Establishing a coherent and replicable measurement model of the Edinburgh Postnatal Depression Scale.

PubMed

Martin, Colin R; Redshaw, Maggie

2018-06-01

The 10-item Edinburgh Postnatal Depression Scale (EPDS) is an established screening tool for postnatal depression. Inconsistent findings in factor structure and replication difficulties have limited the scope of development of the measure as a multi-dimensional tool. The current investigation sought to robustly determine the underlying factor structure of the EPDS and the replicability and stability of the most plausible model identified. A between-subjects design was used. EPDS data were collected postpartum from two independent cohorts using identical data capture methods. Datasets were examined with confirmatory factor analysis, model invariance testing and systematic evaluation of relational and internal aspects of the measure. Participants were two samples of postpartum women in England assessed at three months (n = 245) and six months (n = 217). The findings showed a three-factor seven-item model of the EPDS offered an excellent fit to the data, and was observed to be replicable in both datasets and invariant as a function of time point of assessment. Some EPDS sub-scale scores were significantly higher at six months. The EPDS is multi-dimensional and a robust measurement model comprises three factors that are replicable. The potential utility of the sub-scale components identified requires further research to identify a role in contemporary screening practice. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Method for replicating an array of nucleic acid probes

DOEpatents

Cantor, C.R.; Przetakiewicz, M.; Smith, C.L.; Sano, T.

1998-08-18

The invention relates to the replication of probe arrays and methods for replicating arrays of probes which are useful for the large scale manufacture of diagnostic aids used to screen biological samples for specific target sequences. Arrays created using PCR technology may comprise probes with 5{prime}- and/or 3{prime}-overhangs. 16 figs.

Viral Activation of Cellular Metabolism

PubMed Central

Sanchez, Erica L.; Lagunoff, Michael

2015-01-01

To ensure optimal environments for their replication and spread, viruses have evolved to alter many host cell pathways. In the last decade, metabolomic studies have shown that eukaryotic viruses induce large-scale alterations in host cellular metabolism. Most viruses examined to date induce aerobic glycolysis also known as the Warburg effect. Many viruses tested also induce fatty acid synthesis as well as glutaminolysis. These modifications of carbon source utilization by infected cells can increase available energy for virus replication and virion production, provide specific cellular substrates for virus particles and create viral replication niches while increasing infected cell survival. Each virus species also likely requires unique metabolic changes for successful spread and recent research has identified additional virus-specific metabolic changes induced by many virus species. A better understanding of the metabolic alterations required for each virus may lead to novel therapeutic approaches through targeted inhibition of specific cellular metabolic pathways. PMID:25812764

Network-scale spatial and temporal variation in Chinook salmon (Oncorhynchus tshawytscha) redd distributions: patterns inferred from spatially continuous replicate surveys

Treesearch

Daniel J. Isaak; Russell F. Thurow

2006-01-01

Spatially continuous sampling designs, when temporally replicated, provide analytical flexibility and are unmatched in their ability to provide a dynamic system view. We have compiled such a data set by georeferencing the network-scale distribution of Chinook salmon (Oncorhynchus tshawytscha) redds across a large wilderness basin (7330 km2) in...

The Newport Button: The Large Scale Replication Of Combined Three-And Two-Dimensional Holographic Images

NASA Astrophysics Data System (ADS)

Cowan, James J.

1984-05-01

A unique type of holographic imagery and its large scale replication are described. The "Newport Button", which was designed as an advertising premium item for the Newport Corporation, incorporates a complex overlay of holographic diffraction gratings surrounding a three-dimensional holographic image of a real object. The combined pattern is recorded onto a photosensitive medium from which a metal master is made. The master is subsequently used to repeatedly emboss the pattern into a thin plastic sheet. Individual patterns are then die cut from the metallized plastic and mounted onto buttons. A discussion is given of the diffraction efficiencies of holograms made in this particular fashion and of the special requirements of the replication process.

An Open, Large-Scale, Collaborative Effort to Estimate the Reproducibility of Psychological Science.

PubMed

2012-11-01

Reproducibility is a defining feature of science. However, because of strong incentives for innovation and weak incentives for confirmation, direct replication is rarely practiced or published. The Reproducibility Project is an open, large-scale, collaborative effort to systematically examine the rate and predictors of reproducibility in psychological science. So far, 72 volunteer researchers from 41 institutions have organized to openly and transparently replicate studies published in three prominent psychological journals in 2008. Multiple methods will be used to evaluate the findings, calculate an empirical rate of replication, and investigate factors that predict reproducibility. Whatever the result, a better understanding of reproducibility will ultimately improve confidence in scientific methodology and findings. © The Author(s) 2012.

The replication domain model: regulating replicon firing in the context of large-scale chromosome architecture.

PubMed

Pope, Benjamin D; Gilbert, David M

2013-11-29

The "Replicon Theory" of Jacob, Brenner, and Cuzin has reliably served as the paradigm for regulating the sites where individual replicons initiate replication. Concurrent with the replicon model was Taylor's demonstration that plant and animal chromosomes replicate segmentally in a defined temporal sequence, via cytologically defined units too large to be accounted for by a single replicon. Instead, there seemed to be a program to choreograph when chromosome units replicate during S phase, executed by initiation at clusters of individual replicons within each segment. Here, we summarize recent molecular evidence for the existence of such units, now known as "replication domains", and discuss how the organization of large chromosomes into structural units has added additional layers of regulation to the original replicon model. Copyright © 2012 Elsevier Ltd. All rights reserved.

Classroom-Based L2 Vocabulary Learning and Comprehension: Replications of Lesaux, Kieffer, Faller & Kelley (2010)

ERIC Educational Resources Information Center

Durgunoglu, Aydin Yücesan; Bigelow, Martha

2017-01-01

The field of language teaching and learning is in dire need of replications of vocabulary and comprehension research with diverse populations of learners. We propose for replication one large-scale vocabulary intervention carried out successfully in a middle-school with monolingual and multilingual students. This study was carried out several…

The leukemia-associated Rho guanine nucleotide exchange factor LARG is required for efficient replication stress signaling

PubMed Central

Beveridge, Ryan D; Staples, Christopher J; Patil, Abhijit A; Myers, Katie N; Maslen, Sarah; Skehel, J Mark; Boulton, Simon J; Collis, Spencer J

2014-01-01

We previously identified and characterized TELO2 as a human protein that facilitates efficient DNA damage response (DDR) signaling. A subsequent yeast 2-hybrid screen identified LARG; Leukemia-Associated Rho Guanine Nucleotide Exchange Factor (also known as Arhgef12), as a potential novel TELO2 interactor. LARG was previously shown to interact with Pericentrin (PCNT), which, like TELO2, is required for efficient replication stress signaling. Here we confirm interactions between LARG, TELO2 and PCNT and show that a sub-set of LARG co-localizes with PCNT at the centrosome. LARG-deficient cells exhibit replication stress signaling defects as evidenced by; supernumerary centrosomes, reduced replication stress-induced γH2AX and RPA nuclear foci formation, and reduced activation of the replication stress signaling effector kinase Chk1 in response to hydroxyurea. As such, LARG-deficient cells are sensitive to replication stress-inducing agents such as hydroxyurea and mitomycin C. Conversely we also show that depletion of TELO2 and the replication stress signaling kinase ATR leads to RhoA signaling defects. These data therefore reveal a level of crosstalk between the RhoA and DDR signaling pathways. Given that mutations in both ATR and PCNT can give rise to the related primordial dwarfism disorders of Seckel Syndrome and Microcephalic osteodysplastic primordial dwarfism type II (MOPDII) respectively, which both exhibit defects in ATR-dependent checkpoint signaling, these data also raise the possibility that mutations in LARG or disruption to RhoA signaling may be contributory factors to the etiology of a sub-set of primordial dwarfism disorders. PMID:25485589

Lessons Learned from Large-Scale Randomized Experiments

ERIC Educational Resources Information Center

Slavin, Robert E.; Cheung, Alan C. K.

2017-01-01

Large-scale randomized studies provide the best means of evaluating practical, replicable approaches to improving educational outcomes. This article discusses the advantages, problems, and pitfalls of these evaluations, focusing on alternative methods of randomization, recruitment, ensuring high-quality implementation, dealing with attrition, and…

Replication of a Test-Retest Factorial Validity Study with the Piers-Harris Children's Self Concept Scale.

ERIC Educational Resources Information Center

Platten, Marvin R.; Williams, Larry R.

1981-01-01

This study largely replicates the findings of a previous study reported by the authors. Further research involving the physical dimension as a possible facet of general self-concept is suggested. (Author/BW)

A Drosophila Toolkit for the Visualization and Quantification of Viral Replication Launched from Transgenic Genomes

PubMed Central

Wernet, Mathias F.; Klovstad, Martha; Clandinin, Thomas R.

2014-01-01

Arthropod RNA viruses pose a serious threat to human health, yet many aspects of their replication cycle remain incompletely understood. Here we describe a versatile Drosophila toolkit of transgenic, self-replicating genomes (‘replicons’) from Sindbis virus that allow rapid visualization and quantification of viral replication in vivo. We generated replicons expressing Luciferase for the quantification of viral replication, serving as useful new tools for large-scale genetic screens for identifying cellular pathways that influence viral replication. We also present a new binary system in which replication-deficient viral genomes can be activated ‘in trans’, through co-expression of an intact replicon contributing an RNA-dependent RNA polymerase. The utility of this toolkit for studying virus biology is demonstrated by the observation of stochastic exclusion between replicons expressing different fluorescent proteins, when co-expressed under control of the same cellular promoter. This process is analogous to ‘superinfection exclusion’ between virus particles in cell culture, a process that is incompletely understood. We show that viral polymerases strongly prefer to replicate the genome that encoded them, and that almost invariably only a single virus genome is stochastically chosen for replication in each cell. Our in vivo system now makes this process amenable to detailed genetic dissection. Thus, this toolkit allows the cell-type specific, quantitative study of viral replication in a genetic model organism, opening new avenues for molecular, genetic and pharmacological dissection of virus biology and tool development. PMID:25386852

Comprehensive replication of the relationship between myopia-related genes and refractive errors in a large Japanese cohort.

PubMed

Yoshikawa, Munemitsu; Yamashiro, Kenji; Miyake, Masahiro; Oishi, Maho; Akagi-Kurashige, Yumiko; Kumagai, Kyoko; Nakata, Isao; Nakanishi, Hideo; Oishi, Akio; Gotoh, Norimoto; Yamada, Ryo; Matsuda, Fumihiko; Yoshimura, Nagahisa

2014-10-21

We investigated the association between refractive error in a Japanese population and myopia-related genes identified in two recent large-scale genome-wide association studies. Single-nucleotide polymorphisms (SNPs) in 51 genes that were reported by the Consortium for Refractive Error and Myopia and/or the 23andMe database were genotyped in 3712 healthy Japanese volunteers from the Nagahama Study using HumanHap610K Quad, HumanOmni2.5M, and/or HumanExome Arrays. To evaluate the association between refractive error and recently identified myopia-related genes, we used three approaches to perform quantitative trait locus analyses of mean refractive error in both eyes of the participants: per-SNP, gene-based top-SNP, and gene-based all-SNP analyses. Association plots of successfully replicated genes also were investigated. In our per-SNP analysis, eight myopia gene associations were replicated successfully: GJD2, RASGRF1, BICC1, KCNQ5, CD55, CYP26A1, LRRC4C, and B4GALNT2.Seven additional gene associations were replicated in our gene-based analyses: GRIA4, BMP2, QKI, BMP4, SFRP1, SH3GL2, and EHBP1L1. The signal strength of the reported SNPs and their tagging SNPs increased after considering different linkage disequilibrium patterns across ethnicities. Although two previous studies suggested strong associations between PRSS56, LAMA2, TOX, and RDH5 and myopia, we could not replicate these results. Our results confirmed the significance of the myopia-related genes reported previously and suggested that gene-based replication analyses are more effective than per-SNP analyses. Our comparison with two previous studies suggested that BMP3 SNPs cause myopia primarily in Caucasian populations, while they may exhibit protective effects in Asian populations. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

A process improvement model for software verification and validation

NASA Technical Reports Server (NTRS)

Callahan, John; Sabolish, George

1994-01-01

We describe ongoing work at the NASA Independent Verification and Validation (IV&V) Facility to establish a process improvement model for software verification and validation (V&V) organizations. This model, similar to those used by some software development organizations, uses measurement-based techniques to identify problem areas and introduce incremental improvements. We seek to replicate this model for organizations involved in V&V on large-scale software development projects such as EOS and space station. At the IV&V Facility, a university research group and V&V contractors are working together to collect metrics across projects in order to determine the effectiveness of V&V and improve its application. Since V&V processes are intimately tied to development processes, this paper also examines the repercussions for development organizations in large-scale efforts.

A process improvement model for software verification and validation

NASA Technical Reports Server (NTRS)

Callahan, John; Sabolish, George

1994-01-01

We describe ongoing work at the NASA Independent Verification and Validation (IV&V) Facility to establish a process improvement model for software verification and validation (V&V) organizations. This model, similar to those used by some software development organizations, uses measurement-based techniques to identify problem areas and introduce incremental improvements. We seek to replicate this model for organizations involved in V&V on large-scale software development projects such as EOS and Space Station. At the IV&V Facility, a university research group and V&V contractors are working together to collect metrics across projects in order to determine the effectiveness of V&V and improve its application. Since V&V processes are intimately tied to development processes, this paper also examines the repercussions for development organizations in large-scale efforts.

Replicability and Robustness of GWAS for Behavioral Traits

PubMed Central

Rietveld, Cornelius A.; Conley, Dalton; Eriksson, Nicholas; Esko, Tõnu; Medland, Sarah E.; Vinkhuyzen, Anna A.E.; Yang, Jian; Boardman, Jason D.; Chabris, Christopher F.; Dawes, Christopher T.; Domingue, Benjamin W.; Hinds, David A.; Johannesson, Magnus; Kiefer, Amy K.; Laibson, David; Magnusson, Patrik K. E.; Mountain, Joanna L.; Oskarsson, Sven; Rostapshova, Olga; Teumer, Alexander; Tung, Joyce Y.; Visscher, Peter M.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.

2015-01-01

A recent genome-wide association study (GWAS) of educational attainment identified three single-nucleotide polymorphisms (SNPs) that, despite their small effect sizes (each R2 ≈ 0.02%), reached genome-wide significance (p < 5×10−8) in a large discovery sample and replicated in an independent sample (p < 0.05). The study also reported associations between educational attainment and indices of SNPs called “polygenic scores.” We evaluate the robustness of these findings. Study 1 finds that all three SNPs replicate in another large (N = 34,428) independent sample. We also find that the scores remain predictive (R2 ≈ 2%) with stringent controls for stratification (Study 2) and in new within-family analyses (Study 3). Our results show that large and therefore well-powered GWASs can identify replicable genetic associations with behavioral traits. The small effect sizes of individual SNPs are likely to be a major contributing explanation for the striking contrast between our results and the disappointing replication record of most candidate gene studies. PMID:25287667

Spatiotemporal coupling and decoupling of gene transcription with DNA replication origins during embryogenesis in C. elegans

PubMed Central

Pourkarimi, Ehsan; Bellush, James M; Whitehouse, Iestyn

2016-01-01

The primary task of developing embryos is genome replication, yet how DNA replication is integrated with the profound cellular changes that occur through development is largely unknown. Using an approach to map DNA replication at high resolution in C. elegans, we show that replication origins are marked with specific histone modifications that define gene enhancers. We demonstrate that the level of enhancer associated modifications scale with the efficiency at which the origin is utilized. By mapping replication origins at different developmental stages, we show that the positions and activity of origins is largely invariant through embryogenesis. Contrary to expectation, we find that replication origins are specified prior to the broad onset of zygotic transcription, yet when transcription initiates it does so in close proximity to the pre-defined replication origins. Transcription and DNA replication origins are correlated, but the association breaks down when embryonic cell division ceases. Collectively, our data indicate that replication origins are fundamental organizers and regulators of gene activity through embryonic development. DOI: http://dx.doi.org/10.7554/eLife.21728.001 PMID:28009254

Distributed design approach in persistent identifiers systems

NASA Astrophysics Data System (ADS)

Golodoniuc, Pavel; Car, Nicholas; Klump, Jens

2017-04-01

The need to identify both digital and physical objects is ubiquitous in our society. Past and present persistent identifier (PID) systems, of which there is a great variety in terms of technical and social implementations, have evolved with the advent of the Internet, which has allowed for globally unique and globally resolvable identifiers. PID systems have catered for identifier uniqueness, integrity, persistence, and trustworthiness, regardless of the identifier's application domain, the scope of which has expanded significantly in the past two decades. Since many PID systems have been largely conceived and developed by small communities, or even a single organisation, they have faced challenges in gaining widespread adoption and, most importantly, the ability to survive change of technology. This has left a legacy of identifiers that still exist and are being used but which have lost their resolution service. We believe that one of the causes of once successful PID systems fading is their reliance on a centralised technical infrastructure or a governing authority. Golodoniuc et al. (2016) proposed an approach to the development of PID systems that combines the use of (a) the Handle system, as a distributed system for the registration and first-degree resolution of persistent identifiers, and (b) the PID Service (Golodoniuc et al., 2015), to enable fine-grained resolution to different information object representations. The proposed approach solved the problem of guaranteed first-degree resolution of identifiers, but left fine-grained resolution and information delivery under the control of a single authoritative source, posing risk to the long-term availability of information resources. Herein, we develop these approaches further and explore the potential of large-scale decentralisation at all levels: (i) persistent identifiers and information resources registration; (ii) identifier resolution; and (iii) data delivery. To achieve large-scale decentralisation, we propose using Distributed Hash Tables (DHT), Peer Exchange networks (PEX), Magnet Links, and peer-to-peer (P2P) file sharing networks - the technologies that enable applications such as BitTorrent (Wu et al., 2010). The proposed approach introduces reliable information replication and caching mechanisms, eliminating the need for a central PID data store, and increases overall system fault tolerance due to the lack of a single point of failure. The proposed PID system's design aims to ensure trustworthiness of the system and incorporates important aspects of governance, such as the notion of the authoritative source, data integrity, caching, and data replication control.

Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome

PubMed Central

Guilbaud, Guillaume; Rappailles, Aurélien; Baker, Antoine; Chen, Chun-Long; Arneodo, Alain; Goldar, Arach; d'Aubenton-Carafa, Yves; Thermes, Claude; Audit, Benjamin; Hyrien, Olivier

2011-01-01

Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general model for their replication kinetics. PMID:22219720

Large-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder.

PubMed

Sacchet, Matthew D; Ho, Tiffany C; Connolly, Colm G; Tymofiyeva, Olga; Lewinn, Kaja Z; Han, Laura Km; Blom, Eva H; Tapert, Susan F; Max, Jeffrey E; Frank, Guido Kw; Paulus, Martin P; Simmons, Alan N; Gotlib, Ian H; Yang, Tony T

2016-11-01

Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period.

Large-Scale Hypoconnectivity Between Resting-State Functional Networks in Unmedicated Adolescent Major Depressive Disorder

PubMed Central

Sacchet, Matthew D; Ho, Tiffany C; Connolly, Colm G; Tymofiyeva, Olga; Lewinn, Kaja Z; Han, Laura KM; Blom, Eva H; Tapert, Susan F; Max, Jeffrey E; Frank, Guido KW; Paulus, Martin P; Simmons, Alan N; Gotlib, Ian H; Yang, Tony T

2016-01-01

Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period. PMID:27238621

Trans-National Scale-Up of Services in Global Health

PubMed Central

Shahin, Ilan; Sohal, Raman; Ginther, John; Hayden, Leigh; MacDonald, John A.; Mossman, Kathryn; Parikh, Himanshu; McGahan, Anita; Mitchell, Will; Bhattacharyya, Onil

2014-01-01

Background Scaling up innovative healthcare programs offers a means to improve access, quality, and health equity across multiple health areas. Despite large numbers of promising projects, little is known about successful efforts to scale up. This study examines trans-national scale, whereby a program operates in two or more countries. Trans-national scale is a distinct measure that reflects opportunities to replicate healthcare programs in multiple countries, thereby providing services to broader populations. Methods Based on the Center for Health Market Innovations (CHMI) database of nearly 1200 health programs, the study contrasts 116 programs that have achieved trans-national scale with 1,068 single-country programs. Data was collected on the programs' health focus, service activity, legal status, and funding sources, as well as the programs' locations (rural v. urban emphasis), and founding year; differences are reported with statistical significance. Findings This analysis examines 116 programs that have achieved trans-national scale (TNS) across multiple disease areas and activity types. Compared to 1,068 single-country programs, we find that trans-nationally scaled programs are more donor-reliant; more likely to focus on targeted health needs such as HIV/AIDS, TB, malaria, or family planning rather than provide more comprehensive general care; and more likely to engage in activities that support healthcare services rather than provide direct clinical care. Conclusion This work, based on a large data set of health programs, reports on trans-national scale with comparison to single-country programs. The work is a step towards understanding when programs are able to replicate their services as they attempt to expand health services for the poor across countries and health areas. A subset of these programs should be the subject of case studies to understand factors that affect the scaling process, particularly seeking to identify mechanisms that lead to improved health outcomes. PMID:25375328

Two Wheels are Better than One: The Importance of Capturing the Home Literacy Environment in Large-Scale Assessments of Reading

ERIC Educational Resources Information Center

Dowd, Amy Jo; Pisani, Lauren

2013-01-01

Children's reading skill development is influenced by availability of reading materials, reading habits and opportunity to read. Save the Children's Literacy Boost data have replicated this finding across numerous developing contexts. Meanwhile international large-scale reading assessments do not capture detail on current home literacy. The…

Assessment and improvement of statistical tools for comparative proteomics analysis of sparse data sets with few experimental replicates.

PubMed

Schwämmle, Veit; León, Ileana Rodríguez; Jensen, Ole Nørregaard

2013-09-06

Large-scale quantitative analyses of biological systems are often performed with few replicate experiments, leading to multiple nonidentical data sets due to missing values. For example, mass spectrometry driven proteomics experiments are frequently performed with few biological or technical replicates due to sample-scarcity or due to duty-cycle or sensitivity constraints, or limited capacity of the available instrumentation, leading to incomplete results where detection of significant feature changes becomes a challenge. This problem is further exacerbated for the detection of significant changes on the peptide level, for example, in phospho-proteomics experiments. In order to assess the extent of this problem and the implications for large-scale proteome analysis, we investigated and optimized the performance of three statistical approaches by using simulated and experimental data sets with varying numbers of missing values. We applied three tools, including standard t test, moderated t test, also known as limma, and rank products for the detection of significantly changing features in simulated and experimental proteomics data sets with missing values. The rank product method was improved to work with data sets containing missing values. Extensive analysis of simulated and experimental data sets revealed that the performance of the statistical analysis tools depended on simple properties of the data sets. High-confidence results were obtained by using the limma and rank products methods for analyses of triplicate data sets that exhibited more than 1000 features and more than 50% missing values. The maximum number of differentially represented features was identified by using limma and rank products methods in a complementary manner. We therefore recommend combined usage of these methods as a novel and optimal way to detect significantly changing features in these data sets. This approach is suitable for large quantitative data sets from stable isotope labeling and mass spectrometry experiments and should be applicable to large data sets of any type. An R script that implements the improved rank products algorithm and the combined analysis is available.

Genotypic variability-based genome-wide association study identifies non-additive loci HLA-C and IL12B for psoriasis.

PubMed

Wei, Wen-Hua; Massey, Jonathan; Worthington, Jane; Barton, Anne; Warren, Richard B

2018-03-01

Genome-wide association studies (GWASs) have identified a number of loci for psoriasis but largely ignored non-additive effects. We report a genotypic variability-based GWAS (vGWAS) that can prioritize non-additive loci without requiring prior knowledge of interaction types or interacting factors in two steps, using a mixed model to partition dichotomous phenotypes into an additive component and non-additive environmental residuals on the liability scale and then the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups genome widely. The vGWAS identified two genome-wide significant (P < 5.0e-08) non-additive loci HLA-C and IL12B that were also genome-wide significant in an accompanying GWAS in the discovery cohort. Both loci were statistically replicated in vGWAS of an independent cohort with a small sample size. HLA-C and IL12B were reported in moderate gene-gene and/or gene-environment interactions in several occasions. We found a moderate interaction with age-of-onset of psoriasis, which was replicated indirectly. The vGWAS also revealed five suggestive loci (P < 6.76e-05) including FUT2 that was associated with psoriasis with environmental aspects triggered by virus infection and/or metabolic factors. Replication and functional investigation are needed to validate the suggestive vGWAS loci.

Proactive replica checking to assure reliability of data in cloud storage with minimum replication

NASA Astrophysics Data System (ADS)

Murarka, Damini; Maheswari, G. Uma

2017-11-01

The two major issues for cloud storage systems are data reliability and storage costs. For data reliability protection, multi-replica replication strategy which is used mostly in current clouds acquires huge storage consumption, leading to a large storage cost for applications within the loud specifically. This paper presents a cost-efficient data reliability mechanism named PRCR to cut back the cloud storage consumption. PRCR ensures data reliability of large cloud information with the replication that might conjointly function as a price effective benchmark for replication. The duplication shows that when resembled to the standard three-replica approach, PRCR will scale back to consume only a simple fraction of the cloud storage from one-third of the storage, thence considerably minimizing the cloud storage price.

Analysis of blood-based gene expression in idiopathic Parkinson disease.

PubMed

Shamir, Ron; Klein, Christine; Amar, David; Vollstedt, Eva-Juliane; Bonin, Michael; Usenovic, Marija; Wong, Yvette C; Maver, Ales; Poths, Sven; Safer, Hershel; Corvol, Jean-Christophe; Lesage, Suzanne; Lavi, Ofer; Deuschl, Günther; Kuhlenbaeumer, Gregor; Pawlack, Heike; Ulitsky, Igor; Kasten, Meike; Riess, Olaf; Brice, Alexis; Peterlin, Borut; Krainc, Dimitri

2017-10-17

To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E-6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E-4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1 , ATP5A1 , and VDAC3 . We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers. © 2017 American Academy of Neurology.

The Social Interaction Phobia Scale: Continued support for the psychometric validity of the SIPS using clinical and non-clinical samples.

PubMed

Menatti, Alison R; Weeks, Justin W; Carleton, R Nicholas; Morrison, Amanda S; Heimberg, Richard G; Hope, Debra A; Blanco, Carlos; Schneier, Franklin R; Liebowitz, Michael R

2015-05-01

The present study sought to extend findings supporting the psychometric validity of a promising measure of social anxiety (SA) symptoms, the Social Interaction Phobia Scale (SIPS; Carleton et al., 2009). Analyses were conducted using three samples: social anxiety disorder (SAD) patients, generalized anxiety disorder (GAD) patients, and healthy controls. SIPS scores of SAD patients demonstrated internal consistency and construct validity, and the previously demonstrated three-factor structure of the SIPS was replicated. Further, the SIPS total score uniquely predicted SA symptoms, and SIPS scores were significantly higher for SAD patients than GAD patients or controls. Two cut-off scores that discriminated SAD patients from GAD patients and from healthy controls were identified. The current study is the first to replicate the SIPS three-factor model in a large, treatment-seeking sample of SAD patients and establish a cut-off score discriminating SAD from GAD patients. Findings support the SIPS as a valid, SAD-specific assessment instrument. Copyright © 2015 Elsevier Ltd. All rights reserved.

Techniques for Large-Scale Bacterial Genome Manipulation and Characterization of the Mutants with Respect to In Silico Metabolic Reconstructions.

PubMed

diCenzo, George C; Finan, Turlough M

2018-01-01

The rate at which all genes within a bacterial genome can be identified far exceeds the ability to characterize these genes. To assist in associating genes with cellular functions, a large-scale bacterial genome deletion approach can be employed to rapidly screen tens to thousands of genes for desired phenotypes. Here, we provide a detailed protocol for the generation of deletions of large segments of bacterial genomes that relies on the activity of a site-specific recombinase. In this procedure, two recombinase recognition target sequences are introduced into known positions of a bacterial genome through single cross-over plasmid integration. Subsequent expression of the site-specific recombinase mediates recombination between the two target sequences, resulting in the excision of the intervening region and its loss from the genome. We further illustrate how this deletion system can be readily adapted to function as a large-scale in vivo cloning procedure, in which the region excised from the genome is captured as a replicative plasmid. We next provide a procedure for the metabolic analysis of bacterial large-scale genome deletion mutants using the Biolog Phenotype MicroArray™ system. Finally, a pipeline is described, and a sample Matlab script is provided, for the integration of the obtained data with a draft metabolic reconstruction for the refinement of the reactions and gene-protein-reaction relationships in a metabolic reconstruction.

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways.

PubMed

Liu, Guiyou; Zhang, Fang; Jiang, Yongshuai; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

2017-02-01

Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date. We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets. Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets. In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2. We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Sequence analysis of malacoherpesvirus proteins: Pan-herpesvirus capsid module and replication enzymes with an ancient connection to "Megavirales".

PubMed

Mushegian, Arcady; Karin, Eli Levy; Pupko, Tal

2018-01-01

The order Herpesvirales includes animal viruses with large double-strand DNA genomes replicating in the nucleus. The main capsid protein in the best-studied family Herpesviridae contains a domain with HK97-like fold related to bacteriophage head proteins, and several virion maturation factors are also homologous between phages and herpesviruses. The origin of herpesvirus DNA replication proteins is less well understood. While analyzing the genomes of herpesviruses in the family Malacohepresviridae, we identified nearly 30 families of proteins conserved in other herpesviruses, including several phage-related domains in morphogenetic proteins. Herpesvirus DNA replication factors have complex evolutionary history: some are related to cellular proteins, but others are closer to homologs from large nucleocytoplasmic DNA viruses. Phylogenetic analyses suggest that the core replication machinery of herpesviruses may have been recruited from the same pool as in the case of other large DNA viruses of eukaryotes. Published by Elsevier Inc.

Educational Attainment: A Genome Wide Association Study in 9538 Australians

PubMed Central

Martin, Nicolas W.; Medland, Sarah E.; Verweij, Karin J. H.; Lee, S. Hong; Nyholt, Dale R.; Madden, Pamela A.; Heath, Andrew C.; Montgomery, Grant W.; Wright, Margaret J.; Martin, Nicholas G.

2011-01-01

Background Correlations between Educational Attainment (EA) and measures of cognitive performance are as high as 0.8. This makes EA an attractive alternative phenotype for studies wishing to map genes affecting cognition due to the ease of collecting EA data compared to other cognitive phenotypes such as IQ. Methodology In an Australian family sample of 9538 individuals we performed a genome-wide association scan (GWAS) using the imputed genotypes of ∼2.4 million single nucleotide polymorphisms (SNP) for a 6-point scale measure of EA. Top hits were checked for replication in an independent sample of 968 individuals. A gene-based test of association was then applied to the GWAS results. Additionally we performed prediction analyses using the GWAS results from our discovery sample to assess the percentage of EA and full scale IQ variance explained by the predicted scores. Results The best SNP fell short of having a genome-wide significant p-value (p = 9.77×10−7). In our independent replication sample six SNPs among the top 50 hits pruned for linkage disequilibrium (r2<0.8) had a p-value<0.05 but only one of these SNPs survived correction for multiple testing - rs7106258 (p = 9.7*10−4) located in an intergenic region of chromosome 11q14.1. The gene based test results were non-significant and our prediction analyses show that the predicted scores explained little variance in EA in our replication sample. Conclusion While we have identified a polymorphism chromosome 11q14.1 associated with EA, further replication is warranted. Overall, the absence of genome-wide significant p-values in our large discovery sample confirmed the high polygenic architecture of EA. Only the assembly of large samples or meta-analytic efforts will be able to assess the implication of common DNA polymorphisms in the etiology of EA. PMID:21694764

Teaching Real Science with a Microcomputer.

ERIC Educational Resources Information Center

Naiman, Adeline

1983-01-01

Discusses various ways science can be taught using microcomputers, including simulations/games which allow large-scale or historic experiments to be replicated on a manageable scale in a brief time. Examples of several computer programs are also presented, including "Experiments in Human Physiology,""Health Awareness…

Conservation lessons from large-mammal manipulations in East African savannas: the KLEE, UHURU, and GLADE experiments

USDA-ARS?s Scientific Manuscript database

African savannas support an iconic fauna, but they are undergoing large-scale population declines and extinctions of large (>5 kg) mammals. Long-term, controlled, replicated experiments that explore the consequences of this defaunation (and its replacement with livestock) are rare. The Mpala Researc...

Using the MMPI-2-RF to discriminate psychometrically identified schizotypic college students from a matched comparison sample.

PubMed

Hunter, Helen K; Bolinskey, P Kevin; Novi, Jonathan H; Hudak, Daniel V; James, Alison V; Myers, Kevin R; Schuder, Kelly M

2014-01-01

This study investigates the extent to which the Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) profiles of 52 individuals making up a psychometrically identified schizotypes (SZT) sample could be successfully discriminated from the protocols of 52 individuals in a matched comparison (MC) sample. Replication analyses were performed with an additional 53 pairs of SZT and MC participants. Results showed significant differences in mean T-score values between these 2 groups across a variety of MMPI-2-RF scales. Results from discriminant function analyses indicate that schizotypy can be predicted effectively using 4 MMPI-2-RF scales and that this method of classification held up on replication. Additional results demonstrated that these MMPI-2-RF scales nominally outperformed MMPI-2 scales suggested by previous research as being indicative of schizophrenia liability. Directions for future research with the MMPI-2-RF are suggested.

Paying for performance: Performance incentives increase desire for the reward object.

PubMed

Hur, Julia D; Nordgren, Loran F

2016-09-01

The current research examines how exposure to performance incentives affects one's desire for the reward object. We hypothesized that the flexible nature of performance incentives creates an attentional fixation on the reward object (e.g., money), which leads people to become more desirous of the rewards. Results from 5 laboratory experiments and 1 large-scale field study provide support for this prediction. When performance was incentivized with monetary rewards, participants reported being more desirous of money (Study 1), put in more effort to earn additional money in an ensuing task (Study 2), and were less willing to donate money to charity (Study 4). We replicated the result with nonmonetary rewards (Study 5). We also found that performance incentives increased attention to the reward object during the task, which in part explains the observed effects (Study 6). A large-scale field study replicated these findings in a real-world setting (Study 7). One laboratory experiment failed to replicate (Study 3). (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Germline whole exome sequencing and large-scale replication identifies FANCM as a likely high grade serous ovarian cancer susceptibility gene.

PubMed

Dicks, Ed; Song, Honglin; Ramus, Susan J; Oudenhove, Elke Van; Tyrer, Jonathan P; Intermaggio, Maria P; Kar, Siddhartha; Harrington, Patricia; Bowtell, David D; Group, Aocs Study; Cicek, Mine S; Cunningham, Julie M; Fridley, Brooke L; Alsop, Jennifer; Jimenez-Linan, Mercedes; Piskorz, Anna; Goranova, Teodora; Kent, Emma; Siddiqui, Nadeem; Paul, James; Crawford, Robin; Poblete, Samantha; Lele, Shashi; Sucheston-Campbell, Lara; Moysich, Kirsten B; Sieh, Weiva; McGuire, Valerie; Lester, Jenny; Odunsi, Kunle; Whittemore, Alice S; Bogdanova, Natalia; Dürst, Matthias; Hillemanns, Peter; Karlan, Beth Y; Gentry-Maharaj, Aleksandra; Menon, Usha; Tischkowitz, Marc; Levine, Douglas; Brenton, James D; Dörk, Thilo; Goode, Ellen L; Gayther, Simon A; Pharoah, D P Paul

2017-08-01

We analyzed whole exome sequencing data in germline DNA from 412 high grade serous ovarian cancer (HGSOC) cases from The Cancer Genome Atlas Project and identified 5,517 genes harboring a predicted deleterious germline coding mutation in at least one HGSOC case. Gene-set enrichment analysis showed enrichment for genes involved in DNA repair (p = 1.8×10 -3 ). Twelve DNA repair genes - APEX1, APLF, ATX, EME1, FANCL, FANCM, MAD2L2, PARP2, PARP3, POLN, RAD54L and SMUG1 - were prioritized for targeted sequencing in up to 3,107 HGSOC cases, 1,491 cases of other epithelial ovarian cancer (EOC) subtypes and 3,368 unaffected controls of European origin. We estimated mutation prevalence for each gene and tested for associations with disease risk. Mutations were identified in both cases and controls in all genes except MAD2L2 , where we found no evidence of mutations in controls. In FANCM we observed a higher mutation frequency in HGSOC cases compared to controls (29/3,107 cases, 0.96 percent; 13/3,368 controls, 0.38 percent; P=0.008) with little evidence for association with other subtypes (6/1,491, 0.40 percent; P=0.82). The relative risk of HGSOC associated with deleterious FANCM mutations was estimated to be 2.5 (95% CI 1.3 - 5.0; P=0.006). In summary, whole exome sequencing of EOC cases with large-scale replication in case-control studies has identified FANCM as a likely novel susceptibility gene for HGSOC, with mutations associated with a moderate increase in risk. These data may have clinical implications for risk prediction and prevention approaches for high-grade serous ovarian cancer in the future and a significant impact on reducing disease mortality.

