Biology subjects

Menzies, J.

Publications and source records attributed to Menzies, J..

4 recordsLinked to original sources

bioRxiv2024

Reporting and justification of sample size in translational chronic variable stress procedures: A systematic review

All in vivo studies using laboratory animals should be guided by the Three Rs: Replacement, Reduction and Refinement. The concept of Reduction is important in sample size estimation; the sample size used should allow the detection of a biologically meaningful effect size using appropriate statistical tests, but not at the expense of animal suffering. Because studies using chronic variable stress (CVS) procedures deliberately impose suffering, we reasoned that Three Rs principles would be a strong consideration in experimental design. To explore this, we conducted a systematic review of CVS studies to ask whether a biologically meaningful effect size was used to determine the sample size. Only one article in our sample of 385 reported doing this. Accordingly, it is questionable whether most of these studies align strongly with the principle of Reduction. While determining a biologically meaningful effect size is not always straightforward, we believe it is central to making biologically informed decisions about study design and interpretation, and we discuss possible ways forward.

physiology↗

bioRxiv2024

In situ generation of Aβ42 oligomers via secondary nucleation triggers neurite degeneration and synaptic dysfunction in human iPSC-derived glutamatergic neurons

The aggregation of A{beta}42 into misfolded oligomers is a central event in the pathogenesis of Alzheimers disease. In this study, we aimed to develop a robust experimental system that recapitulates A{beta}42 oligomerization in living cells to gain insight into their neurotoxicity and to provide a platform to characterize the effects of inhibitors of this process. Our strategy is based on the in situ generation of A{beta}42 oligomers via secondary nucleation by repeatedly treating the cells with A{beta}42 monomers in the presence of pre-formed A{beta}42 fibrils. This approach enables an accurate control over the levels of on-pathway soluble A{beta}42 oligomers and cell-associated aggregates, as well as the study of their neurotoxic effects. By implementing this approach in human glutamatergic neurons derived from induced pluripotent stem cells (iPSCs), we were able to replicate key aspects of Alzheimers disease, including neurite degeneration and synaptic dysfunction. Using BRICHOS, a molecular chaperone that specifically inhibits secondary nucleation, we confirmed that aggregation in this system occurs through secondary nucleation, and that quantitative parameters for comparing potential A{beta}42 aggregation inhibitors can be obtained. Overall, our results demonstrate that by in situ generation of on-pathway A{beta}42 oligomers, one can obtain translational cellular models of AD to bridge the gap between basic research and clinical applications.

cell biology↗

bioRxiv2024

Rodent chronic variable stress procedures: a disjunction between stress entity and impact on behaviour

Chronic variable stress (CVS) procedures are widely used to model depression in laboratory rodents. We systematically documented the experimental design used in mouse CVS studies, and the design of the behavioural tests used to evaluate the effect of CVS. In a subset of studies, we measured effect sizes in behavioural tests. Across 202 mouse studies, 82% used a unique CVS procedure. We took advantage of this variability to ask whether the duration and intensity of CVS procedures correlated with effects sizes obtained in five commonly-used behavioural tests: the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST), the open field test (OFT) and the elevated plus maze (EPM). The most evident impact of CVS procedure design on effect sizes were seen in the FST where longer-duration CVS procedures with more diverse types of stressors were associated with a smaller effect size. Next, we correlated effect sizes between behavioural tests to explore whether these tests might measure similar or different consequences of CVS. We found a positive correlation between effects sizes in the TST and FST, and in the OFT and EPM, but the two strongest positive correlations were between the EPM and TST, and between the EPM and FST. CVS studies deliberately impose suffering over long periods, and our data raise scientific and ethical questions around the stress procedures used and the behavioural tests used to evaluate them.

physiology↗

bioRxiv2022

Molecular insights into the Darwin paradox of coral reefs from the sea anemone Aiptasia

Symbiotic cnidarians such as corals and anemones form highly productive and biodiverse coral-reef ecosystems in nutrient-poor ocean environments, a phenomenon known as Darwins Paradox. Resolving this paradox requires elucidating the molecular bases of efficient nutrient distribution and recycling in the cnidarian-dinoflagellate symbiosis. Using the sea anemone Aiptasia, we show that during symbiosis, the increased availability of glucose and the presence of the algae jointly induce the coordinated upregulation and re-localization of glucose and ammonium transporters. These molecular responses are critical to support symbiont functioning and organism-wide nitrogen assimilation through GS/GOGAT-mediated amino-acid biosynthesis. Our results reveal crucial aspects of the molecular mechanisms underlying nitrogen conservation and recycling in these organisms that allow them to thrive in the nitrogen-poor ocean environments. One-sentence summaryWhole-organism nitrogen assimilation fueled by glucose from symbiotic algae enables corals to flourish in oligotrophic waters.

molecular biology↗