Biology subjects

Stevenson, T.

Publications and source records attributed to Stevenson, T..

10 recordsLinked to original sources

bioRxiv2026

HIDE-Deconv: A hierarchical deconvolution framework for multiscale characterization of cellular remodeling

Most deconvolution methods estimate cellular composition at a single level of cellular resolution despite biological processes often manifesting within fine-grained cellular subpopulations. We present HIDE-Deconv, a hierarchical deconvolution framework that jointly optimizes cellular compositions across multiple levels of a cell-type hierarchy while maintaining consistency between resolutions. In benchmark experiments, HIDE-Deconv achieved the highest overall predictive performance among evaluated methods. Analyses of lung adenocarcinoma, sepsis, COVID-19 and systemic lupus erythematosus revealed biologically relevant cellular remodeling that remained concealed at broader levels of cellular resolution. HIDE-Deconv is available as an open-source framework at https://github.com/dvoelkl/HIDE-deconv.

bioinformatics↗

bioRxiv2025

Population-level temporal decoding and dynamical structure in frontostriatal circuits during decision making

Perceptual decisions unfold over time, requiring neural circuits to evaluate sensory evidence, track elapsed time, and commit to an action. To investigate how these computations are distributed across corticostriatal circuits, we recorded large-scale neural population activity using Neuropixels probes in the rat frontal orienting field (FOF) and anterior dorsal striatum (ADS) during a free-response auditory change detection task. Both regions exhibited structured, highly dynamic population activity during task performance. Using single-trial population decoding, we found that both FOF and ADS robustly encoded retrospective time from stimulus onset and prospective time preceding the decision report. Using a new approach to analyze temporal encoding to identify the dynamical structure supporting decoding, we found that time encoding could be decomposed into two primary dynamical motifs: monotonic ramp-like trajectories and transient bump-like trajectories. While these modes were similarly expressed during early evidence evaluation, FOF exhibited more pronounced decision-aligned changes near the time of the decision report, possibly reflecting a state transition at commitment. Population geometry analyses further revealed stable low-dimensional subspaces during evidence evaluation that transitioned at decision commitment, with significantly larger subspace changes in FOF than ADS. Together, these results reveal a common dynamical framework during evidence evaluation across corticostriatal circuits, while identifying a selective reorganization of FOF dynamics associated with decision commitment.

neuroscience↗

bioRxiv2025

Time-adaptive modulation of evidence evaluation in rat posterior parietal cortex

A crucial component of successful decision making is determining the optimal timescale over which to evaluate evidence. For example, when detecting transient changes in the environment, it is best to focus evaluation on the current evidence as opposed to older evidence. However, it is unclear how this adjustment in timescale is achieved in the brain in terms of how the neurons that process evidence adjust their dynamics. To address this question, we used Neuropixel probes to record spiking activity from neurons in the posterior parietal cortex (PPC) of rats performing a free-response auditory change detection task in which subjects evaluate sensory evidence over short timescales to determine when a change occurs in a noisy sensory stream. Consistent with longer timescale temporal integration tasks, we found that PPC neurons modulated their activity by the strength of evidence leading to decisions, were selective for the rats choices, and had opposing populations of neurons that were positively versus negatively modulated by evidence. However, in contrast to temporal integration tasks, responses of neurons to individual pulses of evidence were transient, such that the effect of the evidence on activity tapered off over a timescale corresponding to the subjects behavioral timescale of evidence evaluation. Intriguingly, PPC also exhibited "gain changes" in the influence of evidence as a function of decision time that were consistent with changes in behavioral urgency. In addition, reversible inactivation revealed an important role for PPC in this auditory change detection, such that PPC inactivation altered choice behavior and the timescale over which rats evaluated evidence. Together, our results suggest important contributions of PPC to free-response decisions that involve adjusting timescales of evidence evaluation.

neuroscience↗

bioRxiv2025

FlickerPrint: An Analysis Package for Measuring Interfacial Tension and Bending Rigidity of Biomolecular Condensates and Vesicles at Scale

