Machine learning interpretable models of cell mechanics from protein images.

Cellular form and function emerge from complex mechanochemical systems within the cytoplasm. Currently, no systematic strategy exists to infer large-scale physical properties of a cell from its molecular components. This is an obstacle to understanding processes such as cell adhesion and migration. Here, we develop a data-driven modeling pipeline to learn the mechanical behavior of adherent cells. We first train neural networks to predict cellular forces from images of cytoskeletal proteins. Strikingly, experimental images of a single focal adhesion (FA) protein, such as zyxin, are sufficient to predict forces and can generalize to unseen biological regimes. Using this observation, we develop two approaches-one constrained by physics and the other agnostic-to construct data-driven continuum models of cellular forces. Both reveal how cellular forces are encoded by two distinct length scales. Beyond adherent cell mechanics, our work serves as a case study for integrating neural networks into predictive models for cell biology.

Task-driven neural network models predict neural dynamics of proprioception.

Proprioception tells the brain the state of the body based on distributed sensory neurons. Yet, the principles that govern proprioceptive processing are poorly understood. Here, we employ a task-driven modeling approach to investigate the neural code of proprioceptive neurons in cuneate nucleus (CN) and somatosensory cortex area 2 (S1). We simulated muscle spindle signals through musculoskeletal modeling and generated a large-scale movement repertoire to train neural networks based on 16 hypotheses, each representing different computational goals. We found that the emerging, task-optimized internal representations generalize from synthetic data to predict neural dynamics in CN and S1 of primates. Computational tasks that aim to predict the limb position and velocity were the best at predicting the neural activity in both areas. Since task optimization develops representations that better predict neural activity during active than passive movements, we postulate that neural activity in the CN and S1 is top-down modulated during goal-directed movements.

Shaping Organs: Shared Structural Principles Across Kingdoms.

Development encapsulates the morphogenesis of an organism from a single fertilized cell to a functional adult. A critical part of development is the specification of organ forms. Beyond the molecular control of morphogenesis, shape in essence entails structural constraints and thus mechanics. Revisiting recent results in biophysics and development, and comparing animal and plant model systems, we derive key overarching principles behind the formation of organs across kingdoms. In particular, we highlight how growing organs are active rather than passive systems and how such behavior plays a role in shaping the organ. We discuss the importance of considering different scales in understanding how organs form. Such an integrative view of organ development generates new questions while calling for more cross-fertilization between scientific fields and model system communities.

Cell Sheet Morphogenesis: Dorsal Closure in Drosophila melanogaster as a Model System.

Dorsal closure is a key process during Drosophila morphogenesis that models cell sheet movements in chordates, including neural tube closure, palate formation, and wound healing. Closure occurs midway through embryogenesis and entails circumferential elongation of lateral epidermal cell sheets that close a dorsal hole filled with amnioserosa cells. Signaling pathways regulate the function of cellular structures and processes, including Actomyosin and microtubule cytoskeletons, cell-cell/cell-matrix adhesion complexes, and endocytosis/vesicle trafficking. These orchestrate complex shape changes and movements that entail interactions between five distinct cell types. Genetic and laser perturbation studies establish that closure is robust, resilient, and the consequence of redundancy that contributes to four distinct biophysical processes: contraction of the amnioserosa, contraction of supracellular Actomyosin cables, elongation (stretching?) of the lateral epidermis, and zipping together of two converging cell sheets. What triggers closure and what the emergent properties are that give rise to its extraordinary resilience and fidelity remain key, extant questions.

Multiscale Structure and Function of the Aortic Valve Apparatus.

