Differences in boundary behavior in the 3D vertex and Voronoi models.

An important open question in the modeling of biological tissues is how to identify the right scale for coarse-graining, or equivalently, the right number of degrees of freedom. For confluent biological tissues, both vertex and Voronoi models, which differ only in their representation of the degrees of freedom, have effectively been used to predict behavior, including fluid-solid transitions and cell tissue compartmentalization, which are important for biological function. However, recent work in 2D has hinted that there may be differences between the two models in systems with heterotypic interfaces between two tissue types, and there is a burgeoning interest in 3D tissue models. Therefore, we compare the geometric structure and dynamic sorting behavior in mixtures of two cell types in both 3D vertex and Voronoi models. We find that while the cell shape indices exhibit similar trends in both models, the registration between cell centers and cell orientation at the boundary are significantly different between the two models. We demonstrate that these macroscopic differences are caused by changes to the cusp-like restoring forces introduced by the different representations of the degrees of freedom at the boundary, and that the Voronoi model is more strongly constrained by forces that are an artifact of the way the degrees of freedom are represented. This suggests that vertex models may be more appropriate for 3D simulations of tissues with heterotypic contacts.

Transient learning degrees of freedom for introducing function in materials.

SignificanceMany protocols used in material design and training have a common theme: they introduce new degrees of freedom, often by relaxing away existing constraints, and then evolve these degrees of freedom based on a rule that leads the material to a desired state at which point these new degrees of freedom are frozen out. By creating a unifying framework for these protocols, we can now understand that some protocols work better than others because the choice of new degrees of freedom matters. For instance, introducing particle sizes as degrees of freedom to the minimization of a jammed particle packing can lead to a highly stable state, whereas particle stiffnesses do not have nearly the same impact.

Demixing in Binary Mixtures with Differential Diffusivity at High Density.

Spontaneous phase separation, or demixing, is important in biological phenomena such as cell sorting. In particle-based models, an open question is whether differences in diffusivity can drive such demixing. While differential-diffusivity-induced phase separation occurs in mixtures with a packing fraction up to 0.7 [S. N. Weber et al. Binary mixtures of particles with different diffusivities demix, Phys. Rev. Lett. 116, 058301 (2016)PRLTAO0031-900710.1103/PhysRevLett.116.058301], here we investigate whether demixing persists at even higher densities relevant for cells. For particle packing fractions between 0.7 and 1.0 the system demixes, but at packing fractions above unity the system remains mixed, exposing re-entrant behavior in the phase diagram that occurs when phase separation can no longer drive a change in entropy production at high densities. We also find that a confluent Voronoi model for tissues does not phase separate, consistent with particle-based simulations.

Scaling regimes and fluctuations of observables in computer glasses approaching the unjamming transition.

Under decompression, disordered solids undergo an unjamming transition where they become under-coordinated and lose their structural rigidity. The mechanical and vibrational properties of these materials have been an object of theoretical, numerical, and experimental research for decades. In the study of low-coordination solids, understanding the behavior and physical interpretation of observables that diverge near the transition is of particular importance. Several such quantities are length scales (ξ or l) that characterize the size of excitations, the decay of spatial correlations, the response to perturbations, or the effect of physical constraints in the boundary or bulk of the material. Additionally, the spatial and sample-to-sample fluctuations of macroscopic observables such as contact statistics or elastic moduli diverge approaching unjamming. Here, we discuss important connections between all of these quantities and present numerical results that characterize the scaling properties of sample-to-sample contact and shear modulus fluctuations in ensembles of low-coordination disordered sphere packings and spring networks. Overall, we highlight three distinct scaling regimes and two crossovers in the disorder quantifiers χz and χµ as functions of system size N and proximity to unjamming δz. As we discuss, χX relates to the standard deviation σX of the sample-to-sample distribution of the quantity X (e.g., excess coordination δz or shear modulus µ) for an ensemble of systems. Importantly, χµ has been linked to experimentally accessible quantities that pertain to sound attenuation and the density of vibrational states in glasses. We investigate similarities and differences in the behaviors of χz and χµ near the transition and discuss the implications of our findings on current literature, unifying findings in previous studies.

