Mechanics limits ecological diversity and promotes heterogeneity in confined bacterial communities.

Multispecies bacterial populations often inhabit confined and densely packed environments where spatial competition determines the ecological diversity of the community. However, the role of mechanical interactions in shaping the ecology is still poorly understood. Here, we study a model system consisting of two populations of nonmotile Escherichia coli bacteria competing within open, monolayer microchannels. The competitive dynamics is observed to be biphasic: After seeding, either one strain rapidly fixates or both strains orient into spatially stratified, stable communities. We find that mechanical interactions with other cells and local spatial constraints influence the resulting community ecology in unexpected ways, severely limiting the overall diversity of the communities while simultaneously allowing for the establishment of stable, heterogeneous populations of bacteria displaying disparate growth rates. Surprisingly, the populations have a high probability of coexisting even when one strain has a significant growth advantage. A more coccus morphology is shown to provide a selective advantage, but agent-based simulations indicate this is due to hydrodynamic and adhesion effects within the microchannel and not from breaking of the nematic ordering. Our observations are qualitatively reproduced by a simple Pólya urn model, which suggests the generality of our findings for confined population dynamics and highlights the importance of early colonization conditions on the resulting diversity and ecology of bacterial communities. These results provide fundamental insights into the determinants of community diversity in dense confined ecosystems where spatial exclusion is central to competition as in organized biofilms or intestinal crypts.

Spatial exclusion leads to "tug-of-war" ecological dynamics between competing species within microchannels.

Competition is ubiquitous in microbial communities, shaping both their spatial and temporal structure and composition. Classical minimal models of competition, such as the Moran model, have been employed in ecology and evolutionary biology to understand the role of fixation and invasion in the maintenance of population diversity. Informed by recent experimental studies of cellular competition in confined spaces, we extend the Moran model to incorporate mechanical interactions between cells that divide within the limited space of a one-dimensional open microchannel. The model characterizes the skewed collective growth of the cells dividing within the channel, causing cells to be expelled at the channel ends. The results of this spatial exclusion model differ significantly from those of its classical well-mixed counterpart. The mean time to fixation of a species is greatly accelerated, scaling logarithmically, rather than algebraically, with the system size, and fixation/extinction probability sharply depends on the species' initial fractional abundance. By contrast, successful takeovers by invasive species, whether through mutation or immigration, are substantially less likely than in the Moran model. We also find that the spatial exclusion tends to attenuate the effects of fitness differences on the fixation times and probabilities. We find that these effects arise from the combination of the quasi-neutral "tug-of-war" diffusion dynamics of the inter-species boundary around an unstable equipoise point and the quasi-deterministic avalanche dynamics away from the fixed point. These results, which can be tested in microfluidic monolayer devices, have implications for the maintenance of species diversity in dense bacterial and cellular ecosystems where spatial exclusion is central to the competition, such as in organized biofilms or intestinal crypts.

Phenomenology and dynamics of competitive ecosystems beyond the niche-neutral regimes.

Structure, composition, and stability of ecological populations are shaped by the inter- and intraspecies interactions within their communities. It remains to be fully understood how the interplay of these interactions with other factors, such as immigration, controls the structure, the diversity, and the long-term stability of ecological systems in the presence of noise and fluctuations. We address this problem using a minimal model of interacting multispecies ecological communities that incorporates competition, immigration, and demographic noise. We find that a complete phase diagram exhibits rich behavior with multiple regimes that go beyond the classical "niche" and "neutral" regimes, extending and modifying the "rare biosphere" or "niche-like" dichotomy. In particular, we observe regimes that cannot be characterized as either niche or neutral where a multimodal species abundance distribution is observed. We characterize the transitions between the different regimes and show how these arise from the underlying kinetics of the species turnover, extinction, and invasion. Our model serves as a minimal null model of noisy competitive ecological systems, against which more complex models that include factors such as mutations and environmental noise can be compared.

Pleiotropy enables specific and accurate signaling in the presence of ligand cross talk.

Living cells sense their environment through the binding of extracellular molecular ligands to cell surface receptors. Puzzlingly, vast numbers of signaling pathways exhibit a high degree of cross talk between different signals whereby different ligands act through the same receptor or shared components downstream. It remains unclear how a cell can accurately process information from the environment in such cross-wired pathways. We show that a feature which commonly accompanies cross talk-signaling pleiotropy (the ability of a receptor to produce multiple outputs)-offers a solution to the cross-talk problem. In a minimal model we show that a single pleiotropic receptor can simultaneously identify and accurately sense the concentrations of arbitrary unknown ligands present individually or in a mixture. We calculate the fundamental limits of the signaling specificity and accuracy of such signaling schemes. The model serves as an elementary "building block" toward understanding more complex cross-wired receptor-ligand signaling networks.

The entry of nanoparticles into solid tumours.

The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation.

Predicting Ancestral Segmentation Phenotypes from Drosophila to Anopheles Using In Silico Evolution.

Molecular evolution is an established technique for inferring gene homology but regulatory DNA turns over so rapidly that inference of ancestral networks is often impossible. In silico evolution is used to compute the most parsimonious path in regulatory space for anterior-posterior patterning linking two Dipterian species. The expression pattern of gap genes has evolved between Drosophila (fly) and Anopheles (mosquito), yet one of their targets, eve, has remained invariant. Our model predicts that stripe 5 in fly disappears and a new posterior stripe is created in mosquito, thus eve stripe modules 3+7 and 4+6 in fly are homologous to 3+6 and 4+5 in mosquito. We can place Clogmia on this evolutionary pathway and it shares the mosquito homologies. To account for the evolution of the other pair-rule genes in the posterior we have to assume that the ancestral Dipterian utilized a dynamic method to phase those genes in relation to eve.