Search

Cell migration in confining physiological environments relies on the concerted dynamics of several cellular components, including protrusions, adhesions with the environment, and the cell nucleus. However, it remains poorly understood how the dynamic interplay of these components and the cell polarity determine the emergent migration behavior at the cellular scale. Here, we combine data-driven inference with a mechanistic bottom-up approach to develop a model for protrusion and polarity dynamics in confined cell migration, revealing how the cellular dynamics adapt to confining geometries. Specifically, we use experimental data of joint protrusion-nucleus migration trajectories of cells on confining micropatterns to systematically determine a mechanistic model linking the stochastic dynamics of cell polarity, protrusions, and nucleus. This model indicates that the cellular dynamics adapt to confining constrictions through a switch in the polarity dynamics from a negative to a positive, self-reinforcing feedback loop. Our model further reveals how this feedback loop leads to stereotypical cycles of protrusion-nucleus dynamics that drive the migration of the cell through constrictions. These cycles are disrupted upon perturbation of cytoskeletal components, indicating that the positive feedback is controlled by cellular migration mechanisms. Our data-driven theoretical approach therefore identifies polarity feedback adaptation as a key mechanism in confined cell migration.

The migratory dynamics of cells in physiological processes, ranging from wound healing to cancer metastasis, rely on contact-mediated cell-cell interactions. These interactions play a key role in shaping the stochastic trajectories of migrating cells. While data-driven physical formalisms for the stochastic migration dynamics of single cells have been developed, such a framework for the behavioral dynamics of interacting cells still remains elusive. Here, we monitor stochastic cell trajectories in a minimal experimental cell collider: a dumbbell-shaped micropattern on which pairs of cells perform repeated cellular collisions. We observe different characteristic behaviors, including cells reversing, following and sliding past each other upon collision. Capitalizing on this large experimental data set of coupled cell trajectories, we infer an interacting stochastic equation of motion that accurately predicts the observed interaction behaviors. Our approach reveals that interacting non-cancerous MCF10A cells can be described by repulsion and friction interactions. In contrast, cancerous MDA-MB-231 cells exhibit attraction and anti-friction interactions, promoting the predominant relative sliding behavior observed for these cells. Based on these experimentally inferred interactions, we show how this framework may generalize to provide a unifying theoretical description of the diverse cellular interaction behaviors of distinct cell types.

$^{229}$Th is the only nucleus currently under investigation for the development of a nuclear optical clock (NOC) of ultra-high accuracy. The insufficient knowledge of the first nuclear excitation energy of $^{229}$Th has so far hindered direct nuclear laser spectroscopy of thorium ions and thus the development of a NOC. Here, a nuclear laser excitation scheme is detailed, which makes use of thorium atoms instead of ions. This concept, besides potentially leading to the first nuclear laser spectroscopy, would determine the isomeric energy to 40 $\mu$eV resolution, corresponding to 10 GHz, which is a $10^4$ times improvement compared to the current best energy constraint. This would determine the nuclear isomeric energy to a sufficient accuracy to allow for nuclear laser spectroscopy of individual thorium ions in a Paul trap and thus the development of a single-ion nuclear optical clock.

$^{229}$Th is the only known nucleus with an excited state that offers the possibility for a direct laser excitation using existing laser technology. Its excitation energy has been measured indirectly to be 7.8(5) eV ($\approx$160 nm). The energy and lifetime of the isomeric state make it the presently only suitable candidate for a nuclear optical clock, the uncertainty of the excitation energy is, however, still too large to allow for a direct laser excitation in a Paul trap. Therefore, a major goal during the past years has been an improved energy determination. One possible approach is to measure the kinetic energy of electrons which are emitted in the internal conversion decay of the first isomeric state in $^{229}$Th. For this reason an electron spectrometer based on a magnetic bottle combined with electrical retarding fields has been built. Its design, as well as first test measurements are presented, which reveal a relative energy resolution of 3 % and thus enable to measure the electrons' expected kinetic energy to better than 0.1 eV. This is sufficiently precise to specify a laser system able to drive the nuclear clock transition in $^{229}$Th.