Cell cycle-dependent active stress drives epithelia remodeling.

Epithelia have distinct cellular architectures which are established in development, reestablished after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here, we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here, we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop an extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly, but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics are arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions, the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics.

A direct link between active matter and sheared granular systems.

The similarity in mechanical properties of dense active matter and sheared amorphous solids has been noted in recent years without a rigorous examination of the underlying mechanism. We develop a mean-field model that predicts that their critical behavior-as measured by their avalanche statistics-should be equivalent in infinite dimensions up to a rescaling factor that depends on the correlation length of the applied field. We test these predictions in two dimensions using a numerical protocol, termed "athermal quasistatic random displacement," and find that these mean-field predictions are surprisingly accurate in low dimensions. We identify a general class of perturbations that smoothly interpolates between the uncorrelated localized forces that occur in the high-persistence limit of dense active matter and system-spanning correlated displacements that occur under applied shear. These results suggest a universal framework for predicting flow, deformation, and failure in active and sheared disordered materials.

Factors influencing general practice nurse's implementation of culturally responsive care, using normalization process theory: A cross-sectional study.

AIMS: To explore levers and barriers to providing culturally responsive care for general practice nurses (GPNs) using normalization process theory. DESIGN: A self-administered online cross-sectional survey. METHODS: A participatory co-designed adapted version of the normalization of complex interventions measure (NoMAD) validated tool was distributed to a convenience sample of GPNs between December 2022 and February 2023. The sample comprised of GPNs working in general practice services in Ireland (n = 122). Data were analysed using descriptive and analytical statistics (Pearson correlations) and principles of content analysis. This study was conducted and reported in line with the Consensus-Based Checklist for Reporting of Survey Studies (CROSS). RESULTS: GPNs in this study indicated their familiarity with, acknowledged the importance of and were committed to, providing culturally responsive care. However, implementing culturally responsive care in daily practice was problematic due to insufficient education and training, scarcity of resources and supports and a lack of organizational leadership. Subsequently, GPNs experience difficulties adapting everyday practices to respond appropriately to the care needs of culturally and linguistically diverse (CaLD) patients. CONCLUSION: This analysis highlights the necessity of exploring the intricacies of factors that influence capabilities and capacity for providing culturally responsive care. Despite demonstrating awareness of the importance of providing nursing care that responds to the needs of CaLD patients, GPNs do not have full confidence or capacity to integrate culturally responsive care into their daily work practices. IMPACT: Using normalization process theory, this study elucidates for the first time how GPNs in Ireland make sense of, legitimize, enact and sustain culturally responsive care as a routine way of working. It illuminates the multitude of micro-level (individual), meso-level (organizational) and macro-level (structural) factors that require attention for normalizing culturally responsive care in general practice services. PATIENT OR PUBLIC CONTRIBUTION: The study question was identified in a participatory research prioritization for Irish research about migrant health that involved migrants in the process.

Essay: Collections of Deformable Particles Present Exciting Challenges for Soft Matter and Biological Physics.

The field of soft matter physics has expanded rapidly over the past several decades, as physicists realize that a broad set of materials and systems are amenable to a physical understanding based on the interplay of entropy, elasticity, and geometry. The fields of biological physics and the physics of living systems have similarly emerged as bona fide independent areas of physics in part because tools from molecular and cell biology and optical physics allow scientists to make new quantitative measurements to test physical principles in living systems. This Essay will highlight two exciting future challenges I see at the intersection of these two fields: characterizing emergent behavior and harnessing actuation in highly deformable active objects. I will attempt to show how this topic is a natural extension of older and more recent discoveries and why I think it is likely to unfurl into a wide range of projects that can transform both fields. Progress in this area will enable new platforms for creating adaptive smart materials that can execute large-scale changes in shape in response to stimuli and improve our understanding of biological function, potentially allowing us to identify new targets for fighting disease. Part of a series of Essays which concisely present author visions for the future of their field.

Anisotropy links cell shapes to tissue flow during convergent extension.

