The biophysical framework of collective cell migration has been extensively investigated in recent years; however, it remains elusive how chemical inputs from neighboring cells are integrated to coordinate the collective movement. Here, we provide evidence that propagation waves of extracellular signal-related kinase (ERK) mitogen-activated protein kinase activation determine the direction of the collective cell migration. A wound-healing assay of Mardin-Darby canine kidney (MDCK) epithelial cells revealed two distinct types of ERK activation wave, a "tidal wave" from the wound, and a self-organized "spontaneous wave" in regions distant from the wound. In both cases, MDCK cells collectively migrated against the direction of the ERK activation wave. The inhibition of ERK activation propagation suppressed collective cell migration. An ERK activation wave spatiotemporally controlled actomyosin contraction and cell density. Furthermore, an optogenetic ERK activation wave reproduced the collective cell migration. These data provide new mechanistic insight into how cells sense the direction of collective cell migration.

The use of machine learning in computational molecular design has great potential to accelerate the discovery of innovative materials. However, its practical benefits still remain unproven in real-world applications, particularly in polymer science. We demonstrate the successful discovery of new polymers with high thermal conductivity, inspired by machine-learning-assisted polymer chemistry. This discovery was made by the interplay between machine intelligence trained on a substantially limited amount of polymeric properties data, expertise from laboratory synthesis and advanced technologies for thermophysical property measurements. Using a molecular design algorithm trained to recognize quantitative structure-property relationships with respect to thermal conductivity and other targeted polymeric properties, we identified thousands of promising hypothetical polymers. From these candidates, three were selected for monomer synthesis and polymerization because of their synthetic accessibility and their potential for ease of processing in further applications. The synthesized polymers reached thermal conductivities of 0.18-0.41 W/mK, which are comparable to those of state-of-the-art polymers in non-composite thermoplastics .

We aim to elucidate the cosurfactant effects, which are expected when junctions of two block copolymers share a common microdomain interface, on morphology and phase behavior of mixtures. Especially this paper addresses the effects involved for binary mixtures composed of polystyrene-block-polyisoprene having about equal molecular weights but complementary compositions, one forming polystyrene (PS) cylinders in polyisoprene (PI) matrix and the other forming PI cylinders in PS matrix. Transmission electron microscopy and small-angle X-ray scattering were used to characterize the phase behavior and domain spacing of the binary mixtures. First, we found an expanding composition range for hexagonally packed cylindrical morphology and a narrowed composition range for lamellae relative to the corresponding composition ranges for neat SI block copolymer under a strong segregation condition. The result indicates that the cosurfactant effects help a block copolymer to take its spontaneous curvature. Second, it was found that the effects enlarged the domain size and interdomain distance of the binary mixtures. Those results were compared with the theory by Birshtein and co-workers, which is proposed to describe the microdomain morphology for strongly segregated binary block copolymers. We found good agreements between experimental and theoretical results in terms of (i) domain size, (ii) interdomain distance, and (iii) the blending compositions where morphological transitions occur.

A coordination polymerization of alkoxyallenes (2a-2f) by the [q3-(allyl)NiOCOCF3] (1) /PPh, system was carried out to obtain a polymer (3) bearing exomethylenes on the main chain. The structure of the obtained polymer was confirmed by 'H-, "C-NMR and IR spectra, and was revealed to consist of two units, one bearing an exomethylene side chain and the other an end ether side chain as a result of 1,2-and 2,3-~olymerization. In the case of methoxyallene, the ratio was estimated as 32:68. The number average molecular weight (M&f t& resulting polymer varied linearly with increasing ratio of monomer to initiator. The molecular weight distributions (MJM,,) of the polymers obtained here were always approximately 1.1.These results may strongly support that the present polymerization proceeds bya living mechanism. Under an inert atmosphere, the propagating end of the polymer was quite stable and could be kept without any decrease in activity for more than a week. The proportion of 1,2-and 2,3-polymerization was a little affected by the substituents on the alkoxyallenes, as the steric bulkiness of the substituents increased the content of 2,3-polymerization units.

