Biology subjects

Frey, E.

Publications and source records attributed to Frey, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Assembly-coupled feedback enables robust control of flagellar number

Bacteria assemble a precise number of flagella to navigate their environment, yet the molecular mechanisms underlying this robust counting remain poorly understood. We propose that robust flagellar number control does not require a strictly conserved transcriptional gene hierarchy, but instead emerges from a conserved network motif in which transcriptional feedback is coupled to the assembly progress of the flagellar C-ring. Specifically, upon C-ring growth, the ATPase FlhG is released from a non-inhibitory FlhG-FliM complex, dimerizes, and inactivates the master regulator FlrA, shutting down early flagellar gene expression. We analyze this assembly-coupled feedback mechanism using stochastic simulations and analytical calculations, revealing a trade-off between robustness to intrinsic fluctuations and to cell-to-cell variability in regulator abundance. Only at the crossover between fast and slow inactivation regimes can robustness to both noise sources be achieved simultaneously. These results provide quantitative, organism-independent insight into flagellar number control and connect to the broader problem of stochastic regulation of absorbing-state statistics.

biophysics↗

bioRxiv2025

Stretchable thin-film metal electronics enabled by multilayered nanomembranes

Metallic thin films are indispensable in flexible electronics, yet their brittleness under tensile strain has impeded their use in intrinsically stretchable devices. Here, we overcome this barrier with a multilayer platform of alternating nanomembranes of metal and porous elastomer assembled via exponential stacking. The porous elastomer layers anchor adjacent metal layers and facilitate vertical percolation. Under strain, they dissipate stress and laterally misalign cracks within successive metal layers, forming crack-bridging conductive pathways. This architecture achieves synergistic scaling of electrical and mechanical performance with increasing layer number, demonstrating bulk-like conductance at strains exceeding 700% across a wide range of metals. Using nanomembrane stacks of gold and platinum, we fabricated stretchable electrode arrays that enabled high-fidelity recordings and electrical stimulation of murine colonic electrophysiology in vivo.

physiology↗

bioRxiv2025

Phase separation strength controls actin filament treadmilling

Cellular motility relies on the dynamic turnover of actin filaments, which treadmill through continuous polymerization at the barbed end and disassembly at the pointed end. Yet, the underlying physical principles remain poorly understood. A long-standing challenge has been experimentally reconstituting stable, persistent treadmilling leading to higher-order actin organization. Here, we reconstitute a minimal in vitro system, in which liquid-liquid phase-separated condensates of zyxin and VASP balance cofilin-driven disassembly to enable persistent treadmilling-like movement of actin bundles. The condensates crosslink filaments into dynamic bundles while promoting barbed-end polymerization. The localized stabilization based on condensate-mediated bundling competes against the activity of cofilin and CAP1, enabling selective disassembly at pointed ends and recycling of monomers. To elucidate the physical basis underlying this emergent behavior, we complement our experiments with agent-based simulations that quantitatively recapitulate key experimental findings. This combined approach demonstrates that an intermediate range of zyxin-VASP self-affinity, driving the phase separation, enables robust treadmilling-like movement. A weakened zyxin-VASP self-affinity fails to stabilize the bundles, whereas an excessive affinity impedes filament dynamics. Experimental reconstitution and theoretical modeling together reveal a physical mechanism by which the material properties of multivalent protein condensates govern cytoskeletal turnover, and suggest a general design principle by which biomolecular condensates can spatiotemporally organize cytoskeletal structures.

biophysics↗

bioRxiv2025

Magnetoelectric nanodiscs diminish motor deficits in a model of Parkinson's disease

Magnetoelectric nanodiscs (MENDs) offer a wireless, minimally invasive route to neuromodulation by converting weak magnetic fields into electric polarization, but their therapeutic applications have remained unrealized. Here, we report the therapeutic development of MENDs for deep brain stimulation (DBS) in the subthalamic nucleus (STN) to alleviate motor deficits in a mouse model of Parkinsons disease. To quantitatively assess therapeutic outcomes, we introduce GaitPattern, a computational pipeline that extracts DBS-induced alterations in salient gait features. Using GaitPattern, we demonstrate that MEND-mediated STN DBS induces motor improvements with precision comparable to clinical electrode-based DBS, while minimizing inflammatory responses associated with the implanted hardware. Notably, MEND-mediated DBS reduces oxidative stress in the brain, a key contributor to neurodegeneration. These findings position MEND-mediated STN DBS as an effective and minimally invasive neuromodulation strategy.

