TY - JOUR AB - The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores (comb jellies) have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes, and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well recognized in ctenophores, many bilaterian neuron-specific genes and genes of 'classical' neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals. AU - Moroz, Leonid L AU - Kocot, Kevin M AU - Citarella, Mathew R AU - Dosung, Sohn AU - Norekian, Tigran P AU - Povolotskaya, Inna AU - Grigorenko, Anastasia P AU - Dailey, Christopher A AU - Berezikov, Eugene AU - Buckley, Katherine M AU - Ptitsyn, Andrey A AU - Reshetov, Denis A AU - Mukherjee, Krishanu AU - Moroz, Tatiana P AU - Bobkova, Yelena V AU - Yu, Fahong AU - Kapitonov, Vladimir V AU - Jurka, Jerzy W AU - Bobkov, Yuriy V AU - Swore, Joshua J AU - Girardo, David O AU - Fodor, Alexander AU - Gusev, Fedor E AU - Sanford, Rachel S AU - Bruders, Rebecca AU - Kittler, Ellen L AU - Mills, Claudia E AU - Rast, Jonathan P AU - Derelle, Romain AU - Solovyev, Victor AU - Fyodor Kondrashov AU - Swalla, Billie J AU - Sweedler, Jonathan V AU - Rogaev, Evgeny I AU - Halanych, Kenneth M AU - Kohn, Andrea B ID - 863 IS - 7503 JF - Nature TI - The ctenophore genome and the evolutionary origins of neural systems VL - 510 ER - TY - JOUR AB - Research on existing drugs often discovers novel mechanisms of their action and leads to the expansion of their therapeutic scope and subsequent remarketing. The Wnt signaling pathway is of the immediate therapeutic relevance, as it plays critical roles in cancer development and progression. However, drugs which disrupt this pathway are unavailable despite the high demand. Here we report an attempt to identify antagonists of the Wnt-FZD interaction among the library of the FDA-approved drugs. We performed an in silico screening which brought up several potential antagonists of the ligand-receptor interaction. 14 of these substances were tested using the TopFlash luciferase reporter assay and four of them identified as active and specific inhibitors of the Wnt3a-induced signaling. However, further analysis through GTP-binding and β-catenin stabilization assays showed that the compounds do not target the Wnt-FZD pair, but inhibit the signaling at downstream levels. We further describe the previously unknown inhibitory activity of an anti-leprosy drug clofazimine in the Wnt pathway and provide data demonstrating its efficiency in suppressing growth of Wnt-dependent triple-negative breast cancer cells. These data provide a basis for further investigations of the efficiency of clofazimine in treatment of Wnt-dependent cancers. AU - Koval, Alexey V AU - Vlasov, Peter K AU - Shichkova, Polina AU - Khunderyakova, S AU - Markov, Yury AU - Panchenko, J AU - Volodina, A AU - Fyodor Kondrashov AU - Katanaev, Vladimir L ID - 865 IS - 4 JF - Biochemical Pharmacology TI - Anti leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling VL - 87 ER - TY - JOUR AB - The morphological stability of biological tubes is crucial for the efficient circulation of fluids and gases. Failure of this stability causes irregularly shaped tubes found in multiple pathological conditions. Here, we report that Drosophila mutants of the ESCRT III component Shrub/Vps32 exhibit a strikingly elongated sinusoidal tube phenotype. This is caused by excessive apical membrane synthesis accompanied by the ectopic accumulation and overactivation of Crumbs in swollen endosomes. Furthermore, we demonstrate that the apical extracellular matrix (aECM) of the tracheal tube is a viscoelastic material coupled with the apical membrane. We present a simple mechanical model in which aECM elasticity, apical membrane growth, and their interaction are three vital parameters determining the stability of biological tubes. Our findings demonstrate a mechanical role for the extracellular matrix and suggest that the interaction of the apical membrane and an elastic aECM determines the final morphology of biological tubes independent of cell shape. AU - Dong, Bo AU - Hannezo, Edouard B AU - Hayashi, Shigeo ID - 925 IS - 4 JF - Cell Reports TI - Balance between apical membrane growth and luminal matrix resistance determines epithelial tubule shape VL - 7 ER - TY - JOUR AB - Morphogenesis during embryo development requires the coordination of mechanical forces to