Biology subjects

Gordon, K. E.

Publications and source records attributed to Gordon, K. E..

8 recordsLinked to original sources

bioRxiv2025

DICER1 syndrome mutations lead to a gain of 3p-miRNA function, HERVH activity and increased metastatic potential

The DICER1 gene is mutated in cancer, including DICER1 syndrome, a rare tumour predisposition syndrome. Cancer-associated hotspot mutations have been reported in both catalytic domains of DICER1 and are predicted to disrupt miRNA biogenesis. To understand how these hotspot mutations contribute to cancer development, we have generated cell lines harbouring single amino acid substitutions within the catalytic RNase IIIa (S1344L) or RNase IIIb (D1709N) domains of the endogenous DICER1 gene. We show that both mutations result in a widespread loss of 5p miRNAs, and, unexpectedly, an increase in 3p passenger strands loading into AGO2. The shared similarities between both mutants can be attributed to the structural proximity of the S1344 residue to the RNase IIIb catalytic centre. Functionally, we found that changes in the repertoire of miRNAs loaded into AGO2 result in altered gene expression, impacting critical pathways for cancer development, including metastatic potential. Additionally, our results indicate that inactivating the processing activity of DICER1 does not result in genomic instability. Instead, mutations cause specific upregulation of human endogenous retrovirus H (HERVH) through miRNA-independent mechanisms, suggesting that both canonical and non-canonical DICER1 functions are important to understand DICER1 syndrome.

molecular biology↗

bioRxiv2025

Interneuron theta phase locking controls seizure susceptibility

The timing of neuronal activity is highly precise and often organized by brain-wide oscillations. Many neurons modulate their firing rates at specific phases of theta (known as theta phase locking), creating discrete windows for information processing. Disrupted theta phase locking has been found across several neurological and psychiatric disorders (e.g., epilepsy), but gaps in technology have prevented its causal influence from being tested. Here, we developed PhaSER, a closed-loop optogenetic system designed to control the phase locking of specific interneurons, and demonstrate a causal role for inhibitory phase locking in seizure susceptibility. We first found that parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the dentate gyrus (DG) show distinct theta phase locking profiles and are differentially impacted in a mouse model of chronic temporal lobe epilepsy. In healthy mice, PV+ interneurons have extremely consistent phase-locked firing near the trough of CA1 theta, aligned with excitatory inputs to DG. However, in epileptic mice, PV+ interneuron activity is dispersed across the theta cycle, suggesting that altered inhibitory phase locking could be a causal mediator of seizure susceptibility in epilepsy. To test this hypothesis, we applied PhaSER to directly control the phase locking of DG interneurons during an acute test of seizure susceptibility. In epileptic mice, re-aligning DG PV+ interneuron theta phase locking reduced seizure susceptibility, while in healthy mice, disrupting normal phase locking of PV+ interneurons increased seizure susceptibility. Together, this provides the first causal evidence that inhibitory theta phase locking can directly control network function by shifting seizure susceptibility in the healthy and epileptic brain.

neuroscience↗

bioRxiv2025

Environmental Consistency, Not Certainty, Governs Predictive Motor Strategies During Walking

Humans rely on predictive control to maintain stability while walking in dynamic environments, yet the strategies driving this control remain unclear when environments are inconsistent or uncertain. We tested how people adapt to repeated lateral force field disruptions of switching directions, manipulating the force fields Consistency (how often switches occurred) and Certainty (how predictable the switches were). We quantified motor adaptation (error reduction) and sought evidence for two predictive strategies: pattern prediction (detecting a global trial pattern) and carryover prediction (assuming the next trial matches the previous). Adaptation profiles revealed a surprising finding: Consistency, not certainty, drove predictive control. When trials were Consistent, participants pursued appropriate predictive strategies (pattern or carryover). However, when trials were Inconsistent, participants exhibited counterproductive strategies, such as carryover prediction (despite the next trial most often being opposite) or no prediction (despite full certainty of each forthcoming trial). Error reduction was likewise dominated by consistency, with certainty exerting negligible influence. These findings, counter to long-held observations in upper-limb control, suggest the central nervous system faces unique challenges in whole-body control of walking and cannot rely on the simpler adaptation strategies observed in isolated limb control. This raises new, important questions for control of walking and whole-body motor adaptation.

animal behavior and cognition↗

bioRxiv2023

Prior Uncertainty Impedes Discrete Locomotor Adaptation

The impact of environmental uncertainty on locomotor adaptation remains unclear. Environmental uncertainty could either aid locomotor adaptation by prompting protective control strategies that stabilize movements to assist learning or impede adaptation by reducing error sensitivity and fostering hesitance to pursue corrective movements. To explore this, we investigated participants adaptation to a consistent viscous force field after experiencing environmental uncertainty in the form of unpredictable balance perturbations. We compared the performance of this group (Perturbation) to the adaptive performance of a Control group that did not experience any unpredictable perturbations. Perturbations were delivered using a cable-driven robotic device applying lateral forces to the pelvis. We assessed whole-body center of mass (COM) trajectory (COM signed deviation), anticipatory postural adjustments (COM lateral offset), and first step width. The Perturbation group exhibited larger disruptions in COM trajectory (greater COM signed deviations) than the Control group when first walking in the force field. While the COM signed deviations of both groups decreased towards baseline values, only the Control group returned to baseline levels. The Perturbation groups COM signed deviations remained higher, indicating they failed to fully adapt to the force field before the end. The Perturbation group also did not adapt their COM lateral offset to counter the predictable effects of the force field as the Control group did, and their first step width increased more slowly. Our findings suggest that exposure to unpredictable perturbations impeded future sensorimotor adaptations to consistent perturbations.

