The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

Integrin, an αβ heterodimeric cell surface receptor for the extracellular matrix (ECM), carries two tyrosine phosphorylation motifs in the cytoplasmic tail of the β subunit. NPXY (Asn-Pro-x-Tyr) is a conserved tyrosine phosphorylation motif that binds to the phospho-tyrosine binding (PTB) domain. We generated a tyrosine to glutamic acid (E) mutation to modify tyrosine (Y) into a negatively charged amino NPXY in the βpat-3 integrin of Caenorhabditis elegans. The transgenic rescue animal displayed defects in gonad migration and tail morphology. Also, the mutant animals produced a high number of males, suggesting that the Y to E mutation in βpat-3 integrin causes a phenotype similar to that of Him mutant. Further analyses revealed that males of pat-3(Y804E) and him-4/hemicentin share additional phenotypes such as abnormal gonad and unsuccessful mating. A pat-3 transgenic rescue mutant with a non-polar phenylalanine (F) in NPXY, pat-3(Y792/804F), suppressed the high male number, defective mating, inviable zygote, and the abnormal gonad of him-4 mutants, indicating that Y to F mutation in both NPXY motifs suppressed the him-4 phenotypes. This finding supports the idea that the ECM determines the activation state in integrin NPXY motifs; him-4/hemicentin may directly or indirectly interact with integrins and maintain the NPXY non-charged. Our findings provide new insight into a suppressive role of an ECM molecule in integrin NPXY phosphorylation.

The size of bottom-up subsidies, food and larvae, from the ocean has a profound impact on inter-tidal communities and populations. Alongshore variations in subsidies are attributed to variation in coastal conditions, but also might be due to variations in surf-zone hydrodynamics. We tested this hypothesis by comparing surf-zone phytoplankton concentrations to surf-zone hydrodynamics as indicated by the width of the surf zones. To minimize the potential effects of alongshore variation in phytoplankton abundance in the coastal ocean, we sampled closely spaced sites (median separation 1km) over short periods (3days). Surf-zone concentrations of coastal phytoplankton taxa (e.g. Chaetoceros spp., Pseudo-nitzschia spp. and dinoflagellates) varied with surf-zone width; 65% to 94% of the variability in their concentration is explained by surf-zone width. Where surf zones were narrow and more reflective, phytoplankton concentrations were one to several orders of magnitude lower than in wider, more dissipative surf zones. The most closely spaced stations were 30m apart, but represented distinct habitats - a reflective and a more dissipative surf zone. Phytoplankton concentrations in the reflective surf zone were an order of magnitude or more lower than in the adjacent more dissipative surf zone. A reanalysis of a published study on phytoplankton subsidies found similar results. Alongshore variation in surf-zone hydrodynamics appears to be an important driver of phytoplankton subsidies to the inter-tidal zone.

We present a plausible account of the origin of the archetypal vertebrate bauplan. We offer a theoretical reconstruction of the geometrically regular structure of the blastula resulting from the sequential subdivision of the egg, followed by mechanical deformations of the blastula in subsequent stages of gastrulation. We suggest that the formation of the vertebrate bauplan during development, as well as fixation of its variants over the course of evolution, have been constrained and guided by global mechanical biases. Arguably, the role of such biases in directing morphology—though all but neglected in previous accounts of both development and macroevolution—is critical to any substantive explanation for the origin of the archetypal vertebrate bauplan. We surmise that the blastula inherently preserves the underlying geometry of the cuboidal array of eight cells produced by the first three cleavages that ultimately define the medial-lateral, dorsal-ventral, and anterior-posterior axes of the future body plan. Through graphical depictions, we demonstrate the formation of principal structures of the vertebrate body via mechanical deformation of predictable geometrical patterns during gastrulation. The descriptive rigor of our model is supported through comparisons with previous characterizations of the embryonic and adult vertebrate bauplane. Though speculative, the model addresses the poignant absence in the literature of any plausible account of the origin of vertebrate morphology. A robust solution to the problem of morphogenesis—currently an elusive goal—will only emerge from consideration of both top-down (e.g., the mechanical constraints and geometric properties considered here) and bottom-up (e.g., molecular and mechano-chemical) influences.

This paper reports the discovery of a geometrical algorithm that provides a coherent step by step mechanical account of the structure of the nervous system, including the vertebrate brain, the spinal cord, the vertebral column, and the spinal nerves. The morphology of these organs and the observed steps of neural development are well described, consequent of centuries of study. But morphogenesis, the origin and cause of these forms, has not been studied since the last half of the nineteenth century. Neurology does not teach how the brain gained its shape, nor have any causative theories of brain formation been published in recent times. This paper proposes a hypothetical construction based on the discovery of a simple algorithm which generates topologically the form of the brain, the spinal cord, and the vertebral column by the deformation of a gridded segmented sphere by the inversion of its surface. The hypothetical model is in close analogy with nature: the blastula is a segmented gridded sphere which results from the subdivision of the egg. The first step of embryogenesis is gastrulation, where blastula is pressed to enter its own interior, pulling the surface inside out, forming the embryo.