While studying the aortic valve in isolation has facilitated the development of life-saving procedures and technologies, the dynamic interplay of the aortic valve and its surrounding structures is vital to preserving their function across the wide range of conditions encountered in an active lifestyle. Our view is that these structures should be viewed as an integrated functional unit, herein referred to as the aortic valve apparatus (AVA). The coupling of the aortic valve and root, left ventricular outflow tract, and blood circulation is crucial for AVA's functions: unidirectional flow out of the left ventricle, coronary perfusion, reservoir function, and supporting left ventricular function. In this review, we explore the multiscale biological and physical phenomena that underly the simultaneous fulfilment of these functions. A brief overview of the tools used to investigate the AVA is included, such as: medical imaging modalities, experimental methods, and computational modelling, specifically fluid-structure interaction (FSI) simulations, is included. Some pathologies affecting the AVA are explored, and insights are provided on treatments and interventions that aim to maintain quality of life. The concepts explained in this paper support the idea of AVA being an integrated functional unit and help identify unanswered research questions. Incorporating phenomena through the molecular, micro, meso and whole tissue scales is crucial for understanding the sophisticated normal functions and diseases of the AVA.

Optical coherence tomography-guided Brillouin microscopy highlights regional tissue stiffness differences during anterior neural tube closure in the Mthfd1l murine mutant.

Neurulation is a highly synchronized biomechanical process leading to the formation of the brain and spinal cord, and its failure leads to neural tube defects (NTDs). Although we are rapidly learning the genetic mechanisms underlying NTDs, the biomechanical aspects are largely unknown. To understand the correlation between NTDs and tissue stiffness during neural tube closure (NTC), we imaged an NTD murine model using optical coherence tomography (OCT), Brillouin microscopy and confocal fluorescence microscopy. Here, we associate structural information from OCT with local stiffness from the Brillouin signal of embryos undergoing neurulation. The stiffness of neuroepithelial tissues in Mthfd1l null embryos was significantly lower than that of wild-type embryos. Additionally, exogenous formate supplementation improved tissue stiffness and gross embryonic morphology in nullizygous and heterozygous embryos. Our results demonstrate the significance of proper tissue stiffness in normal NTC and pave the way for future studies on the mechanobiology of normal and abnormal embryonic development.

The shape of Nature's stingers revealed.

Stinger-like structures in living organisms evolved convergently across taxa for both defensive and offensive purposes, with the main goal being penetration and damage. Our observations over a broad range of taxa and sizes, from microscopic radiolarians to narwhals, reveal a self-similar geometry of the stinger extremity: the diameter (d) increases along the distance from the tip (x) following a power law [Formula: see text] , with the tapering exponent varying universally between 2 and 3. We demonstrate, through analytical and experimental mechanics involving three-dimensional (3D) printing, that this geometry optimizes the stinger's performance; it represents a trade-off between the propensity to buckle, for n smaller than 2, and increased penetration force, for n greater than 3. Moreover, we find that this optimal tapering exponent does not depend on stinger size and aspect ratio (base diameter over length). We conclude that for Nature's stingers, composed of biological materials with moduli ranging from hundreds of megapascals to ten gigapascals, the necessity for a power-law contour increases with sharpness to ensure sufficient stability for penetration of skin-like tissues. Our results offer a solution to the puzzle underlying this universal geometric trait of biological stingers and may provide a new strategy to design needle-like structures for engineering or medical applications.

Buckling-induced sound production in the aeroelastic tymbals of Yponomeuta.

The loss of elastic stability (buckling) can lead to catastrophic failure in the context of traditional engineering structures. Conversely, in nature, buckling often serves a desirable function, such as in the prey-trapping mechanism of the Venus fly trap (Dionaea muscipula). This paper investigates the buckling-enabled sound production in the wingbeat-powered (aeroelastic) tymbals of Yponomeuta moths. The hindwings of Yponomeuta possess a striated band of ridges that snap through sequentially during the up- and downstroke of the wingbeat cycle-a process reminiscent of cellular buckling in compressed slender shells. As a result, bursts of ultrasonic clicks are produced that deter predators (i.e. bats). Using various biological and mechanical characterization techniques, we show that wing camber changes during the wingbeat cycle act as the single actuation mechanism that causes buckling to propagate sequentially through each stria on the tymbal. The snap-through of each stria excites a bald patch of the wing's membrane, thereby amplifying sound pressure levels and radiating sound at the resonant frequencies of the patch. In addition, the interaction of phased tymbal clicks from the two wings enhances the directivity of the acoustic signal strength, suggesting an improvement in acoustic protection. These findings unveil the acousto-mechanics of Yponomeuta tymbals and uncover their buckling-driven evolutionary origin. We anticipate that through bioinspiration, aeroelastic tymbals will encourage novel developments in the context of multi-stable morphing structures, acoustic structural monitoring, and soft robotics.

