase is given

Online Political Communication Strategies: MEPs, E-Representation, and Self-Representation

Research into the communication strategies of legislators has a long history. The European Parliament offers an opportunity to add to understanding of how legislators prioritize styles of communication, with a comparative perspective across 27 nations. Through content analysis of online communication, we investigate how the Internet is used by members of the European Parliament. Our analysis assesses three communication strategies: homestyle, impression management, and participatory. We find that a homestyle strategy predominates, followed by impression management. Participatory communication is emergent, but may earn legislators political capital, as it appears that proactive communicators who offer participatory opportunities are more likely to build an online following

A Drosophila Model of ALS: Human ALS-Associated Mutation in VAP33A Suggests a Dominant Negative Mechanism

ALS8 is caused by a dominant mutation in an evolutionarily conserved protein, VAPB (vesicle-associated membrane protein (VAMP)-associated membrane protein B)/ALS8). We have established a fly model of ALS8 using the corresponding mutation in Drosophila VAPB (dVAP33A) and examined the effects of this mutation on VAP function using genetic and morphological analyses. By simultaneously assessing the effects of VAPwt and VAPP58S on synaptic morphology and structure, we demonstrate that the phenotypes produced by neuronal expression of VAPP58S resemble VAP loss of function mutants and are opposite those of VAP overexpression, suggesting that VAPP58S may function as a dominant negative. This is brought about by aggregation of VAPP58S and recruitment of wild type VAP into these aggregates. Importantly, we also demonstrate that the ALS8 mutation in dVAP33A interferes with BMP signaling pathways at the neuromuscular junction, identifying a new mechanism underlying pathogenesis of ALS8. Furthermore, we show that mutant dVAP33A can serve as a powerful tool to identify genetic modifiers of VAPB. This new fly model of ALS, with its robust pathological phenotypes, should for the first time allow the power of unbiased screens in Drosophila to be applied to study of motor neuron diseases

Interstitial Space and Trapped Sediment Drive Benthic Communities in Artificial Shell and Rock Reefs

Enhancing habitat complexity and thereby biodiversity is a main motivation for the creation of artificial reefs in the marine and coastal environment. Uncertainty remains, however, regarding which types of reef best deliver this aim, and how material properties impact faunal communities. The objective of this study was to assess the macrobenthic infauna in standardized reef-units made from different types of shell and rock and to quantify factors explaining community properties. 70 × 75 × 25 cm reef-units were made from cockle, mussel and oyster shells and rocks. Replicate units were placed on an intertidal sand flat of Swansea Bay (Wales, UK). After 5 months the benthic fauna was washed out of the reef-units and identified to species level. The volume of reef material, interstitial space and trapped sediment in each unit was quantified. A total of 45 invertebrate species were recorded in artificial reef-units compared with 12 species in the reef-free surrounding sands; 37 species were exclusively found in reefs. There was no significant difference between the infauna communities in different reef types in terms of univariate or multivariate diversity descriptors, but multivariate dispersion was lower among rock than shell-reef replicates. Distance-based linear models (DistLM) showed that the volume of interstitial space per reef-unit was the factor best explaining community structure, followed by properties of the trapped sediment. Species richness was significantly correlated with the volume of interstitial space and trapped sediment. Species seemed to use the reef-units fleetingly as shelter during low water, more permanently for protection, or as hunting ground for prey. The study demonstrated that artificial reef-units made of loose shell material and rocks can significantly enhance infauna diversity in sandy coastal environments. The identity of the material seems less relevant as long as it maximizes interstitial space and allows trapping of sediment. This provides practitioners with a degree of creative freedom when designing artificial reefs with the aim to enhance infauna diversity

“The Original Journals of ‘Kitty’ Wilmot”: manufacturing women’s travel writing in the salon of Helen Maria Williams

This article discusses the implications of a previously unknown Romantic-period manuscript by Anglo-Irish traveler Katherine Wilmot (1773–1824). A later version of Wilmot’s epistolary travelogue of 1801–03 has been valued as an artifact of British experience abroad during the Peace of Amiens for its descriptions of Napoleonic Paris. Yet the newly discovered draft reveals a deeper assimilation within and sympathy towards the radical political and literary networks Wilmot documented, as well as a budding relationship with author and salonnière Helen Maria Williams that is occluded from the later narrative. This article examines the complex choices surrounding authorship for British women abroad in the period by considering a refused invitation that Wilmot submit writing to The English Press, the publishing venture of Williams and her companion John Hurford Stone. The article details Wilmot’s evolving writing in terms of Williams’s influence, outlining how British women travel writers reshaped their experiences to meet the expectations of readers at home while also considering the impact of sedition, gendered agency, and political affinity on the production and reception of their writing

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges