Biology subjects

Reynolds, J.

Publications and source records attributed to Reynolds, J..

12 recordsLinked to original sources

bioRxiv2025

Characterizing Variants of Uncertain Drug Resistance (VUDRs) Using Quantitative Measurements at Clinical Exposures

Somatic missense mutations in oncogenes drive resistance to anticancer drugs, yet many variants remain clinically uncharacterized. Analogous to Variants of Uncertain Significance (VUS) in genetic disorders, these Variants of Uncertain Drug Resistance (VUDRs) in cancer lack the functional annotation needed to guide clinical management. Here, we applied a standards-driven deep mutational scanning platform that connects quantitative concentration-response measurements to human pharmacokinetics across 4922 missense variants (>96% coverage) at approved (400 mg QD) and investigational (400 mg and 500 mg BID) human doses of imatinib. Resistance phenotypes for 18 standards spanning 2 orders of magnitude of drug sensitivity showed strong quantitative performance and clinical concordance. Analyzing 257 clinical VUDRs, >10% conferred modest levels of resistance that might be overcome by dose escalation with generic imatinib instead of a branded alternative, potentially alleviating financial toxicity. Integration with global germline data also revealed ancestry-specific variants with the potential to create private VUDRs. These preclinical data establish the first generalizable framework for high throughput resistance variant classification directly tied to known human doses.

bioengineering↗

bioRxiv2025

Life-Stage Transitions Drive Distinct Gut Viral Communities in Dairy Cattle

Ruminant gut microbial communities profoundly influence host health and environmental impacts, yet their viral components remain poorly characterised across developmental transitions. Here, we analysed the dairy cow gut virome across four life stages--calf, heifer, dry adult, and lactating adult. Using hybrid sequencing, we assembled 30,321 viral operational taxonomic units, including 1,338 complete genomes representing mostly novel lineages. Virome composition shifted dramatically with life stage, transitioning from low-diversity, temperate-dominated communities in calves to high-diversity, lytic-dominated communities in adults. Virome transitions paralleled but showed distinct dynamics from bacterial community development, with viral and bacterial diversity negatively correlated during drying-off. Dry cows exhibited elevated viral loads relative to their bacterial hosts. We identified 26 viral sequences targeting the methanogen Methanobrevibacter, absent in calves but present in adults. These findings reveal the dynamic nature of ruminant gut viral communities and highlight phages potential regulatory role during critical life transitions.

microbiology↗

bioRxiv2023

Domain-specific cognitive impairment reflects prefrontal dysfunction in aged common marmosets

Age-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, while those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging, and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus-reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination and a Serial Reversal task, respectively. We found that aged marmosets show transient impairment in "learning-to-learn" but have conserved ability to form stimulus-reward associations. Furthermore, aged marmosets have impaired cognitive flexibility driven by susceptibility to proactive interference. Since these impairments are in domains critically dependent on the prefrontal cortex, our findings support prefrontal cortical dysfunction as a prominent feature of neurocognitive aging. This work positions the marmoset as a key model for understanding the neural underpinnings of cognitive aging. Significance StatementAging is the greatest risk factor for neurodegenerative disease development, and understanding why is critical for the development of effective therapeutics. The common marmoset, a short-lived non-human primate with neuroanatomical similarity to humans, has gained traction for neuroscientific investigations. However, the lack of robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains limits their validity as a model for age-related cognitive impairment. We demonstrate that aging marmosets, like humans, have impairment that is specific to cognitive domains reliant on brain areas that undergo substantial neuroanatomical changes with age. This work validates the marmoset as a key model for understanding region-specific vulnerability to the aging process.

neuroscience↗

bioRxiv2023

The double-drift illusion biases the marmoset oculomotor system

The double-drift illusion has two unique characteristics: the error between the perceived and physical position of the stimulus grows over time, and saccades to the moving target land much closer to the physical than the perceived location. These results suggest that the perceptual and saccade targeting systems integrate visual information over different timescales. Functional imaging studies in humans have revealed several potential cortical areas of interest, including the prefrontal cortex. However, we currently lack an animal model to study the neural mechanisms of location perception that underlie the double-drift illusion. To fill this gap, we trained two marmoset monkeys to fixate and then saccade to the double drift stimulus. In line with human observers for radial double-drift trajectories, we find that saccade endpoints do show a significant bias that is, as it is in humans, smaller than that seen in perception. This bias is modulated by changes in the external and internal speeds of the stimulus. These results demonstrate that the saccade targeting system of the marmoset monkey is influenced by the double-drift illusion.

