Exact solution of the six-vertex model with domain wall boundary condition. Critical line between ferroelectric and disordered phases

This is a continuation of the papers [4] of Bleher and Fokin and [5] of Bleher and Liechty, in which the large $n$ asymptotics is obtained for the partition function $Z_n$ of the six-vertex model with domain wall boundary conditions in the disordered and ferroelectric phases, respectively. In the present paper we obtain the large $n$ asymptotics of $Z_n$ on the critical line between these two phases.Comment: 22 pages, 6 figures, to appear in the Journal of Statistical Physic

Diagonal Ladders: A New Class of Models for Strongly Coupled Electron Systems

We introduce a class of models defined on ladders with a diagonal structure generated by $n_p$ plaquettes. The case $n_p=1$ corresponds to the necklace ladder and has remarkable properties which are studied using DMRG and recurrent variational ansatzes. The AF Heisenberg model on this ladder is equivalent to the alternating spin-1/spin-1/2 AFH chain which is known to have a ferrimagnetic ground state (GS). For doping 1/3 the GS is a fully doped (1,1) stripe with the holes located mostly along the principal diagonal while the minor diagonals are occupied by spin singlets. This state can be seen as a Mott insulator of localized Cooper pairs on the plaquettes. A physical picture of our results is provided by a $t_p-J_p$ model of plaquettes coupled diagonally with a hopping parameter $t_d$. In the limit $t_d \to \infty$ we recover the original $t-J$ model on the necklace ladder while for weak hopping parameter the model is easily solvable. The GS in the strong hopping regime is essentially an "on link" Gutzwiller projection of the weak hopping GS. We generalize the $t_p-J_p-t_d$ model to diagonal ladders with $n_p >1$ and the 2D square lattice. We use in our construction concepts familiar in Statistical Mechanics as medial graphs and Bratelli diagrams.Comment: REVTEX file, 22 pages (twocolumn), 35 figures inserted in text. 12 Table

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Background: The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1

The Short Range RVB State of Even Spin Ladders: A Recurrent Variational Approach

Using a recursive method we construct dimer and nondimer variational ansatzs of the ground state for the two-legged ladder, and compute the number of dimer coverings, the energy density and the spin correlation functions. The number of dimer coverings are given by the Fibonacci numbers for the dimer-RVB state and their generalization for the nondimer ones. Our method relies on the recurrent relations satisfied by the overlaps of the states with different lengths, which can be solved using generating functions. The recurrent relation method is applicable to other short range systems. Based on our results we make a conjecture about the bond amplitudes of the 2-leg ladder.Comment: REVTEX file, 32 pages, 10 EPS figures inserted in text with epsf.st

Exact solution of the six-vertex model with domain wall boundary conditions. Antiferroelectric phase

We obtain the large $n$ asymptotics of the partition function $Z_n$ of the six-vertex model with domain wall boundary conditions in the antiferroelectric phase region, with the weights a=\sinh(\ga-t), b=\sinh(\ga+t), c=\sinh(2\ga), |t|<\ga. We prove the conjecture of Zinn-Justin, that as $n\to\infty$, Z_n=C\th_4(n\om) F^{n^2}[1+O(n^{-1})], where \om and $F$ are given by explicit expressions in \ga and $t$, and $\th_4(z)$ is the Jacobi theta function. The proof is based on the Riemann-Hilbert approach to the large $n$ asymptotic expansion of the underlying discrete orthogonal polynomials and on the Deift-Zhou nonlinear steepest descent method.Comment: 69 pages, 10 figure

Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication

Mechanisms that preserve genome integrity are highly important during the normal life cycle of human cells. Loss of genome protective mechanisms can lead to the development of diseases such as cancer. Checkpoint kinases function in the cellular surveillance pathways that help cells to cope with DNA damage. Importantly, the checkpoint kinases ATR, CHK1 and WEE1 are not only activated in response to exogenous DNA damaging agents, but are active during normal S phase progression. Here, we review recent evidence that these checkpoint kinases are critical to avoid deleterious DNA breakage during DNA replication in normal, unperturbed cell cycle. Possible mechanisms how loss of these checkpoint kinases may cause DNA damage in S phase are discussed. We propose that the majority of DNA damage is induced as a consequence of deregulated CDK activity that forces unscheduled initiation of DNA replication. This could generate structures that are cleaved by DNA endonucleases leading to the formation of DNA double-strand breaks. Finally, we discuss how these S phase effects may impact on our understanding of cancer development following disruption of these checkpoint kinases, as well as on the potential of these kinases as targets for cancer treatment

Rad17 Plays a Central Role in Establishment of the Interaction between TopBP1 and the Rad9-Hus1-Rad1 Complex at Stalled Replication Forks

Rad17 is critical for the ATR-dependent activation of Chk1 during checkpoint responses. It is known that Rad17 loads the Rad9-Hus1-Rad1 (9-1-1) complex onto DNA. We show that Rad17 also mediates the interaction of 9-1-1 with the ATR-activating protein TopBP1 in Xenopus egg extracts. Studies with Rad17 mutants indicate that binding of ATP to Rad17 is essential for the association of 9-1-1 and TopBP1. Furthermore, hydrolysis of ATP by Rad17 is necessary for the loading of 9-1-1 onto DNA and the elevated, checkpoint-dependent accumulation of TopBP1 on chromatin. Significantly, a mutant 9-1-1 complex that cannot bind TopBP1 has a normal capacity to promote elevated accumulation of TopBP1 on chromatin. Taken together, we propose the following mechanism. First, Rad17 loads 9-1-1 onto DNA. Second, TopBP1 accumulates on chromatin in a manner that depends on both Rad17 and 9-1-1. Finally, 9-1-1 and TopBP1 dock in a Rad17-dependent manner before activation of Chk1

Chk2 and p53 Are Haploinsufficient with Dependent and Independent Functions to Eliminate Cells after Telomere Loss

The mechanisms that cells use to monitor telomere integrity, and the array of responses that may be induced, are not fully defined. To date there have been no studies in animals describing the ability of cells to survive and contribute to adult organs following telomere loss. We developed assays to monitor the ability of somatic cells to proliferate and differentiate after telomere loss. Here we show that p53 and Chk2 limit the growth and differentiation of cells that lose a telomere. Furthermore, our results show that two copies of the genes encoding p53 and Chk2 are required for the cell to mount a rapid wildtype response to a missing telomere. Finally, our results show that, while Chk2 functions by activating the p53-dependent apoptotic cascade, Chk2 also functions independently of p53 to limit survival. In spite of these mechanisms to eliminate cells that have lost a telomere, we find that such cells can make a substantial contribution to differentiated adult tissues

DNA Adducts of Decarbamoyl Mitomycin C Efficiently Kill Cells without Wild-Type p53 Resulting from Proteasome-Mediated Degradation of Checkpoint Protein 1

The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 protein (Chk1) was depleted following DMC, and the depletion of Chk1 by DMC was achieved through the ubiquitin proteasome pathway since chemical inhibition of the proteasome protected against Chk1 depletion. Gene silencing of Chk1 by siRNA increased the cytotoxicity of MC. DMC treatment caused a decrease in the level of total ubiquitinated proteins without increasing proteasome activity, suggesting that DMC mediated DNA adducts facilitate signal transduction to a pathway targeting cellular proteins for proteolysis. Thus, the mitosene-1-β stereoisomeric DNA adducts produced by the DMC signal for a p53-independent mode of cell death correlated with reduced nuclear size, persistent DNA damage, increased ubiquitin proteolysis and reduced Chk1 protein