Defined tau phosphospecies differentially inhibit fast axonal transport through activation of two independent signaling pathways

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Morris, S. L., Tsai, M., Aloe, S., Bechberger, K., Konig, S., Morfini, G., & Brady, S. T. Defined tau phosphospecies differentially inhibit fast axonal transport through activation of two independent signaling pathways. Frontiers in Molecular Neuroscience, 13, (2021): 610037, https://doi.org/10.3389/fnmol.2020.610037.Tau protein is subject to phosphorylation by multiple kinases at more than 80 different sites. Some of these sites are associated with tau pathology and neurodegeneration, but other sites are modified in normal tau as well as in pathological tau. Although phosphorylation of tau at residues in the microtubule-binding repeats is thought to reduce tau association with microtubules, the functional consequences of other sites are poorly understood. The AT8 antibody recognizes a complex phosphoepitope site on tau that is detectable in a healthy brain but significantly increased in Alzheimer’s disease (AD) and other tauopathies. Previous studies showed that phosphorylation of tau at the AT8 site leads to exposure of an N-terminal sequence that promotes activation of a protein phosphatase 1 (PP1)/glycogen synthase 3 (GSK3) signaling pathway, which inhibits kinesin-1-based anterograde fast axonal transport (FAT). This finding suggests that phosphorylation may control tau conformation and function. However, the AT8 includes three distinct phosphorylated amino acids that may be differentially phosphorylated in normal and disease conditions. To evaluate the effects of specific phosphorylation sites in the AT8 epitope, recombinant, pseudophosphorylated tau proteins were perfused into the isolated squid axoplasm preparation to determine their effects on axonal signaling pathways and FAT. Results from these studies suggest a mechanism where specific phosphorylation events differentially impact tau conformation, promoting activation of independent signaling pathways that differentially affect FAT. Implications of findings here to our understanding of tau function in health and disease conditions are discussed.This research was funded by NIH grants R21NS096642 (GM); 1R01NS118177-01A1 (GM), R01 NS082730 (SB), a Zenith Award from the Alzheimer’s Association (SB), and a grant from the Tau Consortium/Rainwater Foundation (SB)

Formalized Conceptual Spaces with a Geometric Representation of Correlations

The highly influential framework of conceptual spaces provides a geometric way of representing knowledge. Instances are represented by points in a similarity space and concepts are represented by convex regions in this space. After pointing out a problem with the convexity requirement, we propose a formalization of conceptual spaces based on fuzzy star-shaped sets. Our formalization uses a parametric definition of concepts and extends the original framework by adding means to represent correlations between different domains in a geometric way. Moreover, we define various operations for our formalization, both for creating new concepts from old ones and for measuring relations between concepts. We present an illustrative toy-example and sketch a research project on concept formation that is based on both our formalization and its implementation.Comment: Published in the edited volume "Conceptual Spaces: Elaborations and Applications". arXiv admin note: text overlap with arXiv:1706.06366, arXiv:1707.02292, arXiv:1707.0516

Initial peri- and postoperative antibiotic treatment of infected nonunions: results from 212 consecutive patients after mean follow-up of 34 months

Lars Helbig,1 Maren Bechberger,2 Riyadh Aldeeri,1 Adriana Ivanova,1 Patrick Haubruck,1 Matthias Miska,1 Gerhard Schmidmaier,1 Georg W Omlor1 1Department of Orthopaedics, Trauma Surgery and Paraplegiology, 2Pharmacy Department, Heidelberg University Hospital, Heidelberg, Germany Purpose: Infected nonunions of the long bones belong to the most feared complications in the field of orthopedic and trauma surgery. Optimal antibiotic therapy should start early with the first revision surgery. Therefore, the aim of this study was to evaluate our peri- and postoperative antibiotic regime in context with the microbial spectrum and antibiotic resistances of patients with infected nonunions and to assess the possible impact on healing rates. Methods: We included all patients with first revision surgery during 2010–2015 due to nonunion of long bones with a clinical history of infection treated with radical debridement, local application of a gentamicin-impregnated bone cement, and systemic cefuroxime. Mean follow-up was 34.2 months. Data collection was performed retrospectively using a computerized databank with information about microbial species from intraoperatively acquired tissue samples and respective antibiograms. Bone fusion rates were evaluated based on findings of the latest X-rays and computed tomography scans.Results: Two hundred and twelve patients with nonunion and history of infection were selected; 171 patients had positive intraoperative microbial evidence of infection. Bacterial testing was mostly positive in fractures of the tibia (47.4%) and the femur (27.5%). Coagulase-negative Staphylococcus spp. were the most frequently detected (44.4%) followed by mixed infections (18.7%) and Staphylococcus aureus (10.5%). Antibiograms revealed that 62.6% of our cases were cefuroxime sensitive; 87.7% were gentamicin sensitive. Only 10.5% showed resistance to both cefuroxime and gentamicin. There was no statistically significant difference of fusion rates between patients with different microbial species or different antibiograms. Conclusion: Our data suggest that besides the high variety of different detected species, initial antibiotic treatment with a combination of systemic cefuroxime and local gentamicin-loaded bone cement is effective and in almost 90% the later determined microbial infection was sensitive to this treatment. Therefore, we recommend initial treatment according to this algorithm until specific antibiograms are available from intraoperatively acquired tissue samples. Keywords: infected nonunions, antibiotic treatment, microbial spectrum, antibiogra