Regulation of Anaphase Promoting Complex Coactivators

Ubiquitin-mediated proteolytic degradation is fundamental to eukaryotic cell cycle progression. From late mitosis through early G1, the Anaphase Promoting Complex (APC) is essential for cell-cycle relevant proteolytic degradation, and its activity is targeted to appropriate substrates by the evolutionarily conserved coactivators Cdc20 and Cdh1. After an initial wave of APC-Cdc20 activity, APC-Cdh1 degrades multiple mitotic proteins from mitotic exit through G1; inhibitory phosphorylation of Cdh1 by CDK and Polo kinase may allow accumulation of Cdh1 targets in the subsequent cell cycle. I demonstrate lethality of exact endogenous gene replacement of CDH1 with the CDK-unphosphorylatable CDH1-m11 allele; neither polo kinase sites nor polo interaction motifs are required for Cdh1 regulation. CDH1-m11 cells arrest in the first cycle with replicated DNA;~30% of these cells have bipolar spindles. Construction of bipolar spindles in these cells is strikingly sensitive to gene dosage of the stoichiometric Cdh1 inhibitor ACM1. CDH1-m11 cells with bipolar spindles fail to progress to anaphase, suggesting that Cdh1 inhibits multiple spindle-regulatory pathways. Expression of undegradable mitotic cyclin causes spindle pole body separation (a key step in bipolar spindle assembly) in CDH1-m11 cells; thus mitotic cyclins are a significant target for Cdh1 with respect to bipolar spindle assembly, and reciprocally, cyclin-Cdk activity is the most significant mechanism for Cdh1 inactivation. Cdc20 has been proposed to be a Cdh1 target, but regulation of Cdc20 proteolysis has been controversial. My experiments demonstrate that degradation of Cdc20 can be dependent on Cdh1 and Cdc20 destruction boxes, but Cdh1- and db-independent modes of Cdc20 proteolysis are also effective in limiting Cdc20 levels. To better understand the mechanisms by which multisite CDK phosphorylation inhibits Cdh1, I employed a novel recombination approach to create a series of partially unphosphorylatable CDH1 alleles ablating contiguous sites beginning at either the N or C terminus. Strains lacking N-terminal phosphorylation sites were strictly dependent upon ACM1 and S-phase cyclins for viability, and a fraction of cells displayed evidence of hyperactive APC-Cdh1, in contrast to a non-overlapping larger set of C-terminal site ablations

Liquid crystal defects in the Landau-de Gennes theory in two dimensions-beyond the one-constant approximation

We consider the two-dimensional Landau-de Gennes energy with several elastic constants, subject to general $k$-radially symmetric boundary conditions. We show that for generic elastic constants the critical points consistent with the symmetry of the boundary conditions exist only in the case $k=2$. In this case we identify three types of radial profiles: with two, three of full five components and numerically investigate their minimality and stability depending on suitable parameters. We also numerically study the stability properties of the critical points of the Landau-de Gennes energy and capture the intricate dependence of various qualitative features of these solutions on the elastic constants and the physical regimes of the liquid crystal system

Walker solution for Dzyaloshinskii domain wall in ultrathin ferromagnetic films

We analyze the electric current and magnetic field driven domain wall motion in perpendicularly magnetized ultrathin ferromagnetic films in the presence of interfacial Dzyaloshinskii-Moriya interaction and both out-of-plane and in-plane uniaxial anisotropies. We obtain exact analytical Walker-type solutions in the form of one-dimensional domain walls moving with constant velocity due to both spin-transfer torques and out-of-plane magnetic field. These solutions are embedded into a larger family of propagating solutions found numerically. Within the considered model, we find the dependencies of the domain wall velocity on the material parameters and demonstrate that adding in-plane anisotropy may produce domain walls moving with velocities in excess of 500 m/s in realistic materials under moderate fields and currents.Comment: 6 pages, 2 figure

Regulated degradation of the APC coactivator Cdc20

<p>Abstract</p> <p>Background</p> <p>Cdc20 is a highly conserved activator of the anaphase-promoting complex (APC), promoting cell-cycle-regulated ubiquitination and proteolysis of a number of critical cell-cycle-regulatory targets including securin and mitotic cyclins. APC-Cdc20 activity is tightly regulated, and this regulation is likely important for accurate cell cycle control. One significant component of Cdc20 regulation is thought to be Cdc20 proteolysis. However, published literature suggests different mechanisms and requirements for Cdc20 proteolysis. The degree to which Cdc20 proteolysis is cell-cycle regulated, the dependence of Cdc20 proteolysis on Cdc20 destruction boxes (recognition sequences for APC-mediated ubiqutination, either by Cdc20 or by the related Cdh1 APC activator), and the need for APC itself for Cdc20 proteolysis all have been disputed to varying extents. In animals, Cdc20 proteolysis is thought to be mediated by Cdh1, contributing an intrinsic order of APC activation by Cdc20 and then by Cdh1. One report suggests a Cdh1 requirement for Cdc20 proteolysis in budding yeast; this idea has not been tested further.</p> <p>Results</p> <p>We characterized Cdc20 proteolysis using Cdc20 expressed from its endogenous locus; previous studies generally employed strongly overexpressed Cdc20, which can cause significant artifacts. We analyzed Cdc20 proteolysis with or without mutations in previously identified destruction box sequences, using varying methods of cell cycle synchronization, and in the presence or absence of Cdh1. Cdc20 instability is only partially dependent on destruction boxes. A much stronger dependence on Cdh1 for Cdc20 proteolysis was observed, but Cdh1-independent proteolysis was also clearly observed. Cdc20 proteolysis independent of both destruction boxes and Cdh1 was especially detectable around the G1/S transition; Cdh1-dependent proteolysis was most notable in late mitosis and G1.</p> <p>Conclusions</p> <p>Cdc20 proteolysis is under complex control, with different systems operating at different points in the cell cycle. This complexity is likely to explain apparent conflicts in previously published literature on this subject. A major mode of control of Cdc20 proteolysis occurs in late mitosis/early G1 and is Cdh1-dependent, as in animal cells; this mode may contribute to the known sequential activation of the APC by Cdc20 followed by Cdh1. An independent mode of Cdc20 proteolysis, independent of destruction boxes and Cdh1, occurs at G1/S; we do not know the mechanism or function of this mode of proteolysis, but speculate that it may contribute to sharpening and restricting activation of APC-Cdc20 to early mitosis.</p

Драма-антиутопія: до історії терміна

В статті розглянуто історію терміну "драма-антиутопія" і розкрито його змістове наповнення

Antibiotic Resistance

Antibiotics have been so widely used across the world that organisms have evolved and adapted to them, causing the drug to be less effective. Professionals do not know how to adapt because the bacteria keeps evolving to become resistant against the antibiotics.https://digitalcommons.cedarville.edu/public_health_posters/1014/thumbnail.jp