A Successful Replication of the River Visitor Inventory and Monitoring Process for Capacity Management

Treesearch

Kenneth Chilman; James Vogel; Greg Brown; John H. Burde

2004-01-01

This paper has 3 purposes: to discuss 1. case study research and its utility for recreation management decisionmaking, 2. the recreation visitor inventory and monitoring process developed from case study research, and 3. a successful replication of the process in a large-scale, multi-year application. Although case study research is discussed in research textbooks as...

Replicating annual North Atlantic hurricane activity 1878-2012 from environmental variables

NASA Astrophysics Data System (ADS)

Saunders, Mark A.; Klotzbach, Philip J.; Lea, Adam S. R.

2017-06-01

Statistical models can replicate annual North Atlantic hurricane activity from large-scale environmental field data for August and September, the months of peak hurricane activity. We assess how well the six environmental fields used most often in contemporary statistical modeling of seasonal hurricane activity replicate North Atlantic hurricane numbers and Accumulated Cyclone Energy (ACE) over the 135 year period from 1878 to 2012. We find that these fields replicate historical hurricane activity surprisingly well, showing that contemporary statistical models and their seasonal physical links have long-term robustness. We find that August-September zonal trade wind speed over the Caribbean Sea and the tropical North Atlantic is the environmental field which individually replicates long-term hurricane activity the best and that trade wind speed combined with the difference in sea surface temperature between the tropical Atlantic and the tropical mean is the best multi-predictor model. Comparing the performance of the best single-predictor and best multi-predictor models shows that they exhibit little difference in hindcast skill for predicting long-term ACE but that the best multipredictor model offers improved skill for predicting long-term hurricane numbers. We examine whether replicated real-time prediction skill 1983-2012 increases as the model training period lengthens and find evidence that this happens slowly. We identify a dropout in hurricane replication centered on the 1940s and show that this is likely due to a decrease in data quality which affects all data sets but Atlantic sea surface temperatures in particular. Finally, we offer insights on the implications of our findings for seasonal hurricane prediction.

Extended local similarity analysis (eLSA) of microbial community and other time series data with replicates.

PubMed

Xia, Li C; Steele, Joshua A; Cram, Jacob A; Cardon, Zoe G; Simmons, Sheri L; Vallino, Joseph J; Fuhrman, Jed A; Sun, Fengzhu

2011-01-01

The increasing availability of time series microbial community data from metagenomics and other molecular biological studies has enabled the analysis of large-scale microbial co-occurrence and association networks. Among the many analytical techniques available, the Local Similarity Analysis (LSA) method is unique in that it captures local and potentially time-delayed co-occurrence and association patterns in time series data that cannot otherwise be identified by ordinary correlation analysis. However LSA, as originally developed, does not consider time series data with replicates, which hinders the full exploitation of available information. With replicates, it is possible to understand the variability of local similarity (LS) score and to obtain its confidence interval. We extended our LSA technique to time series data with replicates and termed it extended LSA, or eLSA. Simulations showed the capability of eLSA to capture subinterval and time-delayed associations. We implemented the eLSA technique into an easy-to-use analytic software package. The software pipeline integrates data normalization, statistical correlation calculation, statistical significance evaluation, and association network construction steps. We applied the eLSA technique to microbial community and gene expression datasets, where unique time-dependent associations were identified. The extended LSA analysis technique was demonstrated to reveal statistically significant local and potentially time-delayed association patterns in replicated time series data beyond that of ordinary correlation analysis. These statistically significant associations can provide insights to the real dynamics of biological systems. The newly designed eLSA software efficiently streamlines the analysis and is freely available from the eLSA homepage, which can be accessed at http://meta.usc.edu/softs/lsa.

Extended local similarity analysis (eLSA) of microbial community and other time series data with replicates

PubMed Central

2011-01-01

Background The increasing availability of time series microbial community data from metagenomics and other molecular biological studies has enabled the analysis of large-scale microbial co-occurrence and association networks. Among the many analytical techniques available, the Local Similarity Analysis (LSA) method is unique in that it captures local and potentially time-delayed co-occurrence and association patterns in time series data that cannot otherwise be identified by ordinary correlation analysis. However LSA, as originally developed, does not consider time series data with replicates, which hinders the full exploitation of available information. With replicates, it is possible to understand the variability of local similarity (LS) score and to obtain its confidence interval. Results We extended our LSA technique to time series data with replicates and termed it extended LSA, or eLSA. Simulations showed the capability of eLSA to capture subinterval and time-delayed associations. We implemented the eLSA technique into an easy-to-use analytic software package. The software pipeline integrates data normalization, statistical correlation calculation, statistical significance evaluation, and association network construction steps. We applied the eLSA technique to microbial community and gene expression datasets, where unique time-dependent associations were identified. Conclusions The extended LSA analysis technique was demonstrated to reveal statistically significant local and potentially time-delayed association patterns in replicated time series data beyond that of ordinary correlation analysis. These statistically significant associations can provide insights to the real dynamics of biological systems. The newly designed eLSA software efficiently streamlines the analysis and is freely available from the eLSA homepage, which can be accessed at http://meta.usc.edu/softs/lsa. PMID:22784572

The Impact of Teacher Study Groups in Vocabulary on Teaching Practice, Teacher Knowledge, and Student Vocabulary Knowledge: A Large-Scale Replication Study

ERIC Educational Resources Information Center

Jayanthi, Madhavi; Dimino, Joseph; Gersten, Russell; Taylor, Mary Jo; Haymond, Kelly; Smolkowski, Keith; Newman-Gonchar, Rebecca

2018-01-01

The purpose of this replication study was to examine the impact of the Teacher Study Group (TSG) professional development in vocabulary on first-grade teachers' knowledge of vocabulary instruction and observed teaching practice, and on students' vocabulary knowledge. Sixty-two schools from 16 districts in four states were randomly assigned to…

Corridors Increase Plant Species Richness at Large Scales

DOE Office of Scientific and Technical Information (OSTI.GOV)

Damschen, Ellen I.; Haddad, Nick M.; Orrock,John L.

2006-09-01

Habitat fragmentation is one of the largest threats to biodiversity. Landscape corridors, which are hypothesized to reduce the negative consequences of fragmentation, have become common features of ecological management plans worldwide. Despite their popularity, there is little evidence documenting the effectiveness of corridors in preserving biodiversity at large scales. Using a large-scale replicated experiment, we showed that habitat patches connected by corridors retain more native plant species than do isolated patches, that this difference increases over time, and that corridors do not promote invasion by exotic species. Our results support the use of corridors in biodiversity conservation.

Corridors increase plant species richness at large scales.

PubMed

Damschen, Ellen I; Haddad, Nick M; Orrock, John L; Tewksbury, Joshua J; Levey, Douglas J

2006-09-01

Habitat fragmentation is one of the largest threats to biodiversity. Landscape corridors, which are hypothesized to reduce the negative consequences of fragmentation, have become common features of ecological management plans worldwide. Despite their popularity, there is little evidence documenting the effectiveness of corridors in preserving biodiversity at large scales. Using a large-scale replicated experiment, we showed that habitat patches connected by corridors retain more native plant species than do isolated patches, that this difference increases over time, and that corridors do not promote invasion by exotic species. Our results support the use of corridors in biodiversity conservation.

More than just a metabolic regulator - elucidation and validation of new targets of PdhR in Escherichia coli

PubMed Central

2011-01-01

Background The pyruvate dehydrogenase regulator protein (PdhR) of Escherichia coli acts as a transcriptional regulator in a pyruvate dependent manner to control central metabolic fluxes. However, the complete PdhR regulon has not yet been uncovered. To achieve an extended understanding of its gene regulatory network, we combined large-scale network inference and experimental verification of results obtained by a systems biology approach. Results 22 new genes contained in two operons controlled by PdhR (previously only 20 regulatory targets in eight operons were known) were identified by analysing a large-scale dataset of E. coli from the Many Microbes Microarray Database and novel expression data from a pdhR knockout strain, as well as a PdhR overproducing strain. We identified a regulation of the glycolate utilization operon glcDEFGBA using chromatin immunoprecipitation and gel shift assays. We show that this regulation could be part of a cross-induction between genes necessary for acetate and pyruvate utilisation controlled through PdhR. Moreover, a link of PdhR regulation to the replication machinery of the cell via control of the transcription of the dcw-cluster was verified in experiments. This augments our knowledge of the functions of the PdhR-regulon and demonstrates its central importance for further cellular processes in E. coli. Conclusions We extended the PdhR regulon by 22 new genes contained in two operons and validated the regulation of the glcDEFGBA operon for glycolate utilisation and the dcw-cluster for cell division proteins experimentally. Our results provide, for the first time, a plausible regulatory link between the nutritional status of the cell and cell replication mediated by PdhR. PMID:22168595

ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio

PubMed Central

Meyer, Nuala J.; Li, Mingyao; Feng, Rui; Bradfield, Jonathan; Gallop, Robert; Bellamy, Scarlett; Fuchs, Barry D.; Lanken, Paul N.; Albelda, Steven M.; Rushefski, Melanie; Aplenc, Richard; Abramova, Helen; Atochina-Vasserman, Elena N.; Beers, Michael F.; Calfee, Carolyn S.; Cohen, Mitchell J.; Pittet, Jean-Francois; Christiani, David C.; O'Keefe, Grant E.; Ware, Lorraine B.; May, Addison K.; Wurfel, Mark M.; Hakonarson, Hakon; Christie, Jason D.

2011-01-01

Rationale: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI. Objectives: To identify ALI risk variants after major trauma using a large-scale candidate gene approach. Methods: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease–centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10−4) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot. Measurements and Main Results: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06–1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038). Conclusions: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility. PMID:21257790

Mapping yeast origins of replication via single-stranded DNA detection.

PubMed

Feng, Wenyi; Raghuraman, M K; Brewer, Bonita J

2007-02-01

Studies in th Saccharomyces cerevisiae have provided a framework for understanding how eukaryotic cells replicate their chromosomal DNA to ensure faithful transmission of genetic information to their daughter cells. In particular, S. cerevisiae is the first eukaryote to have its origins of replication mapped on a genomic scale, by three independent groups using three different microarray-based approaches. Here we describe a new technique of origin mapping via detection of single-stranded DNA in yeast. This method not only identified the majority of previously discovered origins, but also detected new ones. We have also shown that this technique can identify origins in Schizosaccharomyces pombe, illustrating the utility of this method for origin mapping in other eukaryotes.

System-wide Analysis of SUMOylation Dynamics in Response to Replication Stress Reveals Novel Small Ubiquitin-like Modified Target Proteins and Acceptor Lysines Relevant for Genome Stability*

PubMed Central

Xiao, Zhenyu; Chang, Jer-Gung; Hendriks, Ivo A.; Sigurðsson, Jón Otti; Olsen, Jesper V.; Vertegaal, Alfred C.O.

2015-01-01

Genotoxic agents can cause replication fork stalling in dividing cells because of DNA lesions, eventually leading to replication fork collapse when the damage is not repaired. Small Ubiquitin-like Modifiers (SUMOs) are known to counteract replication stress, nevertheless, only a small number of relevant SUMO target proteins are known. To address this, we have purified and identified SUMO-2 target proteins regulated by replication stress in human cells. The developed methodology enabled single step purification of His10-SUMO-2 conjugates under denaturing conditions with high yield and high purity. Following statistical analysis on five biological replicates, a total of 566 SUMO-2 targets were identified. After 2 h of hydroxyurea treatment, 10 proteins were up-regulated for SUMOylation and two proteins were down-regulated for SUMOylation, whereas after 24 h, 35 proteins were up-regulated for SUMOylation, and 13 proteins were down-regulated for SUMOylation. A site-specific approach was used to map over 1000 SUMO-2 acceptor lysines in target proteins. The methodology is generic and is widely applicable in the ubiquitin field. A large subset of these identified proteins function in one network that consists of interacting replication factors, transcriptional regulators, DNA damage response factors including MDC1, ATR-interacting protein ATRIP, the Bloom syndrome protein and the BLM-binding partner RMI1, the crossover junction endonuclease EME1, BRCA1, and CHAF1A. Furthermore, centromeric proteins and signal transducers were dynamically regulated by SUMOylation upon replication stress. Our results uncover a comprehensive network of SUMO target proteins dealing with replication damage and provide a framework for detailed understanding of the role of SUMOylation to counteract replication stress. Ultimately, our study reveals how a post-translational modification is able to orchestrate a large variety of different proteins to integrate different nuclear processes with the aim of dealing with the induced DNA damage. PMID:25755297

Replication of engine block cylinder bridge microstructure and mechanical properties with lab scale 319 Al alloy billet castings

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lombardi, A., E-mail: a2lombar@ryerson.ca; D'Elia, F.; Ravindran, C.

2014-01-15

In recent years, aluminum alloy gasoline engine blocks have in large part successfully replaced nodular cast iron engine blocks, resulting in improved vehicle fuel efficiency. However, because of the inadequate wear resistance properties of hypoeutectic Al–Si alloys, gray iron cylinder liners are required. These liners cause the development of large tensile residual stress along the cylinder bores and necessitate the maximization of mechanical properties in this region to prevent premature engine failure. The aim of this study was to replicate the engine cylinder bridge microstructure and mechanical properties following TSR treatment (which removes the sand binder to enable easy castingmore » retrieval) using lab scale billet castings of the same alloy composition with varying cooling rates. Comparisons in microstructure between the engine block and the billet castings were carried out using optical and scanning electron microscopy, while mechanical properties were assessed using tensile testing. The results suggest that the microstructure at the top and middle of the engine block cylinder bridge was successfully replicated by the billet castings. However, the microstructure at the bottom of the cylinder was not completely replicated due to variations in secondary phase morphology and distribution. The successful replication of engine block microstructure will enable the future optimization of heat treatment parameters. - Highlights: • A method to replicate engine block microstructure was developed. • Billet castings will allow cost effective optimization of heat treatment process. • The replication of microstructure in the cylinder region was mostly successful. • Porosity was more clustered in the billet castings compared to the engine block. • Mechanical properties were lower in billet castings due to porosity and inclusions.« less

Benefits and applications of interdisciplinary digital tools for environmental meta-reviews and analyses

NASA Astrophysics Data System (ADS)

Grubert, Emily; Siders, Anne

2016-09-01

Digitally-aided reviews of large bodies of text-based information, such as academic literature, are growing in capability but are not yet common in environmental fields. Environmental sciences and studies can benefit from application of digital tools to create comprehensive, replicable, interdisciplinary reviews that provide rapid, up-to-date, and policy-relevant reports of existing work. This work reviews the potential for applications of computational text mining and analysis tools originating in the humanities to environmental science and policy questions. Two process-oriented case studies of digitally-aided environmental literature reviews and meta-analyses illustrate potential benefits and limitations. A medium-sized, medium-resolution review (∼8000 journal abstracts and titles) focuses on topic modeling as a rapid way to identify thematic changes over time. A small, high-resolution review (∼300 full text journal articles) combines collocation and network analysis with manual coding to synthesize and question empirical field work. We note that even small digitally-aided analyses are close to the upper limit of what can be done manually. Established computational methods developed in humanities disciplines and refined by humanities and social science scholars to interrogate large bodies of textual data are applicable and useful in environmental sciences but have not yet been widely applied. Two case studies provide evidence that digital tools can enhance insight. Two major conclusions emerge. First, digital tools enable scholars to engage large literatures rapidly and, in some cases, more comprehensively than is possible manually. Digital tools can confirm manually identified patterns or identify additional patterns visible only at a large scale. Second, digital tools allow for more replicable and transparent conclusions to be drawn from literature reviews and meta-analyses. The methodological subfields of digital humanities and computational social sciences will likely continue to create innovative tools for analyzing large bodies of text, providing opportunities for interdisciplinary collaboration with the environmental fields.

Commentary: The Observed Association between Autistic Severity Measured by the Social Responsiveness Scale (SRS) and General Psychopathology-- A Response to Hus et al.()

ERIC Educational Resources Information Center

Constantino, John N.; Frazier, Thomas W.

2013-01-01

In their analysis of the accumulated data from the clinically ascertained Simons Simplex Collection (SSC), Hus et al. (2013) provide a large-scale clinical replication of previously reported associations (see Constantino, Hudziak & Todd, 2003) between quantitative autistic traits [as measured by the Social Responsiveness Scale (SRS)] and…

DNA breaks early in replication in B cell cancers

Cancer.gov

Research by scientists at the NCI has identified a new class of DNA sites in cells that break early in the replication process. They found that these break sites correlate with damage often seen in B cell cancers, such as diffuse large B cell lymphoma.

Identification of the ENT1 antagonists dipyridamole and dilazep as amplifiers of oncolytic herpes simplex virus-1 replication.

PubMed

Passer, Brent J; Cheema, Tooba; Zhou, Bingsen; Wakimoto, Hiroaki; Zaupa, Cecile; Razmjoo, Mani; Sarte, Jason; Wu, Shulin; Wu, Chin-lee; Noah, James W; Li, Qianjun; Buolamwini, John K; Yen, Yun; Rabkin, Samuel D; Martuza, Robert L

2010-05-15

Oncolytic herpes simplex virus-1 (oHSV) vectors selectively replicate in tumor cells, where they kill through oncolysis while sparing normal cells. One of the drawbacks of oHSV vectors is their limited replication and spread to neighboring cancer cells. Here, we report the outcome of a high-throughput chemical library screen to identify small-molecule compounds that augment the replication of oHSV G47Delta. Of the 2,640-screened bioactives, 6 compounds were identified and subsequently validated for enhanced G47Delta replication. Two of these compounds, dipyridamole and dilazep, interfered with nucleotide metabolism by potently and directly inhibiting the equilibrative nucleoside transporter-1 (ENT1). Replicative amplification promoted by dipyridamole and dilazep were dependent on HSV mutations in ICP6, the large subunit of ribonucleotide reductase. Our results indicate that ENT1 antagonists augment oHSV replication in tumor cells by increasing cellular ribonucleoside activity. (c)2010 AACR.

Size of Coarse Woody Debris 5 Years After Girdling and Removal Treatments in 50-Year-Old Loblolly Pine Plantations

Treesearch

M. Boyd Edwards

2004-01-01

In 1996, a study began at Savannah River Site to investigate large-scale replicated forest areas to control coarse woody debris for integrated biodiversity objectives. Research design was a randomized complete block with four treatments replicated in four blocks, resulting in 16 plots. The treatments applied to 50-year-old loblolly pine stands were (1) control, (2)...

Large-scale gene-centric analysis identifies novel variants for coronary artery disease.

PubMed

2011-09-01

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.

Scaling Personalization: Exploring the Implementation of an Academic and Social-Emotional Innovation in High Schools

ERIC Educational Resources Information Center

Rutledge, Stacey A.; Brown, Stephanie; Petrova, Kitchka

2017-01-01

Scaling in educational settings has tended to focus on replication of external programs with less focus on the nature of adaptation. In this article, we explore the scaling of Personalization for Academic and Social-emotional Learning (PASL), a systemic high school reform effort that was intentionally identified, developed, and implemented with…

Scaling Personalization: Exploring the Implementation of an Academic and Social Emotional Innovation in High Schools

ERIC Educational Resources Information Center

Rutledge, Stacey; Brown, Stephanie; Petrova, Kitchka

2017-01-01

Scaling in educational settings has tended to focus on replication of external programs with less focus on the nature of adaptation. In this article, we explore the scaling of Personalization for Academic and Social-emotional Learning (PASL), a systemic high school reform effort that was intentionally identified, developed, and implemented with…

Entanglement replication in driven dissipative many-body systems.

PubMed

Zippilli, S; Paternostro, M; Adesso, G; Illuminati, F

2013-01-25

We study the dissipative dynamics of two independent arrays of many-body systems, locally driven by a common entangled field. We show that in the steady state the entanglement of the driving field is reproduced in an arbitrarily large series of inter-array entangled pairs over all distances. Local nonclassical driving thus realizes a scale-free entanglement replication and long-distance entanglement distribution mechanism that has immediate bearing on the implementation of quantum communication networks.

Small-Scale Experiments.10-gallon drum experiment summary

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenberg, David M.

2015-02-05

A series of sub-scale (10-gallon) drum experiments were conducted to characterize the reactivity, heat generation, and gas generation of mixtures of chemicals believed to be present in the drum (68660) known to have breached in association with the radiation release event at the Waste Isolation Pilot Plant (WIPP) on February 14, 2014, at a scale expected to be large enough to replicate the environment in that drum but small enough to be practical, safe, and cost effective. These tests were not intended to replicate all the properties of drum 68660 or the event that led to its breach, or tomore » validate a particular hypothesis of the release event. They were intended to observe, in a controlled environment and with suitable diagnostics, the behavior of simple mixtures of chemicals in order to determine if they could support reactivity that could result in ignition or if some other ingredient or event would be necessary. There is a significant amount of uncertainty into the exact composition of the barrel; a limited sub-set of known components was identified, reviewed with Technical Assessment Team (TAT) members, and used in these tests. This set of experiments was intended to provide a framework to postulate realistic, data-supported hypotheses for processes that occur in a “68660-like” configuration, not definitively prove what actually occurred in 68660.« less

Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans.

PubMed

Bakken, Trygve E; Roddey, J Cooper; Djurovic, Srdjan; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Casey, B J; Chang, Linda; Ernst, Thomas M; Gruen, Jeffrey R; Jernigan, Terry L; Kaufmann, Walter E; Kenet, Tal; Kennedy, David N; Kuperman, Joshua M; Murray, Sarah S; Sowell, Elizabeth R; Rimol, Lars M; Mattingsdal, Morten; Melle, Ingrid; Agartz, Ingrid; Andreassen, Ole A; Schork, Nicholas J; Dale, Anders M; Weiner, Michael; Aisen, Paul; Petersen, Ronald; Jack, Clifford R; Jagust, William; Trojanowki, John Q; Toga, Arthur W; Beckett, Laurel; Green, Robert C; Saykin, Andrew J; Morris, John; Liu, Enchi; Montine, Tom; Gamst, Anthony; Thomas, Ronald G; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Harvey, Danielle; Kornak, John; Dale, Anders; Bernstein, Matthew; Felmlee, Joel; Fox, Nick; Thompson, Paul; Schuff, Norbert; Alexander, Gene; DeCarli, Charles; Bandy, Dan; Koeppe, Robert A; Foster, Norm; Reiman, Eric M; Chen, Kewei; Mathis, Chet; Cairns, Nigel J; Taylor-Reinwald, Lisa; Trojanowki, J Q; Shaw, Les; Lee, Virginia M Y; Korecka, Magdalena; Crawford, Karen; Neu, Scott; Foroud, Tatiana M; Potkin, Steven; Shen, Li; Kachaturian, Zaven; Frank, Richard; Snyder, Peter J; Molchan, Susan; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Dolen, Sara; Schneider, Lon S; Pawluczyk, Sonia; Spann, Bryan M; Brewer, James; Vanderswag, Helen; Heidebrink, Judith L; Lord, Joanne L; Johnson, Kris; Doody, Rachelle S; Villanueva-Meyer, Javier; Chowdhury, Munir; Stern, Yaakov; Honig, Lawrence S; Bell, Karen L; Morris, John C; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A; Schneider, Stacy; Marson, Daniel; Griffith, Randall; Clark, David; Grossman, Hillel; Mitsis, Effie; Romirowsky, Aliza; deToledo-Morrell, Leyla; Shah, Raj C; Duara, Ranjan; Varon, Daniel; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; Kielb, Stephanie; Rusinek, Henry; de Leon, Mony J; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P Murali; Petrella, Jeffrey R; Coleman, R Edward; Arnold, Steven E; Karlawish, Jason H; Wolk, David; Smith, Charles D; Jicha, Greg; Hardy, Peter; Lopez, Oscar L; Oakley, MaryAnn; Simpson, Donna M; Porsteinsson, Anton P; Goldstein, Bonnie S; Martin, Kim; Makino, Kelly M; Ismail, M Saleem; Brand, Connie; Mulnard, Ruth A; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I; Lah, James J; Cellar, Janet S; Burns, Jeffrey M; Anderson, Heather S; Swerdlow, Russell H; Apostolova, Liana; Lu, Po H; Bartzokis, George; Silverman, Daniel H S; Graff-Radford, Neill R; Parfitt, Francine; Johnson, Heather; Farlow, Martin R; Hake, Ann Marie; Matthews, Brandy R; Herring, Scott; van Dyck, Christopher H; Carson, Richard E; MacAvoy, Martha G; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Ging-Yuek; Hsiung, Robin; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Trost, Dick; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristina; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A; Johnson, Keith A; Marshall, Gad; Frey, Meghan; Yesavage, Jerome; Taylor, Joy L; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan; Belden, Christine; Jacobson, Sandra; Kowall, Neil; Killiany, Ronald; Budson, Andrew E; Norbash, Alexander; Johnson, Patricia Lynn; Obisesan, Thomas O; Wolday, Saba; Bwayo, Salome K; Lerner, Alan; Hudson, Leon; Ogrocki, Paula; Fletcher, Evan; Carmichael, Owen; Olichney, John; Kittur, Smita; Borrie, Michael; Lee, T-Y; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M; Potkin, Steven G; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Fleisher, Adam; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W; Kataki, Maria; Zimmerman, Earl A; Celmins, Dzintra; Brown, Alice D; Pearlson, Godfrey D; Blank, Karen; Anderson, Karen; Santulli, Robert B; Schwartz, Eben S; Sink, Kaycee M; Williamson, Jeff D; Garg, Pradeep; Watkins, Franklin; Ott, Brian R; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J; Miller, Bruce L; Mintzer, Jacobo; Longmire, Crystal Flynn; Spicer, Kenneth; Finger, Elizabether; Rachinsky, Irina; Drost, Dick; Jernigan, Terry; McCabe, Connor; Grant, Ellen; Ernst, Thomas; Kuperman, Josh; Chung, Yoon; Murray, Sarah; Bloss, Cinnamon; Darst, Burcu; Pritchett, Lexi; Saito, Ashley; Amaral, David; DiNino, Mishaela; Eyngorina, Bella; Sowell, Elizabeth; Houston, Suzanne; Soderberg, Lindsay; Kaufmann, Walter; van Zijl, Peter; Rizzo-Busack, Hilda; Javid, Mohsin; Mehta, Natasha; Ruberry, Erika; Powers, Alisa; Rosen, Bruce; Gebhard, Nitzah; Manigan, Holly; Frazier, Jean; Kennedy, David; Yakutis, Lauren; Hill, Michael; Gruen, Jeffrey; Bosson-Heenan, Joan; Carlson, Heatherly

2012-03-06

Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.

No association between FOXP2 rs10447760 and schizophrenia in a replication study of the Chinese Han population.

PubMed

Yin, Jiajun; Jia, Ningren; Liu, Yansong; Jin, Chunhui; Zhang, Fuquan; Yu, Shui; Wang, Jun; Yuan, Jianmin

2018-04-01

Schizophrenia (SCZ) is a severe and heritable psychiatric disorder, and previous studies have shown that regulation of the forkhead-box P2 gene (FOXP2) may play a role in schizophrenia. Moreover, just a few studies have identified a single nucleotide polymorphism (SNP) rs10447760 within the gene that was a risk variant for SCZ in the Chinese Han population. To examine whether the variant in the FOXP2 gene contributes toward SCZ susceptibility, we carried out an association analysis of the SNP rs10447760 of the FOXP2 gene in a case-control study (1405 cases, 1137 controls) from China. We identified no association of rs10447760 in the FOXP2 gene with SCZ (all P>0.05). In addition, a meta-analysis indicated that the SNP rs10447760 was not associated with susceptibility to SCZ in Han Chinese populations (pooled odds ratio=1.44, 95% confidence interval: 0.63-3.31, P=0.39). Thus, our results did not support the association between FOXP2 rs10447760 and schizophrenia in a Chinese Han population, and large-scale genetic replication studies with different racial and geographic origins are required in the future.

Trace: a high-throughput tomographic reconstruction engine for large-scale datasets

DOE PAGES

Bicer, Tekin; Gursoy, Doga; Andrade, Vincent De; ...

2017-01-28

Here, synchrotron light source and detector technologies enable scientists to perform advanced experiments. These scientific instruments and experiments produce data at such scale and complexity that large-scale computation is required to unleash their full power. One of the widely used data acquisition technique at light sources is Computed Tomography, which can generate tens of GB/s depending on x-ray range. A large-scale tomographic dataset, such as mouse brain, may require hours of computation time with a medium size workstation. In this paper, we present Trace, a data-intensive computing middleware we developed for implementation and parallelization of iterative tomographic reconstruction algorithms. Tracemore » provides fine-grained reconstruction of tomography datasets using both (thread level) shared memory and (process level) distributed memory parallelization. Trace utilizes a special data structure called replicated reconstruction object to maximize application performance. We also present the optimizations we have done on the replicated reconstruction objects and evaluate them using a shale and a mouse brain sinogram. Our experimental evaluations show that the applied optimizations and parallelization techniques can provide 158x speedup (using 32 compute nodes) over single core configuration, which decreases the reconstruction time of a sinogram (with 4501 projections and 22400 detector resolution) from 12.5 hours to less than 5 minutes per iteration.« less

Trace: a high-throughput tomographic reconstruction engine for large-scale datasets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bicer, Tekin; Gursoy, Doga; Andrade, Vincent De

Here, synchrotron light source and detector technologies enable scientists to perform advanced experiments. These scientific instruments and experiments produce data at such scale and complexity that large-scale computation is required to unleash their full power. One of the widely used data acquisition technique at light sources is Computed Tomography, which can generate tens of GB/s depending on x-ray range. A large-scale tomographic dataset, such as mouse brain, may require hours of computation time with a medium size workstation. In this paper, we present Trace, a data-intensive computing middleware we developed for implementation and parallelization of iterative tomographic reconstruction algorithms. Tracemore » provides fine-grained reconstruction of tomography datasets using both (thread level) shared memory and (process level) distributed memory parallelization. Trace utilizes a special data structure called replicated reconstruction object to maximize application performance. We also present the optimizations we have done on the replicated reconstruction objects and evaluate them using a shale and a mouse brain sinogram. Our experimental evaluations show that the applied optimizations and parallelization techniques can provide 158x speedup (using 32 compute nodes) over single core configuration, which decreases the reconstruction time of a sinogram (with 4501 projections and 22400 detector resolution) from 12.5 hours to less than 5 minutes per iteration.« less

Large-scale replication study reveals a limit on probabilistic prediction in language comprehension.

PubMed

Nieuwland, Mante S; Politzer-Ahles, Stephen; Heyselaar, Evelien; Segaert, Katrien; Darley, Emily; Kazanina, Nina; Von Grebmer Zu Wolfsthurn, Sarah; Bartolozzi, Federica; Kogan, Vita; Ito, Aine; Mézière, Diane; Barr, Dale J; Rousselet, Guillaume A; Ferguson, Heather J; Busch-Moreno, Simon; Fu, Xiao; Tuomainen, Jyrki; Kulakova, Eugenia; Husband, E Matthew; Donaldson, David I; Kohút, Zdenko; Rueschemeyer, Shirley-Ann; Huettig, Falk

2018-04-03

Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment ('cloze'). In our direct replication study spanning 9 laboratories ( N =334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words. © 2018, Nieuwland et al.

Large-scale replication study reveals a limit on probabilistic prediction in language comprehension

PubMed Central

Politzer-Ahles, Stephen; Heyselaar, Evelien; Segaert, Katrien; Darley, Emily; Kazanina, Nina; Von Grebmer Zu Wolfsthurn, Sarah; Bartolozzi, Federica; Kogan, Vita; Ito, Aine; Mézière, Diane; Barr, Dale J; Rousselet, Guillaume A; Ferguson, Heather J; Busch-Moreno, Simon; Fu, Xiao; Tuomainen, Jyrki; Kulakova, Eugenia; Husband, E Matthew; Donaldson, David I; Kohút, Zdenko; Rueschemeyer, Shirley-Ann; Huettig, Falk

2018-01-01

Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment (‘cloze’). In our direct replication study spanning 9 laboratories (N=334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words. PMID:29631695

The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration

PubMed Central

Logue, Mark W; Amstadter, Ananda B; Baker, Dewleen G; Duncan, Laramie; Koenen, Karestan C; Liberzon, Israel; Miller, Mark W; Morey, Rajendra A; Nievergelt, Caroline M; Ressler, Kerry J; Smith, Alicia K; Smoller, Jordan W; Stein, Murray B; Sumner, Jennifer A; Uddin, Monica

2015-01-01

The development of posttraumatic stress disorder (PTSD) is influenced by genetic factors. Although there have been some replicated candidates, the identification of risk variants for PTSD has lagged behind genetic research of other psychiatric disorders such as schizophrenia, autism, and bipolar disorder. Psychiatric genetics has moved beyond examination of specific candidate genes in favor of the genome-wide association study (GWAS) strategy of very large numbers of samples, which allows for the discovery of previously unsuspected genes and molecular pathways. The successes of genetic studies of schizophrenia and bipolar disorder have been aided by the formation of a large-scale GWAS consortium: the Psychiatric Genomics Consortium (PGC). In contrast, only a handful of GWAS of PTSD have appeared in the literature to date. Here we describe the formation of a group dedicated to large-scale study of PTSD genetics: the PGC-PTSD. The PGC-PTSD faces challenges related to the contingency on trauma exposure and the large degree of ancestral genetic diversity within and across participating studies. Using the PGC analysis pipeline supplemented by analyses tailored to address these challenges, we anticipate that our first large-scale GWAS of PTSD will comprise over 10 000 cases and 30 000 trauma-exposed controls. Following in the footsteps of our PGC forerunners, this collaboration—of a scope that is unprecedented in the field of traumatic stress—will lead the search for replicable genetic associations and new insights into the biological underpinnings of PTSD. PMID:25904361

Towards scalable Byzantine fault-tolerant replication

NASA Astrophysics Data System (ADS)

Zbierski, Maciej

2017-08-01

Byzantine fault-tolerant (BFT) replication is a powerful technique, enabling distributed systems to remain available and correct even in the presence of arbitrary faults. Unfortunately, existing BFT replication protocols are mostly load-unscalable, i.e. they fail to respond with adequate performance increase whenever new computational resources are introduced into the system. This article proposes a universal architecture facilitating the creation of load-scalable distributed services based on BFT replication. The suggested approach exploits parallel request processing to fully utilize the available resources, and uses a load balancer module to dynamically adapt to the properties of the observed client workload. The article additionally provides a discussion on selected deployment scenarios, and explains how the proposed architecture could be used to increase the dependability of contemporary large-scale distributed systems.

Architectural Implications for Spatial Object Association Algorithms*

PubMed Central

Kumar, Vijay S.; Kurc, Tahsin; Saltz, Joel; Abdulla, Ghaleb; Kohn, Scott R.; Matarazzo, Celeste

2013-01-01

Spatial object association, also referred to as crossmatch of spatial datasets, is the problem of identifying and comparing objects in two or more datasets based on their positions in a common spatial coordinate system. In this work, we evaluate two crossmatch algorithms that are used for astronomical sky surveys, on the following database system architecture configurations: (1) Netezza Performance Server®, a parallel database system with active disk style processing capabilities, (2) MySQL Cluster, a high-throughput network database system, and (3) a hybrid configuration consisting of a collection of independent database system instances with data replication support. Our evaluation provides insights about how architectural characteristics of these systems affect the performance of the spatial crossmatch algorithms. We conducted our study using real use-case scenarios borrowed from a large-scale astronomy application known as the Large Synoptic Survey Telescope (LSST). PMID:25692244

Hierarchical Structure of the Eysenck Personality Inventory in a Large Population Sample: Goldberg's Trait-Tier Mapping Procedure

PubMed Central

Chapman, Benjamin P.; Weiss, Alexander; Barrett, Paul; Duberstein, Paul

2014-01-01

The structure of the Eysenck Personality Inventory (EPI) is poorly understood, and applications have mostly been confined to the broad Neuroticism, Extraversion, and Lie scales. Using a hierarchical factoring procedure, we mapped the sequential differentiation of EPI scales from broad, molar factors to more specific, molecular factors, in a UK population sample of over 6500 persons. Replicable facets at the lowest tier of Neuroticism included emotional fragility, mood lability, nervous tension, and rumination. The lowest order set of replicable Extraversion facets consisted of social dynamism, sociotropy, decisiveness, jocularity, social information seeking, and impulsivity. The Lie scale consisted of an interpersonal virtue and a behavioral diligence facet. Users of the EPI may be well served in some circumstances by considering its broad Neuroticism, Extraversion, and Lie scales as multifactorial, a feature that was explicitly incorporated into subsequent Eysenck inventories and is consistent with other hierarchical trait structures. PMID:25983361

Rapid and accurate species tree estimation for phylogeographic investigations using replicated subsampling.

PubMed

Hird, Sarah; Kubatko, Laura; Carstens, Bryan

2010-11-01

We describe a method for estimating species trees that relies on replicated subsampling of large data matrices. One application of this method is phylogeographic research, which has long depended on large datasets that sample intensively from the geographic range of the focal species; these datasets allow systematicists to identify cryptic diversity and understand how contemporary and historical landscape forces influence genetic diversity. However, analyzing any large dataset can be computationally difficult, particularly when newly developed methods for species tree estimation are used. Here we explore the use of replicated subsampling, a potential solution to the problem posed by large datasets, with both a simulation study and an empirical analysis. In the simulations, we sample different numbers of alleles and loci, estimate species trees using STEM, and compare the estimated to the actual species tree. Our results indicate that subsampling three alleles per species for eight loci nearly always results in an accurate species tree topology, even in cases where the species tree was characterized by extremely rapid divergence. Even more modest subsampling effort, for example one allele per species and two loci, was more likely than not (>50%) to identify the correct species tree topology, indicating that in nearly all cases, computing the majority-rule consensus tree from replicated subsampling provides a good estimate of topology. These results were supported by estimating the correct species tree topology and reasonable branch lengths for an empirical 10-locus great ape dataset. Copyright © 2010 Elsevier Inc. All rights reserved.

Trace: a high-throughput tomographic reconstruction engine for large-scale datasets.

PubMed

Bicer, Tekin; Gürsoy, Doğa; Andrade, Vincent De; Kettimuthu, Rajkumar; Scullin, William; Carlo, Francesco De; Foster, Ian T

2017-01-01

Modern synchrotron light sources and detectors produce data at such scale and complexity that large-scale computation is required to unleash their full power. One of the widely used imaging techniques that generates data at tens of gigabytes per second is computed tomography (CT). Although CT experiments result in rapid data generation, the analysis and reconstruction of the collected data may require hours or even days of computation time with a medium-sized workstation, which hinders the scientific progress that relies on the results of analysis. We present Trace, a data-intensive computing engine that we have developed to enable high-performance implementation of iterative tomographic reconstruction algorithms for parallel computers. Trace provides fine-grained reconstruction of tomography datasets using both (thread-level) shared memory and (process-level) distributed memory parallelization. Trace utilizes a special data structure called replicated reconstruction object to maximize application performance. We also present the optimizations that we apply to the replicated reconstruction objects and evaluate them using tomography datasets collected at the Advanced Photon Source. Our experimental evaluations show that our optimizations and parallelization techniques can provide 158× speedup using 32 compute nodes (384 cores) over a single-core configuration and decrease the end-to-end processing time of a large sinogram (with 4501 × 1 × 22,400 dimensions) from 12.5 h to <5 min per iteration. The proposed tomographic reconstruction engine can efficiently process large-scale tomographic data using many compute nodes and minimize reconstruction times.

A Measurement Invariance Examination of the Revised Child Anxiety and Depression Scale in a Southern Sample: Differential Item Functioning between African American and Caucasian Youth

ERIC Educational Resources Information Center

Trent, Lindsay Rae; Buchanan, Erin; Ebesutani, Chad; Ale, Chelsea M.; Heiden, Laurie; Hight, Terry L.; Damon, John D.; Young, John

2013-01-01

This study examined the psychometric properties of the Revised Child Anxiety and Depression Scale in a large sample of youth from the Southern United States. The authors aimed to determine (a) if the established six-factor Revised Child Anxiety and Depression Scale structure could be replicated in this Southern sample and (b) if scores were…

XPAT: a toolkit to conduct cross-platform association studies with heterogeneous sequencing datasets.

PubMed

Yu, Yao; Hu, Hao; Bohlender, Ryan J; Hu, Fulan; Chen, Jiun-Sheng; Holt, Carson; Fowler, Jerry; Guthery, Stephen L; Scheet, Paul; Hildebrandt, Michelle A T; Yandell, Mark; Huff, Chad D

2018-04-06

High-throughput sequencing data are increasingly being made available to the research community for secondary analyses, providing new opportunities for large-scale association studies. However, heterogeneity in target capture and sequencing technologies often introduce strong technological stratification biases that overwhelm subtle signals of association in studies of complex traits. Here, we introduce the Cross-Platform Association Toolkit, XPAT, which provides a suite of tools designed to support and conduct large-scale association studies with heterogeneous sequencing datasets. XPAT includes tools to support cross-platform aware variant calling, quality control filtering, gene-based association testing and rare variant effect size estimation. To evaluate the performance of XPAT, we conducted case-control association studies for three diseases, including 783 breast cancer cases, 272 ovarian cancer cases, 205 Crohn disease cases and 3507 shared controls (including 1722 females) using sequencing data from multiple sources. XPAT greatly reduced Type I error inflation in the case-control analyses, while replicating many previously identified disease-gene associations. We also show that association tests conducted with XPAT using cross-platform data have comparable performance to tests using matched platform data. XPAT enables new association studies that combine existing sequencing datasets to identify genetic loci associated with common diseases and other complex traits.

Spatial-pattern-induced evolution of a self-replicating loop network.

PubMed

Suzuki, Keisuke; Ikegami, Takashi

2006-01-01

We study a system of self-replicating loops in which interaction rules between individuals allow competition that leads to the formation of a hypercycle-like network. The main feature of the model is the multiple layers of interaction between loops, which lead to both global spatial patterns and local replication. The network of loops manifests itself as a spiral structure from which new kinds of self-replicating loops emerge at the boundaries between different species. In these regions, larger and more complex self-replicating loops live for longer periods of time, managing to self-replicate in spite of their slower replication. Of particular interest is how micro-scale interactions between replicators lead to macro-scale spatial pattern formation, and how these macro-scale patterns in turn perturb the micro-scale replication dynamics.

Heterogeneity of chronic graft-versus-host disease biomarkers: association with CXCL10 and CXCR3+ NK cells

PubMed Central

Kariminia, Amina; Holtan, Shernan G.; Ivison, Sabine; Rozmus, Jacob; Hebert, Marie-Josée; Martin, Paul J.; Lee, Stephanie J.; Wolff, Daniel; Subrt, Peter; Abdossamadi, Sayeh; Sung, Susanna; Storek, Jan; Levings, Megan; Aljurf, Mahmoud; Arora, Mukta; Cutler, Corey; Gallagher, Geneviève; Kuruvilla, John; Lipton, Jeff; Nevill, Thomas J.; Newell, Laura F.; Panzarella, Tony; Pidala, Joseph; Popradi, Gizelle; Szwajcer, David; Tay, Jason; Toze, Cynthia L.; Walker, Irwin; Couban, Stephen; Storer, Barry E.

2016-01-01

Chronic graft-versus-host disease (cGVHD) remains one of the most significant long-term complications after allogeneic blood and marrow transplantation. Diagnostic biomarkers for cGVHD are needed for early diagnosis and may guide identification of prognostic markers. No cGVHD biomarker has yet been validated for use in clinical practice. We evaluated both previously known markers and performed discovery-based analysis for cGVHD biomarkers in a 2 independent test sets (total of 36 cases ≤1 month from diagnosis and 31 time-matched controls with no cGVHD). On the basis of these results, 11 markers were selected and evaluated in 2 independent replication cohorts (total of 134 cGVHD cases and 154 controls). cGVHD cases and controls were evaluated for several clinical covariates, and their impact on biomarkers was identified by univariate analysis. The 2 replications sets were relatively disparate in the biomarkers they replicated. Only sBAFF and, most consistently, CXCL10 were identified as significant in both replication sets. Other markers identified as significant in only 1 replication set included intercellular adhesion molecule 1 (ICAM-1), anti-LG3, aminopeptidase N, CXCL9, endothelin-1, and gelsolin. Multivariate analysis found that all covariates evaluated affected interpretation of the biomarkers. CXCL10 had an increased significance in combination with anti-LG3 and CXCL9, or inversely with CXCR3+CD56bright natural killer (NK) cells. There was significant heterogeneity of cGVHD biomarkers in a large comprehensive evaluation of cGVHD biomarkers impacted by several covariates. Only CXCL10 strongly correlated in both replication sets. Future analyses for plasma cGVHD biomarkers will need to be performed on very large patient groups with consideration of multiple covariates. PMID:27020088

Microbially derived biosensors for diagnosis, monitoring and epidemiology.

PubMed

Chang, Hung-Ju; Voyvodic, Peter L; Zúñiga, Ana; Bonnet, Jérôme

2017-09-01

Living cells have evolved to detect and process various signals and can self-replicate, presenting an attractive platform for engineering scalable and affordable biosensing devices. Microbes are perfect candidates: they are inexpensive and easy to manipulate and store. Recent advances in synthetic biology promise to streamline the engineering of microbial biosensors with unprecedented capabilities. Here we review the applications of microbially-derived biosensors with a focus on environmental monitoring and healthcare applications. We also identify critical challenges that need to be addressed in order to translate the potential of synthetic microbial biosensors into large-scale, real-world applications. © 2017 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

Key principles to improve programmes and interventions in complementary feeding.

PubMed

Lutter, Chessa K; Iannotti, Lora; Creed-Kanashiro, Hilary; Guyon, Agnes; Daelmans, Bernadette; Robert, Rebecca; Haider, Rukhsana

2013-09-01

Although there are some examples of successful complementary feeding programmes to promote healthy growth and prevent stunting at the community level, to date there are few, if any, examples of successful programmes at scale. A lack of systematic process and impact evaluations on pilot projects to generate lessons learned has precluded scaling up of effective programmes. Programmes to effect positive change in nutrition rarely follow systematic planning, implementation, and evaluation (PIE) processes to enhance effectiveness over the long term. As a result a set of programme-oriented key principles to promote healthy growth remains elusive. The purpose of this paper is to fill this gap by proposing a set of principles to improve programmes and interventions to promote healthy growth and development. Identifying such principles for programme success has three requirements: rethinking traditional paradigms used to promote improved infant and young child feeding; ensuring better linkages to delivery platforms; and, improving programming. Following the PIE model for programmes and learning from experiences from four relatively large-scale programmes described in this paper, 10 key principles are identified in the areas of programme planning, programme implementation, programme evaluation, and dissemination, replication, and scaling up. Nonetheless, numerous operational research questions remain, some of which are highlighted in this paper. © 2013 John Wiley & Sons Ltd.

What Should Researchers Expect When They Replicate Studies? A Statistical View of Replicability in Psychological Science.

PubMed

Patil, Prasad; Peng, Roger D; Leek, Jeffrey T

2016-07-01

A recent study of the replicability of key psychological findings is a major contribution toward understanding the human side of the scientific process. Despite the careful and nuanced analysis reported, the simple narrative disseminated by the mass, social, and scientific media was that in only 36% of the studies were the original results replicated. In the current study, however, we showed that 77% of the replication effect sizes reported were within a 95% prediction interval calculated using the original effect size. Our analysis suggests two critical issues in understanding replication of psychological studies. First, researchers' intuitive expectations for what a replication should show do not always match with statistical estimates of replication. Second, when the results of original studies are very imprecise, they create wide prediction intervals-and a broad range of replication effects that are consistent with the original estimates. This may lead to effects that replicate successfully, in that replication results are consistent with statistical expectations, but do not provide much information about the size (or existence) of the true effect. In this light, the results of the Reproducibility Project: Psychology can be viewed as statistically consistent with what one might expect when performing a large-scale replication experiment. © The Author(s) 2016.

Association Studies of Sporadic Parkinson’s Disease in the Genomic Era

PubMed Central

Labbé, Catherine; Ross, Owen A

2014-01-01

Parkinson’s disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson’s disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson’s disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment. PMID:24653658

DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework

PubMed Central

Richmond, Rebecca C.; Ward, Mary E.; Fraser, Abigail; Lyttleton, Oliver; McArdle, Wendy L.; Ring, Susan M.; Gaunt, Tom R.; Lawlor, Debbie A.; Davey Smith, George; Relton, Caroline L.

2016-01-01

Multiple differentially methylated sites and regions associated with adiposity have now been identified in large-scale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation. PMID:26861784

Random codon re-encoding induces stable reduction of replicative fitness of Chikungunya virus in primate and mosquito cells.

PubMed

Nougairede, Antoine; De Fabritus, Lauriane; Aubry, Fabien; Gould, Ernest A; Holmes, Edward C; de Lamballerie, Xavier

2013-02-01

Large-scale codon re-encoding represents a powerful method of attenuating viruses to generate safe and cost-effective vaccines. In contrast to specific approaches of codon re-encoding which modify genome-scale properties, we evaluated the effects of random codon re-encoding on the re-emerging human pathogen Chikungunya virus (CHIKV), and assessed the stability of the resultant viruses during serial in cellulo passage. Using different combinations of three 1.4 kb randomly re-encoded regions located throughout the CHIKV genome six codon re-encoded viruses were obtained. Introducing a large number of slightly deleterious synonymous mutations reduced the replicative fitness of CHIKV in both primate and arthropod cells, demonstrating the impact of synonymous mutations on fitness. Decrease of replicative fitness correlated with the extent of re-encoding, an observation that may assist in the modulation of viral attenuation. The wild-type and two re-encoded viruses were passaged 50 times either in primate or insect cells, or in each cell line alternately. These viruses were analyzed using detailed fitness assays, complete genome sequences and the analysis of intra-population genetic diversity. The response to codon re-encoding and adaptation to culture conditions occurred simultaneously, resulting in significant replicative fitness increases for both re-encoded and wild type viruses. Importantly, however, the most re-encoded virus failed to recover its replicative fitness. Evolution of these viruses in response to codon re-encoding was largely characterized by the emergence of both synonymous and non-synonymous mutations, sometimes located in genomic regions other than those involving re-encoding, and multiple convergent and compensatory mutations. However, there was a striking absence of codon reversion (<0.4%). Finally, multiple mutations were rapidly fixed in primate cells, whereas mosquito cells acted as a brake on evolution. In conclusion, random codon re-encoding provides important information on the evolution and genetic stability of CHIKV viruses and could be exploited to develop a safe, live attenuated CHIKV vaccine.

Partial Purification of a Megadalton DNA Replication Complex by Free Flow Electrophoresis.

PubMed

Li, Caroline M; Miao, Yunan; Lingeman, Robert G; Hickey, Robert J; Malkas, Linda H

2016-01-01

We describe a gentle and rapid method to purify the intact multiprotein DNA replication complex using free flow electrophoresis (FFE). In particular, we applied FFE to purify the human cell DNA synthesome, which is a multiprotein complex that is fully competent to carry-out all phases of the DNA replication process in vitro using a plasmid containing the simian virus 40 (SV40) origin of DNA replication and the viral large tumor antigen (T-antigen) protein. The isolated native DNA synthesome can be of use in studying the mechanism by which mammalian DNA replication is carried-out and how anti-cancer drugs disrupt the DNA replication or repair process. Partially purified extracts from HeLa cells were fractionated in a native, liquid based separation by FFE. Dot blot analysis showed co-elution of many proteins identified as part of the DNA synthesome, including proliferating cell nuclear antigen (PCNA), DNA topoisomerase I (topo I), DNA polymerase δ (Pol δ), DNA polymerase ɛ (Pol ɛ), replication protein A (RPA) and replication factor C (RFC). Previously identified DNA synthesome proteins co-eluted with T-antigen dependent and SV40 origin-specific DNA polymerase activity at the same FFE fractions. Native gels show a multiprotein PCNA containing complex migrating with an apparent relative mobility in the megadalton range. When PCNA containing bands were excised from the native gel, mass spectrometric sequencing analysis identified 23 known DNA synthesome associated proteins or protein subunits.

Intelligence in DSM-IV combined type attention-deficit/hyperactivity disorder is not predicted by either dopamine receptor/transporter genes or other previously identified risk alleles for attention-deficit/hyperactivity disorder.

PubMed

Sonuga-Barke, Edmund J S; Brookes, Keeley-Joanne; Buitelaar, Jan; Anney, Richard; Bitsakou, Paraskevi; Baeyens, Dieter; Buschgens, Cathelijne; Chen, Wai; Christiansen, Hanna; Eisenberg, Jacques; Kuntsi, Jonna; Manor, Iris; Meliá, Amanda; Mulligan, Aisling; Rommelse, Nanda; Müller, Ueli C; Uebel, Henrik; Banaschewski, Tobias; Ebstein, Richard; Franke, Barbara; Gill, Michael; Miranda, Ana; Oades, Robert D; Roeyers, Herbert; Rothenberger, Aribert; Sergeant, Joseph; Steinhausen, Hans Christoph; Thompson, Margaret; Taylor, Eric; Asherson, Philip; Faraone, Stephen V

2008-04-05

A major goal of genetic studies of attention deficit hyperactivity disorder (ADHD) is to identify individual characteristics that might help segregate the disorder's inherent heterogeneity. [Mill et al. (2006); Arch Ger Psychiatry 63:462-469] recently reported a potentially important association between two dopamine-related risk polymorphisms (DRD4 variable number tandem repeat (VNTR) in exon 3 and DAT1 VNTR in the 3' UTR) and lowered IQ in ADHD. The objective of the current study was to replicate the [Mill et al. (2006); Arch Ger Psychiatry 63:462-469] findings in a clinical sample and to extend the analysis to a large range of alternative SNP markers of putative ADHD risk alleles identified in a recent study [Brookes et al. (2006); Mol Genet 11:934-953]. Participants were 1081 children and adolescents with a research-confirmed combined type ADHD diagnosis and 1300 unaffected siblings who took part in the International Multi-centre ADHD Genetics (IMAGE) project. They were recruited from multiple settings from across Europe: Belgium, Britain, Germany, Ireland, Israel, Netherlands, Spain and Switzerland. The results were that ADHD was associated with reduced IQ. However, there was no association between the two dopamine-related risk polymorphisms and IQ in either the probands or their siblings. Furthermore, other selected genetic markers previously demonstrated to be associated with ADHD in this sample were not associated with IQ. This large scale study with a clinically ascertained and regorously diagnosed sample failed to replicate the association between genetic polymorphisms in the dopamine system and IQ in ADHD. We also observed no association of other SNPs with IQ in ADHD. Copyright 2007 Wiley-Liss, Inc.

Taming parallel I/O complexity with auto-tuning

DOE PAGES

Behzad, Babak; Luu, Huong Vu Thanh; Huchette, Joseph; ...

2013-11-17

We present an auto-tuning system for optimizing I/O performance of HDF5 applications and demonstrate its value across platforms, applications, and at scale. The system uses a genetic algorithm to search a large space of tunable parameters and to identify effective settings at all layers of the parallel I/O stack. The parameter settings are applied transparently by the auto-tuning system via dynamically intercepted HDF5 calls. To validate our auto-tuning system, we applied it to three I/O benchmarks (VPIC, VORPAL, and GCRM) that replicate the I/O activity of their respective applications. We tested the system with different weak-scaling configurations (128, 2048, andmore » 4096 CPU cores) that generate 30 GB to 1 TB of data, and executed these configurations on diverse HPC platforms (Cray XE6, IBM BG/P, and Dell Cluster). In all cases, the auto-tuning framework identified tunable parameters that substantially improved write performance over default system settings. In conclusion, we consistently demonstrate I/O write speedups between 2x and 100x for test configurations.« less

Large-scale assessment of benthic communities across multiple marine protected areas using an autonomous underwater vehicle.

PubMed

Ferrari, Renata; Marzinelli, Ezequiel M; Ayroza, Camila Rezende; Jordan, Alan; Figueira, Will F; Byrne, Maria; Malcolm, Hamish A; Williams, Stefan B; Steinberg, Peter D

2018-01-01

Marine protected areas (MPAs) are designed to reduce threats to biodiversity and ecosystem functioning from anthropogenic activities. Assessment of MPAs effectiveness requires synchronous sampling of protected and non-protected areas at multiple spatial and temporal scales. We used an autonomous underwater vehicle to map benthic communities in replicate 'no-take' and 'general-use' (fishing allowed) zones within three MPAs along 7o of latitude. We recorded 92 taxa and 38 morpho-groups across three large MPAs. We found that important habitat-forming biota (e.g. massive sponges) were more prevalent and abundant in no-take zones, while short ephemeral algae were more abundant in general-use zones, suggesting potential short-term effects of zoning (5-10 years). Yet, short-term effects of zoning were not detected at the community level (community structure or composition), while community structure varied significantly among MPAs. We conclude that by allowing rapid, simultaneous assessments at multiple spatial scales, autonomous underwater vehicles are useful to document changes in marine communities and identify adequate scales to manage them. This study advanced knowledge of marine benthic communities and their conservation in three ways. First, we quantified benthic biodiversity and abundance, generating the first baseline of these benthic communities against which the effectiveness of three large MPAs can be assessed. Second, we identified the taxonomic resolution necessary to assess both short and long-term effects of MPAs, concluding that coarse taxonomic resolution is sufficient given that analyses of community structure at different taxonomic levels were generally consistent. Yet, observed differences were taxa-specific and may have not been evident using our broader taxonomic classifications, a classification of mid to high taxonomic resolution may be necessary to determine zoning effects on key taxa. Third, we provide an example of statistical analyses and sampling design that once temporal sampling is incorporated will be useful to detect changes of marine benthic communities across multiple spatial and temporal scales.

Large-scale assessment of benthic communities across multiple marine protected areas using an autonomous underwater vehicle

PubMed Central

Ayroza, Camila Rezende; Jordan, Alan; Figueira, Will F.; Byrne, Maria; Malcolm, Hamish A.; Williams, Stefan B.; Steinberg, Peter D.

2018-01-01

Marine protected areas (MPAs) are designed to reduce threats to biodiversity and ecosystem functioning from anthropogenic activities. Assessment of MPAs effectiveness requires synchronous sampling of protected and non-protected areas at multiple spatial and temporal scales. We used an autonomous underwater vehicle to map benthic communities in replicate ‘no-take’ and ‘general-use’ (fishing allowed) zones within three MPAs along 7o of latitude. We recorded 92 taxa and 38 morpho-groups across three large MPAs. We found that important habitat-forming biota (e.g. massive sponges) were more prevalent and abundant in no-take zones, while short ephemeral algae were more abundant in general-use zones, suggesting potential short-term effects of zoning (5–10 years). Yet, short-term effects of zoning were not detected at the community level (community structure or composition), while community structure varied significantly among MPAs. We conclude that by allowing rapid, simultaneous assessments at multiple spatial scales, autonomous underwater vehicles are useful to document changes in marine communities and identify adequate scales to manage them. This study advanced knowledge of marine benthic communities and their conservation in three ways. First, we quantified benthic biodiversity and abundance, generating the first baseline of these benthic communities against which the effectiveness of three large MPAs can be assessed. Second, we identified the taxonomic resolution necessary to assess both short and long-term effects of MPAs, concluding that coarse taxonomic resolution is sufficient given that analyses of community structure at different taxonomic levels were generally consistent. Yet, observed differences were taxa-specific and may have not been evident using our broader taxonomic classifications, a classification of mid to high taxonomic resolution may be necessary to determine zoning effects on key taxa. Third, we provide an example of statistical analyses and sampling design that once temporal sampling is incorporated will be useful to detect changes of marine benthic communities across multiple spatial and temporal scales. PMID:29547656

Identification of novel host factors via conserved domain search: Cns1 cochaperone is a novel restriction factor of tombusvirus replication in yeast.

PubMed

Lin, Jing-Yi; Nagy, Peter D

2013-12-01

A large number of host-encoded proteins affect the replication of plus-stranded RNA viruses by acting as susceptibility factors. Many other cellular proteins are known to function as restriction factors of viral infections. Previous studies with tomato bushy stunt tombusvirus (TBSV) in a yeast model host have revealed the inhibitory function of TPR (tetratricopeptide repeat) domain-containing cyclophilins, which are members of the large family of host prolyl isomerases, in TBSV replication. In this paper, we tested additional TPR-containing yeast proteins in a cell-free TBSV replication assay and identified the Cns1p cochaperone for heat shock protein 70 (Hsp70) and Hsp90 chaperones as a strong inhibitor of TBSV replication. Cns1p interacted with the viral replication proteins and inhibited the assembly of the viral replicase complex and viral RNA synthesis in vitro. Overexpression of Cns1p inhibited TBSV replication in yeast. The use of a temperature-sensitive (TS) mutant of Cns1p in yeast revealed that at a semipermissive temperature, TS Cns1p could not inhibit TBSV replication. Interestingly, Cns1p and the TPR-containing Cpr7p cyclophilin have similar inhibitory functions during TBSV replication, although some of the details of their viral restriction mechanisms are different. Our observations indicate that TPR-containing cellular proteins could act as virus restriction factors.

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure.

PubMed

Sung, Yun J; Winkler, Thomas W; de Las Fuentes, Lisa; Bentley, Amy R; Brown, Michael R; Kraja, Aldi T; Schwander, Karen; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Lu, Yingchang; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Feitosa, Mary F; Kilpeläinen, Tuomas O; Richard, Melissa A; Noordam, Raymond; Aslibekyan, Stella; Aschard, Hugues; Bartz, Traci M; Dorajoo, Rajkumar; Liu, Yongmei; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert Vernon; Tajuddin, Salman M; Tayo, Bamidele O; Warren, Helen R; Zhao, Wei; Zhou, Yanhua; Matoba, Nana; Sofer, Tamar; Alver, Maris; Amini, Marzyeh; Boissel, Mathilde; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gandin, Ilaria; Gao, Chuan; Giulianini, Franco; Goel, Anuj; Harris, Sarah E; Hartwig, Fernando Pires; Horimoto, Andrea R V R; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Kühnel, Brigitte; Leander, Karin; Lee, Wen-Jane; Lin, Keng-Hung; 'an Luan, Jian; McKenzie, Colin A; Meian, He; Nelson, Christopher P; Rauramaa, Rainer; Schupf, Nicole; Scott, Robert A; Sheu, Wayne H H; Stančáková, Alena; Takeuchi, Fumihiko; van der Most, Peter J; Varga, Tibor V; Wang, Heming; Wang, Yajuan; Ware, Erin B; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Alfred, Tamuno; Amin, Najaf; Arking, Dan; Aung, Tin; Barr, R Graham; Bielak, Lawrence F; Boerwinkle, Eric; Bottinger, Erwin P; Braund, Peter S; Brody, Jennifer A; Broeckel, Ulrich; Cabrera, Claudia P; Cade, Brian; Caizheng, Yu; Campbell, Archie; Canouil, Mickaël; Chakravarti, Aravinda; Chauhan, Ganesh; Christensen, Kaare; Cocca, Massimiliano; Collins, Francis S; Connell, John M; de Mutsert, Renée; de Silva, H Janaka; Debette, Stephanie; Dörr, Marcus; Duan, Qing; Eaton, Charles B; Ehret, Georg; Evangelou, Evangelos; Faul, Jessica D; Fisher, Virginia A; Forouhi, Nita G; Franco, Oscar H; Friedlander, Yechiel; Gao, He; Gigante, Bruna; Graff, Misa; Gu, C Charles; Gu, Dongfeng; Gupta, Preeti; Hagenaars, Saskia P; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Hofman, Albert; Howard, Barbara V; Hunt, Steven; Irvin, Marguerite R; Jia, Yucheng; Joehanes, Roby; Justice, Anne E; Katsuya, Tomohiro; Kaufman, Joel; Kerrison, Nicola D; Khor, Chiea Chuen; Koh, Woon-Puay; Koistinen, Heikki A; Komulainen, Pirjo; Kooperberg, Charles; Krieger, Jose E; Kubo, Michiaki; Kuusisto, Johanna; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lim, Sing Hui; Lin, Shiow; Liu, Ching-Ti; Liu, Jianjun; Liu, Jingmin; Liu, Kiang; Liu, Yeheng; Loh, Marie; Lohman, Kurt K; Long, Jirong; Louie, Tin; Mägi, Reedik; Mahajan, Anubha; Meitinger, Thomas; Metspalu, Andres; Milani, Lili; Momozawa, Yukihide; Morris, Andrew P; Mosley, Thomas H; Munson, Peter; Murray, Alison D; Nalls, Mike A; Nasri, Ubaydah; Norris, Jill M; North, Kari; Ogunniyi, Adesola; Padmanabhan, Sandosh; Palmas, Walter R; Palmer, Nicholette D; Pankow, James S; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Polasek, Ozren; Raitakari, Olli T; Renström, Frida; Rice, Treva K; Ridker, Paul M; Robino, Antonietta; Robinson, Jennifer G; Rose, Lynda M; Rudan, Igor; Sabanayagam, Charumathi; Salako, Babatunde L; Sandow, Kevin; Schmidt, Carsten O; Schreiner, Pamela J; Scott, William R; Seshadri, Sudha; Sever, Peter; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Uitterlinden, André G; Waldenberger, Melanie; Wang, Lihua; Wang, Ya X; Wei, Wen Bin; Williams, Christine; Wilson, Gregory; Wojczynski, Mary K; Yao, Jie; Yuan, Jian-Min; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Chen, Yii-Der Ida; de Faire, Ulf; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Forrester, Terrence; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Horta, Bernardo Lessa; Hung, Yi-Jen; Jonas, Jost B; Kato, Norihiro; Kooner, Jaspal S; Laakso, Markku; Lehtimäki, Terho; Liang, Kae-Woei; Magnusson, Patrik K E; Newman, Anne B; Oldehinkel, Albertine J; Pereira, Alexandre C; Redline, Susan; Rettig, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Kamatani, Yoichiro; Laurie, Cathy C; Bouchard, Claude; Cooper, Richard S; Evans, Michele K; Gudnason, Vilmundur; Kardia, Sharon L R; Kritchevsky, Stephen B; Levy, Daniel; O'Connell, Jeff R; Psaty, Bruce M; van Dam, Rob M; Sims, Mario; Arnett, Donna K; Mook-Kanamori, Dennis O; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; Fornage, Myriam; Rotimi, Charles N; Province, Michael A; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Loos, Ruth J F; Reiner, Alex P; Rotter, Jerome I; Zhu, Xiaofeng; Bierut, Laura J; Gauderman, W James; Caulfield, Mark J; Elliott, Paul; Rice, Kenneth; Munroe, Patricia B; Morrison, Alanna C; Cupples, L Adrienne; Rao, Dabeeru C; Chasman, Daniel I

2018-03-01

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined ∼18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p < 5 × 10 -8 ) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p < 5 × 10 -8 ). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling (MSRA, EBF2). Copyright © 2018 American Society of Human Genetics. All rights reserved.

Identification of legionella effectors using bioinformatic approaches.

PubMed

Segal, Gil

2013-01-01

Legionella pneumophila the causative agent of Legionnaires' disease, actively manipulates host cell processes to establish a replication niche inside host cells. The establishment of its replication niche requires a functional Icm/Dot type IV secretion system which translocates about 300 effector proteins into host cells during infection. Many of these effectors were first identified as effector candidates by several bioinformatic approaches, and these predicted effectors were later examined experimentally for translocation and a large number of which were validated as effector proteins. Here, I summarized the bioinformatic approaches that were used to identify these effectors.

Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease

PubMed Central

2011-01-01

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10−33; LPA:p<10−19; 1p13.3:p<10−17) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10−7). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. PMID:21966275

Establishing the Brief Assessment of Cognition - Short form.

PubMed

Lam, Max; Wang, Mingyuan; Huang, Wanping; Eng, Goi Khia; Rapisarda, Attilio; Kraus, Michael; Kang, Sim; Keefe, R S E; Lee, Jimmy

2017-10-01

The study aims to identify and validate a parsimonious subset of tests in the commonly used Brief Assessment of Cognition in Schizophrenia (BACS) that allows the evaluation of global cognitive ability. Several permutations of subtests from the BACS were examined to identify the best subset of tests to compose the short form measure. The Brief Assessment of Cognition-Short Form (BAC-SF) was evaluated for convergent validity in healthy and psychiatric samples (N = 3718). Verbal Memory, Digit Sequencing, and Symbol Coding subtests were found to best summarize the variance of composite scores in both Asian and US Norming samples (r = 0.91) indicating that BAC-SF is an appropriate approximation of cognitive deficits. Test re-test reliability of the BAC-SF was adequate (Intraclass Correlation Coefficient (ICC) = 0.73) and showed sufficient separation between healthy controls and schizophrenia (Average Predictive Accuracy = 79.9%; replication = 76.5%). Findings indicate that the BAC-SF an could be used as a cognitive screener for large-scale clinical and epidemiological studies. The short form does not replace the need for comprehensive neuropsychological batteries purposed for detailed neuropsychological and clinical investigation of cognitive function. Further replication of the construct might be necessary in other clinical populations. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Phylogenetic congruence of lichenised fungi and algae is affected by spatial scale and taxonomic diversity.

PubMed

Buckley, Hannah L; Rafat, Arash; Ridden, Johnathon D; Cruickshank, Robert H; Ridgway, Hayley J; Paterson, Adrian M

2014-01-01

The role of species' interactions in structuring biological communities remains unclear. Mutualistic symbioses, involving close positive interactions between two distinct organismal lineages, provide an excellent means to explore the roles of both evolutionary and ecological processes in determining how positive interactions affect community structure. In this study, we investigate patterns of co-diversification between fungi and algae for a range of New Zealand lichens at the community, genus, and species levels and explore explanations for possible patterns related to spatial scale and pattern, taxonomic diversity of the lichens considered, and the level sampling replication. We assembled six independent datasets to compare patterns in phylogenetic congruence with varied spatial extent of sampling, taxonomic diversity and level of specimen replication. For each dataset, we used the DNA sequences from the ITS regions of both the fungal and algal genomes from lichen specimens to produce genetic distance matrices. Phylogenetic congruence between fungi and algae was quantified using distance-based redundancy analysis and we used geographic distance matrices in Moran's eigenvector mapping and variance partitioning to evaluate the effects of spatial variation on the quantification of phylogenetic congruence. Phylogenetic congruence was highly significant for all datasets and a large proportion of variance in both algal and fungal genetic distances was explained by partner genetic variation. Spatial variables, primarily at large and intermediate scales, were also important for explaining genetic diversity patterns in all datasets. Interestingly, spatial structuring was stronger for fungal than algal genetic variation. As the spatial extent of the samples increased, so too did the proportion of explained variation that was shared between the spatial variables and the partners' genetic variation. Different lichen taxa showed some variation in their phylogenetic congruence and spatial genetic patterns and where greater sample replication was used, the amount of variation explained by partner genetic variation increased. Our results suggest that the phylogenetic congruence pattern, at least at small spatial scales, is likely due to reciprocal co-adaptation or co-dispersal. However, the detection of these patterns varies among different lichen taxa, across spatial scales and with different levels of sample replication. This work provides insight into the complexities faced in determining how evolutionary and ecological processes may interact to generate diversity in symbiotic association patterns at the population and community levels. Further, it highlights the critical importance of considering sample replication, taxonomic diversity and spatial scale in designing studies of co-diversification.

Architectural Implications for Spatial Object Association Algorithms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, V S; Kurc, T; Saltz, J

2009-01-29

Spatial object association, also referred to as cross-match of spatial datasets, is the problem of identifying and comparing objects in two or more datasets based on their positions in a common spatial coordinate system. In this work, we evaluate two crossmatch algorithms that are used for astronomical sky surveys, on the following database system architecture configurations: (1) Netezza Performance Server R, a parallel database system with active disk style processing capabilities, (2) MySQL Cluster, a high-throughput network database system, and (3) a hybrid configuration consisting of a collection of independent database system instances with data replication support. Our evaluation providesmore » insights about how architectural characteristics of these systems affect the performance of the spatial crossmatch algorithms. We conducted our study using real use-case scenarios borrowed from a large-scale astronomy application known as the Large Synoptic Survey Telescope (LSST).« less

Regulating DNA Replication in Plants

PubMed Central

Sanchez, Maria de la Paz; Costas, Celina; Sequeira-Mendes, Joana; Gutierrez, Crisanto

2012-01-01

Chromosomal DNA replication in plants has requirements and constraints similar to those in other eukaryotes. However, some aspects are plant-specific. Studies of DNA replication control in plants, which have unique developmental strategies, can offer unparalleled opportunities of comparing regulatory processes with yeast and, particularly, metazoa to identify common trends and basic rules. In addition to the comparative molecular and biochemical studies, genomic studies in plants that started with Arabidopsis thaliana in the year 2000 have now expanded to several dozens of species. This, together with the applicability of genomic approaches and the availability of a large collection of mutants, underscores the enormous potential to study DNA replication control in a whole developing organism. Recent advances in this field with particular focus on the DNA replication proteins, the nature of replication origins and their epigenetic landscape, and the control of endoreplication will be reviewed. PMID:23209151

Chromosome evolution in the Thermotogales: large-scale inversions and strain diversification of CRISPR sequences.

PubMed

DeBoy, Robert T; Mongodin, Emmanuel F; Emerson, Joanne B; Nelson, Karen E

2006-04-01

In the present study, the chromosomes of two members of the Thermotogales were compared. A whole-genome alignment of Thermotoga maritima MSB8 and Thermotoga neapolitana NS-E has revealed numerous large-scale DNA rearrangements, most of which are associated with CRISPR DNA repeats and/or tRNA genes. These DNA rearrangements do not include the putative origin of DNA replication but move within the same replichore, i.e., the same replicating half of the chromosome (delimited by the replication origin and terminus). Based on cumulative GC skew analysis, both the T. maritima and T. neapolitana lineages contain one or two major inverted DNA segments. Also, based on PCR amplification and sequence analysis of the DNA joints that are associated with the major rearrangements, the overall chromosome architecture was found to be conserved at most DNA joints for other strains of T. neapolitana. Taken together, the results from this analysis suggest that the observed chromosomal rearrangements in the Thermotogales likely occurred by successive inversions after their divergence from a common ancestor and before strain diversification. Finally, sequence analysis shows that size polymorphisms in the DNA joints associated with CRISPRs can be explained by expansion and possibly contraction of the DNA repeat and spacer unit, providing a tool for discerning the relatedness of strains from different geographic locations.

New Evidence on Self-Affirmation Effects and Theorized Sources of Heterogeneity from Large-Scale Replications

PubMed Central

Hanselman, Paul; Rozek, Christopher S.; Grigg, Jeffrey; Borman, Geoffrey D.

2016-01-01

Brief, targeted self-affirmation writing exercises have recently been offered as a way to reduce racial achievement gaps, but evidence about their effects in educational settings is mixed, leaving ambiguity about the likely benefits of these strategies if implemented broadly. A key limitation in interpreting these mixed results is that they come from studies conducted by different research teams with different procedures in different settings; it is therefore impossible to isolate whether different effects are the result of theorized heterogeneity, unidentified moderators, or idiosyncratic features of the different studies. We addressed this limitation by conducting a well-powered replication of self-affirmation in a setting where a previous large-scale field experiment demonstrated significant positive impacts, using the same procedures. We found no evidence of effects in this replication study and estimates were precise enough to reject benefits larger than an effect size of 0.10. These null effects were significantly different from persistent benefits in the prior study in the same setting, and extensive testing revealed that currently theorized moderators of self-affirmation effects could not explain the difference. These results highlight the potential fragility of self-affirmation in educational settings when implemented widely and the need for new theory, measures, and evidence about the necessary conditions for self-affirmation success. PMID:28450753

Methods and apparatus of analyzing electrical power grid data

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hafen, Ryan P.; Critchlow, Terence J.; Gibson, Tara D.

Apparatus and methods of processing large-scale data regarding an electrical power grid are described. According to one aspect, a method of processing large-scale data regarding an electrical power grid includes accessing a large-scale data set comprising information regarding an electrical power grid; processing data of the large-scale data set to identify a filter which is configured to remove erroneous data from the large-scale data set; using the filter, removing erroneous data from the large-scale data set; and after the removing, processing data of the large-scale data set to identify an event detector which is configured to identify events of interestmore » in the large-scale data set.« less

A Psychoevolutionary Approach to Identifying Preferred Nature Scenes With Potential to Provide Restoration From Stress.

PubMed

Thake, Carol L; Bambling, Matthew; Edirippulige, Sisira; Marx, Eric

2017-10-01

Research supports therapeutic use of nature scenes in healthcare settings, particularly to reduce stress. However, limited literature is available to provide a cohesive guide for selecting scenes that may provide optimal therapeutic effect. This study produced and tested a replicable process for selecting nature scenes with therapeutic potential. Psychoevolutionary theory informed the construction of the Importance for Survival Scale (IFSS), and its usefulness for identifying scenes that people generally prefer to view and that hold potential to reduce stress was tested. Relationships between Importance for Survival (IFS), preference, and restoration were tested. General community participants ( N = 20 males, 20 females; M age = 48 years) Q-sorted sets of landscape photographs (preranked by the researcher in terms of IFS using the IFSS) from most to least preferred, and then completed the Short-Version Revised Restoration Scale in response to viewing a selection of the scenes. Results showed significant positive relationships between IFS and each of scene preference (large effect), and restoration potential (medium effect), as well as between scene preference and restoration potential across the levels of IFS (medium effect), and for individual participants and scenes (large effect). IFS was supported as a framework for identifying nature scenes that people will generally prefer to view and that hold potential for restoration from emotional distress; however, greater therapeutic potential may be expected when people can choose which of the scenes they would prefer to view. Evidence for the effectiveness of the IFSS was produced.

Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

PubMed

Boraska, Vesna; Day-Williams, Aaron; Franklin, Christopher S; Elliott, Katherine S; Panoutsopoulou, Kalliope; Tachmazidou, Ioanna; Albrecht, Eva; Bandinelli, Stefania; Beilin, Lawrence J; Bochud, Murielle; Cadby, Gemma; Ernst, Florian; Evans, David M; Hayward, Caroline; Hicks, Andrew A; Huffman, Jennifer; Huth, Cornelia; James, Alan L; Klopp, Norman; Kolcic, Ivana; Kutalik, Zoltán; Lawlor, Debbie A; Musk, Arthur W; Pehlic, Marina; Pennell, Craig E; Perry, John R B; Peters, Annette; Polasek, Ozren; St Pourcain, Beate; Ring, Susan M; Salvi, Erika; Schipf, Sabine; Staessen, Jan A; Teumer, Alexander; Timpson, Nicholas; Vitart, Veronique; Warrington, Nicole M; Yaghootkar, Hanieh; Zemunik, Tatijana; Zgaga, Lina; An, Ping; Anttila, Verneri; Borecki, Ingrid B; Holmen, Jostein; Ntalla, Ioanna; Palotie, Aarno; Pietiläinen, Kirsi H; Wedenoja, Juho; Winsvold, Bendik S; Dedoussis, George V; Kaprio, Jaakko; Province, Michael A; Zwart, John-Anker; Burnier, Michel; Campbell, Harry; Cusi, Daniele; Smith, George Davey; Frayling, Timothy M; Gieger, Christian; Palmer, Lyle J; Pramstaller, Peter P; Rudan, Igor; Völzke, Henry; Wichmann, H-Erich; Wright, Alan F; Zeggini, Eleftheria

2012-01-01

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Genome-Wide Association Study to Identify Common Variants Associated with Brachial Circumference: A Meta-Analysis of 14 Cohorts

PubMed Central

Boraska, Vesna; Day-Williams, Aaron; Franklin, Christopher S.; Elliott, Katherine S.; Panoutsopoulou, Kalliope; Tachmazidou, Ioanna; Albrecht, Eva; Bandinelli, Stefania; Beilin, Lawrence J.; Bochud, Murielle; Cadby, Gemma; Ernst, Florian; Evans, David M.; Hayward, Caroline; Hicks, Andrew A.; Huffman, Jennifer; Huth, Cornelia; James, Alan L.; Klopp, Norman; Kolcic, Ivana; Kutalik, Zoltán; Lawlor, Debbie A.; Musk, Arthur W.; Pehlic, Marina; Pennell, Craig E.; Perry, John R. B.; Peters, Annette; Polasek, Ozren; Pourcain, Beate St; Ring, Susan M.; Salvi, Erika; Schipf, Sabine; Staessen, Jan A.; Teumer, Alexander; Timpson, Nicholas; Vitart, Veronique; Warrington, Nicole M.; Yaghootkar, Hanieh; Zemunik, Tatijana; Zgaga, Lina; An, Ping; Anttila, Verneri; Borecki, Ingrid B.; Holmen, Jostein; Ntalla, Ioanna; Palotie, Aarno; Pietiläinen, Kirsi H.; Wedenoja, Juho; Winsvold, Bendik S.; Dedoussis, George V.; Kaprio, Jaakko; Province, Michael A.; Zwart, John-Anker; Burnier, Michel; Campbell, Harry; Cusi, Daniele; Davey Smith, George; Frayling, Timothy M.; Gieger, Christian; Palmer, Lyle J.; Pramstaller, Peter P.; Rudan, Igor; Völzke, Henry; Wichmann, H. -Erich; Wright, Alan F.; Zeggini, Eleftheria

2012-01-01

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC. PMID:22479309

Identification of significant features by the Global Mean Rank test.

PubMed

Klammer, Martin; Dybowski, J Nikolaj; Hoffmann, Daniel; Schaab, Christoph

2014-01-01

With the introduction of omics-technologies such as transcriptomics and proteomics, numerous methods for the reliable identification of significantly regulated features (genes, proteins, etc.) have been developed. Experimental practice requires these tests to successfully deal with conditions such as small numbers of replicates, missing values, non-normally distributed expression levels, and non-identical distributions of features. With the MeanRank test we aimed at developing a test that performs robustly under these conditions, while favorably scaling with the number of replicates. The test proposed here is a global one-sample location test, which is based on the mean ranks across replicates, and internally estimates and controls the false discovery rate. Furthermore, missing data is accounted for without the need of imputation. In extensive simulations comparing MeanRank to other frequently used methods, we found that it performs well with small and large numbers of replicates, feature dependent variance between replicates, and variable regulation across features on simulation data and a recent two-color microarray spike-in dataset. The tests were then used to identify significant changes in the phosphoproteomes of cancer cells induced by the kinase inhibitors erlotinib and 3-MB-PP1 in two independently published mass spectrometry-based studies. MeanRank outperformed the other global rank-based methods applied in this study. Compared to the popular Significance Analysis of Microarrays and Linear Models for Microarray methods, MeanRank performed similar or better. Furthermore, MeanRank exhibits more consistent behavior regarding the degree of regulation and is robust against the choice of preprocessing methods. MeanRank does not require any imputation of missing values, is easy to understand, and yields results that are easy to interpret. The software implementing the algorithm is freely available for academic and commercial use.

Form and function of topologically associating genomic domains in budding yeast.

PubMed

Eser, Umut; Chandler-Brown, Devon; Ay, Ferhat; Straight, Aaron F; Duan, Zhijun; Noble, William Stafford; Skotheim, Jan M

2017-04-11

The genome of metazoan cells is organized into topologically associating domains (TADs) that have similar histone modifications, transcription level, and DNA replication timing. Although similar structures appear to be conserved in fission yeast, computational modeling and analysis of high-throughput chromosome conformation capture (Hi-C) data have been used to argue that the small, highly constrained budding yeast chromosomes could not have these structures. In contrast, herein we analyze Hi-C data for budding yeast and identify 200-kb scale TADs, whose boundaries are enriched for transcriptional activity. Furthermore, these boundaries separate regions of similarly timed replication origins connecting the long-known effect of genomic context on replication timing to genome architecture. To investigate the molecular basis of TAD formation, we performed Hi-C experiments on cells depleted for the Forkhead transcription factors, Fkh1 and Fkh2, previously associated with replication timing. Forkhead factors do not regulate TAD formation, but do promote longer-range genomic interactions and control interactions between origins near the centromere. Thus, our work defines spatial organization within the budding yeast nucleus, demonstrates the conserved role of genome architecture in regulating DNA replication, and identifies a molecular mechanism specifically regulating interactions between pericentric origins.

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

PubMed Central

Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Gapstur, Susan M; Gaudet, Mia M; Diver, W Ryan; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Berg, Christine D; Chanock, Stephen; Figueroa, Jonine; Hoover, Robert N; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A; van der Luijt, Rob B; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm WR; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; TAN, Gie-Hooi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John WM; Collée, J Margriet; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N; Nord, Silje; Alnaes, Grethe I Grenaker; Giles, Graham G; Milne, Roger L; McLean, Catriona; Canzian, Federico; Trichopoulos, Dmitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Swerdlow, Anthony J; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert AEM; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul PDP; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

2015-01-01

Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1. PMID:25751625

Leveraging Genomic Annotations and Pleiotropic Enrichment for Improved Replication Rates in Schizophrenia GWAS

PubMed Central

Wang, Yunpeng; Thompson, Wesley K.; Schork, Andrew J.; Holland, Dominic; Chen, Chi-Hua; Bettella, Francesco; Desikan, Rahul S.; Li, Wen; Witoelar, Aree; Zuber, Verena; Devor, Anna; Nöthen, Markus M.; Rietschel, Marcella; Chen, Qiang; Werge, Thomas; Cichon, Sven; Weinberger, Daniel R.; Djurovic, Srdjan; O’Donovan, Michael; Visscher, Peter M.; Andreassen, Ole A.; Dale, Anders M.

2016-01-01

Most of the genetic architecture of schizophrenia (SCZ) has not yet been identified. Here, we apply a novel statistical algorithm called Covariate-Modulated Mixture Modeling (CM3), which incorporates auxiliary information (heterozygosity, total linkage disequilibrium, genomic annotations, pleiotropy) for each single nucleotide polymorphism (SNP) to enable more accurate estimation of replication probabilities, conditional on the observed test statistic (“z-score”) of the SNP. We use a multiple logistic regression on z-scores to combine information from auxiliary information to derive a “relative enrichment score” for each SNP. For each stratum of these relative enrichment scores, we obtain nonparametric estimates of posterior expected test statistics and replication probabilities as a function of discovery z-scores, using a resampling-based approach that repeatedly and randomly partitions meta-analysis sub-studies into training and replication samples. We fit a scale mixture of two Gaussians model to each stratum, obtaining parameter estimates that minimize the sum of squared differences of the scale-mixture model with the stratified nonparametric estimates. We apply this approach to the recent genome-wide association study (GWAS) of SCZ (n = 82,315), obtaining a good fit between the model-based and observed effect sizes and replication probabilities. We observed that SNPs with low enrichment scores replicate with a lower probability than SNPs with high enrichment scores even when both they are genome-wide significant (p < 5x10-8). There were 693 and 219 independent loci with model-based replication rates ≥80% and ≥90%, respectively. Compared to analyses not incorporating relative enrichment scores, CM3 increased out-of-sample yield for SNPs that replicate at a given rate. This demonstrates that replication probabilities can be more accurately estimated using prior enrichment information with CM3. PMID:26808560

Impact of Data Placement on Resilience in Large-Scale Object Storage Systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carns, Philip; Harms, Kevin; Jenkins, John

Distributed object storage architectures have become the de facto standard for high-performance storage in big data, cloud, and HPC computing. Object storage deployments using commodity hardware to reduce costs often employ object replication as a method to achieve data resilience. Repairing object replicas after failure is a daunting task for systems with thousands of servers and billions of objects, however, and it is increasingly difficult to evaluate such scenarios at scale on realworld systems. Resilience and availability are both compromised if objects are not repaired in a timely manner. In this work we leverage a high-fidelity discrete-event simulation model tomore » investigate replica reconstruction on large-scale object storage systems with thousands of servers, billions of objects, and petabytes of data. We evaluate the behavior of CRUSH, a well-known object placement algorithm, and identify configuration scenarios in which aggregate rebuild performance is constrained by object placement policies. After determining the root cause of this bottleneck, we then propose enhancements to CRUSH and the usage policies atop it to enable scalable replica reconstruction. We use these methods to demonstrate a simulated aggregate rebuild rate of 410 GiB/s (within 5% of projected ideal linear scaling) on a 1,024-node commodity storage system. We also uncover an unexpected phenomenon in rebuild performance based on the characteristics of the data stored on the system.« less

Shear repair methods for conventionally reinforced concrete girders and bent caps.

DOT National Transportation Integrated Search

2009-12-01

Thirteen large-scale girders and two bent caps that replicated as close as possible bridge components from the 1950s were cast and loaded to cause initial cracking similar to that observed in the field. The girders were repaired with epoxy crack inje...

Shear repair methods for conventionally reinforced concrete girders and bent caps : appendices.

DOT National Transportation Integrated Search

2009-12-01

Thirteen large-scale girders and two bent caps that replicated as close as possible bridge components from the 1950s were cast and loaded to cause initial cracking similar to that observed in the field. The girders were repaired with epoxy crack inje...

Is Implicit Theory of Mind a Real and Robust Phenomenon? Results From a Systematic Replication Study.

PubMed

Kulke, Louisa; von Duhn, Britta; Schneider, Dana; Rakoczy, Hannes

2018-06-01

Recently, theory-of-mind research has been revolutionized by findings from novel implicit tasks suggesting that at least some aspects of false-belief reasoning develop earlier in ontogeny than previously assumed and operate automatically throughout adulthood. Although these findings are the empirical basis for far-reaching theories, systematic replications are still missing. This article reports a preregistered large-scale attempt to replicate four influential anticipatory-looking implicit theory-of-mind tasks using original stimuli and procedures. Results showed that only one of the four paradigms was reliably replicated. A second set of studies revealed, further, that this one paradigm was no longer replicated once confounds were removed, which calls its validity into question. There were also no correlations between paradigms, and thus, no evidence for their convergent validity. In conclusion, findings from anticipatory-looking false-belief paradigms seem less reliable and valid than previously assumed, thus limiting the conclusions that can be drawn from them.

In the Shadow of Coal: How Large-Scale Industries Contributed to Present-Day Regional Differences in Personality and Well-Being.

PubMed

Obschonka, Martin; Stuetzer, Michael; Rentfrow, Peter J; Shaw-Taylor, Leigh; Satchell, Max; Silbereisen, Rainer K; Potter, Jeff; Gosling, Samuel D

2017-11-20

Recent research has identified regional variation of personality traits within countries but we know little about the underlying drivers of this variation. We propose that the Industrial Revolution, as a key era in the history of industrialized nations, has led to a persistent clustering of well-being outcomes and personality traits associated with psychological adversity via processes of selective migration and socialization. Analyzing data from England and Wales, we examine relationships between the historical employment share in large-scale coal-based industries (coal mining and steam-powered manufacturing industries that used this coal as fuel for their steam engines) and today's regional variation in personality and well-being. Even after controlling for possible historical confounds (historical energy supply, education, wealth, geology, climate, population density), we find that the historical local dominance of large-scale coal-based industries predicts today's markers of psychological adversity (lower Conscientiousness [and order facet scores], higher Neuroticism [and anxiety and depression facet scores], lower activity [an Extraversion facet], and lower life satisfaction and life expectancy). An instrumental variable analysis, using the historical location of coalfields, supports the causal assumption behind these effects (with the exception of life satisfaction). Further analyses focusing on mechanisms hint at the roles of selective migration and persisting economic hardship. Finally, a robustness check in the U.S. replicates the effect of the historical concentration of large-scale industries on today's levels of psychological adversity. Taken together, the results show how today's regional patterns of personality and well-being (which shape the future trajectories of these regions) may have their roots in major societal changes underway decades or centuries earlier. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Chromatin Landscapes of Retroviral and Transposon Integration Profiles

PubMed Central

Badhai, Jitendra; Rust, Alistair G.; Rad, Roland; Hilkens, John; Berns, Anton; van Lohuizen, Maarten; Wessels, Lodewyk F. A.; de Ridder, Jeroen

2014-01-01

The ability of retroviruses and transposons to insert their genetic material into host DNA makes them widely used tools in molecular biology, cancer research and gene therapy. However, these systems have biases that may strongly affect research outcomes. To address this issue, we generated very large datasets consisting of to unselected integrations in the mouse genome for the Sleeping Beauty (SB) and piggyBac (PB) transposons, and the Mouse Mammary Tumor Virus (MMTV). We analyzed (epi)genomic features to generate bias maps at both local and genome-wide scales. MMTV showed a remarkably uniform distribution of integrations across the genome. More distinct preferences were observed for the two transposons, with PB showing remarkable resemblance to bias profiles of the Murine Leukemia Virus. Furthermore, we present a model where target site selection is directed at multiple scales. At a large scale, target site selection is similar across systems, and defined by domain-oriented features, namely expression of proximal genes, proximity to CpG islands and to genic features, chromatin compaction and replication timing. Notable differences between the systems are mainly observed at smaller scales, and are directed by a diverse range of features. To study the effect of these biases on integration sites occupied under selective pressure, we turned to insertional mutagenesis (IM) screens. In IM screens, putative cancer genes are identified by finding frequently targeted genomic regions, or Common Integration Sites (CISs). Within three recently completed IM screens, we identified 7%–33% putative false positive CISs, which are likely not the result of the oncogenic selection process. Moreover, results indicate that PB, compared to SB, is more suited to tag oncogenes. PMID:24721906

A new method for culturing Plasmodium falciparum shows replication at the highest erythrocyte densities

NASA Technical Reports Server (NTRS)

Li, Tao; Glushakova, Svetlana; Zimmerberg, Joshua

2003-01-01

Plasmodium falciparum replicates poorly in erythrocyte densities greater than a hematocrit of 20%. A new method to culture the major malaria parasite was developed by using a hollow fiber bioreactor that preserves healthy erythrocytes at hematocrit up to 100%. P. falciparum replicated equally well at all densities studied. This method proved advantageous for large-scale preparation of parasitized erythrocytes (and potentially immunogens thereof), because high yields ( approximately 10(10) in 4 days) could be prepared with less cost and labor. Concomitantly, secreted proteins were concentrated by molecular sieving during culture, perhaps contributing to the parasitemic limit of 8%-12% with the 3D7 strain. The finding that P. falciparum can replicate at packed erythrocyte densities suggests that this system may be useful for study of the pathogenesis of fatal cerebral malaria, of which one feature is densely packed blood cells in brain microvasculature.

Systems Genetics Analysis of GWAS reveals Novel Associations between Key Biological Processes and Coronary Artery Disease

PubMed Central

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre FR; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2016-01-01

Objective Genome-wide association (GWA) studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Approaches and Results Employing pathways (gene sets) from Reactome, we carried out a two-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CADGWAS data sets (9,889 cases/11,089 controls), nominally significant gene-sets were tested for replication in a meta-analysis of 9 additional studies (15,502 cases/55,730 controls) from the CARDIoGRAM Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication p<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the TGF-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (e.g. semaphorin regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared to random networks (p<0.001). Network centrality analysis (‘degree’ and ‘betweenness’) further identified genes (e.g. NCAM1, FYN, FURIN etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. Conclusions These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. PMID:25977570

Factors limiting recruitment in valley and coast live oak

Treesearch

Claudia M. Tyler; Bruce E. Mahall; Frank W. Davis; Michael Hall

2002-01-01

The Santa Barbara County Oak Restoration Program was initiated in 1994 to determine the major factors limiting recruitment of valley oak (Quercus lobata) and coast live oak (Q. agrifolia). At Sedgwick Reserve in Santa Barbara County, California, we have replicated large-scale planting experiments in four different years to...

The Management of Large-Scale Change in Pakistani Education

ERIC Educational Resources Information Center

Razzaq, Jamila; Forde, Christine

2014-01-01

This article argues that although there are increasing similarities in priorities across different national education systems, contextual differences raise questions about the replication of sets of change strategies based on particular understandings of the nature of educational change across these different systems. This article begins with an…

Shear repair methods for conventionally reinforced concrete girders and bent caps : final report, December 2009.

DOT National Transportation Integrated Search

2009-12-01

Thirteen large-scale girders and two bent caps that replicated as close as possible bridge components from the 1950s were cast and loaded to cause initial cracking similar to that observed in the field. The girders were repaired with epoxy crack inje...

Motivation to Read among Rural Adolescents

ERIC Educational Resources Information Center

Belken, Gloria

2013-01-01

This study used quantitative methods to investigate motivation to read among high school students in a tenth-grade English course at a rural high school in the Midwestern USA. Data were collected and analyzed to replicate previous studies. In this study, when compared to large-scale surveys, respondents showed more positive attitudes toward…

Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease.

PubMed

Ghosh, Sujoy; Vivar, Juan; Nelson, Christopher P; Willenborg, Christina; Segrè, Ayellet V; Mäkinen, Ville-Petteri; Nikpay, Majid; Erdmann, Jeannette; Blankenberg, Stefan; O'Donnell, Christopher; März, Winfried; Laaksonen, Reijo; Stewart, Alexandre F R; Epstein, Stephen E; Shah, Svati H; Granger, Christopher B; Hazen, Stanley L; Kathiresan, Sekar; Reilly, Muredach P; Yang, Xia; Quertermous, Thomas; Samani, Nilesh J; Schunkert, Heribert; Assimes, Themistocles L; McPherson, Ruth

2015-07-01

Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks. Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF (platelet-derived growth factor), NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc) likely to play critical roles in the maintenance and functioning of several of the replicated pathways. These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD. © 2015 American Heart Association, Inc.

Large-scale replication and heterogeneity in Parkinson disease genetic loci

PubMed Central

Ioannidis, John P.A.; Aasly, Jan O.; Annesi, Grazia; Brice, Alexis; Van Broeckhoven, Christine; Bertram, Lars; Bozi, Maria; Crosiers, David; Clarke, Carl; Facheris, Maurizio; Farrer, Matthew; Garraux, Gaetan; Gispert, Suzana; Auburger, Georg; Vilariño-Güell, Carles; Hadjigeorgiou, Georgios M.; Hicks, Andrew A.; Hattori, Nobutaka; Jeon, Beom; Lesage, Suzanne; Lill, Christina M.; Lin, Juei-Jueng; Lynch, Timothy; Lichtner, Peter; Lang, Anthony E.; Mok, Vincent; Jasinska-Myga, Barbara; Mellick, George D.; Morrison, Karen E.; Opala, Grzegorz; Pramstaller, Peter P.; Pichler, Irene; Park, Sung Sup; Quattrone, Aldo; Rogaeva, Ekaterina; Ross, Owen A.; Stefanis, Leonidas; Stockton, Joanne D.; Satake, Wataru; Silburn, Peter A.; Theuns, Jessie; Tan, Eng-King; Toda, Tatsushi; Tomiyama, Hiroyuki; Uitti, Ryan J.; Wirdefeldt, Karin; Wszolek, Zbigniew; Xiromerisiou, Georgia; Yueh, Kuo-Chu; Zhao, Yi; Gasser, Thomas; Maraganore, Demetrius; Krüger, Rejko

2012-01-01

Objective: Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Methods: Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. Results: In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78–0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14–1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I2 estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Conclusion: Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity. Neurology® 2012;79:659–667 PMID:22786590

Large-scale replication and heterogeneity in Parkinson disease genetic loci.

PubMed

Sharma, Manu; Ioannidis, John P A; Aasly, Jan O; Annesi, Grazia; Brice, Alexis; Van Broeckhoven, Christine; Bertram, Lars; Bozi, Maria; Crosiers, David; Clarke, Carl; Facheris, Maurizio; Farrer, Matthew; Garraux, Gaetan; Gispert, Suzana; Auburger, Georg; Vilariño-Güell, Carles; Hadjigeorgiou, Georgios M; Hicks, Andrew A; Hattori, Nobutaka; Jeon, Beom; Lesage, Suzanne; Lill, Christina M; Lin, Juei-Jueng; Lynch, Timothy; Lichtner, Peter; Lang, Anthony E; Mok, Vincent; Jasinska-Myga, Barbara; Mellick, George D; Morrison, Karen E; Opala, Grzegorz; Pramstaller, Peter P; Pichler, Irene; Park, Sung Sup; Quattrone, Aldo; Rogaeva, Ekaterina; Ross, Owen A; Stefanis, Leonidas; Stockton, Joanne D; Satake, Wataru; Silburn, Peter A; Theuns, Jessie; Tan, Eng-King; Toda, Tatsushi; Tomiyama, Hiroyuki; Uitti, Ryan J; Wirdefeldt, Karin; Wszolek, Zbigniew; Xiromerisiou, Georgia; Yueh, Kuo-Chu; Zhao, Yi; Gasser, Thomas; Maraganore, Demetrius; Krüger, Rejko

2012-08-14

Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.

Bunyaviridae and Their Replication. Part 2. Replication of Bunyaviridae

DTIC Science & Technology

1990-01-01

Ivatt RJ. Synthesis and processing of asparagine- mulates intracellularly: cellular process of the large glycopro- linked oligosaccharides . Anna Rev...the high-mannose rather than complex type, and no evidence for the presence of 0-linked oligosaccharides A- has been obtained (86,87,93,120,146). AA ’U...and Pulse -chase experiments revealed no precursor/prod- G2 has not been identified. However, an intergenic uct relationship between the 78- and 14-kd

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data.

PubMed

Thompson, Paul M; Stein, Jason L; Medland, Sarah E; Hibar, Derrek P; Vasquez, Alejandro Arias; Renteria, Miguel E; Toro, Roberto; Jahanshad, Neda; Schumann, Gunter; Franke, Barbara; Wright, Margaret J; Martin, Nicholas G; Agartz, Ingrid; Alda, Martin; Alhusaini, Saud; Almasy, Laura; Almeida, Jorge; Alpert, Kathryn; Andreasen, Nancy C; Andreassen, Ole A; Apostolova, Liana G; Appel, Katja; Armstrong, Nicola J; Aribisala, Benjamin; Bastin, Mark E; Bauer, Michael; Bearden, Carrie E; Bergmann, Orjan; Binder, Elisabeth B; Blangero, John; Bockholt, Henry J; Bøen, Erlend; Bois, Catherine; Boomsma, Dorret I; Booth, Tom; Bowman, Ian J; Bralten, Janita; Brouwer, Rachel M; Brunner, Han G; Brohawn, David G; Buckner, Randy L; Buitelaar, Jan; Bulayeva, Kazima; Bustillo, Juan R; Calhoun, Vince D; Cannon, Dara M; Cantor, Rita M; Carless, Melanie A; Caseras, Xavier; Cavalleri, Gianpiero L; Chakravarty, M Mallar; Chang, Kiki D; Ching, Christopher R K; Christoforou, Andrea; Cichon, Sven; Clark, Vincent P; Conrod, Patricia; Coppola, Giovanni; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Deary, Ian J; de Geus, Eco J C; den Braber, Anouk; Delvecchio, Giuseppe; Depondt, Chantal; de Haan, Lieuwe; de Zubicaray, Greig I; Dima, Danai; Dimitrova, Rali; Djurovic, Srdjan; Dong, Hongwei; Donohoe, Gary; Duggirala, Ravindranath; Dyer, Thomas D; Ehrlich, Stefan; Ekman, Carl Johan; Elvsåshagen, Torbjørn; Emsell, Louise; Erk, Susanne; Espeseth, Thomas; Fagerness, Jesen; Fears, Scott; Fedko, Iryna; Fernández, Guillén; Fisher, Simon E; Foroud, Tatiana; Fox, Peter T; Francks, Clyde; Frangou, Sophia; Frey, Eva Maria; Frodl, Thomas; Frouin, Vincent; Garavan, Hugh; Giddaluru, Sudheer; Glahn, David C; Godlewska, Beata; Goldstein, Rita Z; Gollub, Randy L; Grabe, Hans J; Grimm, Oliver; Gruber, Oliver; Guadalupe, Tulio; Gur, Raquel E; Gur, Ruben C; Göring, Harald H H; Hagenaars, Saskia; Hajek, Tomas; Hall, Geoffrey B; Hall, Jeremy; Hardy, John; Hartman, Catharina A; Hass, Johanna; Hatton, Sean N; Haukvik, Unn K; Hegenscheid, Katrin; Heinz, Andreas; Hickie, Ian B; Ho, Beng-Choon; Hoehn, David; Hoekstra, Pieter J; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hoogman, Martine; Hong, L Elliot; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Hwang, Kristy S; Jack, Clifford R; Jenkinson, Mark; Johnston, Caroline; Jönsson, Erik G; Kahn, René S; Kasperaviciute, Dalia; Kelly, Sinead; Kim, Sungeun; Kochunov, Peter; Koenders, Laura; Krämer, Bernd; Kwok, John B J; Lagopoulos, Jim; Laje, Gonzalo; Landen, Mikael; Landman, Bennett A; Lauriello, John; Lawrie, Stephen M; Lee, Phil H; Le Hellard, Stephanie; Lemaître, Herve; Leonardo, Cassandra D; Li, Chiang-Shan; Liberg, Benny; Liewald, David C; Liu, Xinmin; Lopez, Lorna M; Loth, Eva; Lourdusamy, Anbarasu; Luciano, Michelle; Macciardi, Fabio; Machielsen, Marise W J; Macqueen, Glenda M; Malt, Ulrik F; Mandl, René; Manoach, Dara S; Martinot, Jean-Luc; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mattingsdal, Morten; Meyer-Lindenberg, Andreas; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meisenzahl, Eva; Melle, Ingrid; Milaneschi, Yuri; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Moses, Eric K; Mueller, Bryon A; Muñoz Maniega, Susana; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Mwangi, Benson; Nauck, Matthias; Nho, Kwangsik; Nichols, Thomas E; Nilsson, Lars-Göran; Nugent, Allison C; Nyberg, Lars; Olvera, Rene L; Oosterlaan, Jaap; Ophoff, Roel A; Pandolfo, Massimo; Papalampropoulou-Tsiridou, Melina; Papmeyer, Martina; Paus, Tomas; Pausova, Zdenka; Pearlson, Godfrey D; Penninx, Brenda W; Peterson, Charles P; Pfennig, Andrea; Phillips, Mary; Pike, G Bruce; Poline, Jean-Baptiste; Potkin, Steven G; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rietschel, Marcella; Rijpkema, Mark; Risacher, Shannon L; Roffman, Joshua L; Roiz-Santiañez, Roberto; Romanczuk-Seiferth, Nina; Rose, Emma J; Royle, Natalie A; Rujescu, Dan; Ryten, Mina; Sachdev, Perminder S; Salami, Alireza; Satterthwaite, Theodore D; Savitz, Jonathan; Saykin, Andrew J; Scanlon, Cathy; Schmaal, Lianne; Schnack, Hugo G; Schork, Andrew J; Schulz, S Charles; Schür, Remmelt; Seidman, Larry; Shen, Li; Shoemaker, Jody M; Simmons, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soares, Jair C; Sponheim, Scott R; Sprooten, Emma; Starr, John M; Steen, Vidar M; Strakowski, Stephen; Strike, Lachlan; Sussmann, Jessika; Sämann, Philipp G; Teumer, Alexander; Toga, Arthur W; Tordesillas-Gutierrez, Diana; Trabzuni, Daniah; Trost, Sarah; Turner, Jessica; Van den Heuvel, Martijn; van der Wee, Nic J; van Eijk, Kristel; van Erp, Theo G M; van Haren, Neeltje E M; van 't Ent, Dennis; van Tol, Marie-Jose; Valdés Hernández, Maria C; Veltman, Dick J; Versace, Amelia; Völzke, Henry; Walker, Robert; Walter, Henrik; Wang, Lei; Wardlaw, Joanna M; Weale, Michael E; Weiner, Michael W; Wen, Wei; Westlye, Lars T; Whalley, Heather C; Whelan, Christopher D; White, Tonya; Winkler, Anderson M; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Zilles, David; Zwiers, Marcel P; Thalamuthu, Anbupalam; Schofield, Peter R; Freimer, Nelson B; Lawrence, Natalia S; Drevets, Wayne

2014-06-01

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.

