Role for polo-like kinase 4 in mediation of cytokinesis.

The mitotic protein polo-like kinase 4 (PLK4) plays a critical role in centrosome duplication for cell division. By using immunofluorescence, we confirm that PLK4 is localized to centrosomes. In addition, we find that phospho-PLK4 (pPLK4) is cleaved and distributed to kinetochores (metaphase and anaphase), spindle midzone/cleavage furrow (anaphase and telophase), and midbody (cytokinesis) during cell division in immortalized epithelial cells as well as breast, ovarian, and colorectal cancer cells. The distribution of pPLK4 midzone/cleavage furrow and midbody positions pPLK4 to play a functional role in cytokinesis. Indeed, we found that inhibition of PLK4 kinase activity with a small-molecule inhibitor, CFI-400945, prevents translocation to the spindle midzone/cleavage furrow and prevents cellular abscission, leading to the generation of cells with polyploidy, increased numbers of duplicated centrosomes, and vulnerability to anaphase or mitotic catastrophe. The regulatory role of PLK4 in cytokinesis makes it a potential target for therapeutic intervention in appropriately selected cancers

Structural and energetic properties of nickel clusters: 2≤N≤1502 \le N \le 150

The four most stable structures of Ni$_N$ clusters with $N$ from 2 to 150 have been determined using a combination of the embedded-atom method in the version of Daw, Baskes and Foiles, the {\it variable metric/quasi-Newton} method, and our own {\it Aufbau/Abbau} method. A systematic study of energetics, structure, growth, and stability of also larger clusters has been carried through without more or less severe assumptions on the initial geometries in the structure optimization, on the symmetry, or on bond lengths. It is shown that cluster growth is predominantly icosahedral with $islands$ of {\it fcc}, {\it tetrahedral} and {\it decahedral} growth. For the first time in unbiased computations it is found that Ni$_{147}$ is the multilayer (third Mackay) icosahedron. Further, we point to an enhanced ability of {\it fcc} clusters to compete with the icosahedral and decahedral structures in the vicinity of N=79. In addition, it is shown that conversion from the {\it hcp}/anti-Mackay kind of icosahedral growth to the {\it fcc}/Mackay one occurs within a transition layer including several cluster sizes. Moreover, we present and apply different analytical tools in studying structural and energetic properties of such a large class of clusters. These include means for identifying the overall shape, the occurrence of atomic shells, the similarity of the clusters with, e.g., fragments of the {\it fcc} crystal or of a large icosahedral cluster, and a way of analysing whether the $N$-atom cluster can be considered constructed from the $(N-1)$-atom one by adding an extra atom. In addition, we compare in detail with results from chemical-probe experiment. Maybe the most central result is that first for clusters with $N$ above 80 general trends can be identified.Comment: 37 pages, 11 figure

Mott transition in one dimension: Benchmarking dynamical cluster approaches

The variational cluster approach (VCA) is applied to the one-dimensional Hubbard model at zero temperature using clusters (chains) of up to ten sites with full diagonalization and the Lanczos method as cluster solver. Within the framework of the self-energy-functional theory (SFT), different cluster reference systems with and without bath degrees of freedom, in different topologies and with different sets of variational parameters are considered. Static and one-particle dynamical quantities are calculated for half-filling as a function of U as well as for fixed U as a function of the chemical potential to study the interaction- and filling-dependent metal-insulator (Mott) transition. The recently developed Q-matrix technique is used to compute the SFT grand potential. For benchmarking purposes we compare the VCA results with exact results available from the Bethe ansatz, with essentially exact dynamical DMRG data, with (cellular) dynamical mean-field theory and full diagonalization of isolated Hubbard chains. Several issues are discussed including convergence of the results with cluster size, the ability of cluster approaches to access the critical regime of the Mott transition, efficiency in the optimization of correlated-site vs. bath-site parameters and of multi-dimensional parameter optimization. We also study the role of bath sites for the description of excitation properties and as charge reservoirs for the description of filling dependencies. The VCA turns out to be a computationally cheap method which is competitive with established cluster approaches.Comment: 19 pages, 19 figures, v3 with minor corrections, extended discussio

Antibody Targeting Facilitates Effective Intratumoral SiRNA Nanoparticle Delivery to HER2-Overexpressing Cancer Cells

The therapeutic potential of RNA interference (RNAi) has been limited by inefficient delivery of short interfering RNA (siRNA). Tumor-specific recognition can be effectively achieved by antibodies directed against highly expressed cancer cell surface receptors. We investigated the utility of linking an internalizing streptavidinconjugated HER2 antibody to an endosome-disruptive biotinylated polymeric nanocarrier to improve the functional cytoplasmic delivery of siRNA in breast and ovarian cancer cells in vitro and in an intraperitoneal ovarian cancer xenograft model in vivo, yielding an 80% reduction of target mRNA and protein levels with sustained repression for at least 96 hours. RNAi-mediated site specific cleavage of target mRNA was demonstrated using the 5\u27 RLM-RACE (RNA ligase mediated-rapid amplification of cDNA ends) assay. Mice bearing intraperitoneal human ovarian tumor xenografts demonstrated increased tumor accumulation of Cy5.5 fluorescently labeled siRNA and 70% target gene suppression after treatment with HER2 antibody-directed siRNA nanocarriers. Detection of the expected mRNA cleavage product by 5\u27 RLM-RACE assay confirmed that suppression occurs via the expected RNAi pathway. Delivery of siRNA via antibody-directed endosomolytic nanoparticles may be a promising strategy for cancer therapy

