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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.

Intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) perform diverse functions in cellular organization, transport and signaling. Unlike the well-defined structures of the classical natively folded proteins, IDPs and IDRs dynamically span large conformational and structural ensembles. This dynamic disorder impedes the study of the relationship between the amino acid sequences of the IDPs and their spatial structures and dynamics, with different experimental techniques often offering seemingly contradictory results. Although experimental and theoretical evidence indicates that some IDP properties can be understood based on their average biophysical properties and amino acid composition, other aspects of IDP function are dictated by the specifics of the amino acid sequence. We investigate the effects of several key variables on the dimensions and the dynamics of IDPs using coarse-grained polymer models. We focus on the sequence “patchiness” informed by the sequence and biophysical properties of different classes of IDPs—and in particular FG nucleoporins of the nuclear pore complex (NPC). We show that the sequence composition and patterning are well reflected in the global conformational variables such as the radius of gyration and hydrodynamic radius, while the end-to-end distance and dynamics are highly sequence-specific. We find that in good solvent conditions highly heterogeneous sequences of IDPs can be well mapped onto averaged minimal polymer models for the purpose of prediction of the IDPs dimensions and dynamic relaxation times. The coarse-grained simulations are in a good agreement with the results of atomistic MD. We discuss the implications of these results for the interpretation of the recent experimental measurements, and for the further applications of mesoscopic models of FG nucleoporins and IDPs more broadly.

The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.

Nucleocytoplasmic transport is tightly regulated by the nuclear pore complex (NPC). Among the thousands of molecules that cross the NPC, even very large (>15 nm) cargoes such as pathogens, mRNAs and pre-ribosomes can pass the NPC intact. For these cargoes, there is little quantitative understanding of the requirements for their nuclear import, especially the role of multivalent binding to transport receptors via nuclear localisation sequences (NLSs) and the effect of size on import efficiency. Here, we assayed nuclear import kinetics of 30 large cargo models based on four capsid-like particles in the size range of 17–36 nm, with tuneable numbers of up to 240 NLSs. We show that the requirements for nuclear transport can be recapitulated by a simple two-parameter biophysical model that correlates the import flux with the energetics of large cargo transport through the NPC. Together, our results reveal key molecular determinants of large cargo import in cells.

Synergistic and antagonistic interactions in multi-species populations—such as resource sharing and competition—result in remarkably diverse behaviours in populations of interacting cells, such as in soil or human microbiomes, or clonal competition in cancer. The degree of inter- and intra-specific interaction can often be quantified through the notion of an ecological ‘niche’. Typically, weakly interacting species that occupy largely distinct niches result in stable mixed populations, while strong interactions and competition for the same niche result in rapid extinctions of some species and fixations of others. We investigate the transition of a deterministically stable mixed population to a stochasticity-induced fixation as a function of the niche overlap between the two species. We also investigate the effect of the niche overlap on the population stability with respect to external invasions. Our results have important implications for a number of experimental systems.

The key component of the nuclear pore complex (NPC) controlling permeability, selectivity, and the speed of nucleocytoplasmic transport is an assembly of natively unfolded polypeptides, which contain phenylalanine-glycine (FG) binding sites for nuclear transport receptors. The architecture and dynamics of the FG-network have been refractory to characterization due to the paucity of experimental methods able to probe the mobility and density of the FG-polypeptides and embedded macromolecules within intact NPCs. Combining fluorescence polarization, super-resolution microscopy, and mathematical analyses, we examined the rotational mobility of fluorescent probes at various locations within the FG-network under different conditions. We demonstrate that polarization PALM (p-PALM) provides a rich source of information about low rotational mobilities that are inaccessible with bulk fluorescence anisotropy approaches, and anticipate that p-PALM is well-suited to explore numerous crowded cellular environments. In total, our findings indicate that the NPC’s internal organization consists of multiple dynamic environments with different local properties.

Nuclear Pore Complexes (NPCs) are key cellular transporter that control nucleocytoplasmic transport in eukaryotic cells, but its transport mechanism is still not understood. The centerpiece of NPC transport is the assembly of intrinsically disordered polypeptides, known as FG nucleoporins, lining its passageway. Their conformations and collective dynamics during transport are difficult to assess in vivo. In vitro investigations provide partially conflicting results, lending support to different models of transport, which invoke various conformational transitions of the FG nucleoporins induced by the cargo-carrying transport proteins. We show that the spatial organization of FG nucleoporin assemblies with the transport proteins can be understood within a first principles biophysical model with a minimal number of key physical variables, such as the average protein interaction strengths and spatial densities. These results address some of the outstanding controversies and suggest how molecularly divergent NPCs in different species can perform essentially the same function.

Quantitative understanding of the kinetics of lymphocyte proliferation and death upon activation with an antigen is crucial for elucidating factors determining the magnitude, duration and efficiency of the immune response. Recent advances in quantitative experimental techniques, in particular intracellular labeling and multi-channel flow cytometry, allow one to measure the population structure of proliferating and dying lymphocytes for several generations with high precision. These new experimental techniques require novel quantitative methods of analysis. We review several recent mathematical approaches used to describe and analyze cell proliferation data. Using a rigorous mathematical framework, we show that two commonly used models that are based on the theories of age-structured cell populations and of branching processes, are mathematically identical. We provide several simple analytical solutions for a model in which the distribution of inter-division times follows a gamma distribution and show that this model can fit both simulated and experimental data. We also show that the estimates of some critical kinetic parameters, such as the average inter-division time, obtained by fitting models to data may depend on the assumed distribution of inter-division times, highlighting the challenges in quantitative understanding of cell kinetics.

The functioning of living cells requires efficient and selective transport of materials into and out of the cell, and between different cellular compartments. Much of this transport occurs through nano-scale channels that do not require large scale molecular re-arrangements (such as transition from a 'closed' to an 'open' state) and do not require a direct input of metabolic energy during transport. Nevertheless, these 'always open' channels are highly selective and pass only their cognate molecules, while efficiently excluding all others; indeed, these channels can efficiently transport specific molecules even in the presence of a vast excess of non-specific molecules. Such biological transporters have inspired the creation of artificial nano-channels. These channels can be used as nano-molecular sorters, and can also serve as testbeds for examining modes of biological transport. In this paper, we propose a simple kinetic mechanism that explains how the selectivity of such 'always open' channels can be based on the exclusion of non-specific molecules by specific ones, due to the competition for limited space inside the channel. The predictions of the theory account for the behavior of the nuclear pore complex and of artificial nanopores that mimic its function. This theory provides the basis for future work aimed at understanding the selectivity of various biological transport phenomena.

All materials enter or exit the cell nucleus through nuclear pore complexes (NPCs), efficient transport devices that combine high selectivity and throughput. NPC-associated proteins containing phenylalanine-glycine repeats (FG nups) have large, flexible, unstructured proteinaceous regions, and line the NPC. A central feature of NPC-mediated transport is the binding of cargo-carrying soluble transport factors to the unstructured regions of FG nups. Here, we model the dynamics of nucleocytoplasmic transport as diffusion in an effective potential resulting from the interaction of the transport factors with the flexible FG nups, using a minimal number of assumptions consistent with the most well-established structural and functional properties of NPC transport. We discuss how specific binding of transport factors to the FG nups facilitates transport, and how this binding and competition between transport factors and other macromolecules for binding sites and space inside the NPC accounts for the high selectivity of transport. We also account for why transport is relatively insensitive to changes in the number and distribution of FG nups in the NPC, providing an explanation for recent experiments where up to half the total mass of the FG nups has been deleted without abolishing transport. Our results suggest strategies for the creation of artificial nanomolecular sorting devices.