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Edited by Gianni CesareniKeywords: Annexin S100 protein Cell-cell interaction Protein interaction a b s t r a c t Annexin A2 (AnxA2) and S100A10 are known to form a molecular complex. Using fluorescencebased binding assays, we show that both proteins are localised on the cell surface, in a molecular form that allows mutual interaction. We hypothesized that binding between these proteins could facilitate cell-cell interactions. For cells that express surface S100A10 and surface annexin A2, cell-cell interactions can be blocked by competing with the interaction between these proteins. Thus an annexin A2-S100A10 molecular bridge participates in cell-cell interactions, revealing a hitherto unexplored function of this protein interaction.

S100 proteins are small adaptors that regulate the activity of partner proteins by virtue of direct protein interactions. Here, we describe the first small molecule blockers of the interaction between S100A10 and annexin A2. Molecular docking yielded candidate blockers that were screened for competition of the binding of an annexin A2 peptide to S100A10. Several inhibitory clusters were identified with some containing compounds with potency in the lower micromolar range. We chose 3-hydroxy-1-(2-hydroxypropyl)-5-(4-isopropylphenyl)-4-(4-methylbenzoyl)-1H-pyrrol-2(5H)-one (1a) as a starting point for structure−activity studies. These confirmed the hypothetical binding mode from the virtual screen for this series of molecules. Selected compounds disrupted the physiological complex of annexin A2 and S100A10, both in a broken cell preparation and inside MDA-MB-231 breast cancer cells. Thus, this class of compounds has promising properties as inhibitors of the interaction between annexin A2 and S100A10 and may help to elucidate the cellular function of this protein interaction.

Malformations of the sympathetic nervous system have been associated with cardiovascular instability, gastrointestinal dysfunction, and neuroblastoma. A better understanding of the factors regulating sympathetic nervous system development is critical to the development of potential therapies. Here, we have uncovered a temporal requirement for the LIM homeodomain transcription factor ISL1 during sympathetic nervous system development by the analysis of two mutant mouse lines: an Isl1 hypomorphic line and mice with Isl1 ablated in neural crest lineages. During early development, ISL1 is required for sympathetic neuronal fate determination, differentiation, and repression of glial differentiation, although it is dispensable for initial noradrenergic differentiation. ISL1 also plays an essential role in sympathetic neuron proliferation by controlling cell cycle gene expression. During later development, ISL1 is required for axon growth and sympathetic neuron diversification by maintaining noradrenergic differentiation, but repressing cholinergic differentiation. RNA-seq analyses of sympathetic ganglia from Isl1 mutant and control embryos, together with ISL1 ChIP-seq analysis on sympathetic ganglia, demonstrated that ISL1 regulates directly or indirectly several distinct signaling pathways that orchestrate sympathetic neurogenesis. A number of genes implicated in neuroblastoma pathogenesis are direct downstream targets of ISL1. Our study revealed a temporal requirement for ISL1 in multiple aspects of sympathetic neuron development, and suggested Isl1 as a candidate gene for neuroblastoma.

Controllable directional transport of liquid droplets on a functionalized surface has been a challenge in the field of microfluidics because it does not require energy supply, and the physical mechanism of such self-driving transport exhibits extraordinary contribution to fundamental understanding of some biological processes and the design of microfluidic apparatus. In this paper, we report a novel design of a surface microstructure that can realize unidirectional self-driving liquid mercury (Hg) droplet transport on a graphene-covered copper (Cu) substrate with a three-dimensional surface microstructure. We have demonstrated that a liquid Hg droplet spontaneously propagates on a grooved Cu substrate covered by a monolayer graphene without any external force fields. Classical molecular dynamics results provide a profound insight on the self-driving process of Hg droplets. It shows that the Hg droplet undergoes acceleration, deceleration, and return stages successively from the narrow to wide ends of the gradient groove. Intriguingly, Hg droplets can move continuously and unidirectionally on the three-dimensional graphene-covered surface microstructure when they accumulate enough kinetic energy from the gradient groove to break the energy barrier at the step junctions between the two neighboring unit cells. The design of the zigzag textured surface covered by a monolayer graphene artfully uses the facts; (1) the monolayer graphene can effectively reduce the droplet pinning on the textured surface, (2) the hydrophobic graphene layer reduces the friction between Hg droplets and the substrate, and (3) the textured surface can permeably interact with the droplets through the monolayer graphene to achieve a continuous self-driving process. The findings reported here open a door to explore the graphene-covered functional surface to directional transport of liquid droplets and provide an in-depth understanding of the self-driving mechanism for liquid droplets on graphene-covered textured substrates.

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