neuroscience↗

bioRxiv2024

Basic interactions responsible for thymus function explain convoluted medulla shape

The thymus is one of the most important organs of the immune system. It is responsible for both the production of T cells and the prevention of their autoimmunity. It comprises two types of tissue: the cortex, where nascent T cells (thymocytes) are generated; and the medulla, embedded within the cortex, where autoreactive thymocytes are eliminated through negative selection. In mice, the medulla exhibits a complex, convoluted morphology, which has raised the question of whether its form impacts its function. Intriguingly, experiments also reveal a reverse dependency: the interactions between medullary stroma and thymocytes shape the medullary structure. However, understanding the underlying mechanisms of medulla morphogenesis emerging from these interactions remains elusive. Here, we present a conceptual theoretical model which shows that central, experimentally verified signaling pathways suffice to shape the convoluted medullary structure. The mathematical analysis of the model explains the observed effects of chemotaxis on thymocyte localization, as well as the reported morphological changes resulting from the modulation of thymocyte production. Our findings reveal that the established cross-talk between medulla growth and negative selection of thymocytes not only regulates medullary volume but also orchestrates the morphology of the thymus medulla. This mechanism of structure formation robustly organizes the medulla in a way that accelerates thymocyte negative selection by improving their chemotactic migration into the medulla. Thereby, we identify a feedback between the function of the thymus medulla and its form. Our theoretical study motivates further experimental analysis of the spatial distribution of thymic cell populations and predicts morphological changes under genetic perturbations.

biophysics↗

bioRxiv2023

Robust and resource-optimal dynamic pattern formation of Min proteins in vivo

The Min system in Escherichia coli plays a crucial role in cellular reproduction by preventing minicell formation through pole-to-pole oscillations. Despite extensive research, predicting the onset of Min protein concentrations for oscillation and understanding the systems robustness under physiological perturbations remains challenging. Our study aims to address these gaps. We show that the Min systems dynamic pattern formation is robust across a wide range of Min protein levels and varying growth physiology. Using genetically engineered E. coli strains, we independently modulated the expression of minCD and minE in E. coli under both fast and slow growth conditions. This led to the construction of a MinD-MinE phase diagram, which revealed not just a large oscillation regime but also complex dynamic patterns such as traveling and standing waves. Interestingly, we found that the natural expression level of Min proteins is nearly optimal. Our work combines experimental findings with biophysical theory based on reaction-diffusion models, reproducing the experimental phase diagram and other key properties quantitatively. This includes the observation of an invariant wavelength of dynamic Min patterns across our phase diagram. Crucially, the success of our model depends on the switching of MinE between its latent and active states, indicating its essential role as a robustness module for Min oscillation in vivo. Our results underline the potential of integrating quantitative cell physiology and biophysical modeling in understanding the fundamental mechanisms controlling cell division machinery, offering insights applicable to other biological processes.

biophysics↗

bioRxiv2023

Relict duck-billed dinosaurs survived into the last age of the dinosaurs in subantarctic Chile

In the dusk of the dinosaur era, the advanced duck-billed dinosaurs (Family Hadrosauridae) are thought to have outcompeted other herbivores, making ecosystems less diverse and more vulnerable to the Cretaceous-Paleogene asteroid impact. They were also among the first terrestrial organisms to disperse from North America into South America. Here, we present the first new species of subantarctic duck-billed dinosaur, CPAP 3054, of early Maastrichtian age in Magallanes, Chile. Surprisingly, unlike duckbills further north in Patagonia, CPAP 3054 is not an advanced duckbill, but descends from North American forms that were transitional to Hadrosauridae, diverging shortly before the origin of this family. In North America, these forms were replaced by hadrosaurids in the late Campanian. The survival into the Maastrichtian of a pre-hadrosaurid lineage suggests the ancestors of CPAP 3054 arrived earlier in South America than the hadrosaurids, reaching further south before the Cretaceous-Paleogene mass extinction, where they avoided competition from hadrosaurids. Additional noteThis work contains a new biological name. New names in preprints are not considered available by the ICZN. To avoid ambiguity, the new biological name is not included in this preprint, and the holotype specimen number CPAP 3054 is used as a placeholder. Paratypes described in this preprint are also used in the diagnosis.