The impact of sampling, PCR, and sequencing replication on discerning changes in drinking water bacterial community over diurnal time-scales.

PubMed

Bautista-de Los Santos, Quyen Melina; Schroeder, Joanna L; Blakemore, Oliver; Moses, Jonathan; Haffey, Mark; Sloan, William; Pinto, Ameet J

2016-03-01

High-throughput and deep DNA sequencing, particularly amplicon sequencing, is being increasingly utilized to reveal spatial and temporal dynamics of bacterial communities in drinking water systems. Whilst the sampling and methodological biases associated with PCR and sequencing have been studied in other environments, they have not been quantified for drinking water. These biases are likely to have the greatest effect on the ability to characterize subtle spatio-temporal patterns influenced by process/environmental conditions. In such cases, intra-sample variability may swamp any underlying small, systematic variation. To evaluate this, we undertook a study with replication at multiple levels including sampling sites, sample collection, PCR amplification, and high throughput sequencing of 16S rRNA amplicons. The variability inherent to the PCR amplification and sequencing steps is significant enough to mask differences between bacterial communities from replicate samples. This was largely driven by greater variability in detection of rare bacteria (relative abundance <0.01%) across PCR/sequencing replicates as compared to replicate samples. Despite this, we captured significant changes in bacterial community over diurnal time-scales and find that the extent and pattern of diurnal changes is specific to each sampling location. Further, we find diurnal changes in bacterial community arise due to differences in the presence/absence of the low abundance bacteria and changes in the relative abundance of dominant bacteria. Finally, we show that bacterial community composition is significantly different across sampling sites for time-periods during which there are typically rapid changes in water use. This suggests hydraulic changes (driven by changes in water demand) contribute to shaping the bacterial community in bulk drinking water over diurnal time-scales. Copyright © 2015 Elsevier Ltd. All rights reserved.

Unstable genomes elevate transcriptome dynamics

PubMed Central

Stevens, Joshua B.; Liu, Guo; Abdallah, Batoul Y.; Horne, Steven D.; Ye, Karen J.; Bremer, Steven W.; Ye, Christine J.; Krawetz, Stephen A.; Heng, Henry H.

2015-01-01

The challenge of identifying common expression signatures in cancer is well known, however the reason behind this is largely unclear. Traditionally variation in expression signatures has been attributed to technological problems, however recent evidence suggests that chromosome instability (CIN) and resultant karyotypic heterogeneity may be a large contributing factor. Using a well-defined model of immortalization, we systematically compared the pattern of genome alteration and expression dynamics during somatic evolution. Co-measurement of global gene expression and karyotypic alteration throughout the immortalization process reveals that karyotype changes influence gene expression as major structural and numerical karyotypic alterations result in large gene expression deviation. Replicate samples from stages with stable genomes are more similar to each other than are replicate samples with karyotypic heterogeneity. Karyotypic and gene expression change during immortalization is dynamic as each stage of progression has a unique expression pattern. This was further verified by comparing global expression in two replicates grown in one flask with known karyotypes. Replicates with higher karyotypic instability were found to be less similar than replicates with stable karyotypes. This data illustrates the karyotype, transcriptome, and transcriptome determined pathways are in constant flux during somatic cellular evolution (particularly during the macroevolutionary phase) and this flux is an inextricable feature of CIN and essential for cancer formation. The findings presented here underscore the importance of understanding the evolutionary process of cancer in order to design improved treatment modalities. PMID:24122714

Interaction between genes and macronutrient intake on the risk of developing type 2 diabetes: systematic review and findings from European Prospective Investigation into Cancer (EPIC)-InterAct.

PubMed

Li, Sherly X; Imamura, Fumiaki; Ye, Zheng; Schulze, Matthias B; Zheng, Jusheng; Ardanaz, Eva; Arriola, Larraitz; Boeing, Heiner; Dow, Courtney; Fagherazzi, Guy; Franks, Paul W; Agudo, Antonio; Grioni, Sara; Kaaks, Rudolf; Katzke, Verena A; Key, Timothy J; Khaw, Kay Tee; Mancini, Francesca R; Navarro, Carmen; Nilsson, Peter M; Onland-Moret, N Charlotte; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, J Ramón; Rolandsson, Olov; Sacerdote, Carlotta; Sánchez, María-José; Slimani, Nadia; Sluijs, Ivonne; Spijkerman, Annemieke Mw; Tjonneland, Anne; Tumino, Rosario; Sharp, Stephen J; Riboli, Elio; Langenberg, Claudia; Scott, Robert A; Forouhi, Nita G; Wareham, Nicholas J

2017-07-01

Background: Gene-diet interactions have been reported to contribute to the development of type 2 diabetes (T2D). However, to our knowledge, few examples have been consistently replicated to date. Objective: We aimed to identify existing evidence for gene-macronutrient interactions and T2D and to examine the reported interactions in a large-scale study. Design: We systematically reviewed studies reporting gene-macronutrient interactions and T2D. We searched the MEDLINE, Human Genome Epidemiology Network, and WHO International Clinical Trials Registry Platform electronic databases to identify studies published up to October 2015. Eligibility criteria included assessment of macronutrient quantity (e.g., total carbohydrate) or indicators of quality (e.g., dietary fiber) by use of self-report or objective biomarkers of intake. Interactions identified in the review were subsequently examined in the EPIC (European Prospective Investigation into Cancer)-InterAct case-cohort study ( n = 21,148, with 9403 T2D cases; 8 European countries). Prentice-weighted Cox regression was used to estimate country-specific HRs, 95% CIs, and P -interaction values, which were then pooled by random-effects meta-analysis. A primary model was fitted by using the same covariates as reported in the published studies, and a second model adjusted for additional covariates and estimated the effects of isocaloric macronutrient substitution. Results: Thirteen observational studies met the eligibility criteria ( n < 1700 cases). Eight unique interactions were reported to be significant between macronutrients [carbohydrate, fat, saturated fat, dietary fiber, and glycemic load derived from self-report of dietary intake and circulating n-3 (ω-3) polyunsaturated fatty acids] and genetic variants in or near transcription factor 7-like 2 ( TCF7L2 ), gastric inhibitory polypeptide receptor ( GIPR ), caveolin 2 ( CAV2 ), and peptidase D ( PEPD ) ( P -interaction < 0.05). We found no evidence of interaction when we tried to replicate previously reported interactions. In addition, no interactions were detected in models with additional covariates. Conclusions: Eight gene-macronutrient interactions were identified for the risk of T2D from the literature. These interactions were not replicated in the EPIC-InterAct study, which mirrored the analyses undertaken in the original reports. Our findings highlight the importance of independent replication of reported interactions.

Bridging the gap between evidence-based innovation and national health-sector reform in Ghana.

PubMed

Awoonor-Williams, John Koku; Feinglass, Ellie S; Tobey, Rachel; Vaughan-Smith, Maya N; Nyonator, Frank K; Jones, Tanya C

2004-09-01

Although experimental trials often identify optimal strategies for improving community health, transferring operational innovation from well-funded research programs to resource-constrained settings often languishes. Because research initiatives are based in institutions equipped with unique resources and staff capabilities, results are often dismissed by decisionmakers as irrelevant to large-scale operations and national health policy. This article describes an initiative undertaken in Nkwanta District, Ghana, focusing on this problem. The Nkwanta District initiative is a critical link between the experimental study conducted in Navrongo, Ghana, and a national effort to scale up the innovations developed in that study. A 2002 Nkwanta district-level survey provides the basis for assessing the likelihood that the Navrongo model is replicable elsewhere in Ghana. The effect of community-based health planning and services exposure on family planning and safe-motherhood indicators supports the hypothesis that Navrongo effects are transferable to impoverished rural settings elsewhere, confirming the need for strategies to bridge the gap between Navrongo evidence-based innovation and national health-sector reform.

The PhenX Toolkit: Get the Most From Your Measures

PubMed Central

Hamilton, Carol M.; Strader, Lisa C.; Pratt, Joseph G.; Maiese, Deborah; Hendershot, Tabitha; Kwok, Richard K.; Hammond, Jane A.; Huggins, Wayne; Jackman, Dean; Pan, Huaqin; Nettles, Destiney S.; Beaty, Terri H.; Farrer, Lindsay A.; Kraft, Peter; Marazita, Mary L.; Ordovas, Jose M.; Pato, Carlos N.; Spitz, Margaret R.; Wagener, Diane; Williams, Michelle; Junkins, Heather A.; Harlan, William R.; Ramos, Erin M.; Haines, Jonathan

2011-01-01

The potential for genome-wide association studies to relate phenotypes to specific genetic variation is greatly increased when data can be combined or compared across multiple studies. To facilitate replication and validation across studies, RTI International (Research Triangle Park, North Carolina) and the National Human Genome Research Institute (Bethesda, Maryland) are collaborating on the consensus measures for Phenotypes and eXposures (PhenX) project. The goal of PhenX is to identify 15 high-priority, well-established, and broadly applicable measures for each of 21 research domains. PhenX measures are selected by working groups of domain experts using a consensus process that includes input from the scientific community. The selected measures are then made freely available to the scientific community via the PhenX Toolkit. Thus, the PhenX Toolkit provides the research community with a core set of high-quality, well-established, low-burden measures intended for use in large-scale genomic studies. PhenX measures will have the most impact when included at the experimental design stage. The PhenX Toolkit also includes links to standards and resources in an effort to facilitate data harmonization to legacy data. Broad acceptance and use of PhenX measures will promote cross-study comparisons to increase statistical power for identifying and replicating variants associated with complex diseases and with gene-gene and gene-environment interactions. PMID:21749974

Measurement of replication structures at the nanometer scale using super-resolution light microscopy

PubMed Central

Baddeley, D.; Chagin, V. O.; Schermelleh, L.; Martin, S.; Pombo, A.; Carlton, P. M.; Gahl, A.; Domaing, P.; Birk, U.; Leonhardt, H.; Cremer, C.; Cardoso, M. C.

2010-01-01

DNA replication, similar to other cellular processes, occurs within dynamic macromolecular structures. Any comprehensive understanding ultimately requires quantitative data to establish and test models of genome duplication. We used two different super-resolution light microscopy techniques to directly measure and compare the size and numbers of replication foci in mammalian cells. This analysis showed that replication foci vary in size from 210 nm down to 40 nm. Remarkably, spatially modulated illumination (SMI) and 3D-structured illumination microscopy (3D-SIM) both showed an average size of 125 nm that was conserved throughout S-phase and independent of the labeling method, suggesting a basic unit of genome duplication. Interestingly, the improved optical 3D resolution identified 3- to 5-fold more distinct replication foci than previously reported. These results show that optical nanoscopy techniques enable accurate measurements of cellular structures at a level previously achieved only by electron microscopy and highlight the possibility of high-throughput, multispectral 3D analyses. PMID:19864256

Is psychology suffering from a replication crisis? What does "failure to replicate" really mean?

PubMed

Maxwell, Scott E; Lau, Michael Y; Howard, George S

2015-09-01

Psychology has recently been viewed as facing a replication crisis because efforts to replicate past study findings frequently do not show the same result. Often, the first study showed a statistically significant result but the replication does not. Questions then arise about whether the first study results were false positives, and whether the replication study correctly indicates that there is truly no effect after all. This article suggests these so-called failures to replicate may not be failures at all, but rather are the result of low statistical power in single replication studies, and the result of failure to appreciate the need for multiple replications in order to have enough power to identify true effects. We provide examples of these power problems and suggest some solutions using Bayesian statistics and meta-analysis. Although the need for multiple replication studies may frustrate those who would prefer quick answers to psychology's alleged crisis, the large sample sizes typically needed to provide firm evidence will almost always require concerted efforts from multiple investigators. As a result, it remains to be seen how many of the recently claimed failures to replicate will be supported or instead may turn out to be artifacts of inadequate sample sizes and single study replications. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

A systematic analysis of host factors reveals a Med23-interferon-λ regulatory axis against herpes simplex virus type 1 replication.

PubMed

Griffiths, Samantha J; Koegl, Manfred; Boutell, Chris; Zenner, Helen L; Crump, Colin M; Pica, Francesca; Gonzalez, Orland; Friedel, Caroline C; Barry, Gerald; Martin, Kim; Craigon, Marie H; Chen, Rui; Kaza, Lakshmi N; Fossum, Even; Fazakerley, John K; Efstathiou, Stacey; Volpi, Antonio; Zimmer, Ralf; Ghazal, Peter; Haas, Jürgen

2013-01-01

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus causing vesicular oral or genital skin lesions, meningitis and other diseases particularly harmful in immunocompromised individuals. To comprehensively investigate the complex interaction between HSV-1 and its host we combined two genome-scale screens for host factors (HFs) involved in virus replication. A yeast two-hybrid screen for protein interactions and a RNA interference (RNAi) screen with a druggable genome small interfering RNA (siRNA) library confirmed existing and identified novel HFs which functionally influence HSV-1 infection. Bioinformatic analyses found the 358 HFs were enriched for several pathways and multi-protein complexes. Of particular interest was the identification of Med23 as a strongly anti-viral component of the largely pro-viral Mediator complex, which links specific transcription factors to RNA polymerase II. The anti-viral effect of Med23 on HSV-1 replication was confirmed in gain-of-function gene overexpression experiments, and this inhibitory effect was specific to HSV-1, as a range of other viruses including Vaccinia virus and Semliki Forest virus were unaffected by Med23 depletion. We found Med23 significantly upregulated expression of the type III interferon family (IFN-λ) at the mRNA and protein level by directly interacting with the transcription factor IRF7. The synergistic effect of Med23 and IRF7 on IFN-λ induction suggests this is the major transcription factor for IFN-λ expression. Genotypic analysis of patients suffering recurrent orofacial HSV-1 outbreaks, previously shown to be deficient in IFN-λ secretion, found a significant correlation with a single nucleotide polymorphism in the IFN-λ3 (IL28b) promoter strongly linked to Hepatitis C disease and treatment outcome. This paper describes a link between Med23 and IFN-λ, provides evidence for the crucial role of IFN-λ in HSV-1 immune control, and highlights the power of integrative genome-scale approaches to identify HFs critical for disease progression and outcome.

Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction.

PubMed

Diamond, Joshua M; Akimova, Tatiana; Kazi, Altaf; Shah, Rupal J; Cantu, Edward; Feng, Rui; Levine, Matthew H; Kawut, Steven M; Meyer, Nuala J; Lee, James C; Hancock, Wayne W; Aplenc, Richard; Ware, Lorraine B; Palmer, Scott M; Bhorade, Sangeeta; Lama, Vibha N; Weinacker, Ann; Orens, Jonathan; Wille, Keith; Crespo, Maria; Lederer, David J; Arcasoy, Selim; Demissie, Ejigayehu; Christie, Jason D

2014-03-01

Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted.

Online Learning Experiences of New versus Continuing Learners: A Large-Scale Replication Study

ERIC Educational Resources Information Center

Li, Nai; Marsh, Vicky; Rienties, Bart; Whitelock, Denise

2017-01-01

A vast body of research has indicated the importance of distinguishing new vs. continuing students' learning experiences in blended and online environments. Continuing learners may have developed learning and coping mechanisms for "surviving" in such learning environments, while new learners might still need to adjust their learning…

Replicating Experimental Impact Estimates Using a Regression Discontinuity Approach. NCEE 2012-4025

ERIC Educational Resources Information Center

Gleason, Philip M.; Resch, Alexandra M.; Berk, Jillian A.

2012-01-01

This NCEE Technical Methods Paper compares the estimated impacts of an educational intervention using experimental and regression discontinuity (RD) study designs. The analysis used data from two large-scale randomized controlled trials--the Education Technology Evaluation and the Teach for America Study--to provide evidence on the performance of…

Construction of a Food Grade Recombinant Bacillus subtilis Based on Replicative Plasmids with an Auxotrophic Marker for Biotransformation of d-Fructose to d-Allulose.

PubMed

He, Weiwei; Mu, Wanmeng; Jiang, Bo; Yan, Xin; Zhang, Tao

2016-04-27

A food grade recombinant Bacillus subtilis that produces d-psicose 3-epimerase (DPEase; EC 5.1.3.30) was constructed by transforming a replicative multicopy plasmid with a d-alanine racemase gene marker into B. subtilis 1A751 with the d-alanine racemase gene knocked out. The DPEase was expressed in B. subtilis without antibiotic resistance genes and without adding antibiotics during fermentation. Whole cells of the food grade recombinant B. subtilis were used to biotransform d-fructose to d-allulose. The two tandem promoters, including the HpaII and P43 promoters, increased expression levels compared to the use of one promoter, HpaII. For large-scale d-allulose production, the optimal enzyme dose was 40 enzyme activity units of dry cells per gram of d-fructose, which produced a 28.5% turnover yield in 60 min. The recombinant plasmid exhibited stability over 100 generations. This food grade recombinant B. subtilis may be used for large-scale d-allulose production in the food industry.

Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions

PubMed Central

Liharska, Lora; Harvey, Philip D.; Atkins, Alexandra; Ulshen, Daniel; Keefe, Richard S.E.

2017-01-01

Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms. PMID:29410935

Genome-wide association study (GWAS) for molar-incisor hypomineralization (MIH).

PubMed

Kühnisch, Jan; Thiering, Elisabeth; Heitmüller, Daniela; Tiesler, Carla M T; Grallert, Harald; Heinrich-Weltzien, Roswitha; Hickel, Reinhard; Heinrich, Joachim

2014-01-01

This genome-wide association study (GWAS) investigated the relationship between molar-incisor hypomineralization (MIH) and possible genetic loci. Clinical and genetic data from the 10-year follow-up of 668 children from the Munich GINI-plus and LISA-plus birth cohort studies were analyzed. The dental examinations included the diagnosis of MIH according to the criteria of the European Academy of Paediatric Dentistry (EAPD). Children with MIH were categorized as those with a minimum of one hypomineralized first permanent molar. A GWAS was implemented following a quality-control step and an additive genetic effect was assumed. A total of 2,013,491 single-nucleotide polymorphisms (SNPs) were available for analysis. Rs13058467, which is located near the SCUBE1 gene on chromosome 22 (p < 3.72E-7), was identified as a possible locus linked to MIH when using a threshold of p value <1E-6. After considering the limitations of the present study (e.g., limited sample size and lack of an independent replication sample), it can be concluded that (1) replication analyses in an independent cohort study are strongly recommended and (2) large-scale and well-powered studies are needed to investigate a possible genetic link to MIH.

Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

PubMed Central

Lange, Leslie A.; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M.; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M.; Smith, Joshua D.; Turner, Emily H.; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A.; Holmen, Oddgeir L.; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A.; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C.; Correa, Adolfo; Griswold, Michael E.; Jakobsdottir, Johanna; Smith, Albert V.; Schreiner, Pamela J.; Feitosa, Mary F.; Zhang, Qunyuan; Huffman, Jennifer E.; Crosby, Jacy; Wassel, Christina L.; Do, Ron; Franceschini, Nora; Martin, Lisa W.; Robinson, Jennifer G.; Assimes, Themistocles L.; Crosslin, David R.; Rosenthal, Elisabeth A.; Tsai, Michael; Rieder, Mark J.; Farlow, Deborah N.; Folsom, Aaron R.; Lumley, Thomas; Fox, Ervin R.; Carlson, Christopher S.; Peters, Ulrike; Jackson, Rebecca D.; van Duijn, Cornelia M.; Uitterlinden, André G.; Levy, Daniel; Rotter, Jerome I.; Taylor, Herman A.; Gudnason, Vilmundur; Siscovick, David S.; Fornage, Myriam; Borecki, Ingrid B.; Hayward, Caroline; Rudan, Igor; Chen, Y. Eugene; Bottinger, Erwin P.; Loos, Ruth J.F.; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M.; Gabriel, Stacey B.; O’Donnell, Christopher J.; Post, Wendy S.; North, Kari E.; Reiner, Alexander P.; Boerwinkle, Eric; Psaty, Bruce M.; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P.; Cupples, L. Adrienne; Kooperberg, Charles; Wilson, James G.; Nickerson, Deborah A.; Abecasis, Goncalo R.; Rich, Stephen S.; Tracy, Russell P.; Willer, Cristen J.; Gabriel, Stacey B.; Altshuler, David M.; Abecasis, Gonçalo R.; Allayee, Hooman; Cresci, Sharon; Daly, Mark J.; de Bakker, Paul I.W.; DePristo, Mark A.; Do, Ron; Donnelly, Peter; Farlow, Deborah N.; Fennell, Tim; Garimella, Kiran; Hazen, Stanley L.; Hu, Youna; Jordan, Daniel M.; Jun, Goo; Kathiresan, Sekar; Kang, Hyun Min; Kiezun, Adam; Lettre, Guillaume; Li, Bingshan; Li, Mingyao; Newton-Cheh, Christopher H.; Padmanabhan, Sandosh; Peloso, Gina; Pulit, Sara; Rader, Daniel J.; Reich, David; Reilly, Muredach P.; Rivas, Manuel A.; Schwartz, Steve; Scott, Laura; Siscovick, David S.; Spertus, John A.; Stitziel, Nathaniel O.; Stoletzki, Nina; Sunyaev, Shamil R.; Voight, Benjamin F.; Willer, Cristen J.; Rich, Stephen S.; Akylbekova, Ermeg; Atwood, Larry D.; Ballantyne, Christie M.; Barbalic, Maja; Barr, R. Graham; Benjamin, Emelia J.; Bis, Joshua; Boerwinkle, Eric; Bowden, Donald W.; Brody, Jennifer; Budoff, Matthew; Burke, Greg; Buxbaum, Sarah; Carr, Jeff; Chen, Donna T.; Chen, Ida Y.; Chen, Wei-Min; Concannon, Pat; Crosby, Jacy; Cupples, L. Adrienne; D’Agostino, Ralph; DeStefano, Anita L.; Dreisbach, Albert; Dupuis, Josée; Durda, J. Peter; Ellis, Jaclyn; Folsom, Aaron R.; Fornage, Myriam; Fox, Caroline S.; Fox, Ervin; Funari, Vincent; Ganesh, Santhi K.; Gardin, Julius; Goff, David; Gordon, Ora; Grody, Wayne; Gross, Myron; Guo, Xiuqing; Hall, Ira M.; Heard-Costa, Nancy L.; Heckbert, Susan R.; Heintz, Nicholas; Herrington, David M.; Hickson, DeMarc; Huang, Jie; Hwang, Shih-Jen; Jacobs, David R.; Jenny, Nancy S.; Johnson, Andrew D.; Johnson, Craig W.; Kawut, Steven; Kronmal, Richard; Kurz, Raluca; Lange, Ethan M.; Lange, Leslie A.; Larson, Martin G.; Lawson, Mark; Lewis, Cora E.; Levy, Daniel; Li, Dalin; Lin, Honghuang; Liu, Chunyu; Liu, Jiankang; Liu, Kiang; Liu, Xiaoming; Liu, Yongmei; Longstreth, William T.; Loria, Cay; Lumley, Thomas; Lunetta, Kathryn; Mackey, Aaron J.; Mackey, Rachel; Manichaikul, Ani; Maxwell, Taylor; McKnight, Barbara; Meigs, James B.; Morrison, Alanna C.; Musani, Solomon K.; Mychaleckyj, Josyf C.; Nettleton, Jennifer A.; North, Kari; O’Donnell, Christopher J.; O’Leary, Daniel; Ong, Frank; Palmas, Walter; Pankow, James S.; Pankratz, Nathan D.; Paul, Shom; Perez, Marco; Person, Sharina D.; Polak, Joseph; Post, Wendy S.; Psaty, Bruce M.; Quinlan, Aaron R.; Raffel, Leslie J.; Ramachandran, Vasan S.; Reiner, Alexander P.; Rice, Kenneth; Rotter, Jerome I.; Sanders, Jill P.; Schreiner, Pamela; Seshadri, Sudha; Shea, Steve; Sidney, Stephen; Silverstein, Kevin; Smith, Nicholas L.; Sotoodehnia, Nona; Srinivasan, Asoke; Taylor, Herman A.; Taylor, Kent; Thomas, Fridtjof; Tracy, Russell P.; Tsai, Michael Y.; Volcik, Kelly A.; Wassel, Chrstina L.; Watson, Karol; Wei, Gina; White, Wendy; Wiggins, Kerri L.; Wilk, Jemma B.; Williams, O. Dale; Wilson, Gregory; Wilson, James G.; Wolf, Phillip; Zakai, Neil A.; Hardy, John; Meschia, James F.; Nalls, Michael; Singleton, Andrew; Worrall, Brad; Bamshad, Michael J.; Barnes, Kathleen C.; Abdulhamid, Ibrahim; Accurso, Frank; Anbar, Ran; Beaty, Terri; Bigham, Abigail; Black, Phillip; Bleecker, Eugene; Buckingham, Kati; Cairns, Anne Marie; Caplan, Daniel; Chatfield, Barbara; Chidekel, Aaron; Cho, Michael; Christiani, David C.; Crapo, James D.; Crouch, Julia; Daley, Denise; Dang, Anthony; Dang, Hong; De Paula, Alicia; DeCelie-Germana, Joan; Drumm, Allen DozorMitch; Dyson, Maynard; Emerson, Julia; Emond, Mary J.; Ferkol, Thomas; Fink, Robert; Foster, Cassandra; Froh, Deborah; Gao, Li; Gershan, William; Gibson, Ronald L.; Godwin, Elizabeth; Gondor, Magdalen; Gutierrez, Hector; Hansel, Nadia N.; Hassoun, Paul M.; Hiatt, Peter; Hokanson, John E.; Howenstine, Michelle; Hummer, Laura K.; Kanga, Jamshed; Kim, Yoonhee; Knowles, Michael R.; Konstan, Michael; Lahiri, Thomas; Laird, Nan; Lange, Christoph; Lin, Lin; Lin, Xihong; Louie, Tin L.; Lynch, David; Make, Barry; Martin, Thomas R.; Mathai, Steve C.; Mathias, Rasika A.; McNamara, John; McNamara, Sharon; Meyers, Deborah; Millard, Susan; Mogayzel, Peter; Moss, Richard; Murray, Tanda; Nielson, Dennis; Noyes, Blakeslee; O’Neal, Wanda; Orenstein, David; O’Sullivan, Brian; Pace, Rhonda; Pare, Peter; Parker, H. Worth; Passero, Mary Ann; Perkett, Elizabeth; Prestridge, Adrienne; Rafaels, Nicholas M.; Ramsey, Bonnie; Regan, Elizabeth; Ren, Clement; Retsch-Bogart, George; Rock, Michael; Rosen, Antony; Rosenfeld, Margaret; Ruczinski, Ingo; Sanford, Andrew; Schaeffer, David; Sell, Cindy; Sheehan, Daniel; Silverman, Edwin K.; Sin, Don; Spencer, Terry; Stonebraker, Jackie; Tabor, Holly K.; Varlotta, Laurie; Vergara, Candelaria I.; Weiss, Robert; Wigley, Fred; Wise, Robert A.; Wright, Fred A.; Wurfel, Mark M.; Zanni, Robert; Zou, Fei; Nickerson, Deborah A.; Rieder, Mark J.; Green, Phil; Shendure, Jay; Akey, Joshua M.; Bustamante, Carlos D.; Crosslin, David R.; Eichler, Evan E.; Fox, P. Keolu; Fu, Wenqing; Gordon, Adam; Gravel, Simon; Jarvik, Gail P.; Johnsen, Jill M.; Kan, Mengyuan; Kenny, Eimear E.; Kidd, Jeffrey M.; Lara-Garduno, Fremiet; Leal, Suzanne M.; Liu, Dajiang J.; McGee, Sean; O’Connor, Timothy D.; Paeper, Bryan; Robertson, Peggy D.; Smith, Joshua D.; Staples, Jeffrey C.; Tennessen, Jacob A.; Turner, Emily H.; Wang, Gao; Yi, Qian; Jackson, Rebecca; Peters, Ulrike; Carlson, Christopher S.; Anderson, Garnet; Anton-Culver, Hoda; Assimes, Themistocles L.; Auer, Paul L.; Beresford, Shirley; Bizon, Chris; Black, Henry; Brunner, Robert; Brzyski, Robert; Burwen, Dale; Caan, Bette; Carty, Cara L.; Chlebowski, Rowan; Cummings, Steven; Curb, J. David; Eaton, Charles B.; Ford, Leslie; Franceschini, Nora; Fullerton, Stephanie M.; Gass, Margery; Geller, Nancy; Heiss, Gerardo; Howard, Barbara V.; Hsu, Li; Hutter, Carolyn M.; Ioannidis, John; Jiao, Shuo; Johnson, Karen C.; Kooperberg, Charles; Kuller, Lewis; LaCroix, Andrea; Lakshminarayan, Kamakshi; Lane, Dorothy; Lasser, Norman; LeBlanc, Erin; Li, Kuo-Ping; Limacher, Marian; Lin, Dan-Yu; Logsdon, Benjamin A.; Ludlam, Shari; Manson, JoAnn E.; Margolis, Karen; Martin, Lisa; McGowan, Joan; Monda, Keri L.; Kotchen, Jane Morley; Nathan, Lauren; Ockene, Judith; O’Sullivan, Mary Jo; Phillips, Lawrence S.; Prentice, Ross L.; Robbins, John; Robinson, Jennifer G.; Rossouw, Jacques E.; Sangi-Haghpeykar, Haleh; Sarto, Gloria E.; Shumaker, Sally; Simon, Michael S.; Stefanick, Marcia L.; Stein, Evan; Tang, Hua; Taylor, Kira C.; Thomson, Cynthia A.; Thornton, Timothy A.; Van Horn, Linda; Vitolins, Mara; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Zeng, Donglin; Applebaum-Bowden, Deborah; Feolo, Michael; Gan, Weiniu; Paltoo, Dina N.; Sholinsky, Phyliss; Sturcke, Anne

2014-01-01

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. PMID:24507775

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

PubMed

Lange, Leslie A; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M; Smith, Joshua D; Turner, Emily H; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-Ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A; Holmen, Oddgeir L; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C; Correa, Adolfo; Griswold, Michael E; Jakobsdottir, Johanna; Smith, Albert V; Schreiner, Pamela J; Feitosa, Mary F; Zhang, Qunyuan; Huffman, Jennifer E; Crosby, Jacy; Wassel, Christina L; Do, Ron; Franceschini, Nora; Martin, Lisa W; Robinson, Jennifer G; Assimes, Themistocles L; Crosslin, David R; Rosenthal, Elisabeth A; Tsai, Michael; Rieder, Mark J; Farlow, Deborah N; Folsom, Aaron R; Lumley, Thomas; Fox, Ervin R; Carlson, Christopher S; Peters, Ulrike; Jackson, Rebecca D; van Duijn, Cornelia M; Uitterlinden, André G; Levy, Daniel; Rotter, Jerome I; Taylor, Herman A; Gudnason, Vilmundur; Siscovick, David S; Fornage, Myriam; Borecki, Ingrid B; Hayward, Caroline; Rudan, Igor; Chen, Y Eugene; Bottinger, Erwin P; Loos, Ruth J F; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M; Gabriel, Stacey B; O'Donnell, Christopher J; Post, Wendy S; North, Kari E; Reiner, Alexander P; Boerwinkle, Eric; Psaty, Bruce M; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P; Cupples, L Adrienne; Kooperberg, Charles; Wilson, James G; Nickerson, Deborah A; Abecasis, Goncalo R; Rich, Stephen S; Tracy, Russell P; Willer, Cristen J

2014-02-06

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

PubMed

Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Gapstur, Susan M; Gaudet, Mia M; Diver, W Ryan; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Berg, Christine D; Chanock, Stephen J; Figueroa, Jonine; Hoover, Robert N; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A; van der Luijt, Rob B; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; Tan, Gie-Hooi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N; Nord, Silje; Alnaes, Grethe I Grenaker; Giles, Graham G; Milne, Roger L; McLean, Catriona; Canzian, Federico; Trichopoulos, Dimitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Swerdlow, Anthony J; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul P D P; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

2015-04-01

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

The Development of Replicated Optical Integral Field Spectrographs and their Application to the Study of Lyman-alpha Emission at Moderate Redshifts

NASA Astrophysics Data System (ADS)

Chonis, Taylor Steven

In the upcoming era of extremely large ground-based astronomical telescopes, the design of wide-field spectroscopic survey instrumentation has become increasingly complex due to the linear growth of instrument pupil size with telescope diameter for a constant spectral resolving power. The upcoming Visible Integral field Replicable Unit Spectrograph (VIRUS), a baseline array of 150 copies of a simple integral field spectrograph that will be fed by 3:36 x 104 optical fibers on the upgraded Hobby-Eberly Telescope (HET) at McDonald Observatory, represents one of the first uses of large-scale replication to break the relationship between instrument pupil size and telescope diameter. By dividing the telescope's field of view between a large number of smaller and more manageable instruments, the total information grasp of a traditional monolithic survey spectrograph can be achieved at a fraction of the cost and engineering complexity. To highlight the power of this method, VIRUS will execute the HET Dark Energy Experiment (HETDEX) and survey & 420 degrees2 of sky to an emission line flux limit of ˜ 10-17 erg s-1 cm -2 to detect ˜ 106 Lyman-alpha emitting galaxies (LAEs) as probes of large-scale structure at redshifts of 1:9 < z < 3:5. HETDEX will precisely measure the evolution of dark energy at that epoch, and will simultaneously amass an LAE sample that will be unprecedented for extragalactic astrophysics at the redshifts of interest. Large-scale replication has clear advantages to increasing the total information grasp of a spectrograph, but there are also challenges. In this dissertation, two of these challenges with respect to VIRUS are detailed. First, the VIRUS cryogenic system is discussed, specifically the design and tests of a novel thermal connector and internal camera croygenic components that link the 150 charge-coupled device detectors to the instrument's liquid nitrogen distribution system. Second, the design, testing, and mass production of the suite of volume phase holographic (VPH) diffraction gratings for VIRUS is presented, which highlights the challenge and success associated with producing of a very large number of highly customized optical elements whose performance is crucial to meeting the efficiency requirements of the spectrograph system. To accommodate VIRUS, the HET is undergoing a substantial wide-field upgrade to increase its field of view to 22' in diameter. The previous HET facility Low Resolution Spectrograph (LRS), which was directly fed by the telescope's previous spherical aberration corrector, must be removed from the prime focus instrument package as a result of the telescope upgrades and instead be fiber-coupled to the telescope focal plane. For a similar cost as modifying LRS to accommodate these changes, a new second generation instrument (LRS2) will be based on the VIRUS unit spectrograph. The design, operational concept, construction, and laboratory testing and characterization of LRS2 is the primary focus of this dissertation, which highlights the benefits of leveraging the large engineering investment, economies of scale, and laboratory and observatory infrastructure associated with the massively replicated VIRUS instrument. LRS2 will provide integral field spectroscopy for a seeing-limited field of 12" x 6". The multiplexed VIRUS framework facilitates broad wavelength coverage from 370 nm to 1.0 mum spread between two dual-channel spectrographs at a moderate spectral resolving power of R ≈ 2000. The design departures from VIRUS are presented, including the novel integral field unit, VPH grism dispersers, and various optical changes for accommodating the broadband wavelength coverage. Laboratory testing has verified that LRS2 largely meets its image quality specification and is nearly ready for delivery to the HET where its final verification and validation tasks will be executed. LRS2 will enable the continuation of most legacy LRS science programs and provide improved capability for future investigations. (Abstract shortened by ProQuest.).