Cell-cell signaling is subject to variability in the extracellular volume, cell number, and dilution that potentially increase uncertainty in the absolute concentrations of the extracellular signaling molecules. To direct cell aggregation, the social amoebae Dictyostelium discoideum collectively give rise to oscillations and waves of cyclic adenosine 3′,5′-monophosphate (cAMP) under a wide range of cell density. To date, the systems-level mechanism underlying the robustness is unclear. By using quantitative live-cell imaging, here we show that the magnitude of the cAMP relay response of individual cells is determined by fold change in the extracellular cAMP concentrations. The range of cell density and exogenous cAMP concentrations that support oscillations at the population level agrees well with conditions that support a large fold-change-dependent response at the singlecell level. Mathematical analysis suggests that invariance of the oscillations to density transformation is a natural outcome of combining secrete-and-sense systems with a fold-change detection mechanism.fold-change detection | oscillations | collective behavior | Dictyostelium | robustness C ell-cell signaling lies at the basis of development and maintenance of multicellular forms of life. Extracellular signals are often subject to greater fluctuations in the size of extracellular space and the number of cells (Fig. 1A), not to mention nonspecific binding to other molecules, degradation, and dilution. These factors introduce an uncertainty to the detectable number of extracellular ligand molecules, thus posing a threat to the fidelity of cell-cell communication. One of the means by which cells could cope with such uncertainties is to base their behavioral decisions on temporal changes in the extracellular signals. Persistent stimuli are often ignored while their changes in time elicit transient responses-a property collectively called adaptation (1-3). Recent studies have highlighted cellular response whose magnitude appears to be dictated by the fold change in the input stimuli-a property referred to as "fold-change detection" (FCD) (4, 5). In bacterial chemotaxis, cells respond adaptively to a fold change in chemoattractant concentration (6) so that their search patterns depend only on the spatial profiles of the chemoattractant irrespective of its absolute level. Fold-change dependence is also implied in eukaryotic chemotactic response (7, 8) as well as cell fate control and gene regulation in Xenopus embryo (9), Drosophila imaginal disk (10), and mammalian cells (11). These studies have shed light on the role of FCD for a simple unidirectional signal transduction from an extracellular ligand-receptor interaction (input) to a cellular response (output). However, cell-cell signaling and multicellular systems as a whole often use secretion and sensing of the same molecules (12), whereby the output is fed back to the responding cell itself in addition to the neighboring cells, thus forming a complex bidirectional signal transduction system. Th...

The stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38 are important players in cell-fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in inflammatory and stress responses. However, it is unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. We established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses activated JNK and p38 with various dynamics. In all cases, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition generates cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress.

Actomyosin contractility generated cooperatively by nonmuscle myosin II and actin filaments plays essential roles in a wide range of biological processes, such as cell motility, cytokinesis, and tissue morphogenesis. However, subcellular dynamics of actomyosin contractility underlying such processes remains elusive. Here, we demonstrate an optogenetic method to induce relaxation of actomyosin contractility at the subcellular level. The system, named OptoMYPT, combines a protein phosphatase 1c (PP1c)-binding domain of MYPT1 with an optogenetic dimerizer, so that it allows light-dependent recruitment of endogenous PP1c to the plasma membrane. Blue-light illumination is sufficient to induce dephosphorylation of myosin regulatory light chains and a decrease in actomyosin contractile force in mammalian cells and Xenopus embryos. The OptoMYPT system is further employed to understand the mechanics of actomyosin-based cortical tension and contractile ring tension during cytokinesis. We find that the relaxation of cortical tension at both poles by OptoMYPT accelerated the furrow ingression rate, revealing that the cortical tension substantially antagonizes constriction of the cleavage furrow. Based on these results, the OptoMYPT system provides opportunities to understand cellular and tissue mechanics.

Leaf form diversification in an ornamental heirloom tomato results from alterations in two different HOMEOBOX genes Graphical abstract Highlights d Two HOMEOBOX genes are responsible for the leaf shape in an heirloom tomato, SiFT d BIP regulates leaf complexity; SlWOX1 regulates leaflet width and vascular density d SlWOX1 is mutated in the classical tomato mutant, solanifolia d The bip mutation in SiFT arose de novo during the breeding process