Crystal structure of the catalytic fragment of murine poly(ADP-ribose) polymerase-2.

Poly(ADP-ribose) polymerase-1 (PARP-1) has become an important pharmacological target in the treatment of cancer due to its cellular role as a 'DNA-strand break sensor', which leads in part to resistance to some existing chemo- and radiological treatments. Inhibitors have now been developed which prevent PARP-1 from synthesizing poly(ADP-ribose) in response to DNA-breaks and potentiate the cytotoxicity of DNA damaging agents. However, with the recent discoveries of PARP-2, which has a similar DNA-damage dependent catalytic activity, and additional members containing the 'PARP catalytic' signature, the isoform selectivity and resultant pharmacological effects of existing inhibitors are brought into question. We present here the crystal structure of the catalytic fragment of murine PARP-2, at 2.8 A resolution, and compare this to the catalytic fragment of PARP-1, with an emphasis on providing a possible framework for rational drug design in order to develop future isoform-specific inhibitors

Core subjects at the end of primary school : identifying and explaining relative strengths of children with specific language impairment (SLI)

Background In general, children with specific language impairment (SLI) tend to fall behind their typically developing (TD) peers in educational attainment. Less is known about how children with SLI fare in particular areas of the curriculum and what predicts their levels of performance. Aims To compare the distributions of performance of children with SLI in three core school subjects (English, Mathematics and Science); to test the possibility that performance would vary across the core subjects; and to examine the extent to which language impairment predicts performance. Methods & Procedures This study was conducted in England and reports historical data on educational attainments. Teacher assessment and test scores of 176 eleven-year-old children with SLI were examined in the three core subjects and compared with known national norms. Possible predictors of performance were measured, including language ability at ages 7 and 11, educational placement type, and performance IQ. Outcomes & Results Children with SLI, compared with national norms, were found to be at a disadvantage in core school subjects. Nevertheless, some children attained the levels expected of TD peers. Performance was poorest in English; relative strengths were indicated in Science and, to a lesser extent, in Mathematics. Language skills were significant predictors of performance in all three core subjects. PIQ was the strongest predictor for Mathematics. For Science, both early language skills at 7 years and PIQ made significant contributions. Conclusions & Implications Language impacts on the school performance of children with SLI, but differentially across subjects. English for these children is the most challenging of the core subjects, reflecting the high levels of language demand it incurs. Science is an area of relative strength and mathematics appears to be intermediate, arguably because some tasks in these subjects can be performed with less reliance on verbal processing. Many children with SLI do have the potential to reach or exceed educational targets that are set at national levels for TD children

Equilibration through local information exchange in networks

We study the equilibrium states of energy functions involving a large set of real variables, defined on the links of sparsely connected networks, and interacting at the network nodes, using the cavity and replica methods. When applied to the representative problem of network resource allocation, an efficient distributed algorithm is devised, with simulations showing full agreement with theory. Scaling properties with the network connectivity and the resource availability are found.Comment: v1: 7 pages, 1 figure, v2: 4 pages, 2 figures, simplified analysis and more organized results, v3: minor change

Explanation and Elaboration Document for the STROBE-Vet Statement: Strengthening the Reporting of Observational Studies in Epidemiology—Veterinary Extension

The STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement was first published in 2007 and again in 2014. The purpose of the original STROBE was to provide guidance for authors, reviewers and editors to improve the comprehensiveness of reporting; however, STROBE has a unique focus on observational studies. Although much of the guidance provided by the original STROBE document is directly applicable, it was deemed useful to map those statements to veterinary concepts, provide veterinary examples and highlight unique aspects of reporting in veterinary observational studies. Here, we present the examples and explanations for the checklist items included in the STROBE-Vet Statement. Thus, this is a companion document to the STROBE-Vet Statement Methods and process document, which describes the checklist and how it was developed

Replicated Bethe Free Energy: A Variational Principle behind Survey Propagation

A scheme to provide various mean-field-type approximation algorithms is presented by employing the Bethe free energy formalism to a family of replicated systems in conjunction with analytical continuation with respect to the number of replicas. In the scheme, survey propagation (SP), which is an efficient algorithm developed recently for analyzing the microscopic properties of glassy states for a fixed sample of disordered systems, can be reproduced by assuming the simplest replica symmetry on stationary points of the replicated Bethe free energy. Belief propagation and generalized SP can also be offered in the identical framework under assumptions of the highest and broken replica symmetries, respectively.Comment: appeared in Journal of the Physical Society of Japan 74, 2133-2136 (2005

Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes

Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6-(Hsp90)2-Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes

Optimal Location of Sources in Transportation Networks

We consider the problem of optimizing the locations of source nodes in transportation networks. A reduction of the fraction of surplus nodes induces a glassy transition. In contrast to most constraint satisfaction problems involving discrete variables, our problem involves continuous variables which lead to cavity fields in the form of functions. The one-step replica symmetry breaking (1RSB) solution involves solving a stable distribution of functionals, which is in general infeasible. In this paper, we obtain small closed sets of functional cavity fields and demonstrate how functional recursions are converted to simple recursions of probabilities, which make the 1RSB solution feasible. The physical results in the replica symmetric (RS) and the 1RSB frameworks are thus derived and the stability of the RS and 1RSB solutions are examined.Comment: 38 pages, 18 figure

Quantifying Self-Organization with Optimal Predictors

Despite broad interest in self-organizing systems, there are few quantitative, experimentally-applicable criteria for self-organization. The existing criteria all give counter-intuitive results for important cases. In this Letter, we propose a new criterion, namely an internally-generated increase in the statistical complexity, the amount of information required for optimal prediction of the system's dynamics. We precisely define this complexity for spatially-extended dynamical systems, using the probabilistic ideas of mutual information and minimal sufficient statistics. This leads to a general method for predicting such systems, and a simple algorithm for estimating statistical complexity. The results of applying this algorithm to a class of models of excitable media (cyclic cellular automata) strongly support our proposal.Comment: Four pages, two color figure

Peer-to-Peer Secure Multi-Party Numerical Computation Facing Malicious Adversaries

We propose an efficient framework for enabling secure multi-party numerical computations in a Peer-to-Peer network. This problem arises in a range of applications such as collaborative filtering, distributed computation of trust and reputation, monitoring and other tasks, where the computing nodes is expected to preserve the privacy of their inputs while performing a joint computation of a certain function. Although there is a rich literature in the field of distributed systems security concerning secure multi-party computation, in practice it is hard to deploy those methods in very large scale Peer-to-Peer networks. In this work, we try to bridge the gap between theoretical algorithms in the security domain, and a practical Peer-to-Peer deployment. We consider two security models. The first is the semi-honest model where peers correctly follow the protocol, but try to reveal private information. We provide three possible schemes for secure multi-party numerical computation for this model and identify a single light-weight scheme which outperforms the others. Using extensive simulation results over real Internet topologies, we demonstrate that our scheme is scalable to very large networks, with up to millions of nodes. The second model we consider is the malicious peers model, where peers can behave arbitrarily, deliberately trying to affect the results of the computation as well as compromising the privacy of other peers. For this model we provide a fourth scheme to defend the execution of the computation against the malicious peers. The proposed scheme has a higher complexity relative to the semi-honest model. Overall, we provide the Peer-to-Peer network designer a set of tools to choose from, based on the desired level of security.Comment: Submitted to Peer-to-Peer Networking and Applications Journal (PPNA) 200

Picturing classical and quantum Bayesian inference

We introduce a graphical framework for Bayesian inference that is sufficiently general to accommodate not just the standard case but also recent proposals for a theory of quantum Bayesian inference wherein one considers density operators rather than probability distributions as representative of degrees of belief. The diagrammatic framework is stated in the graphical language of symmetric monoidal categories and of compact structures and Frobenius structures therein, in which Bayesian inversion boils down to transposition with respect to an appropriate compact structure. We characterize classical Bayesian inference in terms of a graphical property and demonstrate that our approach eliminates some purely conventional elements that appear in common representations thereof, such as whether degrees of belief are represented by probabilities or entropic quantities. We also introduce a quantum-like calculus wherein the Frobenius structure is noncommutative and show that it can accommodate Leifer's calculus of `conditional density operators'. The notion of conditional independence is also generalized to our graphical setting and we make some preliminary connections to the theory of Bayesian networks. Finally, we demonstrate how to construct a graphical Bayesian calculus within any dagger compact category.Comment: 38 pages, lots of picture