Measuring strategies for learning regulation in medical education: scale reliability and dimensionality in a Swedish sample.

PubMed

Edelbring, Samuel

2012-08-15

The degree of learners' self-regulated learning and dependence on external regulation influence learning processes in higher education. These regulation strategies are commonly measured by questionnaires developed in other settings than in which they are being used, thereby requiring renewed validation. The aim of this study was to psychometrically evaluate the learning regulation strategy scales from the Inventory of Learning Styles with Swedish medical students (N = 206). The regulation scales were evaluated regarding their reliability, scale dimensionality and interrelations. The primary evaluation focused on dimensionality and was performed with Mokken scale analysis. To assist future scale refinement, additional item analysis, such as item-to-scale correlations, was performed. Scale scores in the Swedish sample displayed good reliability in relation to published results: Cronbach's alpha: 0.82, 0.72, and 0.65 for self-regulation, external regulation and lack of regulation scales respectively. The dimensionalities in scales were adequate for self-regulation and its subscales, whereas external regulation and lack of regulation displayed less unidimensionality. The established theoretical scales were largely replicated in the exploratory analysis. The item analysis identified two items that contributed little to their respective scales. The results indicate that these scales have an adequate capacity for detecting the three theoretically proposed learning regulation strategies in the medical education sample. Further construct validity should be sought by interpreting scale scores in relation to specific learning activities. Using established scales for measuring students' regulation strategies enables a broad empirical base for increasing knowledge on regulation strategies in relation to different disciplinary settings and contributes to theoretical development.

Transfer of movement sequences: bigger is better.

PubMed

Dean, Noah J; Kovacs, Attila J; Shea, Charles H

2008-02-01

Experiment 1 was conducted to determine if proportional transfer from "small to large" scale movements is as effective as transferring from "large to small." We hypothesize that the learning of larger scale movement will require the participant to learn to manage the generation, storage, and dissipation of forces better than when practicing smaller scale movements. Thus, we predict an advantage for transfer of larger scale movements to smaller scale movements relative to transfer from smaller to larger scale movements. Experiment 2 was conducted to determine if adding a load to a smaller scale movement would enhance later transfer to a larger scale movement sequence. It was hypothesized that the added load would require the participants to consider the dynamics of the movement to a greater extent than without the load. The results replicated earlier findings of effective transfer from large to small movements, but consistent with our hypothesis, transfer was less effective from small to large (Experiment 1). However, when a load was added during acquisition transfer from small to large was enhanced even though the load was removed during the transfer test. These results are consistent with the notion that the transfer asymmetry noted in Experiment 1 was due to factors related to movement dynamics that were enhanced during practice of the larger scale movement sequence, but not during the practice of the smaller scale movement sequence. The findings that the movement structure is unaffected by transfer direction but the movement dynamics are influenced by transfer direction is consistent with hierarchal models of sequence production.

Genetically distinct populations of northern shrimp, Pandalus borealis, in the North Atlantic: adaptation to different temperatures as an isolation factor.

PubMed

Jorde, Per Erik; Søvik, Guldborg; Westgaard, Jon-Ivar; Albretsen, Jon; André, Carl; Hvingel, Carsten; Johansen, Torild; Sandvik, Anne Dagrun; Kingsley, Michael; Jørstad, Knut Eirik

2015-04-01

The large-scale population genetic structure of northern shrimp, Pandalus borealis, was investigated over the species' range in the North Atlantic, identifying multiple genetically distinct groups. Genetic divergence among sample localities varied among 10 microsatellite loci (range: FST = -0.0002 to 0.0475) with a highly significant average (FST = 0.0149; P < 0.0001). In contrast, little or no genetic differences were observed among temporal replicates from the same localities (FST = 0.0004; P = 0.33). Spatial genetic patterns were compared to geographic distances, patterns of larval drift obtained through oceanographic modelling, and temperature differences, within a multiple linear regression framework. The best-fit model included all three factors and explained approximately 29% of all spatial genetic divergence. However, geographic distance and larval drift alone had only minor effects (2.5-4.7%) on large-scale genetic differentiation patterns, whereas bottom temperature differences explained most (26%). Larval drift was found to promote genetic homogeneity in parts of the study area with strong currents, but appeared ineffective across large temperature gradients. These findings highlight the breakdown of gene flow in a species with a long pelagic larval phase (up to 3 months) and indicate a role for local adaptation to temperature conditions in promoting evolutionary diversification and speciation in the marine environment. © 2015 John Wiley & Sons Ltd.

Assessing Landscape Scale Wildfire Exposure for Highly Valued Resources in a Mediterranean Area

NASA Astrophysics Data System (ADS)

Alcasena, Fermín J.; Salis, Michele; Ager, Alan A.; Arca, Bachisio; Molina, Domingo; Spano, Donatella

2015-05-01

We used a fire simulation modeling approach to assess landscape scale wildfire exposure for highly valued resources and assets (HVR) on a fire-prone area of 680 km2 located in central Sardinia, Italy. The study area was affected by several wildfires in the last half century: some large and intense fire events threatened wildland urban interfaces as well as other socioeconomic and cultural values. Historical wildfire and weather data were used to inform wildfire simulations, which were based on the minimum travel time algorithm as implemented in FlamMap. We simulated 90,000 fires that replicated recent large fire events in the area spreading under severe weather conditions to generate detailed maps of wildfire likelihood and intensity. Then, we linked fire modeling outputs to a geospatial risk assessment framework focusing on buffer areas around HVR. The results highlighted a large variation in burn probability and fire intensity in the vicinity of HVRs, and allowed us to identify the areas most exposed to wildfires and thus to a higher potential damage. Fire intensity in the HVR buffers was mainly related to fuel types, while wind direction, topographic features, and historically based ignition pattern were the key factors affecting fire likelihood. The methodology presented in this work can have numerous applications, in the study area and elsewhere, particularly to address and inform fire risk management, landscape planning and people safety on the vicinity of HVRs.

Greenhouse gas emissions during composting of dairy manure: Delaying pile mixing does not reduce overall emissions

USDA-ARS?s Scientific Manuscript database

The effect of the timing of pile mixing on greenhouse gas (GHG) emissions during dairy manure composting was determined using large flux chambers designed to completely cover replicate pilot-scale compost piles. GHG emissions from compost piles that were mixed at 2, 3, 4, or 5 weeks after initial c...

Teacher Self-Efficacy and Occupational Stress: A Major Australian Curriculum Reform Revisited

ERIC Educational Resources Information Center

McCormick, John; Ayres, Paul L.

2009-01-01

Purpose: The purpose of this research was to study teachers' self-efficacy and occupational stress in the context of a large-scale curriculum reform in New South Wales, Australia. The study aims to follow up and replicate a study carried out approximately one year earlier. Design/methodology/approach: A theoretical framework, primarily based on…

A Multivariate Analysis of Secondary Students' Experience of Web-Based Language Acquisition

ERIC Educational Resources Information Center

Felix, Uschi

2004-01-01

This paper reports on a large-scale project designed to replicate an earlier investigation of tertiary students (Felix, 2001) in a secondary school environment. The new project was carried out in five settings, again investigating the potential of the Web as a medium of language instruction. Data was collected by questionnaires and observational…

Transition Points for the Gender Gap in Computer Enjoyment

ERIC Educational Resources Information Center

Christensen, Rhonda; Knezek, Gerald; Overall, Theresa

2005-01-01

Data gathered from 10,000 Texas public school students in Grades 3-12 over the years 2000, 2001, 2002, and 2005 were analyzed to replicate findings first discovered as a byproduct of evaluation of a large scale U.S. Department of Education Technology Innovation Challenge Grant. Initial findings were that girls in Grades 4 and 5 reported enjoying…

Accelerating development of late-successional features in second-growth pine stands of the Goosenest Adaptive Management Area

Treesearch

Martin W. Ritchie; Kathleen A. Harcksen

2005-01-01

This paper describes implementation and early results of a large-scale, interdisciplinary experiment in the Goosenest Adaptive Management Area in northeastern California. The study is designed to investigate development of late-successional forest attributes in second-growth ponderosa pine stands. The experiment has four treatments replicated five times and encompasses...

New Evidence on Self-Affirmation Effects and Theorized Sources of Heterogeneity from Large-Scale Replications

ERIC Educational Resources Information Center

Hanselman, Paul; Rozek, Christopher S.; Grigg, Jeffrey; Borman, Geoffrey D.

2017-01-01

Brief, targeted self-affirmation writing exercises have recently been offered as a way to reduce racial achievement gaps, but evidence about their effects in educational settings is mixed, leaving ambiguity about the likely benefits of these strategies if implemented broadly. A key limitation in interpreting these mixed results is that they come…

Memory Transmission in Small Groups and Large Networks: An Agent-Based Model.

PubMed

Luhmann, Christian C; Rajaram, Suparna

2015-12-01

The spread of social influence in large social networks has long been an interest of social scientists. In the domain of memory, collaborative memory experiments have illuminated cognitive mechanisms that allow information to be transmitted between interacting individuals, but these experiments have focused on small-scale social contexts. In the current study, we took a computational approach, circumventing the practical constraints of laboratory paradigms and providing novel results at scales unreachable by laboratory methodologies. Our model embodied theoretical knowledge derived from small-group experiments and replicated foundational results regarding collaborative inhibition and memory convergence in small groups. Ultimately, we investigated large-scale, realistic social networks and found that agents are influenced by the agents with which they interact, but we also found that agents are influenced by nonneighbors (i.e., the neighbors of their neighbors). The similarity between these results and the reports of behavioral transmission in large networks offers a major theoretical insight by linking behavioral transmission to the spread of information. © The Author(s) 2015.

Blood pressure loci identified with a gene-centric array.

PubMed

Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gonçalo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B

2011-12-09

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genetic and Environmental Factors Associated with Cannabis Involvement

PubMed Central

Bogdan, Ryan; Winstone, Jonathan MA; Agrawal, Arpana

2016-01-01

Approximately 50-70% of the variation in cannabis use and use disorders can be attributed to heritable factors. For cannabis use, the remaining variance can be parsed in to familial and person-specific environmental factors while for use disorders, only the latter contribute. While numerous candidate gene studies have identified the role of common variation influencing liability to cannabis involvement, replication has been elusive. To date, no genomewide association study has been sufficiently powered to identify significant loci. Despite this, studies adopting polygenic techniques and integrating genetic variation with neural phenotypes and measures of environmental risk, such as childhood adversity, are providing promising new leads. It is likely that the small effect sizes associated with variants related to cannabis involvement will only be robustly identified in substantially larger samples. Results of such large-scale efforts will provide valuable single variant targets for translational research in neurogenetic, pharmacogenetic and non-human animal models as well as polygenic risk indices that can be used to explore a host of other genetic hypotheses related to cannabis use and misuse. PMID:27642547

Genetic Variant in ACVR2B Is Associated with Lean Mass.

PubMed

Klimentidis, Yann C; Bea, Jennifer W; Thompson, Patricia; Klimecki, Walter T; Hu, Chengcheng; Wu, Guanglin; Nicholas, J Skye; Ryckman, Kelli K; Chen, Zhao

2016-07-01

Low lean mass (LM) is a risk factor for chronic disease, a major cause of disability and diminished quality of life, and is a heritable trait. However, relatively few specific genetic factors have been identified as potentially influencing this trait. In this study, we selected 1493 single-nucleotide polymorphisms (SNP) in 155 candidate genes involved in anabolic, catabolic, growth hormone, and other related pathways and examined their association with LM, assessed by dual-energy x-ray absorptiometry, in a sample of 2760 non-Hispanic and Hispanic white postmenopausal women from the Women's Health Initiative (WHI) Observational Study. We assessed the replication of our top findings in a meta-analysis of 20 genome-wide association studies (n = 38,292) conducted by the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium Musculoskeletal Working Group. We identified 32 SNPs that had nominally significant associations with LM in the WHI cohort. In the replication stage, we find that SNP rs2276541 in the activin A receptor, type IIB (ACVR2B), was significantly associated with LM (β = 0.15, P = 2.17 × 10). ACVR2B codes for a receptor for a negative regulator of skeletal muscle, myostatin, and has previously been identified in a candidate gene study as a determinant of skeletal muscle mass. Our findings support a previously proposed role of ACVR2B allelic variation as a determinant of muscle mass and extend prior findings in men and women. Additional large-scale studies will be needed to confirm our findings in different populations.

Genetic evolution of Human Enterovirus A71 subgenotype C4 in Shenzhen, China, 1998-2013.

PubMed

He, Yaqing; Zou, Linjie; Chong, Marc Ka Chun; Men, Ruoting; Xu, Wenbo; Yang, Hong; Yao, Xiangjie; Chen, Long; Xian, Huixia; Zhang, Hailong; Luo, Min; Cheng, Jinquan; Ma, Hanwu; Feng, Qianjin; Huang, Yun; Wang, Yujie; Yeoh, Eng-Kiong; Zee, Benny Chung-Ying; Zhou, Yuanping; He, Ming-Liang; Wang, Maggie Haitian

2016-06-01

Human Enterovirus A71 (EV-A71) is one of the severest enteroviruses that causes hand, foot, and mouth disease (HFMD) among children. This study identified the mutations of EV-A71 VP1 amino acid residues over a number of years and explored the possible association of identified mutations and HFMD epidemic outbreaks in Shenzhen, China. A total of 3760 stool specimens were collected from HFMD patients by Shenzhen Centers for Disease Control and Prevention (CDC) between 1998 and 2013. In total 289 VP1 strains were sequenced in this study, and amino acids mutation frequency was calculated. There were 2040 China nationwide sequences downloaded from Genebank as replication data. In our samples, 1036 subjects (27.6%) were EV-A71 infected. Three amino acid positions on VP1 protein were found to have high mutation prevalence. These are Q22H, S283T, and A289H. Site 22 showed a fast mutation fixation in the year 2008, at the time of the large scale epidemic outbreak in Shenzhen. Analysis of the nationwide data replicated the same trend of mutation prevalence of the three sites. The switching from Q to H on site 22 of the EV-A71 VP1 strain might be associated with the HFMD outbreak in Shenzhen in 2008. The identified amino acid sites 22, 283 and 289 provided information for developing anti-viral drugs against EV-A71 in the future. Copyright © 2016 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

DNA Methylation and BMI: Investigating Identified Methylation Sites at HIF3A in a Causal Framework.

PubMed

Richmond, Rebecca C; Sharp, Gemma C; Ward, Mary E; Fraser, Abigail; Lyttleton, Oliver; McArdle, Wendy L; Ring, Susan M; Gaunt, Tom R; Lawlor, Debbie A; Davey Smith, George; Relton, Caroline L

2016-05-01

Multiple differentially methylated sites and regions associated with adiposity have now been identified in large-scale cross-sectional studies. We tested for replication of associations between previously identified CpG sites at HIF3A and adiposity in ∼1,000 mother-offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC). Availability of methylation and adiposity measures at multiple time points, as well as genetic data, allowed us to assess the temporal associations between adiposity and methylation and to make inferences regarding causality and directionality. Overall, our results were discordant with those expected if HIF3A methylation has a causal effect on BMI and provided more evidence for causality in the reverse direction (i.e., an effect of BMI on HIF3A methylation). These results are based on robust evidence from longitudinal analyses and were also partially supported by Mendelian randomization analysis, although this latter analysis was underpowered to detect a causal effect of BMI on HIF3A methylation. Our results also highlight an apparent long-lasting intergenerational influence of maternal BMI on offspring methylation at this locus, which may confound associations between own adiposity and HIF3A methylation. Further work is required to replicate and uncover the mechanisms underlying the direct and intergenerational effect of adiposity on DNA methylation. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Genome-Wide Screen Reveals Valosin-Containing Protein Requirement for Coronavirus Exit from Endosomes

PubMed Central

Wong, Hui Hui; Kumar, Pankaj; Tay, Felicia Pei Ling; Moreau, Dimitri

2015-01-01

ABSTRACT Coronaviruses are RNA viruses with a large zoonotic reservoir and propensity for host switching, representing a real threat for public health, as evidenced by severe acute respiratory syndrome (SARS) and the emerging Middle East respiratory syndrome (MERS). Cellular factors required for their replication are poorly understood. Using genome-wide small interfering RNA (siRNA) screening, we identified 83 novel genes supporting infectious bronchitis virus (IBV) replication in human cells. Thirty of these hits can be placed in a network of interactions with viral proteins and are involved in RNA splicing, membrane trafficking, and ubiquitin conjugation. In addition, our screen reveals an unexpected role for valosin-containing protein (VCP/p97) in early steps of infection. Loss of VCP inhibits a previously uncharacterized degradation of the nucleocapsid N protein. This inhibition derives from virus accumulation in early endosomes, suggesting a role for VCP in the maturation of virus-loaded endosomes. The several host factors identified in this study may provide avenues for targeted therapeutics. IMPORTANCE Coronaviruses are RNA viruses representing a real threat for public health, as evidenced by SARS and the emerging MERS. However, cellular factors required for their replication are poorly understood. Using genome-wide siRNA screening, we identified novel genes supporting infectious bronchitis virus (IBV) replication in human cells. The several host factors identified in this study may provide directions for future research on targeted therapeutics. PMID:26311884

Intragenic origins due to short G1 phases underlie oncogene-induced DNA replication stress.

PubMed

Macheret, Morgane; Halazonetis, Thanos D

2018-03-01

Oncogene-induced DNA replication stress contributes critically to the genomic instability that is present in cancer. However, elucidating how oncogenes deregulate DNA replication has been impeded by difficulty in mapping replication initiation sites on the human genome. Here, using a sensitive assay to monitor nascent DNA synthesis in early S phase, we identified thousands of replication initiation sites in cells before and after induction of the oncogenes CCNE1 and MYC. Remarkably, both oncogenes induced firing of a novel set of DNA replication origins that mapped within highly transcribed genes. These ectopic origins were normally suppressed by transcription during G1, but precocious entry into S phase, before all genic regions had been transcribed, allowed firing of origins within genes in cells with activated oncogenes. Forks from oncogene-induced origins were prone to collapse, as a result of conflicts between replication and transcription, and were associated with DNA double-stranded break formation and chromosomal rearrangement breakpoints both in our experimental system and in a large cohort of human cancers. Thus, firing of intragenic origins caused by premature S phase entry represents a mechanism of oncogene-induced DNA replication stress that is relevant for genomic instability in human cancer.

A maize root tip system to study DNA replication programmes in somatic and endocycling nuclei during plant development.

PubMed

Bass, Hank W; Wear, Emily E; Lee, Tae-Jin; Hoffman, Gregg G; Gumber, Hardeep K; Allen, George C; Thompson, William F; Hanley-Bowdoin, Linda

2014-06-01

The progress of nuclear DNA replication is complex in both time and space, and may reflect several levels of chromatin structure and 3-dimensional organization within the nucleus. To understand the relationship between DNA replication and developmental programmes, it is important to examine replication and nuclear substructure in different developmental contexts including natural cell-cycle progressions in situ. Plant meristems offer an ideal opportunity to analyse such processes in the context of normal growth of an organism. Our current understanding of large-scale chromosomal DNA replication has been limited by the lack of appropriate tools to visualize DNA replication with high resolution at defined points within S phase. In this perspective, we discuss a promising new system that can be used to visualize DNA replication in isolated maize (Zea mays L.) root tip nuclei after in planta pulse labelling with the thymidine analogue, 5-ethynyl-2'-deoxyuridine (EdU). Mixed populations of EdU-labelled nuclei are then separated by flow cytometry into sequential stages of S phase and examined directly using 3-dimensional deconvolution microscopy to characterize spatial patterns of plant DNA replication. Combining spatiotemporal analyses with studies of replication and epigenetic inheritance at the molecular level enables an integrated experimental approach to problems of mitotic inheritance and cellular differentiation. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Non-steady wind turbine response to daytime atmospheric turbulence.

PubMed

Nandi, Tarak N; Herrig, Andreas; Brasseur, James G

2017-04-13

Relevant to drivetrain bearing fatigue failures, we analyse non-steady wind turbine responses from interactions between energy-dominant daytime atmospheric turbulence eddies and the rotating blades of a GE 1.5 MW wind turbine using a unique dataset from a GE field experiment and computer simulation. Time-resolved local velocity data were collected at the leading and trailing edges of an instrumented blade together with generator power, revolutions per minute, pitch and yaw. Wind velocity and temperature were measured upwind on a meteorological tower. The stability state and other atmospheric conditions during the field experiment were replicated with a large-eddy simulation in which was embedded a GE 1.5 MW wind turbine rotor modelled with an advanced actuator line method. Both datasets identify three important response time scales: advective passage of energy-dominant eddies (≈25-50 s), blade rotation (once per revolution (1P), ≈3 s) and sub-1P scale (<1 s) response to internal eddy structure. Large-amplitude short-time ramp-like and oscillatory load fluctuations result in response to temporal changes in velocity vector inclination in the aerofoil plane, modulated by eddy passage at longer time scales. Generator power responds strongly to large-eddy wind modulations. We show that internal dynamics of the blade boundary layer near the trailing edge is temporally modulated by the non-steady external flow that was measured at the leading edge, as well as blade-generated turbulence motions.This article is part of the themed issue 'Wind energy in complex terrains'. © 2017 The Author(s).

Non-steady wind turbine response to daytime atmospheric turbulence

PubMed Central

Nandi, Tarak N.; Herrig, Andreas

2017-01-01

Relevant to drivetrain bearing fatigue failures, we analyse non-steady wind turbine responses from interactions between energy-dominant daytime atmospheric turbulence eddies and the rotating blades of a GE 1.5 MW wind turbine using a unique dataset from a GE field experiment and computer simulation. Time-resolved local velocity data were collected at the leading and trailing edges of an instrumented blade together with generator power, revolutions per minute, pitch and yaw. Wind velocity and temperature were measured upwind on a meteorological tower. The stability state and other atmospheric conditions during the field experiment were replicated with a large-eddy simulation in which was embedded a GE 1.5 MW wind turbine rotor modelled with an advanced actuator line method. Both datasets identify three important response time scales: advective passage of energy-dominant eddies (≈25–50 s), blade rotation (once per revolution (1P), ≈3 s) and sub-1P scale (<1 s) response to internal eddy structure. Large-amplitude short-time ramp-like and oscillatory load fluctuations result in response to temporal changes in velocity vector inclination in the aerofoil plane, modulated by eddy passage at longer time scales. Generator power responds strongly to large-eddy wind modulations. We show that internal dynamics of the blade boundary layer near the trailing edge is temporally modulated by the non-steady external flow that was measured at the leading edge, as well as blade-generated turbulence motions. This article is part of the themed issue ‘Wind energy in complex terrains’. PMID:28265026

Brief Report: An Independent Replication and Extension of Psychometric Evidence Supporting the Theory of Mind Inventory.

PubMed

Greenslade, Kathryn J; Coggins, Truman E

2016-08-01

This study presents an independent replication and extension of psychometric evidence supporting the Theory of Mind Inventory (ToMI). Parents of 20 children with ASD (4; 1-6; 7 years; months) and 20 with typical development (3; 1-6; 5), rated their child's theory of mind abilities in everyday situations. Other parent report and child behavioral assessments included the Social Responsiveness Scale-2, Vineland Adaptive Behavior Scales-2, Peabody Picture Vocabulary Test-4, and Clinical Evaluation of Language Fundamentals-Preschool, 2. Results revealed high internal consistency, expected developmental changes in children with typical development, expected group differences between children with and without ASD, and strong correlations with other measures of social and communication abilities. The ToMI demonstrates strong psychometrics, suggesting considerable utility in identifying theory of mind deficits in children with ASD.

Open chromatin structures regulate the efficiencies of pre-RC formation and replication initiation in Epstein-Barr virus

PubMed Central

Papior, Peer; Arteaga-Salas, José M.; Günther, Thomas; Grundhoff, Adam

2012-01-01

Whether or not metazoan replication initiates at random or specific but flexible sites is an unsolved question. The lack of sequence specificity in origin recognition complex (ORC) DNA binding complicates genome-scale chromatin immunoprecipitation (ChIP)-based studies. Epstein-Barr virus (EBV) persists as chromatinized minichromosomes that are replicated by the host replication machinery. We used EBV to investigate the link between zones of pre-replication complex (pre-RC) assembly, replication initiation, and micrococcal nuclease (MNase) sensitivity at different cell cycle stages in a genome-wide fashion. The dyad symmetry element (DS) of EBV’s latent origin, a well-established and very efficient pre-RC assembly region, served as an internal control. We identified 64 pre-RC zones that correlate spatially with 57 short nascent strand (SNS) zones. MNase experiments revealed that pre-RC and SNS zones were linked to regions of increased MNase sensitivity, which is a marker of origin strength. Interestingly, although spatially correlated, pre-RC and SNS zones were characterized by different features. We propose that pre-RCs are formed at flexible but distinct sites, from which only a few are activated per single genome and cell cycle. PMID:22891264

Analysis of JC virus DNA replication using a quantitative and high-throughput assay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shin, Jong; Phelan, Paul J.; Chhum, Panharith

2014-11-15

Progressive Multifocal Leukoencephalopathy (PML) is caused by lytic replication of JC virus (JCV) in specific cells of the central nervous system. Like other polyomaviruses, JCV encodes a large T-antigen helicase needed for replication of the viral DNA. Here, we report the development of a luciferase-based, quantitative and high-throughput assay of JCV DNA replication in C33A cells, which, unlike the glial cell lines Hs 683 and U87, accumulate high levels of nuclear T-ag needed for robust replication. Using this assay, we investigated the requirement for different domains of T-ag, and for specific sequences within and flanking the viral origin, in JCVmore » DNA replication. Beyond providing validation of the assay, these studies revealed an important stimulatory role of the transcription factor NF1 in JCV DNA replication. Finally, we show that the assay can be used for inhibitor testing, highlighting its value for the identification of antiviral drugs targeting JCV DNA replication. - Highlights: • Development of a high-throughput screening assay for JCV DNA replication using C33A cells. • Evidence that T-ag fails to accumulate in the nuclei of established glioma cell lines. • Evidence that NF-1 directly promotes JCV DNA replication in C33A cells. • Proof-of-concept that the HTS assay can be used to identify pharmacological inhibitor of JCV DNA replication.« less

Symbolic magnitude processing in elementary school children: A group administered paper-and-pencil measure (SYMP Test).

PubMed

Brankaer, Carmen; Ghesquière, Pol; De Smedt, Bert

2017-08-01

The ability to compare symbolic numerical magnitudes correlates with children's concurrent and future mathematics achievement. We developed and evaluated a quick timed paper-and-pencil measure that can easily be used, for example in large-scale research, in which children have to cross out the numerically larger of two Arabic one- and two-digit numbers (SYMP Test). We investigated performance on this test in 1,588 primary school children (Grades 1-6) and examined in each grade its associations with mathematics achievement. The SYMP Test had satisfactory test-retest reliability. The SYMP Test showed significant and stable correlations with mathematics achievement for both one-digit and two-digit comparison, across all grades. This replicates the previously observed association between symbolic numerical magnitude processing and mathematics achievement, but extends it by showing that the association is observed in all grades in primary education and occurs for single- as well as multi-digit processing. Children with mathematical learning difficulties performed significantly lower on one-digit comparison and two-digit comparison in all grades. This all suggests satisfactory construct and criterion-related validity of the SYMP Test, which can be used in research, when performing large-scale (intervention) studies, and by practitioners, as screening measure to identify children at risk for mathematical difficulties or dyscalculia.

Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis.

PubMed

Wei, Wen-Hua; Bowes, John; Plant, Darren; Viatte, Sebastien; Yarwood, Annie; Massey, Jonathan; Worthington, Jane; Eyre, Stephen

2016-04-25

Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals.

Investigation of Hydrological Response of Three Identical Artificial Hillslopes at the Landscape Evolution Observatory

NASA Astrophysics Data System (ADS)

Matos, K.; Alves Meira Neto, A.; Troch, P. A. A.; Volkmann, T.

2017-12-01

Hydrological processes at the hillslope scale are complex and heterogeneous, but monitoring hillslopes with a large number of sensors or replicate experimental designs is rarely feasible. The Landscape Evolution Observatory (LEO) at Biosphere 2 consists of three replicated, large (330 m2) artificial hillslopes (East, Center and West) packed with 1-m depth of initially homogeneous, basaltic soil. Each landscape contains a spatially dense network of sensors capable of resolving meter-scale lateral heterogeneity and sub-meter scale vertical heterogeneity in moisture content and water potential, as well as the hillslope-integrated water balance components. A sophisticated irrigation system allows performing controlled forcing experiments. The three hillslopes are thought to be nearly identical, however recent data showed significant differences in discharge and storage behavior. A 45-day periodic-steady-state tracer experiment was conducted in November and December of 2016, where a 3.5-day long, identical irrigation sequence was repeated 15 times. Each sequence's rainfall, runoff, and storage dynamics were recorded, and distributed moisture characteristics were derived using paired moisture content and matric potential data from 496 positions in each hillslope. In order to understand why the three hillslopes behave hydrologically different, we analyzed soil water retention characteristics at various scales ranging from individually paired moisture and matric potential to whole-hillslope soil water retention characteristics. The results confirm the distinct hydrological behavior between the three hillslopes. The East and West hillslopes behave more similar with respect to the release of water. In contrast, the East and Center hillslopes are more similar with respect to their storage behavior. The differences in hillslope behavior arising from three identically built hillslopes are a surprising and beneficial opportunity to explore how differences in small-scale heterogeneity can impact hydrological dynamics at the hillslope scale.

Genetic Variation in the Prostaglandin E2 Pathway Is Associated with Primary Graft Dysfunction

PubMed Central

Akimova, Tatiana; Kazi, Altaf; Shah, Rupal J.; Cantu, Edward; Feng, Rui; Levine, Matthew H.; Kawut, Steven M.; Meyer, Nuala J.; Lee, James C.; Hancock, Wayne W.; Aplenc, Richard; Ware, Lorraine B.; Palmer, Scott M.; Bhorade, Sangeeta; Lama, Vibha N.; Weinacker, Ann; Orens, Jonathan; Wille, Keith; Crespo, Maria; Lederer, David J.; Arcasoy, Selim; Demissie, Ejigayehu; Christie, Jason D.

2014-01-01

Rationale: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. Objectives: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. Methods: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. Measurements and Main Results: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 × 10−5) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5′ promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 × 10−5). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. Conclusions: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted. PMID:24467603

Cascading Effects of Canopy Opening and Debris Deposition from a Large-Scale Hurricane Experiment in a Tropical Rain Forest

Treesearch

Aaron B. Shiels; Grizelle Gonzalez; D. Jean Lodge; Michael R Willig; Jess K. Zimmerman

2015-01-01

Intense hurricanes disturb many tropical forests, but the key mechanisms driving post-hurricane forest changes are not fully understood. In Puerto Rico, we used a replicated factorial experiment to determine the mechanisms of forest change associated with canopy openness and organic matter (debris) addition. Cascading effects from canopy openness accounted for...

Influence of winter-spring livestock grazing on survival and growth of Quercus lobata and Q. agrifolia seedlings

Treesearch

Claudia M. Tyler; Bruce E. Mahall; Frank W. Davis

2008-01-01

The relative importance of livestock grazing in limiting or enhancing oak recruitment remains unclear because results from previous studies have been contradictory. In Santa Barbara County, we have replicated large-scale planting experiments from 1997 to 2001 to determine the effects of cattle and other factors on seedling establishment of valley oak (Quercus...

New Evidence on Self-Affirmation Effects and Theorized Sources of Heterogeneity from Two Cohorts in a Large-Scale Replication

ERIC Educational Resources Information Center

Hanselman, Paul; Rozek, Christopher S.; Grigg, Jeffrey; Pyne, Jaymes; Borman, Geoffrey

2016-01-01

One approach to reducing persistent racial/ethnic achievement gaps is to tackle their social-psychological dimensions, including the negative consequences of stereotype threat and other identity threats in school. Initial research suggested that a particularly promising approach is brief self-affirmation writing exercises for 7th grade students;…

Complex dynamics and empirical evidence (Invited Paper)

NASA Astrophysics Data System (ADS)

Delli Gatti, Domenico; Gaffeo, Edoardo; Giulioni, Gianfranco; Gallegati, Mauro; Kirman, Alan; Palestrini, Antonio; Russo, Alberto

2005-05-01

Standard macroeconomics, based on a reductionist approach centered on the representative agent, is badly equipped to explain the empirical evidence where heterogeneity and industrial dynamics are the rule. In this paper we show that a simple agent-based model of heterogeneous financially fragile agents is able to replicate a large number of scaling type stylized facts with a remarkable degree of statistical precision.

Integrity of chromatin and replicating DNA in nuclei released from fission yeast by semi-automated grinding in liquid nitrogen

PubMed Central

2011-01-01

Background Studies of nuclear function in many organisms, especially those with tough cell walls, are limited by lack of availability of simple, economical methods for large-scale preparation of clean, undamaged nuclei. Findings Here we present a useful method for nuclear isolation from the important model organism, the fission yeast, Schizosaccharomyces pombe. To preserve in vivo molecular configurations, we flash-froze the yeast cells in liquid nitrogen. Then we broke their tough cell walls, without damaging their nuclei, by grinding in a precision-controlled motorized mortar-and-pestle apparatus. The cryo-ground cells were resuspended and thawed in a buffer designed to preserve nuclear morphology, and the nuclei were enriched by differential centrifugation. The washed nuclei were free from contaminating nucleases and have proven well-suited as starting material for genome-wide chromatin analysis and for preparation of fragile DNA replication intermediates. Conclusions We have developed a simple, reproducible, economical procedure for large-scale preparation of endogenous-nuclease-free, morphologically intact nuclei from fission yeast. With appropriate modifications, this procedure may well prove useful for isolation of nuclei from other organisms with, or without, tough cell walls. PMID:22088094

Integrity of chromatin and replicating DNA in nuclei released from fission yeast by semi-automated grinding in liquid nitrogen.

PubMed

Givens, Robert M; Mesner, Larry D; Hamlin, Joyce L; Buck, Michael J; Huberman, Joel A

2011-11-16

Studies of nuclear function in many organisms, especially those with tough cell walls, are limited by lack of availability of simple, economical methods for large-scale preparation of clean, undamaged nuclei. Here we present a useful method for nuclear isolation from the important model organism, the fission yeast, Schizosaccharomyces pombe. To preserve in vivo molecular configurations, we flash-froze the yeast cells in liquid nitrogen. Then we broke their tough cell walls, without damaging their nuclei, by grinding in a precision-controlled motorized mortar-and-pestle apparatus. The cryo-ground cells were resuspended and thawed in a buffer designed to preserve nuclear morphology, and the nuclei were enriched by differential centrifugation. The washed nuclei were free from contaminating nucleases and have proven well-suited as starting material for genome-wide chromatin analysis and for preparation of fragile DNA replication intermediates. We have developed a simple, reproducible, economical procedure for large-scale preparation of endogenous-nuclease-free, morphologically intact nuclei from fission yeast. With appropriate modifications, this procedure may well prove useful for isolation of nuclei from other organisms with, or without, tough cell walls.

Self-organizing network services with evolutionary adaptation.

PubMed

Nakano, Tadashi; Suda, Tatsuya

2005-09-01

This paper proposes a novel framework for developing adaptive and scalable network services. In the proposed framework, a network service is implemented as a group of autonomous agents that interact in the network environment. Agents in the proposed framework are autonomous and capable of simple behaviors (e.g., replication, migration, and death). In this paper, an evolutionary adaptation mechanism is designed using genetic algorithms (GAs) for agents to evolve their behaviors and improve their fitness values (e.g., response time to a service request) to the environment. The proposed framework is evaluated through simulations, and the simulation results demonstrate the ability of autonomous agents to adapt to the network environment. The proposed framework may be suitable for disseminating network services in dynamic and large-scale networks where a large number of data and services need to be replicated, moved, and deleted in a decentralized manner.

A parallel genome-wide RNAi screening strategy to identify host proteins important for entry of Marburg virus and H5N1 influenza virus.