Effect of skull morphology on fox snow diving.

Certain fox species plunge-dive into snow to catch prey (e.g., rodents), a hunting mechanism called mousing. Red and arctic foxes can dive into snow at speeds ranging between 2 and 4 m/s. Such mousing behavior is facilitated by a slim, narrow facial structure. Here, we investigate how foxes dive into snow efficiently by studying the role of skull morphology on impact forces it experiences. In this study, we reproduce the mousing behavior in the lab using three-dimensional (3D) printed fox skulls dropped into fresh snow to quantify the dynamic force of impact. Impact force into snow is modeled using hydrodynamic added mass during the initial impact phase. This approach is based on two key facts: the added mass effect in granular media at high Reynolds numbers and the characteristics of snow as a granular medium. Our results show that the curvature of the snout plays a critical role in determining the impact force, with an inverse relationship. A sharper skull leads to a lower average impact force, which allows foxes to dive head-first into the snow with minimal tissue damage.

It pays to follow the leader: Metabolic cost of flight is lower for trailing birds in small groups.

Many bird species commonly aggregate in flocks for reasons ranging from predator defense to navigation. Available evidence suggests that certain types of flocks-the V and echelon formations of large birds-may provide a benefit that reduces the aerodynamic cost of flight, whereas cluster flocks typical of smaller birds may increase flight costs. However, metabolic flight costs have not been directly measured in any of these group flight contexts [Zhang and Lauder, J. Exp. Biol. 226, jeb245617 (2023)]. Here, we measured the energetic benefits of flight in small groups of two or three birds and the requirements for realizing those benefits, using metabolic energy expenditure and flight position measurements from European Starlings flying in a wind tunnel. The starlings continuously varied their relative position during flights but adopted a V formation motif on average, with a modal spanwise and streamwise spacing of [0.81, 0.91] wingspans. As measured via CO2 production, flight costs for follower birds were significantly reduced compared to their individual solo flight benchmarks. However, followers with more positional variability with respect to leaders did less well, even increasing their costs above solo flight. Thus, we directly demonstrate energetic costs and benefits for group flight followers in an experimental context amenable to further investigation of the underlying aerodynamics, wake interactions, and bird characteristics that produce these metabolic effects.

Liquid-like condensates mediate competition between actin branching and bundling.

Cellular remodeling of actin networks underlies cell motility during key morphological events, from embryogenesis to metastasis. In these transformations, there is an inherent competition between actin branching and bundling, because steric clashes among branches create a mechanical barrier to bundling. Recently, liquid-like condensates consisting purely of proteins involved in either branching or bundling of the cytoskeleton have been found to catalyze their respective functions. Yet in the cell, proteins that drive branching and bundling are present simultaneously. In this complex environment, which factors determine whether a condensate drives filaments to branch or become bundled? To answer this question, we added the branched actin nucleator, Arp2/3, to condensates composed of VASP, an actin bundling protein. At low actin to VASP ratios, branching activity, mediated by Arp2/3, robustly inhibited VASP-mediated bundling of filaments, in agreement with agent-based simulations. In contrast, as the actin to VASP ratio increased, addition of Arp2/3 led to formation of aster-shaped structures, in which bundled filaments emerged from a branched actin core, analogous to filopodia emerging from a branched lamellipodial network. These results demonstrate that multi-component, liquid-like condensates can modulate the inherent competition between bundled and branched actin morphologies, leading to organized, higher-order structures, similar to those found in motile cells.

Dehydration-induced corrugated folding in Rhapis excelsa plant leaves.

