Recently, the steady sedimentation profile of a dilute suspension of chemically powered colloids was studied experimentally [J. Palacci et al., Phys. Rev. Lett. 105, 088304 (2010)]. It was found that the sedimentation length increases quadratically with the swimming speed of the active Brownian particles. Here we investigate theoretically the sedimentation of self-propelled particles undergoing translational and rotational diffusion. We find that the measured increase of the sedimentation length is coupled to a partial alignment of the suspension with the mean swimming direction oriented against the gravitational field. We suggest realistic parameter values to observe this polar order. Furthermore, we find that the dynamics of the active suspension can be derived from a generalized free energy functional.

Cells migrate through a crowded environment during processes such as metastasis or wound healing, and must generate and withstand substantial forces. The cellular motility responses to environmental forces are represented by their force-velocity relation, which has been measured for fish keratocytes but remains unexplained. Even pN opposing forces slow down lamellipodium motion by three orders of magnitude. At larger opposing forces, the retrograde flow of the actin network accelerates until it compensates for polymerization, and cell motion stalls. Subsequently, the lamellipodium adapts to the stalled state. We present a mechanism quantitatively explaining the cell's force-velocity relation and its changes upon application of drugs that hinder actin polymerization or actomyosin-based contractility. Elastic properties of filaments, close to the lamellipodium leading edge, and retrograde flow shape the force-velocity relation. To our knowledge, our results shed new light on how these migratory responses are regulated, and on the mechanics and structure of the lamellipodium.

Mutations causing aberrant splicing are frequently implicated in human diseases including cancer. Here, we establish a high-throughput screen of randomly mutated minigenes to decode the cis-regulatory landscape that determines alternative splicing of exon 11 in the proto-oncogene MST1R (RON). Mathematical modelling of splicing kinetics enables us to identify more than 1000 mutations affecting RON exon 11 skipping, which corresponds to the pathological isoform RON∆165. Importantly, the effects correlate with RON alternative splicing in cancer patients bearing the same mutations. Moreover, we highlight heterogeneous nuclear ribonucleoprotein H (HNRNPH) as a key regulator of RON splicing in healthy tissues and cancer. Using iCLIP and synergy analysis, we pinpoint the functionally most relevant HNRNPH binding sites and demonstrate how cooperative HNRNPH binding facilitates a splicing switch of RON exon 11. Our results thereby offer insights into splicing regulation and the impact of mutations on alternative splicing in cancer.

We propose a mathematical model for simulating the leading-edge dynamics of a migrating cell from the interplay among elastic properties, architecture of the actin cytoskeleton, and the mechanics of the membrane. Our approach is based on the description of the length and attachment dynamics of actin filaments in the lamellipodium network. It is used to determine the total force exerted on the membrane at each position along the leading edge and at each time step. The model reproduces the marked state switches in protrusion morphodynamics found experimentally between epithelial cells in control conditions and cells expressing constitutively active Rac, a signaling molecule involved in the regulation of lamellipodium network assembly. The model also suggests a mechanistic explanation of experimental distortions in protrusion morphodynamics induced by deregulation of Arp2/3 and cofilin activity.

We present a model for actin-based motility that combines the dynamics of the semiflexible region at the leading edge of the lamellipodium with actomyosin gel properties in the bulk described by the theory of active polar gels. We calculate the velocity of the lamellipodium determined by the interaction of the gel and adhesion with forces in the semiflexible region. The stationary concave force-velocity relation of the model reproduces experimental results. We suggest that it is determined by retrograde flow at small forces and gel formation and retrograde flow at large ones. The variety of dynamic regimes of the semiflexible region reproducing experimentally observed morphodynamics is conserved when we couple the leading edge to the gel.