paleontology↗

bioRxiv2022

Control of protein-based pattern formation via guiding cues

Proteins control many vital functions in living cells, such as cell growth and cell division. Reliable coordination of these functions requires the spatial and temporal organizaton of proteins inside cells, which encodes information about the cells geometry and the cell-cycle stage. Such protein patterns arise from protein transport and reaction kinetics, and they can be controlled by various guiding cues within the cell. Here, we review how protein patterns are guided by cell size and shape, by other protein patterns that act as templates, and by the mechanical properties of the cell. The basic mechanisms of guided pattern formation are elucidated with reference to recent observations in various biological model organisms. We posit that understanding the controlled formation of protein patterns in cells will be an essential part of understanding information processing in living systems.

biophysics↗

bioRxiv2021

Directing Min protein patterns with advective bulk flow

The Min proteins constitute the best-studied model system for pattern formation in cell biology. We theoretically predict and experimentally show that the propagation direction of in vitro Min protein patterns can be controlled by a hydrodynamic flow of the bulk solution. We find downstream propagation of Min wave patterns for low MinE:MinD concentration ratios, upstream propagation for large ratios, but multistability of both propagation directions in between. Whereas downstream propagation can be described by a minimal model that disregards MinE conformational switching, upstream propagation can be reproduced by a reduced switch model, where increased MinD bulk concentrations on the upstream side promote protein attachment. Our study demonstrates that a differential flow, where bulk flow advects protein concentrations in the bulk, but not on the surface, can control surface-pattern propagation. This suggests that flow can be used to probe these features and to constrain mathematical models for pattern-forming systems.

biophysics↗

bioRxiv2021

The Time Complexity of Self-Assembly

Time efficiency of self-assembly is crucial for many biological processes. Moreover, with the advances of nanotechnology, time efficiency in artificial self-assembly becomes ever more important. While structural determinants and the final assembly yield are increasingly well understood, kinetic aspects concerning the time efficiency, however, remain much more elusive. In computer science, the concept of time complexity is used to characterize the efficiency of an algorithm and describes how the algorithms runtime depends on the size of the input data. Here we characterize the time complexity of non-equilibrium self-assembly processes by exploring how the time required to realize a certain, substantial yield of a given target structure scales with its size. We identify distinct classes of assembly scenarios, i.e. algorithms to accomplish this task, and show that they exhibit drastically different degrees of complexity. Our analysis enables us to identify optimal control strategies for non-equilibrium self-assembly processes. Furthermore, we suggest an efficient irreversible scheme for the artificial self-assembly of nanostructures, which complements the state-of-the-art approach using reversible binding reactions and requires no fine-tuning of binding energies.

biophysics↗

bioRxiv2021

Tissue flow through pores: a computational study

AO_SCPLOWBSTRACTC_SCPLOWCell migration is of major importance for the understanding of phenomena such as morphogenesis, cancer metastasis, or wound healing. In many of these situations cells are under external confinement. In this work we show by means of computer simulations with a Cellular Potts Model (CPM) that the presence of a bottleneck in an otherwise straight channel has a major influence on the internal organisation of an invading cellular monolayer and the motion of individual cells therein. Comparable to a glass or viscoelastic material, the cell sheet is found to exhibit features of both classical solids and classical fluids. The local ordering on average corresponds to a regular hexagonal lattice, while the relative motion of cells is unbounded. Compared to an unconstricted channel, we observe that a bottleneck perturbs the formation of regular hexagonal arrangements in the epithelial sheet and leads to pile-ups and backflow of cells near the entrance to the constriction, which also affects the overall invasion speed. The scale of these various phenomena depends on the dimensions of the different channel parts, as well as the shape of the funnel domain that connects wider to narrower regions.

biophysics↗

bioRxiv2020

PomX, a ParA/MinD ATPase activating protein, is a triple regulator of cell division in Myxococcus xanthus