PubMed

Cheng, Han; Koning, Katie; O'Hearn, Aileen; Wang, Minxiu; Rumschlag-Booms, Emily; Varhegyi, Elizabeth; Rong, Lijun

2015-11-24

Genome-wide RNAi screening has been widely used to identify host proteins involved in replication and infection of different viruses, and numerous host factors are implicated in the replication cycles of these viruses, demonstrating the power of this approach. However, discrepancies on target identification of the same viruses by different groups suggest that high throughput RNAi screening strategies need to be carefully designed, developed and optimized prior to the large scale screening. Two genome-wide RNAi screens were performed in parallel against the entry of pseudotyped Marburg viruses and avian influenza virus H5N1 utilizing an HIV-1 based surrogate system, to identify host factors which are important for virus entry. A comparative analysis approach was employed in data analysis, which alleviated systematic positional effects and reduced the false positive number of virus-specific hits. The parallel nature of the strategy allows us to easily identify the host factors for a specific virus with a greatly reduced number of false positives in the initial screen, which is one of the major problems with high throughput screening. The power of this strategy is illustrated by a genome-wide RNAi screen for identifying the host factors important for Marburg virus and/or avian influenza virus H5N1 as described in this study. This strategy is particularly useful for highly pathogenic viruses since pseudotyping allows us to perform high throughput screens in the biosafety level 2 (BSL-2) containment instead of the BSL-3 or BSL-4 for the infectious viruses, with alleviated safety concerns. The screening strategy together with the unique comparative analysis approach makes the data more suitable for hit selection and enables us to identify virus-specific hits with a much lower false positive rate.

Inhibition of HIV-1 Replication by Secondary Metabolites From Endophytic Fungi of Desert Plants

PubMed Central

Wellensiek, Brian P.; Ramakrishnan, Rajesh; Bashyal, Bharat P.; Eason, Yvette; Gunatilaka, A. A. Leslie; Ahmad, Nafees

2013-01-01

Most antiretroviral drugs currently in use to treat an HIV-1 infection are chemically synthesized and lead to the development of viral resistance, as well as cause severe toxicities. However, a largely unexplored source for HIV-1 drug discovery is endophytic fungi that live in a symbiotic relationship with plants. These fungi produce biologically active secondary metabolites, which are natural products that are beneficial to the host. We prepared several hundred extracts from endophytic fungi of desert plants and evaluated the inhibitory effects on HIV-1 replication of those extracts that showed less than 30% cytotoxicity in T-lymphocytes. Those extracts that inhibited viral replication were fractionated in order to isolate the compounds responsible for activity. Multiple rounds of fractionation and antiviral evaluation lead to the identification of four compounds, which almost completely impede HIV-1 replication. These studies demonstrate that metabolites from endophytic fungi of desert plants can serve as a viable source for identifying potent inhibitors of HIV-1 replication. PMID:23961302

Meta-analysis of heterogeneous data sources for genome-scale identification of risk genes in complex phenotypes.

PubMed

Pers, Tune H; Hansen, Niclas Tue; Lage, Kasper; Koefoed, Pernille; Dworzynski, Piotr; Miller, Martin Lee; Flint, Tracey J; Mellerup, Erling; Dam, Henrik; Andreassen, Ole A; Djurovic, Srdjan; Melle, Ingrid; Børglum, Anders D; Werge, Thomas; Purcell, Shaun; Ferreira, Manuel A; Kouskoumvekaki, Irene; Workman, Christopher T; Hansen, Torben; Mors, Ole; Brunak, Søren

2011-07-01

Meta-analyses of large-scale association studies typically proceed solely within one data type and do not exploit the potential complementarities in other sources of molecular evidence. Here, we present an approach to combine heterogeneous data from genome-wide association (GWA) studies, protein-protein interaction screens, disease similarity, linkage studies, and gene expression experiments into a multi-layered evidence network which is used to prioritize the entire protein-coding part of the genome identifying a shortlist of candidate genes. We report specifically results on bipolar disorder, a genetically complex disease where GWA studies have only been moderately successful. We validate one such candidate experimentally, YWHAH, by genotyping five variations in 640 patients and 1,377 controls. We found a significant allelic association for the rs1049583 polymorphism in YWHAH (adjusted P = 5.6e-3) with an odds ratio of 1.28 [1.12-1.48], which replicates a previous case-control study. In addition, we demonstrate our approach's general applicability by use of type 2 diabetes data sets. The method presented augments moderately powered GWA data, and represents a validated, flexible, and publicly available framework for identifying risk genes in highly polygenic diseases. The method is made available as a web service at www.cbs.dtu.dk/services/metaranker. © 2011 Wiley-Liss, Inc.

High-throughput analysis of yeast replicative aging using a microfluidic system

PubMed Central

Jo, Myeong Chan; Liu, Wei; Gu, Liang; Dang, Weiwei; Qin, Lidong

2015-01-01

Saccharomyces cerevisiae has been an important model for studying the molecular mechanisms of aging in eukaryotic cells. However, the laborious and low-throughput methods of current yeast replicative lifespan assays limit their usefulness as a broad genetic screening platform for research on aging. We address this limitation by developing an efficient, high-throughput microfluidic single-cell analysis chip in combination with high-resolution time-lapse microscopy. This innovative design enables, to our knowledge for the first time, the determination of the yeast replicative lifespan in a high-throughput manner. Morphological and phenotypical changes during aging can also be monitored automatically with a much higher throughput than previous microfluidic designs. We demonstrate highly efficient trapping and retention of mother cells, determination of the replicative lifespan, and tracking of yeast cells throughout their entire lifespan. Using the high-resolution and large-scale data generated from the high-throughput yeast aging analysis (HYAA) chips, we investigated particular longevity-related changes in cell morphology and characteristics, including critical cell size, terminal morphology, and protein subcellular localization. In addition, because of the significantly improved retention rate of yeast mother cell, the HYAA-Chip was capable of demonstrating replicative lifespan extension by calorie restriction. PMID:26170317

A Gene Co-Expression Network in Whole Blood of Schizophrenia Patients Is Independent of Antipsychotic-Use and Enriched for Brain-Expressed Genes

PubMed Central

de Jong, Simone; Boks, Marco P. M.; Fuller, Tova F.; Strengman, Eric; Janson, Esther; de Kovel, Carolien G. F.; Ori, Anil P. S.; Vi, Nancy; Mulder, Flip; Blom, Jan Dirk; Glenthøj, Birte; Schubart, Chris D.; Cahn, Wiepke; Kahn, René S.; Horvath, Steve; Ophoff, Roel A.

2012-01-01

Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network. PMID:22761806

Lunar and Planetary Science XXXVI, Part 2

NASA Technical Reports Server (NTRS)

2005-01-01

Topics covered include: Ringwoodite-olivine assemblages in Dhofar L6 melt veins; Amorphization of forsterite grains due to high energy heavy ion irradiation: Implications for grain processing in ISM; Validation of AUTODYN in replicating large-scale planetary impact events; A network of geophysical observatories for mars; Modelling catastrophic floods on the surface of mars; Impact into coarse grained spheres; The diderot meteorite: The second chassignite; Galileo global color mosaics of Io; Ganymede's sulci on global and regional scales; and The cold traps near the south pole of the moon.

Investigate zero-stress replicated optics

NASA Technical Reports Server (NTRS)

Engelhaupt, Darell; Rood, Robert

1993-01-01

The contracted activities for the procurement of 'Investigate Zero-Stress Replicated Optics' to support the AXAF-S x-ray spectrometer mirrors has been completed. To date four large Wolter I grazing incidence x-ray optical shells have been electroformed from nickel. The mirrors were fabricated utilizing each of two nickel alloy plated aluminum substrates twice. A wide variety of testing has been completed by NASA MSFC and UAH. This testing includes heat treatment control tests, subscale plating and fixture testing, alloy control of the electroless nickel, adhesion and release testing of the gold to electroless nickel, electroforming instrumentation and software and fabrication of subscale models. The full scale shells are one millimeter thick nickel electrodeposited over a thin gold layer which in turn has the optical surface on the inside. The optical surface is the replicate of the surface prepared on the substrate. Appendix I briefly outlines the fabrication process. Major objectives which were shared by UAH and MSFC include the design of facilities, equipment and tooling and procurement of materials and equipment. Process development followed with the fabrication of small scale pilot units. Procurement commenced immediately and equipment and materials were ordered to implement the fabrication of first surface full scale substrates (mandrels) and the second surface electroformed optical components. All principal objectives have been achieved. Inspection of the mirrors in visible and x-ray modes validates that the required performance and the quality can be achieved by an electroforming replication process. A very distinct progressive improvement has been achieved with each of the four mirrors produced. The final mirror exceeded the original goals and set an improved standard for flight hardware. The future goal of a 30 arc second resolution at 8 KEV x-ray appears to be achievable by this process when proper cleanliness and process control is utilized.

Performance analysis of data intensive cloud systems based on data management and replication: a survey

DOE Office of Scientific and Technical Information (OSTI.GOV)

Malik, Saif Ur Rehman; Khan, Samee U.; Ewen, Sam J.

2015-03-14

As we delve deeper into the ‘Digital Age’, we witness an explosive growth in the volume, velocity, and variety of the data available on the Internet. For example, in 2012 about 2.5 quintillion bytes of data was created on a daily basis that originated from myriad of sources and applications including mobiledevices, sensors, individual archives, social networks, Internet of Things, enterprises, cameras, software logs, etc. Such ‘Data Explosions’ has led to one of the most challenging research issues of the current Information and Communication Technology era: how to optimally manage (e.g., store, replicated, filter, and the like) such large amountmore » of data and identify new ways to analyze large amounts of data for unlocking information. It is clear that such large data streams cannot be managed by setting up on-premises enterprise database systems as it leads to a large up-front cost in buying and administering the hardware and software systems. Therefore, next generation data management systems must be deployed on cloud. The cloud computing paradigm provides scalable and elastic resources, such as data and services accessible over the Internet Every Cloud Service Provider must assure that data is efficiently processed and distributed in a way that does not compromise end-users’ Quality of Service (QoS) in terms of data availability, data search delay, data analysis delay, and the like. In the aforementioned perspective, data replication is used in the cloud for improving the performance (e.g., read and write delay) of applications that access data. Through replication a data intensive application or system can achieve high availability, better fault tolerance, and data recovery. In this paper, we survey data management and replication approaches (from 2007 to 2011) that are developed by both industrial and research communities. The focus of the survey is to discuss and characterize the existing approaches of data replication and management that tackle the resource usage and QoS provisioning with different levels of efficiencies. Moreover, the breakdown of both influential expressions (data replication and management) to provide different QoS attributes is deliberated. Furthermore, the performance advantages and disadvantages of data replication and management approaches in the cloud computing environments are analyzed. Open issues and future challenges related to data consistency, scalability, load balancing, processing and placement are also reported.« less

Future of the Particle Replication in Nonwetting Templates (PRINT) Technology

PubMed Central

Xu, Jing; Wong, Dominica H. C.; Byrne, James D.; Chen, Kai; Bowerman, Charles

2014-01-01

Particle replication in nonwetting templates (PRINT) is a continuous, roll-to-roll, high-resolution molding technology which allows the design and synthesis of precisely defined micro- and nanoparticles. This technology adapts the lithographic techniques from the microelectronics industry and marries these with the roll-to-roll processes from the photographic film industry to enable researchers to have unprecedented control over particle size, shape, chemical composition, cargo, modulus, and surface properties. In addition, PRINT is a GMP-compliant (GMP = good manufacturing practice) platform amenable for particle fabrication on a large scale. Herein, we describe some of our most recent work involving the PRINT technology for application in the biomedical and material sciences. PMID:23670869

The Characteristics of Turbulent Flows on Forested Floodplains

NASA Astrophysics Data System (ADS)

Darby, S. E.; Richardson, K.; Sear, D. A.

2008-12-01

Forested floodplain environments represent the undisturbed land cover of most river systems, but they are under threat from human activities. An understanding of forest floodplain processes therefore has relevance to ecosystem conservation and restoration, and the interpretation of pre-historic river and floodplain evolution. However, relatively little research has been undertaken within forested floodplain environments, a particular limitation being an absence of empirical data regarding the hydraulic characteristics of over bank flows, which inhibits the development of flow, sediment and solute transport models. Forest floodplain flows are strongly modified by floodplain topography and the presence of vegetation and organic debris on the woodland floor. In such instances flow blockage and diversions are common, and there is the possibility of intense turbulence generation, both by wakes and by shear. To address this gap we have undertaken a study based on a floodplain reach located in the Highland Water Research Catchment (southern England), a UK national reference site for lowland floodplain forest streams. Given the difficulties of acquiring spatially-distributed hydraulic data sets during floods, our methodological approach has been to attempt to replicate over bank flow observed at the study site within a laboratory flume. This is necessary to acquire flow velocity data at sufficiently high spatial resolution to evaluate the underlying flow mechanics and has been achieved using (i) a large (21m) flume to achieve 1:1 hydraulic scaling and (ii) a novel method of precisely replicating the floodplain topography within the flume. Specifically, accurate replication of a representative floodplain patch was achieved by creating a 1:1 scale Physical Terrain Model (PTM) from high-density polyurethane using a computer-controlled milling process based on Digital Terrain Model (DTM) data, the latter acquired via terrestrial laser scanning (TLS) survey. The PTM was deployed within the flume immediately downstream of a 8m long hydraulically smooth 'run-in' section with a steady discharge replicating an over bank flow observed in the field, thus achieving 1:1 hydraulic scaling. Above the PTM 3D flow velocity time-series were acquired at each node on a dense (5-10cm horizontal spatial resolution) sampling grid using Acoustic Doppler Velocimeters (ADVs). The data were analysed by visualising the 3D structure of flow velocity and derivative statistics (turbulent intensity, turbulent kinetic energy, Reynolds stresses, etc), combined with quadrant analysis to identify the spatial variation of each quadrant's contribution to the turbulence intensity. These analyses have been used to delineate flow regions dominated by different structures, and construct an empirical model that will be helpful in defining relevant modelling strategies in future research.

Validation of the BESS TRS-P Structure with an Independent Sample of Teacher Ratings

ERIC Educational Resources Information Center

DiStefano, Christine; Greer, Fred; Liu, Jin

2016-01-01

The underlying structure of the Behavioral and Emotional Screening System, Teacher Rating Scale-Preschool was investigated with a replication sample. Ratings from more than 3,000 students were used and four alternative models were investigated. As with prior research, a bifactor model with four factors was identified. The results supported an…

VIRUS: first deployment of the massively replicated fiber integral field spectrograph for the upgraded Hobby-Eberly Telescope

NASA Astrophysics Data System (ADS)

Hill, Gary J.; Tuttle, Sarah E.; Vattiat, Brian L.; Lee, Hanshin; Drory, Niv; Kelz, Andreas; Ramsey, Jason; Peterson, Trent W.; DePoy, D. L.; Marshall, J. L.; Gebhardt, Karl; Chonis, Taylor; Dalton, Gavin; Farrow, Daniel; Good, John M.; Haynes, Dionne M.; Indahl, Briana L.; Jahn, Thomas; Kriel, Hermanus; Montesano, Francesco; Nicklas, Harald; Noyola, Eva; Prochaska, Travis; Allen, Richard D.; Bender, Ralf; Blanc, Guillermo; Fabricius, Maximilian H.; Finkelstein, Steve; Landriau, Martin; MacQueen, Phillip J.; Roth, M. M.; Savage, R. D.; Snigula, Jan M.; Anwad, Heiko

2016-08-01

The Visible Integral-field Replicable Unit Spectrograph (VIRUS) consists of 156 identical spectrographs (arrayed as 78 pairs) fed by 35,000 fibers, each 1.5 arcsec diameter, at the focus of the upgraded 10 m Hobby-Eberly Telescope (HET). VIRUS has a fixed bandpass of 350-550 nm and resolving power R 700. VIRUS is the first example of industrial-scale replication applied to optical astronomy and is capable of surveying large areas of sky, spectrally. The VIRUS concept offers significant savings of engineering effort, cost, and schedule when compared to traditional instruments. The main motivator for VIRUS is to map the evolution of dark energy for the Hobby-Eberly Telescope Dark Energy Experiment (HETDEX‡), using 0.8M Lyman-alpha emitting galaxies as tracers. The VIRUS array is undergoing staged deployment during 2016 and 2017. It will provide a powerful new facility instrument for the HET, well suited to the survey niche of the telescope, and will open up large spectroscopic surveys of the emission line universe for the first time. We will review the production, lessons learned in reaching volume production, characterization, and first deployment of this massive instrument.

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome.

PubMed

Morgan, Thomas M; House, John A; Cresci, Sharon; Jones, Philip; Allayee, Hooman; Hazen, Stanley L; Patel, Yesha; Patel, Riyaz S; Eapen, Danny J; Waddy, Salina P; Quyyumi, Arshed A; Kleber, Marcus E; März, Winfried; Winkelmann, Bernhard R; Boehm, Bernhard O; Krumholz, Harlan M; Spertus, John A

2011-09-29

Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

Network-directed cis-mediator analysis of normal prostate tissue expression profiles reveals downstream regulatory associations of prostate cancer susceptibility loci.

PubMed

Larson, Nicholas B; McDonnell, Shannon K; Fogarty, Zach; Larson, Melissa C; Cheville, John; Riska, Shaun; Baheti, Saurabh; Weber, Alexandra M; Nair, Asha A; Wang, Liang; O'Brien, Daniel; Davila, Jaime; Schaid, Daniel J; Thibodeau, Stephen N

2017-10-17

Large-scale genome-wide association studies have identified multiple single-nucleotide polymorphisms associated with risk of prostate cancer. Many of these genetic variants are presumed to be regulatory in nature; however, follow-up expression quantitative trait loci (eQTL) association studies have to-date been restricted largely to cis -acting associations due to study limitations. While trans -eQTL scans suffer from high testing dimensionality, recent evidence indicates most trans -eQTL associations are mediated by cis -regulated genes, such as transcription factors. Leveraging a data-driven gene co-expression network, we conducted a comprehensive cis -mediator analysis using RNA-Seq data from 471 normal prostate tissue samples to identify downstream regulatory associations of previously identified prostate cancer risk variants. We discovered multiple trans -eQTL associations that were significantly mediated by cis -regulated transcripts, four of which involved risk locus 17q12, proximal transcription factor HNF1B , and target trans -genes with known HNF response elements ( MIA2 , SRC , SEMA6A , KIF12 ). We additionally identified evidence of cis -acting down-regulation of MSMB via rs10993994 corresponding to reduced co-expression of NDRG1 . The majority of these cis -mediator relationships demonstrated trans -eQTL replicability in 87 prostate tissue samples from the Gene-Tissue Expression Project. These findings provide further biological context to known risk loci and outline new hypotheses for investigation into the etiology of prostate cancer.

A large-scale forest fragmentation experiment: the Stability of Altered Forest Ecosystems Project.

PubMed

Ewers, Robert M; Didham, Raphael K; Fahrig, Lenore; Ferraz, Gonçalo; Hector, Andy; Holt, Robert D; Kapos, Valerie; Reynolds, Glen; Sinun, Waidi; Snaddon, Jake L; Turner, Edgar C

2011-11-27

Opportunities to conduct large-scale field experiments are rare, but provide a unique opportunity to reveal the complex processes that operate within natural ecosystems. Here, we review the design of existing, large-scale forest fragmentation experiments. Based on this review, we develop a design for the Stability of Altered Forest Ecosystems (SAFE) Project, a new forest fragmentation experiment to be located in the lowland tropical forests of Borneo (Sabah, Malaysia). The SAFE Project represents an advance on existing experiments in that it: (i) allows discrimination of the effects of landscape-level forest cover from patch-level processes; (ii) is designed to facilitate the unification of a wide range of data types on ecological patterns and processes that operate over a wide range of spatial scales; (iii) has greater replication than existing experiments; (iv) incorporates an experimental manipulation of riparian corridors; and (v) embeds the experimentally fragmented landscape within a wider gradient of land-use intensity than do existing projects. The SAFE Project represents an opportunity for ecologists across disciplines to participate in a large initiative designed to generate a broad understanding of the ecological impacts of tropical forest modification.

A large-scale forest fragmentation experiment: the Stability of Altered Forest Ecosystems Project

PubMed Central

Ewers, Robert M.; Didham, Raphael K.; Fahrig, Lenore; Ferraz, Gonçalo; Hector, Andy; Holt, Robert D.; Kapos, Valerie; Reynolds, Glen; Sinun, Waidi; Snaddon, Jake L.; Turner, Edgar C.

2011-01-01

Opportunities to conduct large-scale field experiments are rare, but provide a unique opportunity to reveal the complex processes that operate within natural ecosystems. Here, we review the design of existing, large-scale forest fragmentation experiments. Based on this review, we develop a design for the Stability of Altered Forest Ecosystems (SAFE) Project, a new forest fragmentation experiment to be located in the lowland tropical forests of Borneo (Sabah, Malaysia). The SAFE Project represents an advance on existing experiments in that it: (i) allows discrimination of the effects of landscape-level forest cover from patch-level processes; (ii) is designed to facilitate the unification of a wide range of data types on ecological patterns and processes that operate over a wide range of spatial scales; (iii) has greater replication than existing experiments; (iv) incorporates an experimental manipulation of riparian corridors; and (v) embeds the experimentally fragmented landscape within a wider gradient of land-use intensity than do existing projects. The SAFE Project represents an opportunity for ecologists across disciplines to participate in a large initiative designed to generate a broad understanding of the ecological impacts of tropical forest modification. PMID:22006969

Processing of cellulosic material by a cellulase-containing cell-free fermentate produced from cellulase-producing bacteria, ATCC 55702

DOEpatents

Dees, H.C.

1998-08-04

Bacteria which produce large amounts of a cellulase-containing cell-free fermentate, have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase degrading bacterium ATCC 55702, which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic materials. 5 figs.

Processing of cellulosic material by a cellulase-containing cell-free fermentate produced from cellulase-producing bacteria, ATCC 55702

DOEpatents

Dees, H. Craig

1998-01-01

Bacteria which produce large amounts of a cellulase-containing cell-free fermentate, have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase degrading bacterium ATCC 55702, which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic materials.

[Genetic dissection of intracranial aneurysm].

PubMed

Onda, Hideaki; Yoneyama, Taku; Akagawa, Hiroyuki; Kasuya, Hidetoshi

2008-11-01

Subarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm (IA) is a devastating condition with high mortality and morbidity. Genetic as well as environment factors play important roles in the pathogenesis of SAH and IAs. We review the present knowledge on the genetic factors responsible for SAH or IAs. Linkage analysis and association study are used for genetic dissection. Genome-wide linkage analyses have specified several genetic loci for IAs and 6 loci (1p34-36, 7q11, 11q24-25, 14q22-31, 19q13, and Xp22) have been replicated in different populations. Numerous functional and/or positional candidate genes for IAs have been investigated by case-control association studies. The results of genetic association studies are modest because of small sample sizes. To date, no specific genes have been identified as responsible for IA development or rupture. Recent, large-scale genome-wide association (GWA) studies have revealed consistent and replicable genetic markers of several complex diseases such as coronary artery disease and type 2 diabetes. Although, thus far, no GWA studies have been performed for IAs, such a study may accomplish the breakthrough of genetic dissection of IAs. The identification of susceptible genes might lead to the understanding of the mechanism of IA formation or rupture and to novel therapeutic strategies.

Affordable Options for Ground-Based, Large-Aperture Optical Space Surveillance Systems

NASA Astrophysics Data System (ADS)

Ackermann, M.; Beason, J. D.; Kiziah, R.; Spillar, E.; Vestrand, W. T.; Cox, D.; McGraw, J.; Zimmer, P.; Holland, C.

2013-09-01

The Space Surveillance Telescope (SST) developed by the Defense Advanced Research Projects Agency (DARPA) - has demonstrated significant capability improvements over legacy ground-based optical space surveillance systems. To fulfill better the current and future space situational awareness (SSA) requirements, the Air Force would benefit from a global network of such telescopes, but the high cost to replicate the SST makes such an acquisition decision difficult, particularly in an era of fiscal austerity. Ideally, the Air Force needs the capabilities provided by the SST, but at a more affordable price. To address this issue, an informal study considered a total of 67 alternative optical designs, with each being evaluated for cost, complexity and SSA performance. One promising approach identified in the study uses a single mirror at prime focus with a small number of corrective lenses. This approach results in telescopes that are less complex and estimated to be less expensive than replicated SSTs. They should also be acquirable on shorter time scales. Another approach would use a modest network of smaller telescopes for space surveillance. This approach provides significant cost advantages but faces some challenges with very dim objects. In this paper, we examine the cost and SSA utility for each of the 67 designs considered.

GWAS and admixture mapping identify different asthma-associated loci in Latinos: The GALA II Study

PubMed Central

Galanter, Joshua M; Gignoux, Christopher R; Torgerson, Dara G; Roth, Lindsey A; Eng, Celeste; Oh, Sam S; Nguyen, Elizabeth A; Drake, Katherine A; Huntsman, Scott; Hu, Donglei; Sen, Saunak; Davis, Adam; Farber, Harold J.; Avila, Pedro C.; Brigino-Buenaventura, Emerita; LeNoir, Michael A.; Meade, Kelley; Serebrisky, Denise; Borrell, Luisa N; Rodríguez-Cintrón, William; Estrada, Andres Moreno; Mendoza, Karla Sandoval; Winkler, Cheryl A.; Klitz, William; Romieu, Isabelle; London, Stephanie J.; Gilliland, Frank; Martinez, Fernando; Bustamante, Carlos; Williams, L Keoki; Kumar, Rajesh; Rodríguez-Santana, José R.; Burchard, and Esteban G.

2013-01-01

Background Asthma is a complex disease with both genetic and environmental causes. Genome-wide association studies of asthma have mostly involved European populations and replication of positive associations has been inconsistent. Objective To identify asthma-associated genes in a large Latino population with genome-wide association analysis and admixture mapping. Methods Latino children with asthma (n = 1,893) and healthy controls (n = 1,881) were recruited from five sites in the United States: Puerto Rico, New York, Chicago, Houston, and the San Francisco Bay Area. Subjects were genotyped on an Affymetrix World Array IV chip. We performed genome-wide association and admixture mapping to identify asthma-associated loci. Results We identified a significant association between ancestry and asthma at 6p21 (lowest p-value: rs2523924, p < 5 × 10−6). This association replicates in a meta-analysis of the EVE Asthma Consortium (p = 0.01). Fine mapping of the region in this study and the EVE Asthma Consortium suggests an association between PSORS1C1 and asthma. We confirmed the strong allelic association between the 17q21 asthma in Latinos (IKZF3, lowest p-value: rs90792, OR: 0.67, 95% CI 0.61 – 0.75, p = 6 × 10−13) and replicated associations in several genes that had previously been associated with asthma in genome-wide association studies. Conclusions Admixture mapping and genome-wide association are complementary techniques that provide evidence for multiple asthma-associated loci in Latinos. Admixture mapping identifies a novel locus on 6p21 that replicates in a meta-analysis of several Latino populations, while genome-wide association confirms the previously identified locus on 17q21. PMID:24406073

Genome-Wide Analysis of the Arabidopsis Replication Timing Program1[OPEN

PubMed Central

Brooks, Ashley M.; Wheeler, Emily; LeBlanc, Chantal; Lee, Tae-Jin; Martienssen, Robert A.; Thompson, William F.

2018-01-01

Eukaryotes use a temporally regulated process, known as the replication timing program, to ensure that their genomes are fully and accurately duplicated during S phase. Replication timing programs are predictive of genomic features and activity and are considered to be functional readouts of chromatin organization. Although replication timing programs have been described for yeast and animal systems, much less is known about the temporal regulation of plant DNA replication or its relationship to genome sequence and chromatin structure. We used the thymidine analog, 5-ethynyl-2′-deoxyuridine, in combination with flow sorting and Repli-Seq to describe, at high-resolution, the genome-wide replication timing program for Arabidopsis (Arabidopsis thaliana) Col-0 suspension cells. We identified genomic regions that replicate predominantly during early, mid, and late S phase, and correlated these regions with genomic features and with data for chromatin state, accessibility, and long-distance interaction. Arabidopsis chromosome arms tend to replicate early while pericentromeric regions replicate late. Early and mid-replicating regions are gene-rich and predominantly euchromatic, while late regions are rich in transposable elements and primarily heterochromatic. However, the distribution of chromatin states across the different times is complex, with each replication time corresponding to a mixture of states. Early and mid-replicating sequences interact with each other and not with late sequences, but early regions are more accessible than mid regions. The replication timing program in Arabidopsis reflects a bipartite genomic organization with early/mid-replicating regions and late regions forming separate, noninteracting compartments. The temporal order of DNA replication within the early/mid compartment may be modulated largely by chromatin accessibility. PMID:29301956

Integrating publicly-available data to generate computationally ...

EPA Pesticide Factsheets

The adverse outcome pathway (AOP) framework provides a way of organizing knowledge related to the key biological events that result in a particular health outcome. For the majority of environmental chemicals, the availability of curated pathways characterizing potential toxicity is limited. Methods are needed to assimilate large amounts of available molecular data and quickly generate putative AOPs for further testing and use in hazard assessment. A graph-based workflow was used to facilitate the integration of multiple data types to generate computationally-predicted (cp) AOPs. Edges between graph entities were identified through direct experimental or literature information or computationally inferred using frequent itemset mining. Data from the TG-GATEs and ToxCast programs were used to channel large-scale toxicogenomics information into a cpAOP network (cpAOPnet) of over 20,000 relationships describing connections between chemical treatments, phenotypes, and perturbed pathways measured by differential gene expression and high-throughput screening targets. Sub-networks of cpAOPs for a reference chemical (carbon tetrachloride, CCl4) and outcome (hepatic steatosis) were extracted using the network topology. Comparison of the cpAOP subnetworks to published mechanistic descriptions for both CCl4 toxicity and hepatic steatosis demonstrate that computational approaches can be used to replicate manually curated AOPs and identify pathway targets that lack genomic mar

Assessing landscape scale wildfire exposure for highly valued resources in a Mediterranean area.

PubMed

Alcasena, Fermín J; Salis, Michele; Ager, Alan A; Arca, Bachisio; Molina, Domingo; Spano, Donatella

2015-05-01

We used a fire simulation modeling approach to assess landscape scale wildfire exposure for highly valued resources and assets (HVR) on a fire-prone area of 680 km(2) located in central Sardinia, Italy. The study area was affected by several wildfires in the last half century: some large and intense fire events threatened wildland urban interfaces as well as other socioeconomic and cultural values. Historical wildfire and weather data were used to inform wildfire simulations, which were based on the minimum travel time algorithm as implemented in FlamMap. We simulated 90,000 fires that replicated recent large fire events in the area spreading under severe weather conditions to generate detailed maps of wildfire likelihood and intensity. Then, we linked fire modeling outputs to a geospatial risk assessment framework focusing on buffer areas around HVR. The results highlighted a large variation in burn probability and fire intensity in the vicinity of HVRs, and allowed us to identify the areas most exposed to wildfires and thus to a higher potential damage. Fire intensity in the HVR buffers was mainly related to fuel types, while wind direction, topographic features, and historically based ignition pattern were the key factors affecting fire likelihood. The methodology presented in this work can have numerous applications, in the study area and elsewhere, particularly to address and inform fire risk management, landscape planning and people safety on the vicinity of HVRs.

Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass

PubMed Central

Sham, Pak C; Zintzaras, Elias; Lewis, Cathryn M; Deng, Hong-Wen; Econs, Michael J; Karasik, David; Devoto, Marcella; Kammerer, Candace M; Spector, Tim; Andrew, Toby; Cupples, L Adrienne; Duncan, Emma L; Foroud, Tatiana; Kiel, Douglas P; Koller, Daniel; Langdahl, Bente; Mitchell, Braxton D; Peacock, Munro; Recker, Robert; Shen, Hui; Sol-Church, Katia; Spotila, Loretta D; Uitterlinden, Andre G; Wilson, Scott G; Kung, Annie WC; Ralston, Stuart H

2014-01-01

Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. Introduction BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. Materials and Methods Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. Results For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. Conclusions This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance. PMID:17228994

A hierarchy of distress and invariant item ordering in the General Health Questionnaire-12.

PubMed

Doyle, F; Watson, R; Morgan, K; McBride, O

2012-06-01

Invariant item ordering (IIO) is defined as the extent to which items have the same ordering (in terms of item difficulty/severity - i.e. demonstrating whether items are difficult [rare] or less difficult [common]) for each respondent who completes a scale. IIO is therefore crucial for establishing a scale hierarchy that is replicable across samples, but no research has demonstrated IIO in scales of psychological distress. We aimed to determine if a hierarchy of distress with IIO exists in a large general population sample who completed a scale measuring distress. Data from 4107 participants who completed the 12-item General Health Questionnaire (GHQ-12) from the Northern Ireland Health and Social Wellbeing Survey 2005-6 were analysed. Mokken scaling was used to determine the dimensionality and hierarchy of the GHQ-12, and items were investigated for IIO. All items of the GHQ-12 formed a single, strong unidimensional scale (H=0.58). IIO was found for six of the 12 items (H-trans=0.55), and these symptoms reflected the following hierarchy: anhedonia, concentration, participation, coping, decision-making and worthlessness. The cross-sectional analysis needs replication. The GHQ-12 showed a hierarchy of distress, but IIO is only demonstrated for six of the items, and the scale could therefore be shortened. Adopting brief, hierarchical scales with IIO may be beneficial in both clinical and research contexts. Copyright © 2011 Elsevier B.V. All rights reserved.

Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.

PubMed

Koch, Heike B; Zhang, Ru; Verdoodt, Berlinda; Bailey, Aaron; Zhang, Chang-Dong; Yates, John R; Menssen, Antje; Hermeking, Heiko

2007-01-15

The c-MYC oncogene encodes a transcription factor, which is sufficient and necessary for the induction of cellular proliferation. However, the c-MYC protein is a relatively weak transactivator suggesting that it may have other functions. To identify protein interactors which may reveal new functions or represent regulators of c-MYC we systematically identified proteins associated with c-MYC in vivo using a proteomic approach. We combined tandem affinity purification (TAP) with the mass spectral multidimensional protein identification technology (MudPIT). Thereby, 221 c-MYC-associated proteins were identified. Among them were 17 previously known c-MYC-interactors. Selected new c-MYC-associated proteins (DBC-1, FBX29, KU70, MCM7, Mi2-beta/CHD4, RNA Pol II, RFC2, RFC3, SV40 Large T Antigen, TCP1alpha, U5-116kD, ZNF281) were confirmed independently. For association with MCM7, SV40 Large T Antigen and DBC-1 the functionally important MYC-box II region was required, whereas FBX29 and Mi2-beta interacted via MYC-box II and the BR-HLH-LZ motif. In addition, regulators of c-MYC activity were identified: ectopic expression of FBX29, an E3 ubiquitin ligase, decreased c-MYC protein levels and inhibited c-MYC transactivation, whereas knock-down of FBX29 elevated the concentration of c-MYC. Furthermore, sucrose gradient analysis demonstrated that c-MYC is present in numerous complexes with varying size and composition, which may accommodate the large number of new c-MYC-associated proteins identified here and mediate the diverse functions of c-MYC. Our results suggest that c-MYC, besides acting as a mitogenic transcription factor, regulates cellular proliferation by direct association with protein complexes involved in multiple synthetic processes required for cell division, as for example DNA-replication/repair and RNA-processing. Furthermore, this first comprehensive description of the c-MYC-associated sub-proteome will facilitate further studies aimed to elucidate the biology of c-MYC.

Negative Symptom Dimensions of the Positive and Negative Syndrome Scale Across Geographical Regions: Implications for Social, Linguistic, and Cultural Consistency.