1 In BriefWilliamson, Law et. al. present FlickerPrint, a computational analysis tool which can be used for measuring the interfacial tension and bending rigidity of soft fluctuating bodies, including biomolecular condensates, droplets or vesicles, from confocal microscopy images using flicker spectroscopy. This method is highly scalable so can be used to analyse the properties of whole populations of thousands of such soft bodies. 2 MotivationBiomolecular condensates play fundamental roles in sub-cellular organisation and it is well-known that the composition of condensates can affect their function. Measuring the conden-sates mechanical properties (for example, interfacial tension and bending rigidity) can aid the understanding of their biomolecular composition and cellular functions. However, measuring the properties of individual condensates under physiological conditions is very challenging and cum-bersome to scale to the population level using traditional methods. To overcome these issues, we have developed a software package to run flicker spectroscopy analysis of condensates at scale, to determine their interfacial tension and bending rigidity. At the same time, FlickerPrint can be harnessed to analyse other soft, fluctuating bodies such as lipid vesicles. 3 SummaryAccurate measurement of the mechanical properties of biomolecular condensates is an essential step in understanding their behaviour within cells. We present FlickerPrint, an open-source Python package to determine the interfacial tension and bending rigidity of thousands of biomolecular condensates using flicker spectroscopy by analysing their shape fluctuations in confocal microscopy images. We detail the workflow used by FlickerPrint to scale up these individual measurements to the population level and the computational requirements to run Flicker-Print. We provide examples of experiments in live cells and in vitro which are suitable for analysis with FlickerPrint as well as scenarios where the package cannot be used. Using these examples, we show that the results obtained from the analysis are robust to changes in the imaging setup, including frame rate. This implementation enables a step-change in the capability to measure two key properties of biomolecular condensates, the interfacial tension and bending rigidity. Moreover, the tools in FlickerPrint are also applicable for analysing other soft, fluctuating bodies, which we demonstrate here using vesicles.

cell biology↗

bioRxiv2023

FSHβ links photoperiodic signalling to seasonal reproduction in Japanese quail

Annual cycles in daylength provide an initial predictive environmental cue that plants and animals use to time seasonal biology. Seasonal changes in photoperiodic information acts to entrain endogenous programs in physiology to optimize an animals fitness. Attempts to identify the neural and molecular substrates of photoperiodic time measurement in birds have, to date, focussed on blunt changes in light exposure during a restricted period of photoinducibility. The objectives of these studies were first to characterise a molecular seasonal clock in Japanese quail and second, to identify the key transcripts involved in endogenously generated interval timing that underlies photosensitivity in birds. We hypothesized that the mediobasal hypothalamus (MBH) provides the neuroendocrine control of photoperiod-induced changes in reproductive physiology, and that the pars distalis of the pituitary gland contains an endogenous internal timer for the short photoperiod dependent development of reproductive photosensitivity. Here we report distinct seasonal waveforms of transcript expression in the MBH, and pituitary gland and discovered the patterns were not synchronized across tissues. Follicle-stimulating hormone-{beta} (FSH{beta}) expression increased during the simulated spring equinox, prior to photoinduced increases in prolactin, thyrotropin-stimulating hormone-{beta} and testicular growth. Diurnal analyses of transcript expression showed sustained elevated levels of FSH{beta} under conditions of the spring equinox, compared to autumnal equinox, short (<12L) and long (>12L) photoperiods. FSH{beta} expression increased in quail held in non-stimulatory short photoperiod, indicative of the initiation of an endogenously programmed interval timer. These data identify that FSH{beta} establishes a state of photosensitivity for the external coincidence timing of seasonal physiology. The independent regulation of FSH{beta} expression provides an alternative pathway through which other supplementary environmental cues, such as temperature, can fine tune seasonal reproductive maturation and involution.

zoology↗

bioRxiv2023

An integrated RNA-proteomic landscape of drug induced senescence in a cancer cell line

Senescent cells are characterized by an arrest in proliferation. In addition to replicative senescence resulting from telomere exhaustion, sub-lethal genotoxic stress resulting from DNA damage, oncogene activation, mitochondrial dysfunction or reactive metabolites also elicits a senescence phenotype. Senescence is a controlled programme affecting a wide variety of biological processes with some core hallmarks of senescence as well as tissue specific changes. This study presents an integrative multi-omic analysis of proteomic and RNA-seq from proliferating and senescent osteosarcoma cells. This study demonstrates senescence induction in a widely used cell line which can be used as a model system for characterising cancer cell responses to sub-lethal doses of chemotherapeutic agents, and makes available both RNA-seq and proteomic data from proliferating and senescent cells in open access repositories to aid reuse by the community.

cell biology↗

bioRxiv2021

Investigating Regional Specificity of Alzheimers Disease Pathology in the 5xFAD Mouse Model