Cell division is precisely regulated to generate daughter cells of correct size and shape. In the social bacterium Myxococcus xanthus, the tripartite PomX/Y/Z complex directly stimulates positioning of the cytokinetic FtsZ-ring at midcell to mark the division site. The [~]15 MDa PomX/Y/Z complex associates with the nucleoid in a PomZ-dependent manner, translocates to midcell to stimulate FtsZ-ring formation, and undergoes fission during division. We demonstrate that PomX consists of two functionally distinct domains and has three functions. The N-terminal domain interacts with the ParA/MinD ATPase PomZ and stimulates PomZ ATPase activity. The C-terminal domain mediates PomX self-interaction, interaction to PomY, and serves as a scaffold for PomX/Y/Z complex formation. Moreover, the PomX/PomZ interaction is important for fission. These observations together with previous work support that the architecturally diverse ATPase activating proteins of ParA/MinD ATPases are highly modular and use the same mechanism to activate their cognate ATPase via a short positively charged N-terminal extension.

microbiology↗

bioRxiv2020

Adaptability and evolution of the cell polarization machinery in budding yeast

How can a self-organized cellular function evolve, adapt to perturbations, and acquire new sub-functions? To make progress in answering these basic questions of evolutionary cell biology, we analyze, as a concrete example, the cell polarity machinery of Saccharomyces cerevisiae. This cellular module exhibits an intriguing resilience: it remains operational under genetic perturbations and recovers quickly and reproducibly from the deletion of one of its key components. Using a combination of modeling, conceptual theory, and experiments, we show that multiple, redundant self-organization mechanisms coexist within the protein network underlying cell polarization and are responsible for the modules resilience and adaptability. Based on our mechanistic understanding of polarity establishment, we hypothesize how scaffold proteins, by introducing new connections in the existing network, can increase the redundancy of mechanisms and thus increase the evolvability of other network components. Moreover, our work suggests how a complex, redundant cellular module could have evolved from a more rudimental ancestral form.

evolutionary biology↗

bioRxiv2020

ATP driven diffusiophoresis: active cargo transport without motor proteins

Morphogenesis and homeostasis of biological systems are intricately linked to gradient formation through energy dissipation. Such spatial organization may be achieved via reaction-diffusion or directional cargo transport, as prominently executed by motor proteins. In contrast to these processes that rely on specific protein interactions, active transport based on a non-specific, purely physical mechanism remains poorly explored. Here, by a joint experimental and theoretical approach, we describe a hidden function of the MinDE protein system from E. coli: Besides forming dynamic patterns, this system accomplishes the active transport of large, functionally unrelated cargo on membranes in vitro. Remarkably, this mechanism allows to sort diffusive objects according to their effective size, as evidenced using modular DNA origami-streptavidin nanostructures. We show that the diffusive fluxes of MinDE and cargo couple via density-dependent friction. This non-specific process constitutes a Maxwell-Stefan diffusiophoresis, so far undescribed in a biologically relevant setting. Such nonlinear coupling between diffusive fluxes could represent a generic physical mechanism for the intracellular organization of biomolecules.

biophysics↗

bioRxiv2020

Dynamics of the Bacillus subtilis Min system

Division site selection is a vital process to ensure generation of viable offspring. In many rod-shaped bacteria a dynamic protein system, termed the Min system, acts as a central regulator of division site placement. The Min system is best studied in Escherichia coli where it shows a remarkable oscillation from pole to pole with a time-averaged density minimum at midcell. Several components of the Min system are conserved in the Gram-positive model organism Bacillus subtilis. However, in B. subtilis it is believed that the system forms a stationary bipolar gradient from the cell poles to midcell. Here, we show that the Min system of B. subtilis localizes dynamically to active sites of division, often organized in clusters. We provide physical modelling using measured diffusion constants that describe the observed enrichment of the Min system at the septum. Modelling suggests that the observed localization pattern of Min proteins corresponds to a dynamic equilibrium state. Our data provide evidence for the importance of ongoing septation for the Min dynamics, consistent with a major role of the Min system to control active division sites, but not cell pole areas.

microbiology↗

bioRxiv2020

Bulk-surface coupling reconciles Min-protein pattern formation in vitro and in vivo

Self-organisation of Min proteins is responsible for the spatial control of cell division in Escherichia coli, and has been studied both in vivo and in vitro. Intriguingly, the protein patterns observed in these settings differ qualitatively and quantitatively. This puzzling dichotomy has not been resolved to date. Using reconstituted proteins in laterally wide microchambers with a well-controlled height, we show that the Min protein dynamics on the membrane crucially depend on bulk gradients normal to the membrane. A theoretical analysis shows that in vitro patterns at low bulk height are driven by the same lateral oscillation mode as pole-to-pole oscillations in vivo. At larger bulk height, additional vertical oscillation modes set in, marking the transition to a qualitatively different in vitro regime. Our work qualitatively resolves the Min systems in vivo/in vitro conundrum and provides important insights on the mechanisms underlying protein patterns in bulk-surface coupled systems.