Differences between regular and random order of updates in damage spreading simulations

We investigate the spreading of damage in the three-dimensional Ising model by means of large-scale Monte-Carlo simulations. Within the Glauber dynamics we use different rules for the order in which the sites are updated. We find that the stationary damage values and the spreading temperature are different for different update order. In particular, random update order leads to larger damage and a lower spreading temperature than regular order. Consequently, damage spreading in the Ising model is non-universal not only with respect to different update algorithms (e.g. Glauber vs. heat-bath dynamics) as already known, but even with respect to the order of sites.Comment: final version as published, 4 pages REVTeX, 2 eps figures include

Universality-class dependence of energy distributions in spin glasses

We study the probability distribution function of the ground-state energies of the disordered one-dimensional Ising spin chain with power-law interactions using a combination of parallel tempering Monte Carlo and branch, cut, and price algorithms. By tuning the exponent of the power-law interactions we are able to scan several universality classes. Our results suggest that mean-field models have a non-Gaussian limiting distribution of the ground-state energies, whereas non-mean-field models have a Gaussian limiting distribution. We compare the results of the disordered one-dimensional Ising chain to results for a disordered two-leg ladder, for which large system sizes can be studied, and find a qualitative agreement between the disordered one-dimensional Ising chain in the short-range universality class and the disordered two-leg ladder. We show that the mean and the standard deviation of the ground-state energy distributions scale with a power of the system size. In the mean-field universality class the skewness does not follow a power-law behavior and converges to a nonzero constant value. The data for the Sherrington-Kirkpatrick model seem to be acceptably well fitted by a modified Gumbel distribution. Finally, we discuss the distribution of the internal energy of the Sherrington-Kirkpatrick model at finite temperatures and show that it behaves similar to the ground-state energy of the system if the temperature is smaller than the critical temperature.Comment: 15 pages, 20 figures, 1 tabl

Simple nonlinear models suggest variable star universality

Dramatically improved data from observatories like the CoRoT and Kepler spacecraft have recently facilitated nonlinear time series analysis and phenomenological modeling of variable stars, including the search for strange (aka fractal) or chaotic dynamics. We recently argued [Lindner et al., Phys. Rev. Lett. 114 (2015) 054101] that the Kepler data includes "golden" stars, whose luminosities vary quasiperiodically with two frequencies nearly in the golden ratio, and whose secondary frequencies exhibit power-law scaling with exponent near -1.5, suggesting strange nonchaotic dynamics and singular spectra. Here we use a series of phenomenological models to make plausible the connection between golden stars and fractal spectra. We thereby suggest that at least some features of variable star dynamics reflect universal nonlinear phenomena common to even simple systems.Comment: 9 pages, 9 figures, accepted for publication in Physica

Free Energies of Isolated 5- and 7-fold Disclinations in Hexatic Membranes

We examine the shapes and energies of 5- and 7-fold disclinations in low-temperature hexatic membranes. These defects buckle at different values of the ratio of the bending rigidity, $\kappa$, to the hexatic stiffness constant, $K_A$, suggesting {\em two} distinct Kosterlitz-Thouless defect proliferation temperatures. Seven-fold disclinations are studied in detail numerically for arbitrary $\kappa/K_A$. We argue that thermal fluctuations always drive $\kappa/K_A$ into an ``unbuckled'' regime at long wavelengths, so that disclinations should, in fact, proliferate at the {\em same} critical temperature. We show analytically that both types of defects have power law shapes with continuously variable exponents in the ``unbuckled'' regime. Thermal fluctuations then lock in specific power laws at long wavelengths, which we calculate for 5- and 7-fold defects at low temperatures.Comment: LaTeX format. 17 pages. To appear in Phys. Rev.

Optimized energy calculation in lattice systems with long-range interactions

We discuss an efficient approach to the calculation of the internal energy in numerical simulations of spin systems with long-range interactions. Although, since the introduction of the Luijten-Bl\"ote algorithm, Monte Carlo simulations of these systems no longer pose a fundamental problem, the energy calculation is still an O(N^2) problem for systems of size N. We show how this can be reduced to an O(N logN) problem, with a break-even point that is already reached for very small systems. This allows the study of a variety of, until now hardly accessible, physical aspects of these systems. In particular, we combine the optimized energy calculation with histogram interpolation methods to investigate the specific heat of the Ising model and the first-order regime of the three-state Potts model with long-range interactions.Comment: 10 pages, including 8 EPS figures. To appear in Phys. Rev. E. Also available as PDF file at http://www.cond-mat.physik.uni-mainz.de/~luijten/erikpubs.htm

Disclination Asymmetry in Two-Dimensional Nematic Liquid Crystals with Unequal Frank Constants

The behavior of a thin film of nematic liquid crystal with unequal Frank constants is discussed. Distinct Frank constants are found to imply unequal core energies for $+1/2$ and $-1/2$ disclinations. Even so, a topological constraint is shown to ensure that the bulk densities of the two types of disclinations are the same. For a system with free boundary conditions, such as a liquid membrane, unequal core energies simply renormalize the Gaussian rigidity and line tension.Comment: RevTex forma