Restart : reflections on the British scheme of the 80s for the long term unemployed

The chapter reflects on the first two years of the Restart Scheme introduced by the Manpower Services Commission for Long term unemployed people in the UK from a facilitator's perspective ten years later. It examines the actual weekly program for participants with some case examples from one of the pilot centres, Crawley College, West Sussex, an area of low unemployment. The observations suggested that even in a place where there are many job vacancies, there will be a 3-4% of the population who are unable to compete for jobs and participate in the work force unless sheltered workshops and specialized training initiatives are established.

Random-Restart Reactive Tabu Search Algorithm for Detection in Large-MIMO Systems

We present a low-complexity algorithm based on reactive tabu search (RTS) for near maximum likelihood (ML) detection in large-MIMO systems. The conventional RTS algorithm achieves near-ML performance for 4-QAM in large-MIMO systems. But its performance for higher-order QAM is far from ML performance. Here, we propose a random-restart RTS (R3TS) algorithm which achieves significantly better bit error rate (BER) performance compared to that of the conventional RTS algorithm in higher-order QAM. The key idea is to run multiple tabu searches, each search starting with a random initial vector and choosing the best among the resulting solution vectors. A criterion to limit the number of searches is also proposed. Computer simulations show that the R3TS algorithm achieves almost the ML performance in 16 x 16 V-BLAST MIMO system with 16-QAM and 64-QAM at significantly less complexities than the sphere decoder. Also, in a 32 x 32 V-BLAST MIMO system, the R3TS performs close to ML lower bound within 1.6 dB for 16-QAM (128 bps/Hz), and within 2.4 dB for 64-QAM (192 bps/Hz) at 10(-3) BER.

Mycobacterium tuberculosis RecG Protein but Not RuvAB or RecA Protein Is Efficient at Remodeling the Stalled Replication Forks IMPLICATIONS FOR MULTIPLE MECHANISMS OF REPLICATION RESTART IN MYCOBACTERIA

Aberrant DNA replication, defects in the protection, and restart of stalled replication forks are major causes of genome instability in all organisms. Replication fork reversal is emerging as an evolutionarily conserved physiological response for restart of stalled forks. Escherichia coli RecG, RuvAB, and RecA proteins have been shown to reverse the model replication fork structures in vitro. However, the pathways and the mechanisms by which Mycobacterium tuberculosis, a slow growing human pathogen, responds to different types of replication stress and DNA damage are unclear. Here, we show that M. tuberculosis RecG rescues E. coli Delta recG cells from replicative stress. The purified M. tuberculosis RecG (MtRecG) and RuvAB(MtRuvAB) proteins catalyze fork reversal of model replication fork structures with and without a leading strand single-stranded DNA gap. Interestingly, single-stranded DNA-binding protein suppresses the MtRecG- and MtRuvAB-mediated fork reversal with substrates that contain lagging strand gap. Notably, our comparative studies with fork structures containing template damage and template switching mechanism of lesion bypass reveal that MtRecG but not MtRuvAB or MtRecA is proficient in driving the fork reversal. Finally, unlike MtRuvAB, we find that MtRecG drives efficient reversal of forks when fork structures are tightly bound by protein. These results provide direct evidence and valuable insights into the underlying mechanism of MtRecG-catalyzed replication fork remodeling and restart pathways in vivo.

Mammalian RAD51 paralogs protect nascent DNA at stalled forks and mediate replication restart

Mammalian RAD51 paralogs are implicated in the repair of collapsed replication forks by homologous recombination. However, their physiological roles in replication fork maintenance prior to fork collapse remain obscure. Here, we report on the role of RAD51 paralogs in short-term replicative stress devoid of DSBs. We show that RAD51 paralogs localize to nascent DNA and common fragile sites upon replication fork stalling. Strikingly, RAD51 paralogs deficient cells exhibit elevated levels of 53BP1 nuclear bodies and increased DSB formation, the latter being attributed to extensive degradation of nascent DNA at stalled forks. RAD51C and XRCC3 promote the restart of stalled replication in an ATP hydrolysis dependent manner by disengaging RAD51 and other RAD51 paralogs from the halted forks. Notably, we find that Fanconi anemia (FA)-like disorder and breast and ovarian cancer patient derived mutations of RAD51C fails to protect replication fork, exhibit under-replicated genomic regions and elevated micro-nucleation. Taken together, RAD51 paralogs prevent degradation of stalled forks and promote the restart of halted replication to avoid replication fork collapse, thereby maintaining genomic integrity and suppressing tumorigenesis.

How do I get the Chapter number in Table or Figure captions to restart in Appendices using the University thesis template in Word 2010?

