Estrogen receptor alpha (ERα) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERα, either by blocking estrogen production through aromatase inhibitors or antiestrogens that compete for hormone binding. Due to resistance, new treatment modalities are needed and as ERα dimerization is essential for its activity, interference with receptor dimerization offers a new opportunity to exploit in drug design. Here we describe a unique mechanism of how ERα dimerization is negatively controlled by interaction with 14-3-3 proteins at the extreme C terminus of the receptor. Moreover, the small-molecule fusicoccin (FC) stabilizes this ERα/14-3-3 interaction. Cocrystallization of the trimeric ERα/ 14-3-3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERα-T 594 ) for high-affinity interaction. We confirm that T 594 is a distinct ERα phosphorylation site in the breast cancer cell line MCF-7 using a phospho-T 594 -specific antibody and by mass spectrometry. In line with its ERα/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERα dimerization, inhibits ERα/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERα are provided, together with a small molecule that selectively targets this ERα/14-3-3 interface.T he estrogen receptor alpha (ERα) is a ligand-dependent transcription factor and the driving force of cell proliferation in 75% of all breast cancers. Current therapeutic strategies to treat these tumors rely on selective ER modulators (SERMs), like tamoxifen (TAM) (1) or aromatase inhibitors (AIs) that block estradiol synthesis (2). Although the benefits of treating hormone-sensitive breast cancers with SERMs and AIs are evident, resistance to treatment is commonly observed (3, 4). To overcome resistance, selective ERα down-regulators (SERDs) can for instance be applied that inhibit ERα signaling through receptor degradation (5, 6). Approaches that target the ERα/ DNA or ERα/cofactor interactions are explored as well (5, 7), but other essential steps in the ERα activation cascade are currently unexploited in drug design, also due to a lack of molecular understanding of the processes at hand.One such step that is crucial for many aspects of ERα functioning is ligand-driven receptor dimerization (8, 9). 17β-Estradiol (E2) association with the ERα ligand binding domain (LBD) drives large conformational changes (10) resulting in ERα dissociation from chaperones (11, 12), unmasking of domains for receptor dimerization, and DNA binding (13,14). Whereas the LBD contains the main dimerization domain (15), the extreme C-terminal domain of the receptor (F domain) imposes a restraint on dimerization (15, 16), although the regulation of this remain...

Abstract. A tropical curve Γ is a metric graph with possibly unbounded edges, and tropical rational functions are continuous piecewise linear functions with integer slopes. We define the complete linear system |D| of a divisor D on a tropical curve Γ analogously to the classical counterpart. We investigate the structure of |D| as a cell complex and show that linear systems are quotients of tropical modules, finitely generated by vertices of the cell complex. Using a finite set of generators, |D| defines a map from Γ to a tropical projective space, and the image can be extended to a tropical curve of degree equal to deg(D). The tropical convex hull of the image realizes the linear system |D| as a polyhedral complex. We show that curves for which the canonical divisor is not very ample are hyperelliptic. We also show that the Picard group of a Q-tropical curve is a direct limit of critical groups of finite graphs converging to the curve.

Assignment of values for natural ecological benefits and anthropocentric ecosystem services in riverine landscapes has been problematic, because a firm scientific basis linking these to the river's physical structure has been absent. We highlight some inherent problems in this process and suggest possible solutions on the basis of the hydrogeomorphic classification of rivers. We suggest this link can be useful in fair asset trading (mitigation and offsets), selection of sites for rehabilitation, cost/benefit decisions on incremental steps in restoring ecological functions, and general protection of rivers.

A kinetic mathematical model of crystal growth from the melt is used to describe quantitatively the phenomenon of oscillatory zoning in plagioclase feldspar. In this model, the functional dependence of crystal growth rate on both melt and crystal surface composition and the transport of material within the melt are explicitly considered. Oscillatory zoning is found to develop for a wide variety of such functional dependence and to be sensitive to the initial composition of the melt.

In this paper we lay the foundations for the study of permutation polytopes: the convex hull of a group of permutation matrices.We clarify the relevant notions of equivalence, prove a product theorem, and discuss centrally symmetric permutation polytopes. We provide a number of combinatorial properties of (faces of) permutation polytopes. As an application, we classify 4-dimensional permutation polytopes and the corresponding permutation groups. Classification results and further examples are made available online.We conclude with several questions suggested by a general finiteness result.