Biology subjects

Dinner, A.

Publications and source records attributed to Dinner, A..

9 recordsLinked to original sources

bioRxiv2026

Learning activator-inhibitor dynamics at the cell cortex with neural likelihood ratio estimation

A key question in cell biology is how cell-scale organization emerges from a given set of molecular players and rules of interaction. Given its multiscale nature, addressing this question requires a combination of experimental perturbation, mathematical modeling, and parameter inference. We leverage recent advances in each of these fields, focusing in particular on neural-network methods for simulation-based inference, to study how cell-scale patterns of Rho GTPase activity are defined by molecular-scale activator-inhibitor interactions with filamentous actin. Using an existing model of this interaction, we demonstrate that an over-expressive, regularized classification neural network can approximate the likelihood of data arising from a particular parameter set. We show that variations in F-actin assembly dynamics can be inferred directly from experimental data, but only if the network is made less sensitive to model misspecification. We use our approach to interpret perturbation experiments in which increasing RhoGAP coexpression increases the frequency and coherence of Rho activity waves in frog eggs. After showing that the known functions of RhoGAP are insufficient to explain experimentally-observed dynamics, we use neural methods to suggest an alternative pathway by which RhoGAP could decrease filament nucleation rates to sustain waves. Our work yields specific, experimentally-testable predictions and illustrates how a combination of traditional forward models and modern inference tools can aid in unraveling mechanisms of self-organization.

systems biology↗

bioRxiv2026

An underlying bistability sets amplitude and explains temperature compensation in the cyanobacterial circadian clock

Circadian clocks create free-running biological rhythms with a period close to 24 hours. A universal property of these systems is temperature compensation, where the period of oscillation remains nearly invariant even as the amplitude changes with temperature. In the cyanobacterial system, where the core oscillator can be reconstituted from purified KaiABC proteins, we identify a key temperature-dependent positive feedback process: antagonism between KaiA and KaiB creates a bistable switch in protein-protein interaction. The region of bistability is strongly temperature dependent and correlated with oscillator amplitude. Combining this bistable mechanism with the temperature scaling of phosphorylation and dephosphorylation rates in a mathematical model recapitulates the overall temperature compensation of the oscillator. This capacity for history-dependent switching suggests that bistable dynamics underpin the generation of circadian rhythms. Significance StatementCircadian clocks are biological oscillators that anticipate the day-night cycle. The 24-hour time scale of the clock is remarkably insensitive to temperature owing to compensatory changes in amplitude and speed with temperature. In the cyanobacterial clock, we identify a bistability of the protein interaction network which determines oscillator amplitude and depends strongly on temperature, balancing the temperature dependence of dephosphorylation rates. This bistability indicates that oscillations arise from a combination of positive and negative feedback loops, a design principle used to maintain temperature compensation.

biophysics↗

bioRxiv2025

Actin network heterogeneity tunes activator-inhibitor dynamics at the cell cortex

Biological systems can display diverse patterns of self-organization, even when built on conserved networks of interaction between molecular species. In these cases, reaction-diffusion equations provide a valuable tool to learn how new dynamics could emerge from quantitative tuning of parameters. Bringing these models into quantitative correspondence with biological data remains an outstanding challenge, especially when the data manifest heterogeneities that are difficult to account for mathematically. One particular example occurs in cell biology, where the membrane-bound regulatory protein RhoA interacts with the filamentous actin cortex in an activator-inhibitor loop. Though this core biochemical circuit is conserved across multiple cell types in different organisms, it produces different patterns of RhoA activity in different contexts, from traveling waves in starfish to transient pulses in C. elegans. To understand how this variation emerges, we develop an activator-inhibitor model that accounts explicitly for actin assembly and heterogeneity. By fitting the model to summary statistics of experimental data, subject to known parameter constraints, we show that F-actin assembly dynamics tune the spatiotemporal patterns of RhoA activity. A minimal representation of these dynamics reveals how directional transport (via polymerization) combines with stochasticity in F-actin number and orientation to produce the observed patterns. This work sheds light on how phenotypic diversity arises from heterogeneity and anisotropy, with important implications for the next generation of activator-inhibitor models. SignificanceTo divide, move, and polarize, cells must self-organize their constituent proteins into large-scale patterns with varied spatiotemporal character. The design principles of this process remain poorly understood, primarily because quantitatively matching mathematical models to experimental data is difficult. Here we consider pattern formation from two constituents on the cell cortex: the regulatory protein RhoA and actin filaments. Using a mathematical model, constrained quantitatively by data from multiple organisms, we show how diversity in RhoA activity can arise from intra- and inter-organismal changes in actin filament architecture and assembly dynamics. Our results reveal general principles for pattern formation at the cortex, and our combination of data analysis, modeling, and parameter inference provides a broadly-applicable, interdisciplinary methodology to unravel mechanisms of self-organization.

cell biology↗

bioRxiv2025

Light-induced reversible assembly and actuation in ultrafast Ca2+-driven chemomechanical protein networks