biophysics↗

bioRxiv2020

Drag-induced directionality switching of kinesin-5 Cin8 revealed by cluster-motility analysis

Directed active motion of motor proteins is a vital process in virtually all eukaryotic cells. Nearly a decade ago, the discovery of directionality switching of mitotic kinesin-5 motors challenged the long-standing paradigm that individual kinesin motors are characterized by an intrinsic directionality. While several kinesin motors have now been shown to exhibit context-dependent directionality that can be altered under diverse experimental conditions, the underlying mechanism remains unknown. Here, we studied clustering-induced directionality switching of the mitotic kinesin-5 Cin8, using a fluorescence-based single-molecule motility assay combined with biophysical theory. Based on the detailed characterization of the motility of single motors and clusters of Cin8, we developed a predictive molecular model, that quantitatively agrees with experimental data. This combined approach allowed us to quantify the response of Cin8 motors to external forces as well as the interactions between Cin8 motors, and thereby develop a detailed understanding of the molecular mechanism underlying directionality switching. The main insight is that directionality switching is caused by a single feature of Cin8: an asymmetric response of active motion to forces that oppose motion, here referred to as drag. This general mechanism explains why bidirectional motor proteins are capable of reversing direction in response to seemingly unrelated experimental factors including clustering, changes in the ionic strength of the buffer, increased motor density and molecular crowding, and in motility assays. Significance StatementKinesin-5 motor proteins perform essential functions in chromosome segregation during mitotic cell division. Surprisingly, several kinesin-5 motors have the ability to reverse directionality under different experimental conditions, which contradicts the long-standing paradigm that individual kinesin motors are characterized by an intrinsic directionality. The mechanism underlying this ability to switch directionality has remained elusive. Here, we combine fluorescence-based motility assays and theoretical modeling to analyze cluster-size-dependent motility of the bidirectional kinesin-5 Cin8. Our results show that bidirectional motors can switch directionality because they exhibit an asymmetric response of active motion to drag. This mechanism explains multiple seemingly unrelated experimental factors that have been shown to cause directionality switching of kinesin motors.

biophysics↗

bioRxiv2019

Cell based strain stiffening of a non-fibrous matrix as organizing principle for morphogenesis

Endothelial tube formation on a reconstituted extracellular matrix (Matrigel) is a well-established in vitro model for studying the processes of angiogenesis and vasculogenesis. However, to date, the organizing principles that underlie the morphogenesis of this network, and that shape the initial process of cell-cell finding remain elusive. Furthermore, it is unclear how in vitro results extrapolate to in vivo morphogenesis. Here, we identify a mechanism that allows cells to form networks by mechanically reorganizing and stiffening their extracellular matrix, independent of chemical guidance cues. Interestingly, we find that this cellular self-organization strongly depends on the connectivity and topology of the surrounding matrix, as well as on cell contractility and cell density. Cells rearrange the matrix, and form bridges of matrix material that are stiffer than their surroundings, thus creating a durotactic track for the initiation of cell-cell contacts. This contractility-based communication via strain stiffening and matrix rearrangement might be a general organizing principle during tissue development or regeneration.\n\nSignificance StatementIn addition to chemotactic gradients, biomechanical cues are important for guiding biological pattern formation. Self-assembly of cells has often been ascribed to reorganization of collagen fibres in the extracellular matrix. However, the basement membrane surrounding vascular cells, is per se non-fibrous. Here, we find that this difference in matrix topology can crucially influence cell behaviour and pattern formation. In a homogeneously elastic environment like the basement membrane, endothelial cells rearrange extracellular matrix proteins by contractile force, forming stiff intercellular bridges as tracks for cell-cell contacts. Our findings shine some light why there is a lot of merit in having multiple approaches to matrix elasticity (like continuum theories or dilated network approaches). Our observations might help to understand why vascular nets look different in different tissues and after rearrangement of the extracellular matrix during disease.

cell biology↗