Avoiding chromosome pathology when replication forks collide

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2013 Macmillan Publishers Limited.Chromosome duplication normally initiates through the assembly of replication fork complexes at defined origins1, 2. DNA synthesis by any one fork is thought to cease when it meets another travelling in the opposite direction, at which stage the replication machinery may simply dissociate before the nascent strands are finally ligated. But what actually happens is not clear. Here we present evidence consistent with the idea that every fork collision has the potential to threaten genomic integrity. In Escherichia coli this threat is kept at bay by RecG DNA translocase3 and by single-strand DNA exonucleases. Without RecG, replication initiates where forks meet through a replisome assembly mechanism normally associated with fork repair, replication restart and recombination4, 5, establishing new forks with the potential to sustain cell growth and division without an active origin. This potential is realized when roadblocks to fork progression are reduced or eliminated. It relies on the chromosome being circular, reinforcing the idea that replication initiation is triggered repeatedly by fork collision. The results reported raise the question of whether replication fork collisions have pathogenic potential for organisms that exploit several origins to replicate each chromosome.THe MRC, the Leverhulme Trust, and the BBSRC

AN ASSESSMENT OF THE PROPOSED NEW RISK MANAGEMENT PROGRAMS

The purpose of this assessment as outlined in the terms of reference is: "To obtain an assessment by an independent third party of the expected performance of the proposed new business risk management program's proposed New NISA and production insurance relative to the current set of risk management programming, including NISA, CFIP, crop insurance and companion programs." Within this context, the specific mandate and scope is to assess "the extent to which the current and proposed programs meet the objectives set out by Agriculture Ministers for business risk management programming, as follows: · to ensure programs are responsive to demand and that government dollars are directed to areas of need with respect to income stabilization, disaster mitigation, insurance coverage and investment; · to provide equal treatment for farmers across Canada facing similar risk situations; · to minimize the distortion of farmers' production and marketing decisions; · to focus on management of risks related to the stability of the entire farm and to avoid duplication of payments; · to be relatively simple and easy to understand; and · to facilitate long term planning by farmers."Risk and Uncertainty,

Evolution of a shear zone before, during and after melting

Partial melt in the deforming mid- or lower continental crust causes a strength decrease and drives formation of lithological heterogeneities. However, mechanisms of formation of syn-melt deformation zones and strain partitioning in partially molten rock remain poorly understood. We use field and microstructural observations to unravel the evolution of a partial melt shear zone, Seiland Igneous Province, northern Norway. The Øksfjord shear zone (ØSZ) is one of several paragneiss shear zones present within gabbros of the Seiland Igneous Province, formed by syn-intrusive deep crustal shearing during lithospheric extension related to continental rifting. Microstructures from the ØSZ show evidence for different deformation conditions. The first phase was active pre-melt and involved deformation at high subsolidus temperatures. This was followed by syn-melt deformation of the shear zone causing a relative strength increase towards the shear zone centre upon crystallization. The third phase nucleated two parallel shear zones at the edges of the ØSZ; melt textures are absent and microstructures indicate deformation at lower temperatures and higher stresses. In effect, melt migration towards the shear zone centre ultimately led to strengthening of the shear zone core, with post-crystallization deformation focusing along shear zone margins where significant heterogeneities are present

Seven challenges for model-driven data collection in experimental and observational studies.

Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats

Effect of Continuous Infusion of Relaxin on Progesterone, Oxytocin, and Relaxin Blood Concentrations and Time of Parturition in Beef Heifers

These studies were designed to determine whether continuous intravenous infusion of increasing dosages of porcine relaxin during late pregnancy in beef heifers would influence circulating blood concentrations of relaxin, progesterone, and oxytocin, and time of onset of parturition. Beef heifers were bred by artificial insemination and, on Day 277, fitted with indwelling jugular cannulas for hormone infusion and blood sampling from Day 277 to 286. Intravenous infusion of purified porcine relaxin (pRLX, 3000 U mg-1) was started in heifers (n = 8) at increasing dosages (200 U h-1 on Days 277 and 278, 300 U h-1 on Days 279 and 280, 500 U h-1 on Day 281, 600 U h-1 on Day 282, and 700 U h-1 on Days 283 to 286). Phosphate buffer saline (PBS, 10 ml h-1) was infused during these same times to control (n = 6) animals. Relaxin treatment steadily increased the circulating plasma concentration of immunoreactive relaxin to more than 120 ng ml-1 compared with less than 0.5 ng ml-1 in PBStreated controls. Relaxin infusion in increasing dosages over the treatment time was associated with a significant decrease (P \u3c 0.01) in plasma progesterone concentration compared with the PBS controls. Plasma levels of oxytocin at 4- hour intervals remained similar (P \u3e 0.05) during the pretreatment period and throughout continuous infusion of pRLX and PBS. Although continuous intravenous infusion of relaxin resulted in a decrease in circulating blood levels of progesterone, it did not significantly reduce the interval between the beginning of pRLX treatment and parturition compared with the PBS-infused control heifers. These results indicate that continuous intravenous infusion of high levels of porcine relaxin resulted in a decrease in progesterone secretion in late pregnant beef heifers