Alzheimers disease (AD) is a neurodegenerative disease that affects cognition and memory. Mouse models such as 5xFAD, incorporate mutations found in familial or early-onset (EOAD) AD; these mutations increase the production of the toxic AB species that contributes to plaque formation in the brain. However, not all brain regions in the 5xAD animals accumulate plaques to the same degree. For example, the cerebellum appears to be resistant to AB plaque formation, while other regions such as the cortex and subiculum develop copious plaques. The mechanism(s) underlying this regional specificity remains unclear. Thus, we used a fluorescent antibody to APP/AB to quantify the amount of these proteins in several brain regions of interest, including subiculum, cortex, and cerebellum. We found that the cerebellum had less APP/AB than the other regions quantified, which demonstrates a correlation between the levels of APP/AB and plaque formation. Taken together, this suggests that the regional specificity of AD pathology may be a result of different levels of protein expression.

neuroscience↗

bioRxiv2020

Change point detection with multiple alternatives reveals parallel evaluation of the same stream of evidence along distinct timescales

In order to behave appropriately in a rapidly changing world, individuals must be able to detect when changes occur in that environment. However, at any given moment, there are a multitude of potential changes of behavioral significance that could occur. Here we investigate how knowledge about the space of possible changes affects human change point detection. We used a stochastic auditory change point detection task that allowed model-free and model-based characterization of the decision process people employ. We found that subjects can simultaneously apply distinct timescales of evidence evaluation to the same stream of evidence when there are multiple types of changes possible. Informative cues that specified the nature of the change led to improved accuracy for change point detection through mechanisms involving both the timescales of evidence evaluation and adjustments of decision bounds. These results establish three important capacities of information processing for decision making that any proposed neural mechanism of evidence evaluation must be able to support: the ability to simultaneously employ multiple timescales of evidence evaluation, the ability to rapidly adjust those timescales, and the ability to modify the amount of information required to make a decision in the context of flexible timescales.

neuroscience↗

bioRxiv2020

Drug and siRNA screens identify ROCK2 as a therapeutic target for ciliopathies.

Primary cilia are microtubule-based organelles that act as cellular antennae to mediate vertebrate development and growth factor signalling. Defects in primary cilia result in a group of inherited developmental conditions known as ciliopathies. Ciliopathies often present with cystic kidney disease, a major cause of early renal failure that requires renal replacement therapies. Currently, only one drug, Tolvaptan, is licensed to slow the decline of renal function for the ciliopathy polycystic kidney disease. Novel therapeutic interventions for these conditions remain a pressing clinical need. We screened clinical development compounds for positive effects on cilia formation and function and identified fasudil hydrochloride as the top hit. Fasudil is a generic, off-patent drug that is a potent but broadly selective Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor. In a parallel whole genome siRNA-based reverse genetics phenotypic screen of positive modulators of cilia formation, we identified ROCK2 as the target molecule. We demonstrate that ROCK2 is a key mediator of cilium formation and function through effects on actin cytoskeleton remodelling. Our results indicate that specific ROCK2 inhibitors such as belumosudil (KD-025) could be repurposed for pharmacological intervention in cystic kidney disease. We propose that ROCK2 inhibition represents a novel, disease-modifying therapeutic approach for heterogeneous ciliopathies.

cell biology↗

bioRxiv2020

Vanishing white matter disease expression of truncated EIF2B5 activates induced stress response

Vanishing White Matter disease (VWM) is a severe leukodystrophy of the central nervous system caused by mutations in subunits of the eukaryotic initiation factor 2B complex (eIF2B). Current models only partially recapitulate key disease features, and pathophysiology is poorly understood. Through development and validation of zebrafish (Danio rerio) models of VWM, we demonstrate that zebrafish eif2b mutants phenocopy VWM, including impaired somatic growth, early lethality, impaired myelination, loss of oligodendrocyte precursor cells, increased apoptosis in the CNS, and impaired motor swimming behavior. Expression of human EIF2B2 in the zebrafish eif2b2 mutant rescues lethality and CNS apoptosis, demonstrating conservation of function between zebrafish and human. In the mutants, intron 12 retention leads to expression of a truncated eif2b5 transcript. Expression of the truncated eif2b5 in wild-type larva impairs motor behavior and activates the ISR, suggesting that a feed-forward mechanism in VWM is a significant component of disease pathophysiology.

physiology↗