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

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

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,

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

Quantum Computing in Molecular Magnets

Shor and Grover demonstrated that a quantum computer can outperform any classical computer in factoring numbers and in searching a database by exploiting the parallelism of quantum mechanics. Whereas Shor's algorithm requires both superposition and entanglement of a many-particle system, the superposition of single-particle quantum states is sufficient for Grover's algorithm. Recently, the latter has been successfully implemented using Rydberg atoms. Here we propose an implementation of Grover's algorithm that uses molecular magnets, which are solid-state systems with a large spin; their spin eigenstates make them natural candidates for single-particle systems. We show theoretically that molecular magnets can be used to build dense and efficient memory devices based on the Grover algorithm. In particular, one single crystal can serve as a storage unit of a dynamic random access memory device. Fast electron spin resonance pulses can be used to decode and read out stored numbers of up to 10^5, with access times as short as 10^{-10} seconds. We show that our proposal should be feasible using the molecular magnets Fe8 and Mn12.Comment: 13 pages, 2 figures, PDF, version published in Nature, typos correcte

Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: the role of PCSK9 inhibitors

Familial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low-density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost-effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD

Quantum information processing using Josephson junctions coupled through cavities

Josephson junctions have been shown to be a promising solid-state system for implementation of quantum computation. The significant two-qubit gates are generally realized by the capacitive coupling between the nearest neighbour qubits. We propose an effective Hamiltonian to describe charge qubits coupled through the cavity. We find that nontrivial two-qubit gates may be achieved by this coupling. The ability to interconvert localized charge qubits and flying qubits in the proposed scheme implies that quantum network can be constructed using this large scalable solid-state system.Comment: 5 pages, to appear in Phys Rev A; typos corrected, solutions in last eqs. correcte

Service evaluation of weight outcomes as a function of initial BMI in 34,271 adults referred to a primary care/commercial weight management partnership scheme

Peer reviewedPublisher PD

Phase transitions in contagion processes mediated by recurrent mobility patterns

Human mobility and activity patterns mediate contagion on many levels, including the spatial spread of infectious diseases, diffusion of rumors, and emergence of consensus. These patterns however are often dominated by specific locations and recurrent flows and poorly modeled by the random diffusive dynamics generally used to study them. Here we develop a theoretical framework to analyze contagion within a network of locations where individuals recall their geographic origins. We find a phase transition between a regime in which the contagion affects a large fraction of the system and one in which only a small fraction is affected. This transition cannot be uncovered by continuous deterministic models due to the stochastic features of the contagion process and defines an invasion threshold that depends on mobility parameters, providing guidance for controlling contagion spread by constraining mobility processes. We recover the threshold behavior by analyzing diffusion processes mediated by real human commuting data.Comment: 20 pages of Main Text including 4 figures, 7 pages of Supplementary Information; Nature Physics (2011

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)