Transition of free convection flow inside an inclined parallel walled channel: effects of inclination angle and width of the channel

Transition of free convection flow in an inclined parallel walled channel has been investigated numerically by employing k–ɛ turbulent model. Particular attention is paid on how the inclination angle and width of the channel affect the transition process of the flow developing in the channel. The upper plate of the channel is heated isothermally and facing downward, while the lower one is kept under the adiabatic condition. The inclination angle of the channel is varied from 0° to 85° with respect to its vertical position while the distance separating the two plates is systematically reduced from 0.45 to 0.06 m. Distributions of velocity, turbulent kinetic energy and local heat flux are presented to examine the critical distance and the results obtained show good agreement with experimental data available in the literature

Cluster Analysis of Extremely High Energy Cosmic Rays in the Northern Sky

The arrival directions of extremely high energy cosmic rays (EHECR) above $4\times10^{19}$ eV, observed by four surface array experiments in the northern hemisphere,are examined for coincidences from similar directions in the sky. The total number of cosmic rays is 92.A significant number of double coincidences (doublet) and triple coincidences (triplet) are observed on the supergalactic plane within the experimental angular resolution. The chance probability of such multiplets from a uniform distribution is less than 1 % if we consider a restricted region within $\pm 10^{\circ}$ of the supergalactic plane. Though there is still a possibility of chance coincidence, the present results on small angle clustering along the supergalactic plane may be important in interpreting EHECR enigma. An independent set of data is required to check our claims.Comment: 9 pages, 6 tables, 8 figures. submitted to Astroparticle Physic

Cellular location and activity of Escherichia coli RecG proteins shed light on the function of its structurally unresolved C-terminus

RecG is a DNA translocase encoded by most species of bacteria. The Escherichia coli protein targets branched DNA substrates and drives the unwinding and rewinding of DNA strands. Its ability to remodel replication forks and to genetically interact with PriA protein have led to the idea that it plays an important role in securing faithful genome duplication. Here we report that RecG co-localises with sites of DNA replication and identify conserved arginine and tryptophan residues near its C-terminus that are needed for this localisation. We establish that the extreme C-terminus, which is not resolved in the crystal structure, is vital for DNA unwinding but not for DNA binding. Substituting an alanine for a highly conserved tyrosine near the very end results in a substantial reduction in the ability to unwind replication fork and Holliday junction structures but has no effect on substrate affinity. Deleting or substituting the terminal alanine causes an even greater reduction in unwinding activity, which is somewhat surprising as this residue is not uniformly present in closely related RecG proteins. More significantly, the extreme C-terminal mutations have little effect on localisation. Mutations that do prevent localisation result in only a slight reduction in the capacity for DNA repair. © 2014 The Author(s)

Reciprocity and sensitivity kernels for sea level fingerprints

Reciprocity theorems are established for the elastic sea level fingerprint problem including rotational feedbacks. In their simplest form, these results show that the sea level change at a location x due to melting a unit point mass of ice at x' is equal to the sea level change at x' due to melting a unit point mass of ice at x. This identity holds irrespective of the shoreline geometry or of lateral variations in elastic Earth structure. Using the reciprocity theorems, sensitivity kernels for sea level and related observables with respect to the ice load can be readily derived. It is notable that calculation of the sensitivity kernels is possible using standard fingerprint codes, though for some types of observable a slight generalisation to the fingerprint problem must be considered. These results are of use within coastal hazard assessment and have a range of potential applications within studies of modern-day sea level change.Comment: Paper submitted to Geophysical Journal Internationa