Plant leaves, whose remarkable ability for morphogenesis results in a wide range of petal and leaf shapes in response to environmental cues, have inspired scientific studies as well as the development of engineering structures and devices. Although some typical shape changes in plants and the driving force for such shape evolution have been extensively studied, there remain many poorly understood mechanisms, characteristics, and principles associated with the vast array of shape formation of plant leaves in nature. Here, we present a comprehensive study that combines experiment, theory, and numerical simulations of one such topic-the mechanics and mechanisms of corrugated leaf folding induced by differential shrinking in Rhapis excelsa. Through systematic measurements of the dehydration process in sectioned leaves, we identify a linear correlation between change in the leaf-folding angle and water loss. Building on experimental findings, we develop a generalized model that provides a scaling relationship for water loss in sectioned leaves. Furthermore, our study reveals that corrugated folding induced by dehydration in R. excelsa leaves is achieved by the deformation of a structural architecture-the "hinge" cells. Utilizing such connections among structure, morphology, environmental stimuli, and mechanics, we fabricate several biomimetic machines, including a humidity sensor and morphing devices capable of folding in response to dehydration. The mechanisms of corrugated folding in R. excelsa identified in this work provide a general understanding of the interactions between plant leaves and water. The actuation mechanisms identified in this study also provide insights into the rational design of soft machines.

Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration.

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the ß-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.

Ultrafast sound production mechanism in one of the smallest vertebrates.

Motion is the basis of nearly all animal behavior. Evolution has led to some extraordinary specializations of propulsion mechanisms among invertebrates, including the mandibles of the dracula ant and the claw of the pistol shrimp. In contrast, vertebrate skeletal movement is considered to be limited by the speed of muscle, saturating around 250 Hz. Here, we describe the unique propulsion mechanism by which Danionella cerebrum, a miniature cyprinid fish of only 12 mm length, produces high amplitude sounds exceeding 140 dB (re. 1 µPa, at a distance of one body length). Using a combination of high-speed video, micro-computed tomography (micro-CT), RNA profiling, and finite difference simulations, we found that D. cerebrum employ a unique sound production mechanism that involves a drumming cartilage, a specialized rib, and a dedicated muscle adapted for low fatigue. This apparatus accelerates the drumming cartilage at over 2,000 g, shooting it at the swim bladder to generate a rapid, loud pulse. These pulses are chained together to make calls with either bilaterally alternating or unilateral muscle contractions. D. cerebrum use this remarkable mechanism for acoustic communication with conspecifics.

Unifying fluidic excretion across life from cicadas to elephants.

Can insects weighing mere grams challenge our current understanding of fluid dynamics in urination, jetting fluids like their larger mammalian counterparts? Current fluid urination models, predominantly formulated for mammals, suggest that jetting is confined to animals over 3 kg, owing to viscous and surface tension constraints at microscales. Our findings defy this paradigm by demonstrating that cicadas-weighing just 2 g-possess the capability for jetting fluids through remarkably small orifices. Using dimensional analysis, we introduce a unifying fluid dynamics scaling framework that accommodates a broad range of taxa, from surface-tension-dominated insects to inertia and gravity-reliant mammals. This study not only refines our understanding of fluid excretion across various species but also highlights its potential relevance in diverse fields such as ecology, evolutionary biology, and biofluid dynamics.

Two different jumping mechanisms of water striders are determined by body size.

Current theory for surface tension-dominant jumps on water, created for small- and medium-sized water strider species and used in bioinspired engineering, predicts that jumping individuals are able to match their downward leg movement speed to their size and morphology such that they maximize the takeoff speed and minimize the takeoff delay without breaking the water surface. Here, we use empirical observations and theoretical modeling to show that large species (heavier than ~80 mg) could theoretically perform the surface-dominated jumps according to the existing model, but they do not conform to its predictions, and switch to using surface-breaking jumps in order to achieve jumping performance sufficient for evading attacks from underwater predators. This illustrates how natural selection for avoiding predators may break the theoretical scaling relationship between prey size and its jumping performance within one physical mechanism, leading to an evolutionary shift to another mechanism that provides protection from attacking predators. Hence, the results are consistent with a general idea: Natural selection for the maintenance of adaptive function of a specific behavior performed within environmental physical constraints leads to size-specific shift to behaviors that use a new physical mechanism that secure the adaptive function.

