Identification of and correction for publication bias

Some empirical results are more likely to be published than others. Such selective publication leads to biased estimates and distorted inference. This paper proposes two approaches for identifying the conditional probability of publication as a function of a study's results, the first based on systematic replication studies and the second based on meta-studies. For known conditional publication probabilities, we propose median-unbiased estimators and associated confidence sets that correct for selective publication. We apply our methods to recent large-scale replication studies in experimental economics and psychology, and to meta-studies of the effects of minimum wages and de-worming programs

Enhancement of vaccinia virus based oncolysis with histone deacetylase inhibitors

Histone deacetylase inhibitors (HDI) dampen cellular innate immune response by decreasing interferon production and have been shown to increase the growth of vesicular stomatitis virus and HSV. As attenuated tumour-selective oncolytic vaccinia viruses (VV) are already undergoing clinical evaluation, the goal of this study is to determine whether HDI can also enhance the potency of these poxviruses in infection-resistant cancer cell lines. Multiple HDIs were tested and Trichostatin A (TSA) was found to potently enhance the spread and replication of a tumour selective vaccinia virus in several infection-resistant cancer cell lines. TSA significantly decreased the number of lung metastases in a syngeneic B16F10LacZ lung metastasis model yet did not increase the replication of vaccinia in normal tissues. The combination of TSA and VV increased survival of mice harbouring human HCT116 colon tumour xenografts as compared to mice treated with either agent alone. We conclude that TSA can selectively and effectively enhance the replication and spread of oncolytic vaccinia virus in cancer cells. © 2010 MacTavish et al

A runtime heuristic to selectively replicate tasks for application-specific reliability targets

In this paper we propose a runtime-based selective task replication technique for task-parallel high performance computing applications. Our selective task replication technique is automatic and does not require modification/recompilation of OS, compiler or application code. Our heuristic, we call App_FIT, selects tasks to replicate such that the specified reliability target for an application is achieved. In our experimental evaluation, we show that App FIT selective replication heuristic is low-overhead and highly scalable. In addition, results indicate that complete task replication is overkill for achieving reliability targets. We show that with App FIT, we can tolerate pessimistic exascale error rates with only 53% of the tasks being replicated.This work was supported by FI-DGR 2013 scholarship and the European Community’s Seventh Framework Programme [FP7/2007-2013] under the Mont-blanc 2 Project (www.montblanc-project.eu), grant agreement no. 610402 and in part by the European Union (FEDER funds) under contract TIN2015-65316-P.Peer ReviewedPostprint (author's final draft

The long and winding road: Routine creation and replication in multi-site organizations

Prior research on organizational routines in the ‘capabilities’ literature has either studied how new routines are created during an exploratory process of variation and selection or how existing routines are replicated during a phase of exploitation. Few studies have analyzed the life cycle of new routine creation and replication as an integrated process. In an in-depth case study of England’s Highways Agency, this paper shows that the creation and replication of a new routine across multiple sites involves four sequential steps: envisioning, experimenting, entrenching and enacting. We contribute to the capabilities research in two ways: first, by showing how different organizational levels, capabilities and logics (cognitive and behavioural) shape the development of new routines; and second, by identifying how distinct evolutionary cycles of variation and selective retention occur during each step in the process. In contrast with prior research on replication as an exact copy of a template or existing routine, our study focuses on the replication of an entirely new routine (based on novel principles) that is adapted to fit local operational conditions during its large-scale replication across multiple sites. We draw upon insights from adjacent ‘practice research’ and suggest how capabilities and practice studies may complement each other in future research on the evolution of routines

