Tracing the Sources of Cellular Variation

As the adage says, variety is the spice of life, and despite our best attempts, cells, even those with the same genome, never seem to behave the same. By combining mathematical and experimental analyses, Colman-Lerner and colleagues propose, in a recent issue of Nature, a method to delicately unravel the sources of this variation (Colman-Lerner et al., 2005). Applying their technique to the pheromone response in budding yeast, they show that much of the observed variation originates from cell cycle effects and is dependent on levels of pathway input

Controlling Interneuron Activity in Caenorhabditis Elegans to Evoke Chemotactic Behaviour

Animals locate and track chemoattractive gradients in the environment to find food. With its small nervous system, Caenorhabditis elegans is a good model system in which to understand how the dynamics of neural activity control this search behaviour. Extensive work on the nematode has identified the neurons that are necessary for the different locomotory behaviours underlying chemotaxis through the use of laser ablation, activity recording in immobilized animals and the study of mutants. However, we do not know the neural activity patterns in C. elegans that are sufficient to control its complex chemotactic behaviour. To understand how the activity in its interneurons coordinate different motor programs to lead the animal to food, here we used optogenetics and new optical tools to manipulate neural activity directly in freely moving animals to evoke chemotactic behaviour. By deducing the classes of activity patterns triggered during chemotaxis and exciting individual neurons with these patterns, we identified interneurons that control the essential locomotory programs for this behaviour. Notably, we discovered that controlling the dynamics of activity in just one interneuron pair (AIY) was sufficient to force the animal to locate, turn towards and track virtual light gradients. Two distinct activity patterns triggered in AIY as the animal moved through the gradient controlled reversals and gradual turns to drive chemotactic behaviour. Because AIY neurons are post-synaptic to most chemosensory and thermosensory neurons, it is probable that these activity patterns in AIY have an important role in controlling and coordinating different taxis behaviours of the animal.Engineering and Applied SciencesMolecular and Cellular Biolog

Onset of Propagation of Planar Cracks in Heterogeneous Media

The dynamics of planar crack fronts in hetergeneous media near the critical load for onset of crack motion are investigated both analytically and by numerical simulations. Elasticity of the solid leads to long range stress transfer along the crack front which is non-monotonic in time due to the elastic waves in the medium. In the quasistatic limit with instantaneous stress transfer, the crack front exhibits dynamic critical phenomenon, with a second order like transition from a pinned to a moving phase as the applied load is increased through a critical value. At criticality, the crack-front is self-affine, with a roughness exponent $\zeta =0.34\pm 0.02$. The dynamic exponent $z$ is found to be equal to $0.74\pm 0.03$ and the correlation length exponent $\nu =1.52\pm 0.02$. These results are in good agreement with those obtained from an epsilon expansion. Sound-travel time delays in the stress transfer do not change the static exponents but the dynamic exponent $z$ becomes exactly one. Real elastic waves, however, lead to overshoots in the stresses above their eventual static value when one part of the crack front moves forward. Simplified models of these stress overshoots are used to show that overshoots are relevant at the depinning transition leading to a decrease in the critical load and an apparent jump in the velocity of the crack front directly to a non-zero value. In finite systems, the velocity also shows hysteretic behaviour as a function of the loading. These results suggest a first order like transition. Possible implications for real tensile cracks are discussed.Comment: 51 pages + 20 figur

Pluripotency Factors in Embryonic Stem Cells Regulate Differentiation into Germ Layers

Cell fate decisions are fundamental for development, but we do not know how transcriptional networks reorganize during the transition from a pluripotent to a differentiated cell state. Here, we asked how mouse embryonic stem cells (ESCs) leave the pluripotent state and choose between germ layer fates. By analyzing the dynamics of the transcriptional circuit that maintains pluripotency, we found that Oct4 and Sox2, proteins that maintain ESC identity, also orchestrate germ layer fate selection. Oct4 suppresses neural ectodermal differentiation and promotes mesendodermal differentiation; Sox2 inhibits mesendodermal differentiation and promotes neural ectodermal differentiation. Differentiation signals continuously and asymmetrically modulate Oct4 and Sox2 protein levels, altering their binding pattern in the genome, and leading to cell fate choice. The same factors that maintain pluripotency thus also integrate external signals and control lineage selection. Our study provides a framework for understanding how complex transcription factor networks control cell fate decisions in progenitor cells

Dynamics and Instabilities of Planar Tensile Cracks in Heterogeneous Media

The dynamics of tensile crack fronts restricted to advance in a plane are studied. In an ideal linear elastic medium, a propagating mode along the crack front with a velocity slightly less than the Rayleigh wave velocity, is found to exist. But the dependence of the effective fracture toughness $\Gamma(v)$ on the crack velocity is shown to destabilize the crack front if $(d\Gamma)/(dv)<0$. Short wavelength radiation due to weak random heterogeneities leads to this instability at low velocities. The implications of these results for the crack dynamics are discussed.Comment: 12 page

Statistics of Earthquakes in Simple Models of Heterogeneous Faults

Simple models for ruptures along a heterogeneous earthquake fault zone are studied, focussing on the interplay between the roles of disorder and dynamical effects. A class of models are found to operate naturally at a critical point whose properties yield power law scaling of earthquake statistics. Various dynamical effects can change the behavior to a distribution of small events combined with characteristic system size events. The studies employ various analytic methods as well as simulations.Comment: 4 pages, RevTex, 3 figures (eps-files), uses eps

Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states

The complexity of gene regulatory networks that lead multipotent cells to acquire different cell fates makes a quantitative understanding of differentiation challenging. Using a statistical framework to analyze single-cell transcriptomics data, we infer the gene expression dynamics of early mouse embryonic stem (mES) cell differentiation, uncovering discrete transitions across nine cell states. We validate the predicted transitions across discrete states using flow cytometry. Moreover, using live-cell microscopy, we show that individual cells undergo abrupt transitions from a naïve to primed pluripotent state. Using the inferred discrete cell states to build a probabilistic model for the underlying gene regulatory network, we further predict and experimentally verify that these states have unique response to perturbations, thus defining them functionally. Our study provides a framework to infer the dynamics of differentiation from single cell transcriptomics data and to build predictive models of the gene regulatory networks that drive the sequence of cell fate decisions during development. DOI: http://dx.doi.org/10.7554/eLife.20487.00