DNA Rereplication Is Susceptible to Nucleotide-Level Mutagenesis.

The sources of genome instability, a hallmark of cancer, remain incompletely understood. One potential source is DNA rereplication, which arises when the mechanisms that prevent the reinitiation of replication origins within a single cell cycle are compromised. Using the budding yeast Saccharomyces cerevisiae, we previously showed that DNA rereplication is extremely potent at inducing gross chromosomal alterations and that this arises in part because of the susceptibility of rereplication forks to break. Here, we examine the ability of DNA rereplication to induce nucleotide-level mutations. During normal replication these mutations are restricted by three overlapping error-avoidance mechanisms: the nucleotide selectivity of replicative polymerases, their proofreading activity, and mismatch repair. Using lys2InsEA14 , a frameshift reporter that is poorly proofread, we show that rereplication induces up to a 30× higher rate of frameshift mutations and that this mutagenesis is due to passage of the rereplication fork, not secondary to rereplication fork breakage. Rereplication can also induce comparable rates of frameshift and base-substitution mutations in a more general mutagenesis reporter CAN1, when the proofreading activity of DNA polymerase ε is inactivated. Finally, we show that the rereplication-induced mutagenesis of both lys2InsEA14 and CAN1 disappears in the absence of mismatch repair. These results suggest that mismatch repair is attenuated during rereplication, although at most sequences DNA polymerase proofreading provides enough error correction to mitigate the mutagenic consequences. Thus, rereplication can facilitate nucleotide-level mutagenesis in addition to inducing gross chromosomal alterations, broadening its potential role in genome instability

On the mean values of L-functions in orthogonal and symplectic families

Hybrid Euler-Hadamard products have previously been studied for the Riemann zeta function on its critical line and for Dirichlet L-functions in the context of the calculation of moments and connections with Random Matrix Theory. According to the Katz-Sarnak classification, these are believed to represent families of L-function with unitary symmetry. We here extend the formalism to families with orthogonal & symplectic symmetry. Specifically, we establish formulae for real quadratic Dirichlet L-functions and for the L-functions associated with primitive Hecke eigenforms of weight 2 in terms of partial Euler and Hadamard products. We then prove asymptotic formulae for some moments of these partial products and make general conjectures based on results for the moments of characteristic polynomials of random matrices

On the variance of sums of arithmetic functions over primes in short intervals and pair correlation for L-functions in the Selberg class

We establish the equivalence of conjectures concerning the pair correlation of zeros of $L$-functions in the Selberg class and the variances of sums of a related class of arithmetic functions over primes in short intervals. This extends the results of Goldston & Montgomery [7] and Montgomery & Soundararajan [11] for the Riemann zeta-function to other $L$-functions in the Selberg class. Our approach is based on the statistics of the zeros because the analogue of the Hardy-Littlewood conjecture for the auto-correlation of the arithmetic functions we consider is not available in general. One of our main findings is that the variances of sums of these arithmetic functions over primes in short intervals have a different form when the degree of the associated $L$-functions is 2 or higher to that which holds when the degree is 1 (e.g. the Riemann zeta-function). Specifically, when the degree is 2 or higher there are two regimes in which the variances take qualitatively different forms, whilst in the degree-1 case there is a single regime

Toward Affective Dialogue Modeling using Partially Observable Markov Decision Processes

We propose a novel approach to developing a dialogue model which is able to take into account some aspects of the user’s emotional state and acts appropriately. The dialogue model uses a Partially Observable Markov Decision Process approach with observations composed of the observed user’s emotional state and action. A simple example of route navigation is explained to clarify our approach and preliminary results & future plans are briefly discussed

On Balazard, Saias, and Yor's equivalence to the Riemann Hypothesis

Balazard, Saias, and Yor proved that the Riemann Hypothesis is equivalent to a certain weighted integral of the logarithm of the Riemann zeta-function along the critical line equaling zero. Assuming the Riemann Hypothesis, we investigate the rate at which a truncated version of this integral tends to zero, answering a question of Borwein, Bradley, and Crandall and disproving a conjecture of the same authors. A simple modification of our techniques gives a new proof of a classical Omega theorem for the function S(t) in the theory of the Riemann zeta-function.Comment: 11 page

The influence of oscillations on energy estimates for damped wave models with time-dependent propagation speed and dissipation

The aim of this paper is to derive higher order energy estimates for solutions to the Cauchy problem for damped wave models with time-dependent propagation speed and dissipation. The model of interest is \begin{equation*} u_{tt}-\lambda^2(t)\omega^2(t)\Delta u +\rho(t)\omega(t)u_t=0, \quad u(0,x)=u_0(x), \,\, u_t(0,x)=u_1(x). \end{equation*} The coefficients $\lambda=\lambda(t)$ and $\rho=\rho(t)$ are shape functions and $\omega=\omega(t)$ is an oscillating function. If $\omega(t)\equiv1$ and $\rho(t)u_t$ is an "effective" dissipation term, then $L^2-L^2$ energy estimates are proved in [2]. In contrast, the main goal of the present paper is to generalize the previous results to coefficients including an oscillating function in the time-dependent coefficients. We will explain how the interplay between the shape functions and oscillating behavior of the coefficient will influence energy estimates.Comment: 37 pages, 2 figure