Role of the ubiquitin-selective CDC-48/UFD-1/NPL-4 chaperone in DNA replication

Faithful transmission of genomic information requires tight spatiotemporal regulation of DNA replication factors. Posttranslational modifications, such as ubiquitylation, constitute a fast and effective mechanism to control such complex protein function. The AAA-ATPase CDC-48 plays an essential role in selective protein degradation triggered by ubiquitylation. While initial studies reported a crucial function of CDC-48 in the regulation of mitotic events, an essential role of the CDC-48/UFD-1/NPL-4 complex in DNA replication has been revealed in Caenorhabditis elegans (C. elegans) recently. Since the mechanistic details of CDC-48 activity remained to be elucidated, the identification of key substrates playing a vital role during DNA duplication is of major interest. This work describes a regulatory function of CDC-48 in the coordination of licensing and elongation events of DNA replication in C. elegans. In the licensing step of DNA replication, CDT-1 is loaded onto chromatin to subsequently promote the recruitment of relevant replication factors, including CDC-45 and the GINS complex. Throughout the elongation step CDC-45 and the GINS complex move with the replication fork, however, it is largely unknown how their chromatin association is controlled. CDC-48/UFD-1/NPL-4 deficient embryos stabilize the licensing factor CDT-1 exclusively on mitotic chromatin. Furthermore, worm embryos lacking cdc-48, ufd-1, or npl-4, show persistent chromatin association of CDC-45 and the GINS complex. Notably, the protein levels of CDC-45 and the GINS subunits SLD-5 and PSF-3 are not affected by ufd-1 and npl-4 (RNAi), suggesting a non-proteolytic regulation. Down-regulation of CDT-1 suppresses the chromatin association of the GINS complex in embryos disrupted for a functional CDC-48/UFD-1/NPL-4 complex. Hence, CDC-48 is supposed to orchestrate both, CDT-1 degradation and chromatin dissociation of the CDC-45/GINS complex. In conclusion, this work describes a novel role of the ubiquitin-selective chaperone CDC-48/UFD-1/NPL-4 in the context of chromatin associated processes. Elucidating the key substrates of CDC-48 during DNA replication illustrates a critical function in safeguarding genomic stability by an unexpected principle of target protein regulation

Adenovirus-Mediated Sensitization to the Cytotoxic Drugs Docetaxel and Mitoxantrone Is Dependent on Regulatory Domains in the E1ACR1 Gene-Region

Oncolytic adenoviruses have shown promising efficacy in clinical trials targeting prostate cancers that frequently develop resistance to all current therapies. The replication-selective mutants AdΔΔ and dl922–947, defective in pRb-binding, have been demonstrated to synergise with the current standard of care, mitoxantrone and docetaxel, in prostate cancer models. While expression of the early viral E1A gene is essential for the enhanced cell killing, the specific E1A-regions required for the effects are unknown. Here, we demonstrate that replicating mutants deleted in small E1A-domains, binding pRb (dl1108), p300/CBP (dl1104) and p400/TRRAP or p21 (dl1102) sensitize human prostate cancer cells (PC-3, DU145, 22Rv1) to mitoxantrone and docetaxel. Through generation of non-replicating mutants, we demonstrate that the small E1A12S protein is sufficient to potently sensitize all prostate cancer cells to the drugs even in the absence of viral replication and the E1A transactivating domain, conserved region (CR) 3. Furthermore, the p300/CBP-binding domain in E1ACR1 is essential for drug-sensitisation in the absence (AdE1A1104) but not in the presence of the E1ACR3 (dl1104) domain. AdE1A1104 also failed to increase apoptosis and accumulation of cells in G2/M. All E1AΔCR2 mutants (AdE1A1108, dl922–947) and AdE1A1102 or dl1102 enhance cell killing to the same degree as wild type virus. In PC-3 xenografts in vivo the dl1102 mutant significantly prolongs time to tumor progression that is further enhanced in combination with docetaxel. Neither dl1102 nor dl1104 replicates in normal human epithelial cells (NHBE). These findings suggest that additional E1A-deletions might be included when developing more potent replication-selective oncolytic viruses, such as the AdΔCR2-mutants, to further enhance potency through synergistic cell killing in combination with current chemotherapeutics

Selective pressures on genomes in molecular evolution

We describe the evolution of macromolecules as an information transmission process and apply tools from Shannon information theory to it. This allows us to isolate three independent, competing selective pressures that we term compression, transmission, and neutrality selection. The first two affect genome length: the pressure to conserve resources by compressing the code, and the pressure to acquire additional information that improves the channel, increasing the rate of information transmission into each offspring. Noisy transmission channels (replication with mutations) gives rise to a third pressure that acts on the actual encoding of information; it maximizes the fraction of mutations that are neutral with respect to the phenotype. This neutrality selection has important implications for the evolution of evolvability. We demonstrate each selective pressure in experiments with digital organisms.Comment: 16 pages, 3 figures, to be published in J. theor. Biolog

Designing and modelling selective replication for fault-tolerant HPC applications

Fail-stop errors and Silent Data Corruptions (SDCs) are the most common failure modes for High Performance Computing (HPC) applications. There are studies that address fail-stop errors and studies that address SDCs. However few studies address both types of errors together. In this paper we propose a software-based selective replication technique for HPC applications for both fail-stop errors and SDCs. Since complete replication of applications can be costly in terms of resources, we develop a runtime-based technique for selective replication. Selective replication provides an opportunity to meet HPC reliability targets while decreasing resource costs. Our technique is low-overhead, automatic and completely transparent to the user.This work is supported in part by the European Union Mont-blanc 2 Project (www.montblanc-project.eu), grant agreement no. 610402 and the FEDER funds under contract TIN2015-65316-P.Peer ReviewedPostprint (author's final draft