animal behavior and cognition↗

bioRxiv2022

Spike-phase coupling patterns reveal laminar identity in primate cortex

The cortical column is one of the fundamental computational circuits in the brain. In order to understand the role neurons in different layers of this circuit play in cortical function it is necessary to identify the boundaries that separate the laminar compartments. While histological approaches can reveal ground truth they are not a practical means of identifying cortical layers in vivo. The gold standard for identifying laminar compartments in electrophysiological recordings is current-source density (CSD) analysis. However, laminar CSD analysis requires averaging across reliably evoked responses that target the input layer in cortex, which may be difficult to generate in less well studied cortical regions. Further the analysis can be susceptible to noise on individual channels resulting in errors in assigning laminar boundaries. Here, we have analyzed linear array recordings in multiple cortical areas in both the common marmoset and the rhesus macaque. We describe a pattern of laminar spike-field phase relationships that reliably identifies the transition between input and deep layers in cortical recordings from multiple cortical areas in two different non-human primate species. This measure corresponds well to estimates of the location of the input layer using CSDs, but does not require averaging or specific evoked activity. Laminar identity can be estimated rapidly with as little as a minute of ongoing data and is invariant to many experimental parameters. This method may serve to validate CSD measurements that might otherwise be unreliable or to estimate laminar boundaries when other methods are not practical.

neuroscience↗

bioRxiv2021

Cortical Mechanisms of Saccadic Suppression

Saccades are a ubiquitous and crucial component of our visual system, allowing for the efficient deployment of the fovea and its accompanying neural resources. Initiation of a saccade is known to cause saccadic suppression, a temporary reduction in visual sensitivity1, 2 and visual cortical firing rates3-6. While saccadic suppression has been well characterized at the level of perception and single neurons, relatively little is known about the visual cortical networks governing this phenomenon. Here we examine the effects of saccadic suppression on distinct neural subpopulations within visual area V4. We find cortical layer- and cell type-specific differences in the magnitude and timing of peri-saccadic modulation. Neurons in the input layer show changes in firing rate and inter-neuronal correlations prior to saccade onset, indicating that this layer receives information about impending saccades. Putative inhibitory interneurons in the input layer elevate their firing rate during saccades, suggesting they play a role in suppressing the activity of other cortical subpopulations. A computational model of this circuit recapitulates our empirical observations and demonstrates that an input layer-targeting pathway can initiate saccadic suppression by enhancing local inhibitory activity. Collectively, our results provide a mechanistic understanding of how eye movement signaling interacts with cortical circuitry to enforce visual stability.

neuroscience↗

bioRxiv2019

Spontaneous Traveling Cortical Waves Gate Perception in Awake Behaving Primates

Perceptual sensitivity varies from moment to moment. One potential source of variability is spontaneous fluctuations in cortical activity that can travel as a wave. Spontaneous traveling waves have been reported during anesthesia, but questioned as to whether they are relevant to waking cortical function. Using newly developed analytic techniques, we find spontaneous waves of activity in extrastriate visual cortex of awake marmosets (Callithrix jacchus). In monkeys trained to detect faint visual targets, the timing and position of spontaneous traveling waves, prior to target onset, predict the magnitude of evoked activity and the likelihood of detection. In contrast, spatially disorganized fluctuations of neural activity are much less predictive. These results reveal an important role for spontaneous traveling waves in sensory processing through modulating neural and perceptual sensitivity.\n\nOne Sentence SummaryFluctuations in cortical activity often travel as waves, shape incoming sensory information, and affect conscious perception.

neuroscience↗

bioRxiv2019

Viral manipulation of functionally distinct neurons from mice to humans

Recent success in identifying gene regulatory elements in the context of recombinant adeno-associated virus vectors have enabled cell type-restricted gene expression. However, within the cerebral cortex these tools are presently limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple novel enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we identified enhancers that target the breadth of its expression, including two that are selective for parvalbumin and vasoactive intestinal peptide cortical interneurons. Demonstrating the functional utility of these elements, we found that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across species, from mice to humans. Finally, we demonstrate that our selection method is generalizable to other genes and characterize four additional PV-specific enhancers with exquisite specificity for distinct regions of the brain. Altogether, these viral tools can be used for cell-type specific circuit manipulation and hold considerable promise for use in therapeutic interventions.

neuroscience↗

bioRxiv2018

MicroRNAs are likely part of the molecular toolkit regulating adult reproductive diapause in the mosquito, Culex pipiens