generate the macroscopic shapes of organs. We propose a minimal theoretical model, based on cell adhesion and actomyosin contractility, which describes the various shapes of epithelial cells and the bending and buckling of epithelial sheets, as well as the relative stability of cellular tubes and spheres. We show that, to understand these processes, a full 3D description of the cells is needed, but that simple scaling laws can still be derived. The morphologies observed in vivo can be understood as stable points of mechanical equations and the transitions between them are either continuous or discontinuous. We then focus on epithelial sheet bending, a ubiquitous morphogenetic process. We calculate the curvature of an epithelium as a function of actin belt tension as well as of cell-cell and and cell-substrate tension. The model allows for a comparison of the relative stabilities of spherical or cylindrical cellular structures (acini or tubes). Finally, we propose a unique type of buckling instability of epithelia, driven by a flattening of individual cell shapes, and discuss experimental tests to verify our predictions. AU - Hannezo, Edouard B AU - Prost, Jacques AU - Joanny, Jean ID - 927 IS - 1 JF - PNAS TI - Theory of epithelial sheet morphology in three dimensions VL - 111 ER - TY - JOUR AB - Transposons are selfish genetic sequences that can increase their copy number and inflict substantial damage on their hosts. To combat these genomic parasites, plants have evolved multiple pathways to identify and silence transposons by methylating their DNA. Plants have also evolved mechanisms to limit the collateral damage from the antitransposon machinery. In this review, we examine recent developments that have elucidated many of the molecular workings of these pathways. We also highlight the evidence that the methylation and demethylation pathways interact, indicating that plants have a highly sophisticated, integrated system of transposon defense that has an important role in the regulation of gene expression. AU - Kim, M. Yvonne AU - Zilberman, Daniel ID - 9519 IS - 5 JF - Trends in Plant Science SN - 1360-1385 TI - DNA methylation as a system of plant genomic immunity VL - 19 ER - TY - JOUR AB - Multielectron spin qubits are demonstrated, and performance examined by comparing coherent exchange oscillations in coupled single-electron and multielectron quantum dots, measured in the same device. Fast (>1 GHz) exchange oscillations with a quality factor Q∼15 are found for the multielectron case, compared to Q∼2 for the single-electron case, the latter consistent with experiments in the literature. A model of dephasing that includes voltage and hyperfine noise is developed that is in good agreement with both single- and multielectron data, though in both cases additional exchange-independent dephasing is needed to obtain quantitative agreement across a broad parameter range. AU - Higginbotham, Andrew P AU - Kuemmeth, Ferdinand AU - Hanson, Micah AU - Gossard, Arthur AU - Marcus, Charles ID - 96 IS - 2 JF - APS Physics, Physical Review Letters TI - Coherent operations and screening in multielectron spin qubits VL - 112 ER - TY - JOUR AB - Let d≥3 be a fixed integer. We give an asympotic formula for the expected number of spanning trees in a uniformly random d-regular graph with n vertices. (The asymptotics are as n→∞, restricted to even n if d is odd.) We also obtain the asymptotic distribution of the number of spanning trees in a uniformly random cubic graph, and conjecture that the corresponding result holds for arbitrary (fixed) d. Numerical evidence is presented which supports our conjecture. AU - Greenhill, Catherine AU - Kwan, Matthew Alan AU - Wind, David ID - 9594 IS - 1 JF - The Electronic Journal of Combinatorics TI - On the number of spanning trees in random regular graphs VL - 21 ER - TY - JOUR AB - Correlative microscopy incorporates the specificity of fluorescent protein labeling into high-resolution electron micrographs. Several approaches exist for correlative microscopy, most of which have used the green fluorescent protein (GFP) as the label for light microscopy. Here we use chemical tagging and synthetic fluorophores instead, in order to achieve protein-specific labeling, and to perform multicolor imaging. We show that synthetic fluorophores preserve their post-embedding