If you have added the Chapter number to your Table or Figure captions they will show as 1.1, 1.2 and so on. This is linked to the numbering used in the Heading 1 style. However, once you get to the Appendices the last Chapter number will continue throughout the Appendices as the Appendix heading isn't Heading 1. So what you need to do is get Word to understand that the style from which it should be picking up the first part of the Caption has changed and that it will need to restart the numbering again in each subsequent Appendix. This isn't too complex but you must follow the instructions to the letter or else it won't work.

How do I get the Chapter number in Table or Figure captions to restart in Appendices using the University thesis template in Word 2011?

If you have added the Chapter number to your Table or Figure captions they will show as 1.1, 1.2 and so on. This is linked to the numbering used in the Heading 1 style. However, once you get to the Appendices the last Chapter number will continue throughout the Appendices as the Appendix heading isn't Heading 1.

Chk1 phosphorylation of Metnase enhances DNA repair but inhibits replication fork restart

Chk1 both arrests replication forks and enhances repair of DNA damage by phosphorylating downstream effectors. Although there has been a concerted effort to identify effectors of Chk1 activity, underlying mechanisms of effector action are still being identified. Metnase (also called SETMAR) is a SET and transposase domain protein that promotes both DNA double-strand break (DSB) repair and restart of stalled replication forks. In this study, we show that Metnase is phosphorylated only on Ser495 (S495) in vivo in response to DNA damage by ionizing radiation. Chk1 is the major mediator of this phosphorylation event. We had previously shown that wild-type (wt) Metnase associates with chromatin near DSBs and methylates histone H3 Lys36. Here we show that a Ser495Ala (S495A) Metnase mutant, which is not phosphorylated by Chk1, is defective in DSB-induced chromatin association. The S495A mutant also fails to enhance repair of an induced DSB when compared with wt Metnase. Interestingly, the S495A mutant demonstrated increased restart of stalled replication forks compared with wt Metnase. Thus, phosphorylation of Metnase S495 differentiates between these two functions, enhancing DSB repair and repressing replication fork restart. In summary, these data lend insight into the mechanism by which Chk1 enhances repair of DNA damage while at the same time repressing stalled replication fork restart. Oncogene (2012) 31, 4245-4254; doi:10.1038/onc.2011.586; published online 9 January 2012

Asymptotic optimality of RESTART estimators in highly dependable systems

Abstract We consider a wide class of models that includes the highly reliable Markovian systems (HRMS) often used to represent the evolution of multi-component systems in reliability settings. Repair times and component lifetimes are random variables that follow a general distribution, and the repair service adopts a priority repair rule based on system failure risk. Since crude simulation has proved to be inefficient for highly-dependable systems, the RESTART method is used for the estimation of steady-state unavailability and other reliability measures. In this method, a number of simulation retrials are performed when the process enters regions of the state space where the chance of occurrence of a rare event (e.g., a system failure) is higher. The main difficulty involved in applying this method is finding a suitable function, called the importance function, to define the regions. In this paper we introduce an importance function which, for unbalanced systems, represents a great improvement over the importance function used in previous papers. We also demonstrate the asymptotic optimality of RESTART estimators in these models. Several examples are presented to show the effectiveness of the new approach, and probabilities up to the order of 10-42 are accurately estimated with little computational effort.

Europe’s Sustainability Strategy - A Casualty of the Euro Crisis or an Ambitious Restart?. Policy Brief #2013/06

Europe’s economy should not just grow, it should also target social inclusion and the responsible use of resources. The goal of sustainability may be embedded in the Treaty on European Union and the EU’s economic strategies, but the emphasis on GDP growth and competitiveness in battling the crisis threatens to undermine efforts to establish a common approach for sustainable economic activity. This may be unavoidable during an acute crisis. But in the long term, the EU must show the way forward.

Europe's Sustainability Strategy - A Casualty of the Euro Crisis or an Ambition Restart? Bertelsmann Policy Brief #2013/06, 30.11.2013

Europe’s economy should not just grow, it should also target social inclusion and the responsible use of resources. The goal of sustainability may be embedded in the Treaty on European Union and the EU’s economic strategies, but the emphasis on GDP growth and competitiveness in battling the crisis threatens to undermine efforts to establish a common approach for sustainable economic activity. This may be unavoidable during an acute crisis. But in the long term, the EU must show the way forward.