For many arthropods, including insects, diapause is the primary mechanism for survival during unfavorable seasons. Although the exogenous signals and endogenous hormones that induce and regulate diapause are well-characterized, we still lack a mechanistic understanding of how environmental information is translated into molecular regulators of the diapause pathway. However, short, non-coding microRNAs (miRNAs) are likely involved in generating both the arrested egg follicle development and fat hypertrophy in diapausing females of the Northern house mosquito, Culex pipiens. To determine whether miRNAs might respond to changes in day length and/or regulate diapause pathways, we measured the abundance of candidate miRNAs in diapausing and nondiapausing females of Cx. pipiens across the adult lifespan. Of the selected miRNAs nearly all were more abundant in nondiapausing females relative to diapausing females, but at different times. Specifically, miR-13b-3p, miR-14-3p, miR-277-3p, and miR-305-5p were upregulated in nondiapausing females early in adulthood, while miR-309-3p and miR-375-3p were upregulated later in adult life, and miR-8-3p and miR-275-3p were upregulated both early and late in adult life. Taken together, our data demonstrate that miRNA expression is dynamic, changing across adult lifespan. Further, differential miRNA expression between diapausing and nondiapausing females of Cx. pipiens suggests that this epigenetic mechanism is part of the molecular toolkit regulating diapause.

zoology↗

bioRxiv2018

Astroglia withdraw from potentiated synapses boosting inter-synaptic cross-talk

Extrasynaptic actions of glutamate are limited by high-affinity transporters on perisynaptic astroglial processes (PAPs), which helps to maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodelling, but how this remodelling affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses. Optical glutamate sensors combined with patch-clamp and 3D molecular localisation reveal that LTP induction thus prompts a spatial retreat of glial glutamate transporters, boosting glutamate spillover and NMDA receptor-mediated inter-synaptic cross-talk. The LTP-triggered PAP withdrawal involves NKCC1 transporters and the actin-controlling protein cofilin but does not depend on major Ca2+-dependent cascades in astrocytes. We have therefore uncovered a mechanism by which synaptic potentiation could alter signal handling by multiple nearby connections.

neuroscience↗

bioRxiv2018

Optogenetically induced low-frequency correlations impair perception

Deployment of covert attention to a spatial location can cause large decreases in low-frequency correlated variability among neurons in macaque area V4 whose receptive-fields lie at the attended location. It has been estimated that this reduction accounts for a substantial fraction of the attention-mediated improvement in sensory processing. These estimates depend on assumptions about how population signals are decoded and the conclusion that correlated variability impairs perception, is purely hypothetical. Here we test this proposal directly by optogenetically inducing low-frequency fluctuations, to see if this interferes with performance in an attention-demanding task. We find that low- frequency optical stimulation of neurons in V4 elevates correlations among pairs of neurons and impairs the animals ability to make fine sensory discriminations. Stimulation at higher frequencies does not impair performance, despite comparable modulation of neuronal responses. These results support the hypothesis that attention-dependent reductions in correlated variability contribute to improved perception of attended stimuli.

neuroscience↗

bioRxiv2017

Selectivity matters: rules of thumb for management of plate-sized, sex-changing fish in the live reef food fish trade

Effective management of fisheries depends on the selectivity of different fishing methods, control of fishing effort, and the life history and mating system of the target species. For sex-changing species, it is unclear how the truncation of age structure or selection of specific size or age classes (by fishing for specific markets) affects population dynamics. We specifically address the consequences of plate-sized selectivity, whereby sub-mature, plate-sized fish are preferred in the live reef food fish trade. We use an age-structured model to investigate the decline and recovery of populations fished with three different selectivity scenarios (asymptotic, dome-shaped, and plate-sized) applied to two sexual systems (female-first hermaphroditism and gonochorism). We parameterized our model with life-history data from Brown-marbled grouper (Epinephelus fuscoguttatus) and Napoleon fish (Cheilinus undulatus). Plate-sized selectivity had the greatest negative effect on population trajectories, assuming accumulated fishing effort across ages was equal, while the relative effect of fishing on biomass was greatest with low natural mortality. Fishing such sex-changing species before maturation decreased egg production (and the spawning potential ratio) in two ways: average individual size decreased, and, assuming plasticity, females became males at a smaller size. Somatic growth rate affected biomass if selectivity was based on size-at-age because in slow growers, a smaller proportion of total biomass was vulnerable to fishing. We recommend fisheries avoid taking individuals near their maturation age, regardless of mating system, unless catch is tightly controlled. We also discuss the implications of fishing post-settlement individuals on population dynamics and offer practical management recommendations.

ecology↗