neuroscience↗

bioRxiv2023

Stability and Manoeuvrability Interactions During Human Walking Depend on the Manoeuvre Direction

People use the mechanical interplay between stability and manoeuvrability to successfully walk. During single limb support, body states (position and velocity) that increase lateral stability will inherently resist lateral manoeuvres, decrease medial stability, and facilitate medial manoeuvres. Although not well understood, people can make behavioural decisions exploiting this relationship in anticipation of perturbations or direction changes. To characterize the behavioural component of the stability-manoeuvrability relationship, twenty-four participants performed many repetitions of a discrete stepping task involving mid-trial reactive manoeuvres (medial or lateral direction) in a Baseline (no external perturbations) and Perturbed (random mediolateral perturbations applied to their pelvis) environment. We hypothesized people would make systematic changes in lateral stability dependent on both environment (increasing lateral stability in the Perturbed environment) and anticipated manoeuvre direction (reducing lateral stability to facilitate lateral manoeuvres). Participants increased lateral stability in the Perturbed environment, coinciding with an increase in manoeuvre reaction time for laterally but not medially directed manoeuvres. Moreover, we observed lower lateral stability in both environments when people anticipated making a lateral manoeuvre when compared to medial manoeuvres. These results support the hypothesis that people behaviourally exploit the mechanical relationship between lateral stability and manoeuvrability depending on walk task goals and external environment.

bioengineering↗

bioRxiv2022

The effects of physical and temporal certainty on locomotion with discrete underfoot perturbations

BackgroundAmbulation over complex terrain requires active control of foot placement to maintain a normal kinematic relationship between the center of mass and base of support. Recent investigations have suggested that foot placement location may be selected to anticipate shifts to the underfoot center of pressure. However, it is unclear whether temporal affordance and physical certainty contribute to the selection of a perturbation-specific anticipatory strategy. This study investigates anticipatory and reactive locomotor strategies for repeated underfoot perturbations with varying levels of temporal certainty, temporal affordance, and physical certainty. MethodsThirteen healthy adults walked with random underfoot perturbations from a mechanized shoe. Temporal certainty was challenged by presenting the perturbations with or without warning. Temporal affordance was challenged by adjusting the timing of a warning tone before the perturbation. Physical certainty was challenged with conditions that included only eversion perturbations, only inversion perturbations, or both eversion and inversion perturbations. Linear-mixed effects models assessed the effect of each condition on the percent change of margin of stability and step width, respectively. ResultsFor temporally uncertain perturbations and perturbations with one stride or less of affordance, we observed few changes to step width or margin of stability. As affordance increased to two strides, participants adopted a wider step width in anticipation of the perturbation (p = 0.001). Physical certainty had little effect on gait for the step of the perturbation, but participants recovered normal gait sooner when the physical nature of the perturbation was predictable (p < 0.001). DiscussionDespite having information about the timing and magnitude of upcoming perturbations, individuals do not develop perturbation specific feedforward strategies but instead rely on feedback control to recover normal gait after a perturbation. However, physical certainty appears to improve the efficiency of the feedback controller and allows individuals to recover normal gait sooner.

neuroscience↗

bioRxiv2021

Unique structure and positive selection promote the rapid divergence of Drosophila Y chromosomes

Y chromosomes across diverse species convergently evolve a gene-poor, heterochromatic organization enriched for duplicated genes, LTR retrotransposable elements, and satellite DNA. Sexual antagonism and a loss of recombination play major roles in the degeneration of young Y chromosomes. However, the processes shaping the evolution of mature, already degenerated Y chromosomes are less well-understood. Because Y chromosomes evolve rapidly, comparisons between closely related species are particularly useful. We generated de novo long read assemblies complemented with cytological validation to reveal Y chromosome organization in three closely related species of the Drosophila simulans complex, which diverged only 250,000 years ago and share >98% sequence identity. We find these Y chromosomes are divergent in their organization and repetitive DNA composition and discover new Y-linked gene families whose evolution is driven by both positive selection and gene conversion. These Y chromosomes are also enriched for large deletions, suggesting that the repair of double-strand breaks on Y chromosomes may be biased toward microhomology-mediated end joining over canonical non-homologous end-joining. We propose that this repair mechanism generally contributes to the convergent evolution of Y chromosome organization.

genomics↗

bioRxiv2021

Energy expenditure does not explain step length-width choices during walking

Healthy young adults have a most preferred walking speed, step length, and step width that are close to energetically optimal. However, people can choose to walk with a multitude of different step lengths and widths, which can vary in both energy expenditure and preference. Here we further investigate step length-width preferences and their relationship to energy expenditure. In line with a growing body of research, we hypothesized that peoples preferred stepping patterns would not be fully explained by metabolic energy expenditure. To test this hypothesis we used a two-alternative forced-choice paradigm. Fifteen participants walked on an oversized treadmill. Each trial participants experienced two stepping patterns and then chose the pattern they preferred. Over time, we adapted the choices such that there was 50% chance of choosing one pattern over another (equally preferred). If peoples preferences are based solely on metabolic energy expenditure, then these equally preferred stepping patterns should have equal energy expenditure. We found that energy expenditure differed across equally preferred step length-width patterns (p < 0.001). On average, longer steps with higher energy expenditures were preferred over shorter and wider steps with lower energy expenditures (p < 0.001). We also asked participants to rank a set of shorter, wider, and longer steps from most preferred to least preferred, and from most energy expended to least energy expended. Only 7/15 participants had the same rankings for their preferences and perceived energy expenditure. Our results suggest that energy expenditure is not the only factor influencing a persons conscious gait choices.

neuroscience↗