Programming rapid, repeatable motions in soft materials has remained a challenge in active matter and biomimetic design. Here, we present a light-controlled chemomechanical network based on Tetrahymena thermophila calcium-binding protein 2 (Tcb2), a Ca2+-sensitive contractile protein. These networks--driven by Ca2+-triggered structural rearrangements--exhibit dynamic selfassembly, spatiotemporal growth, and contraction rates comparable to actomyosin systems. By coupling light-sensitive chelators for optically triggered Ca2+ release, we achieve precise growth and repeatable mechanical contractility of Tcb2 networks, revealing emergent phenomena such as boundary-localized active regions and density gradient-driven reversals in motion. A coupled reaction-diffusion and elastic model explains these dynamics, highlighting the interplay between chemical network assembly and mechanical response. We further demonstrate active transport of particles via network-mediated forces in vitro and implement reinforcement learning to program seconds-scale spatiotemporal actuation in silico. These results establish a platform for designing responsive active materials with rapid chemomechanical dynamics and tunable optical control, with applications in synthetic cells, sub-cellular force generation, and programmable biomaterials.

bioengineering↗

bioRxiv2025

Microscopic Control of Cortical Flows in Polarized C. elegans Zygotes

Cell polarization, migration, and cytokinesis rely on flows of the cell cortex, a network of actin filaments, cross-linkers, and motors beneath the plasma membrane of animal cells. While actin network architecture, assembly dynamics, and motor activity are known to be important for cortical flows, how their modulation tunes macroscopic flow dynamics remains poorly quantified in vivo. Here, we use quantitative microscopy to constrain agent-based simulations that account for filament assembly, crosslinking, and motor activity. We calibrate the model to reproduce steady-state flows in polarized C. elegans zygotes and then challenge it to predict the results of RNA interference (RNAi) experiments. Our model predicts, and experiments largely confirm, a biphasic dependence of flow speed on microscopic rates of actin filament assembly and crosslinking. This biphasic dependence reflects a competition between the tendencies of perturbations to disrupt both transmission of and resistance to cortical forces. Our results provide new insights into how variations in microscopic features shape the emergent dynamics of the cell cortex. By establishing a well-calibrated model of cortical flow in a highly tractable model cell, we also provide a foundation for future studies of microscopic origins and biological control of cortical contractility and flow in vivo.

cell biology↗

bioRxiv2024

Chronic infections can generate SARS-CoV-2-like bursts of viral evolution without epistasis

Multiple SARS-CoV-2 variants have arisen during the first years of the pandemic, often bearing many new mutations. Several explanations have been offered for the surprisingly sudden emergence of multiple mutations that enhance viral fitness, including cryptic transmission, spillover from animal reservoirs, epistasis between mutations, and chronic infections. Here, we simulated pathogen evolution combining within-host replication and between-host transmission. We found that, under certain conditions, chronic infections can lead to SARS-CoV-2-like bursts of mutations even without epistasis. Chronic infections can also increase the global evolutionary rate of a pathogen even in the absence of clear mutational bursts. Overall, our study supports chronic infections as a plausible origin for highly mutated SARS-CoV-2 variants. More generally, we also describe how chronic infections can influence pathogen evolution under different scenarios.

evolutionary biology↗

bioRxiv2024

Temperature-Dependent Fold-Switching Mechanism of the Circadian Clock Protein KaiB

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this post-translational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB [->] fsKaiB transition is nearly three times smaller than that for the reverse transition. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both subglobally and near-globally unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.

biochemistry↗

bioRxiv2023

Dietary Restriction Impacts Peripheral Circadian Clock Output Important for Longevity in Drosophila

Circadian clocks may mediate lifespan extension by caloric or dietary restriction (DR). We find that the core clock transcription factor Clock is crucial for a robust longevity and fecundity response to DR in Drosophila. To identify clock-controlled mediators, we performed RNA-sequencing from abdominal fat bodies across the 24 h day after just 5 days under control or DR diets. In contrast to more chronic DR regimens, we did not detect significant changes in the rhythmic expression of core clock genes. Yet we discovered that DR induced de novo rhythmicity or increased expression of rhythmic clock output genes. Network analysis revealed that DR increased network connectivity in one module comprised of genes encoding proteasome subunits. Adult, fat body specific RNAi knockdown demonstrated that proteasome subunits contribute to DR-mediated lifespan extension. Thus, clock control of output links DR-mediated changes in rhythmic transcription to lifespan extension.

genetics↗

bioRxiv2020

Actin crosslinker competition and sorting drive emergent GUV size-dependent actin network architecture

How complex actin network architectures arise and coexist in membrane-enclosed cell environment remains unknown. By encapsulating actin and crosslinking proteins -actinin and fascin in giant unilamellar vesicles (GUVs), we show that physical confinement and its size can lead to formation of complex actin structures, including rings and asters at GUV peripheries and centers. Strikingly, we find that the materials properties of the aster structures depend on the ratio of the relative concentrations of -actinin and fascin, and we demonstrate that this results from -actinin and fascin sorting into separate domains in the structures. We complement our experiments with molecular simulations that capture the spontaneous formation of competing network architectures; these provide a microscopic view of the dynamics and delineate the molecular features that promote sorting. We propose that the observed boundary-imposed effect on protein sorting is a general mechanism for creating emergent structures in biopolymer networks with multiple crosslinkers.

biophysics↗