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending Drosophila germband epithelium, which displays planar-polarized myosin II and experiences anisotropic forces from neighboring tissues. We show that, in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues, two experimentally accessible metrics of cell patterns-the cell shape index and a cell alignment index-are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in the Drosophila germband predict the onset of rapid cell rearrangement in both wild-type and snail twist mutant embryos, where our theoretical prediction is further improved when we also account for cell packing disorder. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue-shape changes during rapid developmental events.

Time to re-envisage culturally responsive care: Intersection of participatory health research and implementation science.

AIM: In the context of widening societal diversity, culturally and linguistically diverse patients continue to experience inequities in healthcare access and deficiencies in standards of nursing care. Re-framing culturally responsive care as a complex intervention spanning multiple interacting factors at micro, meso and macro levels is an essential prerequisite for addressing knowledge translation gaps into everyday nursing practice. To this end, this paper proposes and explicates the potential of applying synergistic participatory implementation methodologies for developing effective implementation strategies with impact at individual and wider structural levels. DESIGN: Discussion Paper. DATA SOURCES: A co-design case study is presented as an example of combining normalization process theory and participatory learning and action to investigate and support the implementation of culturally responsive care in general practice nursing. IMPLICATIONS FOR NURSING: Enacting culturally responsive health care is inherently complex in that it is influenced by multiple interacting factors. Viewing culturally responsive care as a complex intervention and incorporating a synergistic participatory implementation science approach offers possibilities for addressing the documented shortcomings in the implementation of culturally responsive nursing care. CONCLUSION: There is a need to move away from conventional approaches to conceptualizing and generating evidence on culturally responsive care. Incorporating participatory implementation methodologies can provide a new lens to investigate and support whole system implementation strategies. IMPACT: The combination of participatory and implementation methodologies is both theoretically and empirically informed. Engaging stakeholders in the co-design and co-production of evidence and solutions to long standing problems has the potential to increase the likelihood of influencing iterative and sustainable implementation and changes to clinical practice and systems. PATIENT OR PUBLIC CONTRIBUTION: This work is part of a wider programme of participatory health research on migrant health, partnering with a non-governmental organization that supports migrants.

Collective chemotaxis in a Voronoi model for confluent clusters.

Collective chemotaxis, where single cells cannot climb a biochemical signaling gradient but clusters of cells can, has been observed in different biological contexts, including confluent tissues where there are no gaps or overlaps between cells. Although particle-based models have been developed that predict important features of collective chemotaxis, the mechanisms in those models depend on particle overlaps, and so it remains unclear if they can explain behavior in confluent systems. Here, we develop an open-source code that couples a two-dimensional Voronoi simulation for confluent cell mechanics to a dynamic chemical signal that can diffuse, advect, and/or degrade and use the code to study potential mechanisms for collective chemotaxis in cellular monolayers. We first study the impact of advection on collective chemotaxis and delineate a regime where advective terms are important. Next, we investigate two possible chemotactic mechanisms, contact inhibition of locomotion and heterotypic interfacial tension, and demonstrate that both can drive collective chemotaxis in certain parameter regimes. We further demonstrate that the scaling behavior of cluster motion is well captured by simple analytic theories.

Effect of cellular rearrangement time delays on the rheology of vertex models for confluent tissues.

Large-scale tissue deformation during biological processes such as morphogenesis requires cellular rearrangements. The simplest rearrangement in confluent cellular monolayers involves neighbor exchanges among four cells, called a T1 transition, in analogy to foams. But unlike foams, cells must execute a sequence of molecular processes, such as endocytosis of adhesion molecules, to complete a T1 transition. Such processes could take a long time compared to other timescales in the tissue. In this work, we incorporate this idea by augmenting vertex models to require a fixed, finite time for T1 transitions, which we call the "T1 delay time". We study how variations in T1 delay time affect tissue mechanics, by quantifying the relaxation time of tissues in the presence of T1 delays and comparing that to the cell-shape based timescale that characterizes fluidity in the absence of any T1 delays. We show that the molecular-scale T1 delay timescale dominates over the cell shape-scale collective response timescale when the T1 delay time is the larger of the two. We extend this analysis to tissues that become anisotropic under convergent extension, finding similar results. Moreover, we find that increasing the T1 delay time increases the percentage of higher-fold coordinated vertices and rosettes, and decreases the overall number of successful T1s, contributing to a more elastic-like-and less fluid-like-tissue response. Our work suggests that molecular mechanisms that act as a brake on T1 transitions could stiffen global tissue mechanics and enhance rosette formation during morphogenesis.

