Inferring the DNA replication origin density landscape in human cells from replication timing and fork directionality data

The determinants of the locations and firing times of the multiple replication origins are still elusive in human and other metazoan organisms. Experiments can independently profile mean replication timing (MRT) and replication fork directionality (RFD) genome-wide. In the hypothesis of a constant replication fork speed, MRT and RFD are related to each other by an analytical formula so are a priori equivalent. However, we show here that experimental noises result in MRT and RFD profiles containing information at different spatial frequencies. We further demonstrate that one can compute an origin density landscape that, when inserted in an appropriate simulation framework, jointly predicts experimental MRT and RFD profiles with an unprecedented precision. We also extract an analytical formula linking intrinsic origin efficiency with observed origin efficiency and MRT. We then compare the computed origin density landscape with experimental distributions of potential origins (ORC, MCM) or actual initiation events (Bubble-seq, SNS-seq, OK-seq). The results indicate that MRT and RFD data are highly consistent with each other, that our simple model suffices to capture the replication dynamics during S phase given an appropriate initiation probability landscape, but that the density of potential origins is not the sole determinant of this landscape.

Hydrogen peroxide as regeneration-initiation signal that activates pERK to trigger planarian regeneration

Despite the extensive research on molecular pathways controlling the process of regeneration in planarians and other regeneration models, little is known about the actual initiation signals necessary to induce regeneration. Previously the involvement of ROS, EGFR and MAPK/ERK has been demonstrated during planarian regeneration, however the exact interplay has not been yet described. By selectively interfering with major mediators in all three key parts (ROS, EGFR & MAPK/ERK), we were able to identify amputation/wound-induced ROS, and H2O2 specifically, as upstream cue in activating regeneration-initiation. In addition, our results demonstrate new relationships between regeneration related ROS production and MAPK/ERK activation at early regeneration stages, as well as the involvement of the EGFR-signaling pathway. In summary, our results suggest a new and more extensive signaling model with ROS, and H2O2, highlighted as upstream initiation-factor and its important functions in the downstream EGFR-MAPK/ERK pathway during planarian regeneration.

Initiation of PWSCC in Nickel Base Alloy 182

To date, welded nickel base alloy 182 used in Pressurized Water Reactors (PWRs) components have shown a higher susceptibility to Primary Water Stress Corrosion Cracking (PWSCC) during laboratory tests than in power plants. However, an increasing number of cracks reported in American, Swedish and Japanese nuclear power plants on Alloy 182 enlighten the need for a predictive initiation model of PWSCC. Initiation of PWSCC involves several factors such as material, environment and loading history, interacting with each other. Building such a model first requires to focus on these parameters separately, in order to have a better understanding of the involved mechanisms at a local scale in crack initiation. This study focuses on the correlation between EBSD/strain field results to improve the accuracy of the actual initiation model [1] involving local parameters.