Search

Fluorine-containing saturated nitrogen heterocycles are very attractive structures in medicinal and biological chemistry because fluorine can be used to tune conformation as well as key properties such as basicity and bioavailability. At present cyclic fluorinated amines are accessed using hazardous reagents such as DAST or by lengthy synthesis routes. Here we report a modular two-step synthesis of cyclic β-fluoroalkyl amines using a photoredox-catalysed cyclisation/hydrogen atom transfer reaction of bromodifluoroethylamines. [ABSTRACT FROM AUTHOR]

Course-based research experiences (CUREs) are shown to be more engaging for college students, lead to better academic performance, and increase students’ intent to persist in science. This especially holds true when compared to lecture-based science courses with standard lab assignments. Less attention has been given, however, to the nuanced week-by-week experiences of students participating in CURE courses over a semester. This study addresses why it is crucial to understand how student interest is sustained throughout the CURE course, despite potential challenges and frustrations. Conducted over a 15-week period, this longitudinal study examines enrolled students (N = 170) who had one of 13 instructors from six institutions. The results indicate that students’ high frustration with participation in CUREs moderates the relationship between perceived challenge and interest. In addition, higher levels of the variable ‘meaning making’ among students have significant associations with week-by-week interest maintenance throughout the semester. Findings suggest that to sustain high levels of student interest over a semester, CURE instructors should focus more on reducing student frustration within CURE course operations. To further support student interest, these findings also suggest that instructors need to foster and emphasize the connections of CURE course content to students’ own lives and personal goals to sustain their interest. [ABSTRACT FROM AUTHOR]

The microtubule-associated protein Tau is a driver of neuronal dysfunction in Alzheimer's disease and other tauopathies. In this process, Tau initially undergoes subtle changes to its abundance, subcellular localisation and a vast array of post-translational modifications including phosphorylation, that progressively result in the protein's somatodendritic accumulation and dysregulation of multiple Tau-dependent cellular processes. Given the various loss- and gain-of-functions of Tau in disease and the brain-wide changes in the proteome that characterise tauopathies, we asked whether targeting Tau would restore the alterations in proteostasis observed in disease. Therefore, by phage display, we generated a novel pan-Tau antibody, RNJ1, that preferentially binds human Tau and neutralises proteopathic seeding activity in multiple cell lines, and benchmarked it against a clinically tested pan-Tau antibody, HJ8.5 (murine version of tilavonemab). We then evaluated both antibodies, alone and in combination, in the K3 tauopathy mouse model, showing reduced Tau pathology and improvements in neuronal function following 14 weekly treatments, without obtaining synergy for the combination. These effects were more pronounced in female mice. To investigate the molecular mechanisms contributing to improvements in neuronal function, we employed quantitative proteomics, phosphoproteomics and kinase prediction analysis to first establish alterations in K3 mice relative to WT controls at the proteome level. In female K3 mice, we found 342 differentially abundant proteins, which are predominantly involved in metabolic and microtubule-associated processes, strengthening previously reported findings of defects in several functional domains in multiple tauopathy models. We next asked whether antibody-mediated Tau target engagement indirectly affects levels of deregulated proteins in the K3 model. Importantly, both immunotherapies, in particular RNJ1, induced abundance shifts towards a restoration to wild-type levels (proteostasis). A total of 257 of 342 (∼75%) proteins altered in K3 were closer in abundance to WT levels after RNJ1 treatment, and 73% after HJ8.5 treatment. However, the magnitude of these changes was less pronounced than that observed with RNJ1, as reflected by a far smaller number of differentially abundant proteins. Furthermore, analysis of the phosphoproteome showed an even stronger restoration effect with RNJ1, with ∼82% of altered phosphopeptides in K3 showing a shift to WT levels, and 75% with HJ8.5. Gene set over-representation analysis (ORA) further confirmed that proteins undergoing restoration are involved in biological pathways affected in K3 mice. Together, our study suggests that a Tau immunotherapy-induced restoration of proteostasis links target engagement and treatment efficacy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The last few years have seen a boom in using generative models to augment real datasets, as synthetic data can effectively model real data distributions and provide privacy-preserving, shareable datasets that can be used to train deep learning models. However, most of these methods are 2D and provide synthetic datasets that come, at most, with categorical annotations. The generation of paired images and segmentation samples that can be used in downstream, supervised segmentation tasks remains fairly uncharted territory. This work proposes a two-stage generative model capable of producing 2D and 3D semantic label maps and corresponding multi-modal images. We use a latent diffusion model for label synthesis and a VAE-GAN for semantic image synthesis. Synthetic datasets provided by this model are shown to work in a wide variety of segmentation tasks, supporting small, real datasets or fully replacing them while maintaining good performance. We also demonstrate its ability to improve downstream performance on out-of-distribution data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Virginia Fernandez reports financial support, administrative support, and travel were provided by EPSRC Centre for Doctoral Training in Smart Medical Imaging. Tom Vercauteren reports a relationship with Hypervision Surgical that includes: board membership and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)