Avalanche dynamics in sheared athermal particle packings occurs via localized bursts predicted by unstable linear response.

Under applied shear strain, granular and amorphous materials deform via particle rearrangements, which can be small and localized or organized into system-spanning avalanches. While the statistical properties of avalanches under quasi-static shear are well-studied, the dynamics during avalanches is not. In numerical simulations of sheared soft spheres, we find that avalanches can be decomposed into bursts of localized deformations, which we identify using an extension of persistent homology methods. We also study the linear response of unstable systems during an avalanche, demonstrating that eigenvalue dynamics are highly complex during such events, and that the most unstable eigenvector is a poor predictor of avalanche dynamics. Instead, we modify existing tools that identify localized excitations in stable systems, and apply them to these unstable systems with non-positive definite Hessians, quantifying the evolution of such excitations during avalanches. We find that bursts of localized deformations in the avalanche almost always occur at localized excitations identified using the linear spectrum. These new tools will provide an improved framework for validating and extending mesoscale elastoplastic models that are commonly used to explain avalanche statistics in glasses and granular matter.

Non-monotonic fluidization generated by fluctuating edge tensions in confluent tissues.

In development and homeostasis, multi-cellular systems exhibit spatial and temporal heterogeneity in their biochemical and mechanical properties. Nevertheless, it remains unclear how spatiotemporally heterogeneous forces affect the dynamical and mechanical properties of confluent tissue. To address this question, we study the dynamical behavior of the two-dimensional cellular vertex model for epithelial monolayers in the presence of fluctuating cell-cell interfacial tensions, which is a biologically relevant source of mechanical spatiotemporal heterogeneity. In particular, we investigate the effects of the amplitude and persistence time of fluctuating tension on the tissue dynamics. We unexpectedly find that the long-time diffusion constant describing cell rearrangements depends non-monotonically on the persistence time, while it increases monotonically as the amplitude increases. Our analysis indicates that at low and intermediate persistence times tension fluctuations drive motion of vertices and promote cell rearrangements, while at the highest persistence times the tension in the network evolves so slowly that rearrangements become rare.

Searching for structural predictors of plasticity in dense active packings.

In amorphous solids subject to shear or thermal excitation, so-called structural indicators have been developed that predict locations of future plasticity or particle rearrangements. An open question is whether similar tools can be used in dense active materials, but a challenge is that under most circumstances, active systems do not possess well-defined solid reference configurations. We develop a computational model for a dense active crowd attracted to a point of interest, which does permit a mechanically stable reference state in the limit of infinitely persistent motion. Previous work on a similar system suggested that the collective motion of crowds could be predicted by inverting a matrix of time-averaged two-particle correlation functions. Seeking a first-principles understanding of this result, we demonstrate that this active matter system maps directly onto a granular packing in the presence of an external potential, and extend an existing structural indicator based on linear response to predict plasticity in the presence of noisy dynamics. We find that the strong pressure gradient necessitated by the directed activity, as well as a self-generated free boundary, strongly impact the linear response of the system. In low-pressure regions the linear-response-based indicator is predictive, but it does not work well in the high-pressure interior of our active packings. Our findings motivate and inform future work that could better formulate structure-dynamics predictions in systems with strong pressure gradients.

A minimal-length approach unifies rigidity in underconstrained materials.

We present an approach to understand geometric-incompatibility-induced rigidity in underconstrained materials, including subisostatic 2D spring networks and 2D and 3D vertex models for dense biological tissues. We show that in all these models a geometric criterion, represented by a minimal length [Formula: see text], determines the onset of prestresses and rigidity. This allows us to predict not only the correct scalings for the elastic material properties, but also the precise magnitudes for bulk modulus and shear modulus discontinuities at the rigidity transition as well as the magnitude of the Poynting effect. We also predict from first principles that the ratio of the excess shear modulus to the shear stress should be inversely proportional to the critical strain with a prefactor of 3. We propose that this factor of 3 is a general hallmark of geometrically induced rigidity in underconstrained materials and could be used to distinguish this effect from nonlinear mechanics of single components in experiments. Finally, our results may lay important foundations for ways to estimate [Formula: see text] from measurements of local geometric structure and thus help develop methods to characterize large-scale mechanical properties from imaging data.

