Biology subjects

Snell, J.

Publications and source records attributed to Snell, J..

6 recordsLinked to original sources

bioRxiv2026

High Throughput Characterization of Eukaryotic 2A-Like Peptides Identifies Novel Leucine-Associated Reduction in Protein Abundance

Virally-derived ribosomal skipping 2A peptides are a popular tool for protein co-expression. Despite their use in over 9,000 publications, the biochemical and biophysical properties underlying the skipping mechanism remain largely unexplored. We identified 4,218 2A-like peptides originating from non-viral organisms. We developed and utilized the Trifluorescent Reporter fluorescent tool for high-throughput multiplexable analysis of ribosomal skipping, and tested 3,271 2A-like peptide sequences. We identified peptides that skipped, failed to skip, and skipped but failed to restart translation, in addition to peptides that induced a reduction in protein abundance. Peptides that skipped and induced reductions in protein abundance largely originated from eukaryotes. A poly-leucine stretch in an alpha-helix N-terminal to the conserved GDxExNPGP motif drove both skipping and the reduction in protein abundance. Analysis of the native eukaryotic protein contexts revealed that reduction may be harnessed as an expression regulator. The high-throughput approach used in this work greatly expands the functional knowledge of what biophysical and biochemical characteristics lead to ribosomal skipping, including an apparent latent eukaryotic leucine stall-helix motif. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/732966v2_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@d6dc26org.highwire.dtl.DTLVardef@f7475org.highwire.dtl.DTLVardef@a6cb1aorg.highwire.dtl.DTLVardef@603f46_HPS_FORMAT_FIGEXP M_FIG C_FIG

Systems Biology↗

bioRxiv2025

A confound-free method to manipulate pupil size in psychological experiments

Those who study visual perception and visuo-spatial attention are increasingly paying interest to the ways in which these processes are influenced by the size of the pupil. However, this realm of research is complicated by the pupils notorious susceptibility to confounders and difficulties in disentangling cause and effect. Recent studies have sought a solution in the exploitation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which trigger pupil constrictions upon detecting blue light. Experiments typically present stimuli against blue versus red backgrounds of equal perceived luminance, to effectuate systematically smaller pupils in the former than in the latter condition. Here we provide a further validation of this method, by testing a scenario of potential concern. Via retino-hypothalamic pathways, ipRGC activation modulates alertness and arousal. Blue and red backgrounds may therefore differentially impact behavior in addition to the pupil, potentially confounding inferences about the pupils impact on cognition. This was investigated with an auditory task in which participants responded as quickly as possible to sequences of randomly timed beeps while looking at blue versus red displays. Each participant was tested with an easy and a difficult version of the auditory task. Results suggest that the ipRGC method is good to go: in the presence of effects of task difficulty on both pupil size and task performance, the display color exclusively influenced pupil size without affecting task performance.

neuroscience↗

bioRxiv2025

Parallel and dynamic attention allocation during natural reading

During natural reading, attention constantly shifts across words, yet how linguistic properties (e.g., lexical frequency) impact the allocation of attention remains unclear. In this study, we co-registered MEG data and eye movements while participants read one-line sentences containing target words of either low or high lexical frequency. Using rapid invisible frequency tagging (RIFT), we simultaneously tracked attention to target and post-target words by flickering them at different frequencies. First, we provide neural evidence that attention was allocated simultaneously to both foveal target and parafoveal post-target words. Second, we found an early parafoveal lexical effect, whereby lower frequency targets demanded more attention prior to fixation, and, additionally, a foveal load effect whereby lower frequency targets reduced the amount of attention allocated to post-targets. Furthermore, flexibility in attention shifts between foveal and parafoveal processing correlated with individual reading speed. These results suggest attention is distributed across multiple words and is flexibly adjusted during reading.

neuroscience↗

bioRxiv2024

Language models outperform cloze predictability in a cognitive model of reading

Although word predictability is commonly considered an important factor in reading, sophisticated accounts of predictability in theories of reading are yet lacking. Computational models of reading traditionally use cloze norming as a proxy of word predictability, but what cloze norms precisely capture remains unclear. This study investigates whether large language models (LLMs) can fill this gap. Contextual predictions are implemented via a novel parallel-graded mechanism, where all predicted words at a given position are pre-activated as a function of contextual certainty, which varies dynamically as text processing unfolds. Through reading simulations with OB1-reader, a cognitive model of word recognition and eye-movement control in reading, we compare the models fit to eye-movement data when using predictability values derived from a cloze task against those derived from LLMs (GPT2 and LLaMA). Root Mean Square Error between simulated and human eye movements indicates that LLM predictability provides a better fit than Cloze. This is the first study to use LLMs to augment a cognitive model of reading with higher-order language processing while proposing a mechanism on the interplay between word predictability and eye movements. Author SummaryReading comprehension is a crucial skill that is highly predictive of later success in education. One aspect of efficient reading is our ability to predict what is coming next in the text based on the current context. Although we know predictions take place during reading, the mechanism through which contextual facilitation affects ocolarmotor behaviour in reading is not yet well-understood. Here, we model this mechanism and test different measures of predictability (computational vs. empirical) by simulating eye movements with a cognitive model of reading. Our results suggest that, when implemented with our novel mechanism, a computational measure of predictability provide better fits to eye movements in reading than a traditional empirical measure. With this model, we scrutinize how predictions about upcoming input affects eye movements in reading, and how computational approches to measuring predictability may support theory testing. In the short term, modelling aspects of reading comprehension helps reconnect theory building and experimentation in reading research. In the longer term, more understanding of reading comprehension may help improve reading pedagogies, diagnoses and treatments.

neuroscience↗

bioRxiv2021

Leukocyte proliferation mediates disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies. One-Sentence SummaryPharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in the Ndufs4(KO) mouse model of Leigh syndrome.

pathology↗

bioRxiv2020

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood {beta}-hydroxybutarate ({beta}-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. {beta}-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of {beta}-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

physiology↗