Mechanics reveals the role of peristome geometry in prey capture in carnivorous pitcher plants (Nepenthes).

Carnivorous pitcher plants (Nepenthes) are a striking example of a natural pitfall trap. The trap's slippery rim, or peristome, plays a critical role in insect capture via an aquaplaning mechanism that is well documented. While the peristome has received significant research attention, the conspicuous variation in peristome geometry across the genus remains unexplored. We examined the mechanics of prey capture using Nepenthes pitcher plants with divergent peristome geometries. Inspired by living material, we developed a mathematical model that links the peristomes' three-dimensional geometries to the physics of prey capture under the laws of Newtonian mechanics. Linking form and function enables us to test hypotheses related to the function of features such as shape and ornamentation, orientation in a gravitational field, and the presence of "teeth," while analysis of the energetic costs and gains of a given geometry provides a means of inferring potential evolutionary pathways. In a separate modeling approach, we show how prey size may correlate with peristome dimensions for optimal capture. Our modeling framework provides a physical platform to understand how divergence in peristome morphology may have evolved in the genus Nepenthes in response to shifts in prey diversity, availability, and size.

Stiffness transitions in new walls post-cell division differ between Marchantia polymorpha gemmae and Arabidopsis thaliana leaves.

Plant morphogenesis is governed by the mechanics of the cell wall-a stiff and thin polymeric box that encloses the cells. The cell wall is a highly dynamic composite material. New cell walls are added during cell division. As the cells continue to grow, the properties of cell walls are modulated to undergo significant changes in shape and size without breakage. Spatial and temporal variations in cell wall mechanical properties have been observed. However, how they relate to cell division remains an outstanding question. Here, we combine time-lapse imaging with local mechanical measurements via atomic force microscopy to systematically map the cell wall's age and growth, with their stiffness. We make use of two systems, Marchantia polymorpha gemmae, and Arabidopsis thaliana leaves. We first characterize the growth and cell division of M. polymorpha gemmae. We then demonstrate that cell division in M. polymorpha gemmae results in the generation of a temporary stiffer and slower-growing new wall. In contrast, this transient phenomenon is absent in A. thaliana leaves. We provide evidence that this different temporal behavior has a direct impact on the local cell geometry via changes in the junction angle. These results are expected to pave the way for developing more realistic plant morphogenetic models and to advance the study into the impact of cell division on tissue growth.

Imaging the subcellular viscoelastic properties of mouse oocytes.

In recent years, cellular biomechanical properties have been investigated as an alternative to morphological assessments for oocyte selection in reproductive science. Despite the high relevance of cell viscoelasticity characterization, the reconstruction of spatially distributed viscoelastic parameter images in such materials remains a major challenge. Here, a framework for mapping viscoelasticity at the subcellular scale is proposed and applied to live mouse oocytes. The strategy relies on the principles of optical microelastography for imaging in combination with the overlapping subzone nonlinear inversion technique for complex-valued shear modulus reconstruction. The three-dimensional nature of the viscoelasticity equations was accommodated by applying an oocyte geometry-based 3D mechanical motion model to the measured wave field. Five domains-nucleolus, nucleus, cytoplasm, perivitelline space, and zona pellucida-could be visually differentiated in both oocyte storage and loss modulus maps, and statistically significant differences were observed between most of these domains in either property reconstruction. The method proposed herein presents excellent potential for biomechanical-based monitoring of oocyte health and complex transformations across lifespan. It also shows appreciable latitude for generalization to cells of arbitrary shape using conventional microscopy equipment.

Self-organized collective cell behaviors as design principles for synthetic developmental biology.

Over the past two decades, molecular cell biology has graduated from a mostly analytic science to one with substantial synthetic capability. This success is built on a deep understanding of the structure and function of biomolecules and molecular mechanisms. For synthetic biology to achieve similar success at the scale of tissues and organs, an equally deep understanding of the principles of development is required. Here, we review some of the central concepts and recent progress in tissue patterning, morphogenesis and collective cell migration and discuss their value for synthetic developmental biology, emphasizing in particular the power of (guided) self-organization and the role of theoretical advances in making developmental insights applicable in synthesis.