Biology subjects

Akeju, O.

Publications and source records attributed to Akeju, O..

4 recordsLinked to original sources

bioRxiv2026

A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms

Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and pressure overload-induced HF, cardiac delivery of tRNA-Asp-GTC-3'tDR reduced fibrosis and hypertrophy, preserved cardiac function, and improved survival, with limited three doses conferring durable protection after ischemia, whereas silencing it worsened both. Strikingly, tRNA-Asp-GTC-3'tDR acts through distinct mechanisms in different cell types: in fibroblasts, it assembles stress granules that sequester ribosome-loaded profibrotic transcripts, whereas in cardiomyocytes it engages pseudouridine synthase PUS7 to activate RNA autophagy. Its regulation and functions were confirmed in human cardiac cells and tissues. These findings demonstrate that a single tDR coordinates cell-type-specific protective programs in the heart, suggesting a new therapeutic axis to mitigate HF progression.

cell biology↗

bioRxiv2024

Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors

Ketamine is an NMDA-receptor antagonist that produces sedation, analgesia and dissociation at low doses and profound unconsciousness with antinociception at high doses. At high and low doses, ketamine can generate gamma oscillations (>25 Hz) in the electroencephalogram (EEG). The gamma oscillations are interrupted by slow-delta oscillations (0.1-4 Hz) at high doses. Ketamines primary molecular targets and its oscillatory dynamics have been characterized. However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown. By developing a biophysical model of cortical circuits, we demonstrate how NMDA-receptor antagonism by ketamine can produce the oscillatory dynamics observed in human EEG recordings and non-human primate local field potential recordings. We have discovered how impaired NMDA-receptor kinetics can cause disinhibition in neuronal circuits and how a disinhibited interaction between NMDA-receptor-mediated excitation and GABA-receptor-mediated inhibition can produce gamma oscillations at high and low doses, and slow-delta oscillations at high doses. Our work uncovers general mechanisms for generating oscillatory brain dynamics that differs from ones previously reported, and provides important insights into ketamines mechanisms of action as an anesthetic and as a therapy for treatment-resistant depression.

neuroscience↗

bioRxiv2022

Matters Arising: Re-examining the correlations between codon usage and dihedral bond angles using a population genetics model

A recent paper by Rosenberg et al. [2022] found a surprising correlation between synonymous codon usage and the dihedral bond angles of the resulting amino acid. However, their analysis did not account for the strongest known correlate of codon usage: gene expression. We applied the approach of Rosenberg et al. [2022] to simulated protein-coding sequences that (1) maintain the general relationship between codon usage and gene expression and (2) completely random codon usage. The analysis of the simulated data assuming a general relationship between gene expression and codon usage returned results remarkably similar to the real data. More concerning was the large number of significant results detected when sequences with random codon usage were analyzed. We believe that the specific results of Rosenberg et al. [2022] were confounded by the relationship between codon usage and gene expression, but also that their method is generally prone to detecting noise in protein bond angle distributions.

evolutionary biology↗

bioRxiv2022

Characterizing ketamine-induced dissociation using human intracranial neurophysiology: brain dynamics, network activity, and interactions with propofol

Subanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamines effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamines antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamines NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of novel brain dynamic biomarkers and therapeutics for depression.

neuroscience↗