Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication.

The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3' to 5' exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cells.

Constraints on microbial metabolism drive evolutionary diversification in homogeneous environments.

Understanding the evolution of microbial diversity is an important and current problem in evolutionary ecology. In this paper, we investigated the role of two established biochemical trade-offs in microbial diversification using a model that connects ecological and evolutionary processes with fundamental aspects of biochemistry. The trade-offs that we investigated are as follows:(1) a trade-off between the rate and affinity of substrate transport; and (2) a trade-off between the rate and yield of ATP production. Our model shows that these biochemical trade-offs can drive evolutionary diversification under the simplest possible ecological conditions: a homogeneous environment containing a single limiting resource. We argue that the results of a number of microbial selection experiments are consistent with the predictions of our model.

Algorithms for the computation of solutions of the Ornstein-Zernike equation.

We introduce a robust and efficient methodology to solve the Ornstein-Zernike integral equation using the pseudoarc length (PAL) continuation method that reformulates the integral equation in an equivalent but nonstandard form. This enables the computation of solutions in regions where the compressibility experiences large changes or where the existence of multiple solutions and so-called branch points prevents Newton's method from converging. We illustrate the use of the algorithm with a difficult problem that arises in the numerical solution of integral equations, namely the evaluation of the so-called no-solution line of the Ornstein-Zernike hypernetted chain (HNC) integral equation for the Lennard-Jones potential. We are able to use the PAL algorithm to solve the integral equation along this line and to connect physical and nonphysical solution branches (both isotherms and isochores) where appropriate. We also show that PAL continuation can compute solutions within the no-solution region that cannot be computed when Newton and Picard methods are applied directly to the integral equation. While many solutions that we find are new, some correspond to states with negative compressibility and consequently are not physical.