fluorescence in the presence of uranyl acetate. Post-embedding fluorescence is of such quality that the specimen can be prepared with identical protocols for scanning electron microscopy (SEM) and transmission electron microscopy (TEM); this is particularly valuable when singular or otherwise difficult samples are examined. We show that synthetic fluorophores give bright, well-resolved signals in super-resolution light microscopy, enabling us to superimpose light microscopic images with a precision of up to 25 nm in the x–y plane on electron micrographs. To exemplify the preservation quality of our new method we visualize the molecular arrangement of cadherins in adherens junctions of mouse epithelial cells. AU - Perkovic, Mario AU - Kunz, Michael AU - Endesfelder, Ulrike AU - Bunse, Stefanie AU - Wigge, Christoph AU - Yu, Zhou AU - Hodirnau, Victor-Valentin AU - Scheffer, Margot P. AU - Seybert, Anja AU - Malkusch, Sebastian AU - Schuman, Erin M. AU - Heilemann, Mike AU - Frangakis, Achilleas S. ID - 9655 IS - 2 JF - Journal of Structural Biology SN - 1047-8477 TI - Correlative light- and electron microscopy with chemical tags VL - 186 ER - TY - JOUR AB - It is well known that ultrasonic vibration can soften metals, and this phenomenon has been widely exploited in industrial applications concerning metal forming and bonding. Recent experiments show that the simultaneous application of oscillatory stresses from audible to ultrasonic frequency ranges can lead to not only softening but also significant dislocation annihilation and subgrain formation in metal samples from the nano- to macro-size range. These findings indicate that the existing understanding of ultrasound softening – that the vibrations either impose additional stress waves to augment the quasi-static applied load, or cause heating of the metal, whereas the metal’s intrinsic deformation resistance or mechanism remains unaltered – is far from complete. To understand the softening and the associated enhanced subgrain formation and dislocation annihilation, a new simulator based on the dynamics of dislocation-density functions is employed. This new simulator considers the flux, production and annihilation, as well as the Taylor and elastic interactions between dislocation densities. Softening during vibrations as well as enhanced cell formation is predicted. The simulations reveal the main mechanism for subcell formation under oscillatory loadings to be the enhanced elimination of statistically stored dislocations (SSDs) by the oscillatory stress, leaving behind geometrically necessary dislocations with low Schmid factors which then form the subgrain walls. The oscillatory stress helps the depletion of the SSDs, because the chance for them to meet up and annihilate is increased with reversals of dislocation motions. This is the first simulation effort to successfully predict the cell formation phenomenon under vibratory loadings. AU - Cheng, Bingqing AU - Leung, H.S. AU - Ngan, A.H.W. ID - 9686 IS - 16-18 JF - Philosophical Magazine SN - 1478-6435 TI - Strength of metals under vibrations – dislocation-density-function dynamics simulations VL - 95 ER - TY - JOUR AB - Understanding the effects of sex and migration on adaptation to novel environments remains a key problem in evolutionary biology. Using a single-cell alga Chlamydomonas reinhardtii, we investigated how sex and migration affected rates of evolutionary rescue in a sink environment, and subsequent changes in fitness following evolutionary rescue. We show that sex and migration affect both the rate of evolutionary rescue and subsequent adaptation. However, their combined effects change as the populations adapt to a sink habitat. Both sex and migration independently increased rates of evolutionary rescue, but the effect of sex on subsequent fitness improvements, following initial rescue, changed with migration, as sex was beneficial in the absence of migration but constraining adaptation when combined with migration. These results suggest that sex and migration are beneficial during the initial stages of adaptation, but can become detrimental as the population adapts to its environment. AU - Lagator, Mato AU - Morgan, Andrew AU - Neve, Paul AU - Colegrave, Nick ID - 2083 IS - 8 JF - Evolution TI - Role of sex and migration in adaptation to sink environments VL - 68 ER -