Random walk with restart over dynamic graphs

Random Walk with Restart (RWR) is an appealing measure of proximity between nodes based on graph structures. Since real graphs are often large and subject to minor changes, it is prohibitively expensive to recompute proximities from scratch. Previous methods use LU decomposition and degree reordering heuristics, entailing O(|V|^3) time and O(|V|^2) memory to compute all (|V|^2) pairs of node proximities in a static graph. In this paper, a dynamic scheme to assess RWR proximities is proposed: (1) For unit update, we characterize the changes to all-pairs proximities as the outer product of two vectors. We notice that the multiplication of an RWR matrix and its transition matrix, unlike traditional matrix multiplications, is commutative. This can greatly reduce the computation of all-pairs proximities from O(|V|^3) to O(|delta|) time for each update without loss of accuracy, where |delta| (<<|V|^2) is the number of affected proximities. (2) To avoid O(|V|^2) memory for all pairs of outputs, we also devise efficient partitioning techniques for our dynamic model, which can compute all pairs of proximities segment-wisely within O(l|V|) memory and O(|V|/l) I/O costs, where 1<=l<=|V| is a user-controlled trade-off between memory and I/O costs. (3) For bulk updates, we also devise aggregation and hashing methods, which can discard many unnecessary updates further and handle chunks of unit updates simultaneously. Our experimental results on various datasets demonstrate that our methods can be 1–2 orders of magnitude faster than other competitors while securing scalability and exactness.

A Numerical Solution Using an Adaptively Preconditioned Lanczos Method for a Class of Linear Systems Related with the Fractional Poisson Equation

This study considers the solution of a class of linear systems related with the fractional Poisson equation (FPE) (−∇2)α/2φ=g(x,y) with nonhomogeneous boundary conditions on a bounded domain. A numerical approximation to FPE is derived using a matrix representation of the Laplacian to generate a linear system of equations with its matrix A raised to the fractional power α/2. The solution of the linear system then requires the action of the matrix function f(A)=A−α/2 on a vector b. For large, sparse, and symmetric positive definite matrices, the Lanczos approximation generates f(A)b≈β0Vmf(Tm)e1. This method works well when both the analytic grade of A with respect to b and the residual for the linear system are sufficiently small. Memory constraints often require restarting the Lanczos decomposition; however this is not straightforward in the context of matrix function approximation. In this paper, we use the idea of thick-restart and adaptive preconditioning for solving linear systems to improve convergence of the Lanczos approximation. We give an error bound for the new method and illustrate its role in solving FPE. Numerical results are provided to gauge the performance of the proposed method relative to exact analytic solutions.

Multiple human single-stranded DNA binding proteins function in genome maintenance : structural, biochemical and functional analysis

DNA exists predominantly in a duplex form that is preserved via specific base pairing. This base pairing affords a considerable degree of protection against chemical or physical damage and preserves coding potential. However, there are many situations, e.g. during DNA damage and programmed cellular processes such as DNA replication and transcription, in which the DNA duplex is separated into two singlestranded DNA (ssDNA) strands. This ssDNA is vulnerable to attack by nucleases, binding by inappropriate proteins and chemical attack. It is very important to control the generation of ssDNA and protect it when it forms, and for this reason all cellular organisms and many viruses encode a ssDNA binding protein (SSB). All known SSBs use an oligosaccharide/oligonucleotide binding (OB)-fold domain for DNA binding. SSBs have multiple roles in binding and sequestering ssDNA, detecting DNA damage, stimulating strand-exchange proteins and helicases, and mediation of protein–protein interactions. Recently two additional human SSBs have been identified that are more closely related to bacterial and archaeal SSBs. Prior to this it was believed that replication protein A, RPA, was the only human equivalent of bacterial SSB. RPA is thought to be required for most aspects of DNA metabolism including DNA replication, recombination and repair. This review will discuss in further detail the biological pathways in which human SSBs function.

Human single-stranded DNA binding proteins are essential for maintaining genomic stability

The double-stranded conformation of cellular DNA is a central aspect of DNA stabilisation and protection. The helix preserves the genetic code against chemical and enzymatic degradation, metabolic activation, and formation of secondary structures. However, there are various instances where single-stranded DNA is exposed, such as during replication or transcription, in the synthesis of chromosome ends, and following DNA damage. In these instances, single-stranded DNA binding proteins are essential for the sequestration and processing of single-stranded DNA. In order to bind single-stranded DNA, these proteins utilise a characteristic and evolutionary conserved single-stranded DNA-binding domain, the oligonucleotide/oligosaccharide-binding (OB)-fold. In the current review we discuss a subset of these proteins involved in the direct maintenance of genomic stability, an important cellular process in the conservation of cellular viability and prevention of malignant transformation. We discuss the central roles of single-stranded DNA binding proteins from the OB-fold domain family in DNA replication, the restart of stalled replication forks, DNA damage repair, cell cycle-checkpoint activation, and telomere maintenance.