Lower limits for the homogenization of periodic metamaterials made from electric dipolar scatterers

Nonlocal constitutive relations promise to homogenize metamaterials even though the ratio of period over operational wavelength is not much smaller than unity. However, this ability has not yet been verified, as frequently only discrete structures were considered. This denies a systematic variation of the relevant ratio. Here, we explore, using the example of an electric dipolar lattice, the superiority of the nonlocal over local constitutive relation to homogenize metamaterials when the period tends to be comparable to the wavelength. Moreover, we observe a breakdown of the ability to homogenize the metamaterial at shorter lattice constants. This surprising failure occurs when energy is transported across the lattice thanks to a well-pronounced near-field interaction among the particles forming the lattice. Contrary to common wisdom, this suggests that the period should not just be much smaller than the operational wavelength to homogenize a metamaterial, but, for a given size of the inclusion, there is an optimal period

Mechanochemical control of epidermal stem cell divisions by B-plexins

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.Peer reviewe

Identification and characterization of critical determinants in plexin signaling

Semaphorins, a class of soluble and membrane-bound ligands, and their corresponding receptors, plexins, play a pivotal role in organogenesis, physiology of different tissues and organ systems, as well as in the development of diseases. Plexins exert diverse signaling functions via their intracellular domain. One of these functions is the deactivation of R-Ras, a non-classical isoform of the oncogene Ras. So far, the exact mechanism of this plexin-mediated R-Ras deactivation is unknown. In this thesis, the yet unidentified mechanism is elucidated, recently discovered players in the semaphorin-plexin system are investigated and mutations of plexins are characterized for their role in ligand-binding and downstream signaling. For this purpose, molecular biological, biochemical, cell biological and pharmacological methods were combined. It could be shown that mutations of Plexin-B2 occurring in patients with congenital anomalies of the kidney and urinary tract impair the plexin-mediated signaling ability. Moreover, TMEM260, a protein with so far unknown function, serves as an O-mannosyltransferase for plexins and a role for these protein-mediated Plexin-B2 mannosylations was identified in membrane targeting and proteolytic processing. Additionally, Rasal1 was validated and characterized as a GTPase activating protein downstream of plexins, that deactivates R-Ras. In this mechanism plexins bind active R-Ras, without influencing its activity. The binding of semaphorins to plexins induces the release of R-Ras from plexin binding and R-Ras then gets deactivated by Rasal1. Finally, these findings were set in a translational context by identifying a role of the semaphorin-plexin-Rasal1-R-Ras signaling axis in the negative regulation of gastrin gene expression in vitro, a peptide hormone that stimulates gastric acid production. Concluding, these findings illuminate new mechanistic insights into plexin signaling, uncover new molecular functions of plexins in pathophysiology and clear up the controversy about the function of the plexin GTPase activating protein domain in the regulation of R-Ras activity