Simple and Broadly Applicable Definition of Shear Transformation Zones.

Plastic deformation in amorphous solids is known to be carried by stress-induced localized rearrangements of a few tens of particles, accompanied by the conversion of elastic energy to heat. Despite their central role in determining how glasses yield and break, the search for a simple and generally applicable definition of the precursors of those plastic rearrangements-the so-called shear transformation zones (STZs)-is still ongoing. Here we present a simple definition of STZs-based solely on the harmonic approximation of a glass's energy. We explain why and demonstrate directly that our proposed definition of plasticity carriers in amorphous solids is more broadly applicable compared to anharmonic definitions put forward previously. Finally, we offer an open-source library that analyzes low-lying STZs in computer glasses and in laboratory materials such as dense colloidal suspensions for which the harmonic approximation is accessible. Our results constitute a physically motivated methodological advancement towards characterizing mechanical disorder in glasses, and understanding how they yield.

The Cell Adaptation Time Sets a Minimum Length Scale for Patterned Substrates.

The structure and dynamics of tissue cultures depend strongly on the physical and chemical properties of the underlying substrate. Inspired by previous advances in the context of inorganic materials, the use of patterned culture surfaces has been proposed as an effective way to induce space-dependent properties in cell tissues. However, cells move and diffuse, and the transduction of external stimuli to biological signals is not instantaneous. Here, we show that the fidelity of patterns to demix tissue cells depends on the relation between the diffusion (τD) and adaptation (τ) times. Numerical results for the self-propelled Voronoi model reveal that the fidelity decreases with τ/τD, a result that is reproduced by a continuum reaction-diffusion model. Based on recent experimental results for single cells, we derive a minimal length scale for the patterns in the substrate that depends on τ/τD and can be much larger than the cell size.

Identifying the mechanism for superdiffusivity in mouse fibroblast motility.

We seek to characterize the motility of mouse fibroblasts on 2D substrates. Utilizing automated tracking techniques, we find that cell trajectories are super-diffusive, where displacements scale faster than t1/2 in all directions. Two mechanisms have been proposed to explain such statistics in other cell types: run and tumble behavior with Lévy-distributed run times, and ensembles of cells with heterogeneous speed and rotational noise. We develop an automated toolkit that directly compares cell trajectories to the predictions of each model and demonstrate that ensemble-averaged quantities such as the mean-squared displacements and velocity autocorrelation functions are equally well-fit by either model. However, neither model correctly captures the short-timescale behavior quantified by the displacement probability distribution or the turning angle distribution. We develop a hybrid model that includes both run and tumble behavior and heterogeneous noise during the runs, which correctly matches the short-timescale behaviors and indicates that the run times are not Lévy distributed. The analysis tools developed here should be broadly useful for distinguishing between mechanisms for superdiffusivity in other cells types and environments.

Linear and nonlinear mechanical responses can be quite different in models for biological tissues.

The fluidity of biological tissues - whether cells can change neighbors and rearrange - is important for their function. In traditional materials, researchers have used linear response functions, such as the shear modulus, to accurately predict whether a material will behave as a fluid. Similarly, in disordered 2D vertex models for confluent biological tissues, the shear modulus becomes zero precisely when the cells can change neighbors and the tissue fluidizes, at a critical value of control parameter s0* = 3.81. However, the ordered ground states of 2D vertex models become linearly unstable at a lower value of control parameter (3.72), suggesting that there may be a decoupling between linear and nonlinear response. We demonstrate that the linear response does not correctly predict the nonlinear behavior in these systems: when the control parameter is between 3.72 and 3.81, cells cannot freely change neighbors even though the shear modulus is zero. These results highlight that the linear response of vertex models should not be expected to generically predict their rheology. We develop a simple geometric ansatz that correctly predicts the nonlinear response, which may serve as a framework for making nonlinear predictions in other vertex-like models.