PubMed

Khan, Anzalee; Liharska, Lora; Harvey, Philip D; Atkins, Alexandra; Ulshen, Daniel; Keefe, Richard S E

2017-12-01

Objective: Recognizing the discrete dimensions that underlie negative symptoms in schizophrenia and how these dimensions are understood across localities might result in better understanding and treatment of these symptoms. To this end, the objectives of this study were to 1) identify the Positive and Negative Syndrome Scale negative symptom dimensions of expressive deficits and experiential deficits and 2) analyze performance on these dimensions over 15 geographical regions to determine whether the items defining them manifest similar reliability across these regions. Design: Data were obtained for the baseline Positive and Negative Syndrome Scale visits of 6,889 subjects across 15 geographical regions. Using confirmatory factor analysis, we examined whether a two-factor negative symptom structure that is found in schizophrenia (experiential deficits and expressive deficits) would be replicated in our sample, and using differential item functioning, we tested the degree to which specific items from each negative symptom subfactor performed across geographical regions in comparison with the United States. Results: The two-factor negative symptom solution was replicated in this sample. Most geographical regions showed moderate-to-large differential item functioning for Positive and Negative Syndrome Scale expressive deficit items, especially N3 Poor Rapport, as compared with Positive and Negative Syndrome Scale experiential deficit items, showing that these items might be interpreted or scored differently in different regions. Across countries, except for India, the differential item functioning values did not favor raters in the United States. Conclusion: These results suggest that the Positive and Negative Syndrome Scale negative symptom factor can be better represented by a two-factor model than by a single-factor model. Additionally, the results show significant differences in responses to items representing the Positive and Negative Syndrome Scale expressive factors, but not the experiential factors, across regions. This could be due to a lack of equivalence between the original and translated versions, cultural differences with the interpretation of items, dissimilarities in rater training, or diversity in the understanding of scoring anchors. Knowing which items are challenging for raters across regions can help to guide Positive and Negative Syndrome Scale training and improve the results of international clinical trials aimed at negative symptoms.

Reduced anterior temporal and hippocampal functional connectivity during face processing discriminates individuals with social anxiety disorder from healthy controls and panic disorder, and increases following treatment.

PubMed

Pantazatos, Spiro P; Talati, Ardesheer; Schneier, Franklin R; Hirsch, Joy

2014-01-01

Group functional magnetic resonance imaging (fMRI) studies suggest that anxiety disorders are associated with anomalous brain activation and functional connectivity (FC). However, brain-based features sensitive enough to discriminate individual subjects with a specific anxiety disorder and that track symptom severity longitudinally, desirable qualities for putative disorder-specific biomarkers, remain to be identified. Blood oxygen level-dependent (BOLD) fMRI during emotional face perceptual tasks and a new, large-scale and condition-dependent FC and machine learning approach were used to identify features (pair-wise correlations) that discriminated patients with social anxiety disorder (SAD, N=16) from controls (N=19). We assessed whether these features discriminated SAD from panic disorder (PD, N=16), and SAD from controls in an independent replication sample that performed a similar task at baseline (N: SAD=15, controls=17) and following 8-weeks paroxetine treatment (N: SAD=12, untreated controls=7). High SAD vs HCs discrimination (area under the ROC curve, AUC, arithmetic mean of sensitivity and specificity) was achieved with two FC features during unattended neutral face perception (AUC=0.88, P<0.05 corrected). These features also discriminated SAD vs PD (AUC=0.82, P=0.0001) and SAD vs HCs in the independent replication sample (FC during unattended angry face perception, AUC=0.71, P=0.01). The most informative FC was left hippocampus-left temporal pole, which was reduced in both SAD samples (replication sample P=0.027), and this FC increased following the treatment (post>pre, t(11)=2.9, P=0.007). In conclusion, SAD is associated with reduced FC between left temporal pole and left hippocampus during face perception, and results suggest promise for emerging FC-based biomarkers for SAD diagnosis and treatment effects.

Evaluating process in child and family interventions: aggression prevention as an example.

PubMed

Tolan, Patrick H; Hanish, Laura D; McKay, Mary M; Dickey, Mitchell H

2002-06-01

This article reports on 2 studies designed to develop and validate a set of measures for use in evaluating processes of child and family interventions. In Study 1 responses from 187 families attending an outpatient clinic for child behavior problems were factor analyzed to identify scales, consistent across sources: Alliance (Satisfactory Relationship with Interventionist and Program Satisfaction), Parenting Skill Attainment, Child Cooperation During Session, Child Prosocial Behavior, and Child Aggressive Behavior. Study 2 focused on patterns of scale scores among 78 families taking part in a 22-week preventive intervention designed to affect family relationships, parenting, and child antisocial and prosocial behaviors. The factor structure identified in Study 1 was replicated. Scale construct validity was demonstrated through across-source convergence, sensitivity to intervention change, and ability to discriminate individual differences. Path analysis validated the scales' utility in explaining key aspects of the intervention process. Implications for evaluating processes in family interventions are discussed.

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

PubMed Central

Zheng, Hou-Feng; Forgetta, Vincenzo; Hsu, Yi-Hsiang; Estrada, Karol; Rosello-Diez, Alberto; Leo, Paul J; Dahia, Chitra L; Park-Min, Kyung Hyun; Tobias, Jonathan H; Kooperberg, Charles; Kleinman, Aaron; Styrkarsdottir, Unnur; Liu, Ching-Ti; Uggla, Charlotta; Evans, Daniel S; Nielson, Carrie M; Walter, Klaudia; Pettersson-Kymmer, Ulrika; McCarthy, Shane; Eriksson, Joel; Kwan, Tony; Jhamai, Mila; Trajanoska, Katerina; Memari, Yasin; Min, Josine; Huang, Jie; Danecek, Petr; Wilmot, Beth; Li, Rui; Chou, Wen-Chi; Mokry, Lauren E; Moayyeri, Alireza; Claussnitzer, Melina; Cheng, Chia-Ho; Cheung, Warren; Medina-Gómez, Carolina; Ge, Bing; Chen, Shu-Huang; Choi, Kwangbom; Oei, Ling; Fraser, James; Kraaij, Robert; Hibbs, Matthew A; Gregson, Celia L; Paquette, Denis; Hofman, Albert; Wibom, Carl; Tranah, Gregory J; Marshall, Mhairi; Gardiner, Brooke B; Cremin, Katie; Auer, Paul; Hsu, Li; Ring, Sue; Tung, Joyce Y; Thorleifsson, Gudmar; Enneman, Anke W; van Schoor, Natasja M; de Groot, Lisette C.P.G.M.; van der Velde, Nathalie; Melin, Beatrice; Kemp, John P; Christiansen, Claus; Sayers, Adrian; Zhou, Yanhua; Calderari, Sophie; van Rooij, Jeroen; Carlson, Chris; Peters, Ulrike; Berlivet, Soizik; Dostie, Josée; Uitterlinden, Andre G; Williams, Stephen R.; Farber, Charles; Grinberg, Daniel; LaCroix, Andrea Z; Haessler, Jeff; Chasman, Daniel I; Giulianini, Franco; Rose, Lynda M; Ridker, Paul M; Eisman, John A; Nguyen, Tuan V; Center, Jacqueline R; Nogues, Xavier; Garcia-Giralt, Natalia; Launer, Lenore L; Gudnason, Vilmunder; Mellström, Dan; Vandenput, Liesbeth; Karlsson, Magnus K; Ljunggren, Östen; Svensson, Olle; Hallmans, Göran; Rousseau, François; Giroux, Sylvie; Bussière, Johanne; Arp, Pascal P; Koromani, Fjorda; Prince, Richard L; Lewis, Joshua R; Langdahl, Bente L; Hermann, A Pernille; Jensen, Jens-Erik B; Kaptoge, Stephen; Khaw, Kay-Tee; Reeve, Jonathan; Formosa, Melissa M; Xuereb-Anastasi, Angela; Åkesson, Kristina; McGuigan, Fiona E; Garg, Gaurav; Olmos, Jose M; Zarrabeitia, Maria T; Riancho, Jose A; Ralston, Stuart H; Alonso, Nerea; Jiang, Xi; Goltzman, David; Pastinen, Tomi; Grundberg, Elin; Gauguier, Dominique; Orwoll, Eric S; Karasik, David; Davey-Smith, George; Smith, Albert V; Siggeirsdottir, Kristin; Harris, Tamara B; Zillikens, M Carola; van Meurs, Joyce BJ; Thorsteinsdottir, Unnur; Maurano, Matthew T; Timpson, Nicholas J; Soranzo, Nicole; Durbin, Richard; Wilson, Scott G; Ntzani, Evangelia E; Brown, Matthew A; Stefansson, Kari; Hinds, David A; Spector, Tim; Cupples, L Adrienne; Ohlsson, Claes; Greenwood, Celia MT; Jackson, Rebecca D; Rowe, David W; Loomis, Cynthia A; Evans, David M; Ackert-Bicknell, Cheryl L; Joyner, Alexandra L; Duncan, Emma L; Kiel, Douglas P; Rivadeneira, Fernando; Richards, J Brent

2016-01-01

SUMMARY The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population. PMID:26367794

Analysis of potential protein-modifying variants in 9000 endometriosis patients and 150000 controls of European ancestry.

PubMed

Sapkota, Yadav; Vivo, Immaculata De; Steinthorsdottir, Valgerdur; Fassbender, Amelie; Bowdler, Lisa; Buring, Julie E; Edwards, Todd L; Jones, Sarah; O, Dorien; Peterse, Daniëlle; Rexrode, Kathryn M; Ridker, Paul M; Schork, Andrew J; Thorleifsson, Gudmar; Wallace, Leanne M; Kraft, Peter; Morris, Andrew P; Nyholt, Dale R; Edwards, Digna R Velez; Nyegaard, Mette; D'Hooghe, Thomas; Chasman, Daniel I; Stefansson, Kari; Missmer, Stacey A; Montgomery, Grant W

2017-09-12

Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10 -9 ) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.

HiQuant: Rapid Postquantification Analysis of Large-Scale MS-Generated Proteomics Data.

PubMed

Bryan, Kenneth; Jarboui, Mohamed-Ali; Raso, Cinzia; Bernal-Llinares, Manuel; McCann, Brendan; Rauch, Jens; Boldt, Karsten; Lynn, David J

2016-06-03

Recent advances in mass-spectrometry-based proteomics are now facilitating ambitious large-scale investigations of the spatial and temporal dynamics of the proteome; however, the increasing size and complexity of these data sets is overwhelming current downstream computational methods, specifically those that support the postquantification analysis pipeline. Here we present HiQuant, a novel application that enables the design and execution of a postquantification workflow, including common data-processing steps, such as assay normalization and grouping, and experimental replicate quality control and statistical analysis. HiQuant also enables the interpretation of results generated from large-scale data sets by supporting interactive heatmap analysis and also the direct export to Cytoscape and Gephi, two leading network analysis platforms. HiQuant may be run via a user-friendly graphical interface and also supports complete one-touch automation via a command-line mode. We evaluate HiQuant's performance by analyzing a large-scale, complex interactome mapping data set and demonstrate a 200-fold improvement in the execution time over current methods. We also demonstrate HiQuant's general utility by analyzing proteome-wide quantification data generated from both a large-scale public tyrosine kinase siRNA knock-down study and an in-house investigation into the temporal dynamics of the KSR1 and KSR2 interactomes. Download HiQuant, sample data sets, and supporting documentation at http://hiquant.primesdb.eu .

Copy number variation is a fundamental aspect of the placental genome.

PubMed

Hannibal, Roberta L; Chuong, Edward B; Rivera-Mulia, Juan Carlos; Gilbert, David M; Valouev, Anton; Baker, Julie C

2014-05-01

Discovery of lineage-specific somatic copy number variation (CNV) in mammals has led to debate over whether CNVs are mutations that propagate disease or whether they are a normal, and even essential, aspect of cell biology. We show that 1,000 N polyploid trophoblast giant cells (TGCs) of the mouse placenta contain 47 regions, totaling 138 Megabases, where genomic copies are underrepresented (UR). UR domains originate from a subset of late-replicating heterochromatic regions containing gene deserts and genes involved in cell adhesion and neurogenesis. While lineage-specific CNVs have been identified in mammalian cells, classically in the immune system where V(D)J recombination occurs, we demonstrate that CNVs form during gestation in the placenta by an underreplication mechanism, not by recombination nor deletion. Our results reveal that large scale CNVs are a normal feature of the mammalian placental genome, which are regulated systematically during embryogenesis and are propagated by a mechanism of underreplication.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study.

PubMed

Lessard, Christopher J; Adrianto, Indra; Ice, John A; Wiley, Graham B; Kelly, Jennifer A; Glenn, Stuart B; Adler, Adam J; Li, He; Rasmussen, Astrid; Williams, Adrienne H; Ziegler, Julie; Comeau, Mary E; Marion, Miranda; Wakeland, Benjamin E; Liang, Chaoying; Ramos, Paula S; Grundahl, Kiely M; Gallant, Caroline J; Alarcón-Riquelme, Marta E; Alarcón, Graciela S; Anaya, Juan-Manuel; Bae, Sang-Cheol; Boackle, Susan A; Brown, Elizabeth E; Chang, Deh-Ming; Cho, Soo-Kyung; Criswell, Lindsey A; Edberg, Jeffrey C; Freedman, Barry I; Gilkeson, Gary S; Jacob, Chaim O; James, Judith A; Kamen, Diane L; Kimberly, Robert P; Kim, Jae-Hoon; Martin, Javier; Merrill, Joan T; Niewold, Timothy B; Park, So-Yeon; Petri, Michelle A; Pons-Estel, Bernardo A; Ramsey-Goldman, Rosalind; Reveille, John D; Scofield, R Hal; Song, Yeong Wook; Stevens, Anne M; Tsao, Betty P; Vila, Luis M; Vyse, Timothy J; Yu, Chack-Yung; Guthridge, Joel M; Kaufman, Kenneth M; Harley, John B; Wakeland, Edward K; Langefeld, Carl D; Gaffney, Patrick M; Montgomery, Courtney G; Moser, Kathy L

2012-04-06

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as Susceptibility Loci for Systemic Lupus Erythematosus in a Large-Scale Multiracial Replication Study

PubMed Central

Lessard, Christopher J.; Adrianto, Indra; Ice, John A.; Wiley, Graham B.; Kelly, Jennifer A.; Glenn, Stuart B.; Adler, Adam J.; Li, He; Rasmussen, Astrid; Williams, Adrienne H.; Ziegler, Julie; Comeau, Mary E.; Marion, Miranda; Wakeland, Benjamin E.; Liang, Chaoying; Ramos, Paula S.; Grundahl, Kiely M.; Gallant, Caroline J.; Alarcón, Graciela S.; Anaya, Juan-Manuel; Bae, Sang-Cheol; Boackle, Susan A.; Brown, Elizabeth E.; Chang, Deh-Ming; Cho, Soo-Kyung; Criswell, Lindsey A.; Edberg, Jeffrey C.; Freedman, Barry I.; Gilkeson, Gary S.; Jacob, Chaim O.; James, Judith A.; Kamen, Diane L.; Kimberly, Robert P.; Kim, Jae-Hoon; Martin, Javier; Merrill, Joan T.; Niewold, Timothy B.; Park, So-Yeon; Petri, Michelle A.; Pons-Estel, Bernardo A.; Ramsey-Goldman, Rosalind; Reveille, John D.; Scofield, R. Hal; Song, Yeong Wook; Stevens, Anne M.; Tsao, Betty P.; Vila, Luis M.; Vyse, Timothy J.; Yu, Chack-Yung; Guthridge, Joel M.; Kaufman, Kenneth M.; Harley, John B.; Wakeland, Edward K.; Langefeld, Carl D.; Gaffney, Patrick M.; Montgomery, Courtney G.; Moser, Kathy L.

2012-01-01

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; pmeta-Euro = 2.08 × 10−10), transmembrane protein 39A (TMEM39A; rs1132200; pmeta-all = 8.62 × 10−9), and 17q21 (rs1453560; pmeta-all = 3.48 × 10−10) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10−8 < pmeta-Euro < 9.99 × 10−5) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation. PMID:22464253

Overview of Opportunities for Co-Location of Solar Energy Technologies and Vegetation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Macknick, Jordan; Beatty, Brenda; Hill, Graham

2013-12-01

Large-scale solar facilities have the potential to contribute significantly to national electricity production. Many solar installations are large-scale or utility-scale, with a capacity over 1 MW and connected directly to the electric grid. Large-scale solar facilities offer an opportunity to achieve economies of scale in solar deployment, yet there have been concerns about the amount of land required for solar projects and the impact of solar projects on local habitat. During the site preparation phase for utility-scale solar facilities, developers often grade land and remove all vegetation to minimize installation and operational costs, prevent plants from shading panels, and minimizemore » potential fire or wildlife risks. However, the common site preparation practice of removing vegetation can be avoided in certain circumstances, and there have been successful examples where solar facilities have been co-located with agricultural operations or have native vegetation growing beneath the panels. In this study we outline some of the impacts that large-scale solar facilities can have on the local environment, provide examples of installations where impacts have been minimized through co-location with vegetation, characterize the types of co-location, and give an overview of the potential benefits from co-location of solar energy projects and vegetation. The varieties of co-location can be replicated or modified for site-specific use at other solar energy installations around the world. We conclude with opportunities to improve upon our understanding of ways to reduce the environmental impacts of large-scale solar installations.« less

Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression.

PubMed

Kiguoya, Marion W; Mann, Jaclyn K; Chopera, Denis; Gounder, Kamini; Lee, Guinevere Q; Hunt, Peter W; Martin, Jeffrey N; Ball, T Blake; Kimani, Joshua; Brumme, Zabrina L; Brockman, Mark A; Ndung'u, Thumbi

2017-07-01

There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates ( r = 0.51; P = 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-protease-driven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases ( P < 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C < D < intersubtype recombinants ( P < 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gag-protease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes. IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with the replication capacity of whole virus isolates. We further show that subtype B displays a significantly higher Gag-protease-mediated replication capacity than does subtype C, and we identify a major genetic determinant of these differences. Moreover, in two independent East African cohorts we demonstrate a reproducible hierarchy of Gag-protease-driven replicative capacity, whereby recombinants exhibit the greatest replication, followed by subtype D, followed by subtypes A and C. Our data identify Gag-protease as a major determinant of subtype differences in disease progression among HIV-1 subtypes; furthermore, we propose that the poorer viral replicative capacity of subtypes A and C may paradoxically contribute to their more efficient spread in sub-Saharan Africa. Copyright © 2017 American Society for Microbiology.

Keeping the secret: Insights from repeated catchment-scale tracer experiments under transient conditions

NASA Astrophysics Data System (ADS)

Bogner, Christina; Hauhs, Michael; Lange, Holger

2016-04-01

Catchment-level tracer experiments are generally performed to identify site-specific hydrological response functions of the catchment. The existence and uniqueness of these response functions are hardly ever questioned. Here, we report on a series of replicated tracer experiments in two small first-order catchments, G1 (0.6 ha, roofed) and F4 (2.3 ha, without roof) at Gårdsjön in SW Sweden. The soils in both catchments are shallow (< 50 cm) with the bedrock partly visible at the surface. In G1 (irrigated area approximately 1000 m2), tracer experiments were conducted under a roof between 1993 and 2003 during steady state flow conditions. In contrast, in F4 (irrigated area approximately 500 m2) the experiments were done without a roof mostly at transient conditions. The catchment F4 was equipped with a sprinkler system with a watering capacity of around 38-45 m3 day-1. Natural rainfall comes in addition. A bromide tracer solution was injected to groundwater at a single location about 40 m upstream the weir over a period of less than an hour, and was monitored using a set of groundwater tubes and the weir at the outlet over the following 4 days. In addition, discharge was measured. The experiments were repeated each summer from 2007 to 2015. While steady state conditions were guaranteed in G1, steady runoff has been achieved only four times in F4. We investigated tracer recovery rates against cumulated runoff since tracer application. Substantially different transit times and qualitatively different behaviour of the breakthrough curves were observed, even under steady state conditions. In G1, no single system response function could be identified in 5 replicates. Similarly, the catchment response functions in F4 under steady state differed between experiments. However, they remained in a similar range as in G1. Based on these results, we question the identifiability of flow paths and system properties, such as saturated water content or hydrologic transmissivity, at the catchment scale using tracer experiments. Rather, the series demonstrate the utter importance of the initial and boundary conditions which largely determine the response of the system to inert tracer pulses.

Homozygosity for the WRN Helicase-Inactivating Variant, R834C, does not confer a Werner syndrome clinical phenotype

PubMed Central

Kamath-Loeb, Ashwini S.; Zavala-van Rankin, Diego G.; Flores-Morales, Jeny; Emond, Mary J.; Sidorova, Julia M.; Carnevale, Alessandra; Cárdenas-Cortés, Maria del Carmen; Norwood, Thomas H.; Monnat, Raymond J.; Loeb, Lawrence A.; Mercado-Celis, Gabriela E.

2017-01-01

Loss-of-function mutations in the WRN helicase gene cause Werner syndrome- a progeroid syndrome with an elevated risk of cancer and other age-associated diseases. Large numbers of single nucleotide polymorphisms have been identified in WRN. We report here the organismal, cellular, and molecular phenotypes of variant rs3087425 (c. 2500C > T) that results in an arginine to cysteine substitution at residue 834 (R834C) and up to 90% reduction of WRN helicase activity. This variant is present at a high (5%) frequency in Mexico, where we identified 153 heterozygous and three homozygous individuals among 3,130 genotyped subjects. Family studies of probands identified ten additional TT homozygotes. Biochemical analysis of WRN protein purified from TT lymphoblast cell lines confirmed that the R834C substitution strongly and selectively reduces WRN helicase, but not exonuclease activity. Replication track analyses showed reduced replication fork progression in some homozygous cells following DNA replication stress. Among the thirteen TT homozygotes, we identified a previously unreported and statistically significant gender bias in favor of males (p = 0.0016), but none of the clinical findings associated with Werner syndrome. Our results indicate that WRN helicase activity alone is not rate-limiting for the development of clinical WS. PMID:28276523

Masculinity constructs as protective buffers and risk factors for men's health.

PubMed

Levant, Ronald F; Wimer, David J

2014-03-01

This study was designed to replicate the study of Levant, Wimer, and Williams (2011), which reported complex relationships between masculinity and health behaviors using a more diverse sample and updated measures. A sample of 589 college and community-dwelling men responded to an online survey consisting of five scales. Levant et al.'s (2011) study was partially replicated-some masculinity constructs were identified as protective buffers for some health behaviors and others as risk factors. The vast majority of the findings that were replicated were risk factors, suggesting that traditional masculinity is more of risk than a buffer, and occurred in the analyses involving Avoiding Anger and Stress and Avoiding Substance Use subscales, suggesting that these health behaviors are most closely associated with masculinity. The results are discussed in terms of limitations, suggestions for future research, and implications for health care practice.

Spatial planning for a green economy: National-level hydrologic ecosystem services priority areas for Gabon

PubMed Central

Tallis, Heather; Cole, Aaron; Schill, Steven; Martin, Erik; Heiner, Michael; Paiz, Marie-Claire; Aldous, Allison; Apse, Colin; Nickel, Barry

2017-01-01

Rapidly developing countries contain both the bulk of intact natural areas and biodiversity, and the greatest untapped natural resource stocks, placing them at the forefront of “green” economic development opportunities. However, most lack scientific tools to create development plans that account for biodiversity and ecosystem services, diminishing the real potential to be sustainable. Existing methods focus on biodiversity and carbon priority areas across large geographies (e.g., countries, states/provinces), leaving out essential services associated with water supplies, among others. These hydrologic ecosystem services (HES) are especially absent from methods applied at large geographies and in data-limited contexts. Here, we present a novel, spatially explicit, and relatively simple methodology to identify countrywide HES priority areas. We applied our methodology to the Gabonese Republic, a country undergoing a major economic transformation under a governmental commitment to balance conservation and development goals. We present the first national-scale maps of HES priority areas across Gabon for erosion control, nutrient retention, and groundwater recharge. Priority sub-watersheds covered 44% of the country’s extent. Only 3% of the country was identified as a priority area for all HES simultaneously, highlighting the need to conserve different areas for each different hydrologic service. While spatial tradeoffs occur amongst HES, we identified synergies with two other conservation values, given that 66% of HES priority areas intersect regions of above average area-weighted (by sub-watersheds) total forest carbon stocks and 38% intersect with terrestrial national parks. Considering implications for development, we identified HES priority areas overlapping current or proposed major roads, forestry concessions, and active mining concessions, highlighting the need for proactive planning for avoidance areas and compensatory offsets to mitigate potential conflicts. Collectively, our results provide insight into strategies to protect HES as part of Gabon’s development strategy, while providing a replicable methodology for application to new scales, geographies, and policy contexts. PMID:28594870

The simulation of the geosynchronous Earth orbit plasma environment in Chamber A: An assessment of possible experimental investigations

NASA Technical Reports Server (NTRS)

Bernstein, W.

1981-01-01

The possible use of Chamber A for the replication or simulation of space plasma physics processes which occur in the geosynchronous Earth orbit (GEO) environment is considered. It is shown that replication is not possible and that scaling of the environmental conditions is required for study of the important instability processes. Rules for such experimental scaling are given. At the present time, it does not appear technologically feasible to satisfy these requirements in Chamber A. It is, however, possible to study and qualitatively evaluate the problem of vehicle charging at GEO. In particular, Chamber A is sufficiently large that a complete operational spacecraft could be irradiated by beams and charged to high potentials. Such testing would contribute to the assessment of the operational malfunctions expected at GEO and their possible correction. However, because of the many tabulated limitations in such a testing programs, its direct relevance to conditions expected in the geo environment remains questionable.

RE-Europe, a large-scale dataset for modeling a highly renewable European electricity system

PubMed Central

Jensen, Tue V.; Pinson, Pierre

2017-01-01

Future highly renewable energy systems will couple to complex weather and climate dynamics. This coupling is generally not captured in detail by the open models developed in the power and energy system communities, where such open models exist. To enable modeling such a future energy system, we describe a dedicated large-scale dataset for a renewable electric power system. The dataset combines a transmission network model, as well as information for generation and demand. Generation includes conventional generators with their technical and economic characteristics, as well as weather-driven forecasts and corresponding realizations for renewable energy generation for a period of 3 years. These may be scaled according to the envisioned degrees of renewable penetration in a future European energy system. The spatial coverage, completeness and resolution of this dataset, open the door to the evaluation, scaling analysis and replicability check of a wealth of proposals in, e.g., market design, network actor coordination and forecasting of renewable power generation. PMID:29182600

RE-Europe, a large-scale dataset for modeling a highly renewable European electricity system.

PubMed

Jensen, Tue V; Pinson, Pierre

2017-11-28

Future highly renewable energy systems will couple to complex weather and climate dynamics. This coupling is generally not captured in detail by the open models developed in the power and energy system communities, where such open models exist. To enable modeling such a future energy system, we describe a dedicated large-scale dataset for a renewable electric power system. The dataset combines a transmission network model, as well as information for generation and demand. Generation includes conventional generators with their technical and economic characteristics, as well as weather-driven forecasts and corresponding realizations for renewable energy generation for a period of 3 years. These may be scaled according to the envisioned degrees of renewable penetration in a future European energy system. The spatial coverage, completeness and resolution of this dataset, open the door to the evaluation, scaling analysis and replicability check of a wealth of proposals in, e.g., market design, network actor coordination and forecasting of renewable power generation.

RE-Europe, a large-scale dataset for modeling a highly renewable European electricity system

NASA Astrophysics Data System (ADS)

Jensen, Tue V.; Pinson, Pierre

2017-11-01

Future highly renewable energy systems will couple to complex weather and climate dynamics. This coupling is generally not captured in detail by the open models developed in the power and energy system communities, where such open models exist. To enable modeling such a future energy system, we describe a dedicated large-scale dataset for a renewable electric power system. The dataset combines a transmission network model, as well as information for generation and demand. Generation includes conventional generators with their technical and economic characteristics, as well as weather-driven forecasts and corresponding realizations for renewable energy generation for a period of 3 years. These may be scaled according to the envisioned degrees of renewable penetration in a future European energy system. The spatial coverage, completeness and resolution of this dataset, open the door to the evaluation, scaling analysis and replicability check of a wealth of proposals in, e.g., market design, network actor coordination and forecasting of renewable power generation.

Psychometric properties of the Geriatric Anxiety Inventory (GAI) and its short-form (GAI-SF) in a clinical and non-clinical sample of older adults.

PubMed

Johnco, Carly; Knight, Ashleigh; Tadic, Dusanka; Wuthrich, Viviana M

2015-07-01

The Geriatric Anxiety Inventory is a 20-item geriatric-specific measure of anxiety severity. While studies suggest good internal consistency and convergent validity, divergent validity from measures of depression are weak. Clinical cutoffs have been developed that vary across studies due to the small clinical samples used. A six-item short form (GAI-SF) has been developed, and while this scale is promising, the research assessing the psychometrics of this scale is limited. This study examined the psychometric properties of GAI and GAI-SF in a large sample of 197 clinical geriatric participants with a comorbid anxiety and unipolar mood disorder, and a non-clinical control sample (N = 59). The internal consistency and convergent validity with other measures of anxiety was adequate for GAI and GAI-SF. Divergent validity from depressive symptoms was good in the clinical sample but weak in the total and non-clinical samples. Divergent validity from cognitive functioning was good in all samples. The one-factor structure was replicated for both measures. Receiver Operating Characteristic analyses indicated that the GAI is more accurate at identifying clinical status than the GAI-SF, although the sensitivity and specificity for the recommended cutoffs was adequate for both measures. Both GAI and GAI-SF show good psychometric properties for identifying geriatric anxiety. The GAI-SF may be a useful alternative screening measure for identifying anxiety in older adults.

Drosophila mitochondrial DNA: a novel gene order.

PubMed Central

Clary, D O; Goddard, J M; Martin, S C; Fauron, C M; Wolstenholme, D R

1982-01-01

Part of the replication origin-containing A+T-rich region of the Drosophila yakuba mtDNA molecule and segments on either side of this region have been sequenced, and the genes within them identified. The data confirm that the small and large rRNA genes lie in tandem adjacent to that side of the A+T-rich region which is replicated first, and establish that a tRNAval gene lies between the two rRNA genes and that URF1 follows the large rRNA gene. The data further establish that the genes for tRNAile, tRNAgln, tRNAf-met and URF2 lie in the order given, on the opposite side of the A+T-rich region to the rRNA genes and, except for tRNAgln, are contained in the opposite strand to the rRNA, tRNAval and URF1 genes. This is in contrast to mammalian mtDNAs where all of these genes are located on the side of the replication origin which is replicated last, within the order tRNAphe, small (12S) rRNA, tRNAval, large (16S) rRNA, tRNAleu, URF1, tRNAile, tRNAgln, tRNAf-met and URF2, and, except tRNAgln, are all contained in the same (H) strand. In D. yakuba URF1 and URF2, the triplet AGA appears to specify an amino acid, which is again different from the situation found in mammalian mtDNAs, where AGA is used only as a rare termination codon. PMID:6294611

Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

PubMed Central

Hyde, Craig L.; Nagle, Mike W.; Tian, Chao; Chen, Xing; Paciga, Sara A.; Wendland, Jens R.; Tung, Joyce; Hinds, David A.; Perlis, Roy H.; Winslow, Ashley R.

2016-01-01

Despite strong evidence supporting the heritability of Major Depressive Disorder, previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-reported data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 reporting no history of depression through 23andMe, and meta-analyzed these results with published MDD GWAS results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with pval<1.0×10−5 in the meta-analysis were further analyzed in a replication dataset (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint-analysis over all three datasets. Some of these loci were also implicated in GWAS of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to traditional means of ascertainment for neuropsychiatric disease genomics. PMID:27479909

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis

PubMed Central

Zuo, Xianbo; Sun, Liangdan; Yin, Xianyong; Gao, Jinping; Sheng, Yujun; Xu, Jinhua; Zhang, Jianzhong; He, Chundi; Qiu, Ying; Wen, Guangdong; Tian, Hongqing; Zheng, Xiaodong; Liu, Shengxiu; Wang, Wenjun; Li, Weiran; Cheng, Yuyan; Liu, Longdan; Chang, Yan; Wang, Zaixing; Li, Zenggang; Li, Longnian; Wu, Jianping; Fang, Ling; Shen, Changbing; Zhou, Fusheng; Liang, Bo; Chen, Gang; Li, Hui; Cui, Yong; Xu, Aie; Yang, Xueqin; Hao, Fei; Xu, Limin; Fan, Xing; Li, Yuzhen; Wu, Rina; Wang, Xiuli; Liu, Xiaoming; Zheng, Min; Song, Shunpeng; Ji, Bihua; Fang, Hong; Yu, Jianbin; Sun, Yongxin; Hui, Yan; Zhang, Furen; Yang, Rongya; Yang, Sen; Zhang, Xuejun

2015-01-01

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10−08). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D–LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis. PMID:25854761

Analysis of cis and trans Requirements for DNA Replication at the Right-End Hairpin of the Human Bocavirus 1 Genome

PubMed Central

Shen, Weiran; Deng, Xuefeng; Zou, Wei; Engelhardt, John F.; Yan, Ziying

2016-01-01

ABSTRACT Parvoviruses are single-stranded DNA viruses that use the palindromic structures at the ends of the viral genome for their replication. The mechanism of parvovirus replication has been studied mostly in the dependoparvovirus adeno-associated virus 2 (AAV2) and the protoparvovirus minute virus of mice (MVM). Here, we used human bocavirus 1 (HBoV1) to understand the replication mechanism of bocaparvovirus. HBoV1 is pathogenic to humans, causing acute respiratory tract infections, especially in young children under 2 years old. By using the duplex replicative form of the HBoV1 genome in human embryonic kidney 293 (HEK293) cells, we identified the HBoV1 minimal replication origin at the right-end hairpin (OriR). Mutagenesis analyses confirmed the putative NS1 binding and nicking sites within the OriR. Of note, unlike the large nonstructural protein (Rep78/68 or NS1) of other parvoviruses, HBoV1 NS1 did not specifically bind OriR in vitro, indicating that other viral and cellular components or the oligomerization of NS1 is required for NS1 binding to the OriR. In vivo studies demonstrated that residues responsible for NS1 binding and nicking are within the origin-binding domain. Further analysis identified that the small nonstructural protein NP1 is required for HBoV1 DNA replication at OriR. NP1 and other viral nonstructural proteins (NS1 to NS4) colocalized within the viral DNA replication centers in both OriR-transfected cells and virus-infected cells, highlighting a direct involvement of NP1 in viral DNA replication at OriR. Overall, our study revealed the characteristics of HBoV1 DNA replication at OriR, suggesting novel characteristics of autonomous parvovirus DNA replication. IMPORTANCE Human bocavirus 1 (HBoV1) causes acute respiratory tract infections in young children. The duplex HBoV1 genome replicates in HEK293 cells and produces progeny virions that are infectious in well-differentiated airway epithelial cells. A recombinant AAV2 vector pseudotyped with an HBoV1 capsid has been developed to efficiently deliver the cystic fibrosis transmembrane conductance regulator gene to human airway epithelia. Here, we identified both cis-acting elements and trans-acting proteins that are required for HBoV1 DNA replication at the right-end hairpin in HEK293 cells. We localized the minimal replication origin, which contains both NS1 nicking and binding sites, to a 46-nucleotide sequence in the right-end hairpin. The identification of these essential elements of HBoV1 DNA replication acting both in cis and in trans will provide guidance to develop antiviral strategies targeting viral DNA replication at the right-end hairpin and to design next-generation recombinant HBoV1 vectors, a promising tool for gene therapy of lung diseases. PMID:27334591

Analysis of cis and trans Requirements for DNA Replication at the Right-End Hairpin of the Human Bocavirus 1 Genome.

PubMed

Shen, Weiran; Deng, Xuefeng; Zou, Wei; Engelhardt, John F; Yan, Ziying; Qiu, Jianming

2016-09-01

Parvoviruses are single-stranded DNA viruses that use the palindromic structures at the ends of the viral genome for their replication. The mechanism of parvovirus replication has been studied mostly in the dependoparvovirus adeno-associated virus 2 (AAV2) and the protoparvovirus minute virus of mice (MVM). Here, we used human bocavirus 1 (HBoV1) to understand the replication mechanism of bocaparvovirus. HBoV1 is pathogenic to humans, causing acute respiratory tract infections, especially in young children under 2 years old. By using the duplex replicative form of the HBoV1 genome in human embryonic kidney 293 (HEK293) cells, we identified the HBoV1 minimal replication origin at the right-end hairpin (OriR). Mutagenesis analyses confirmed the putative NS1 binding and nicking sites within the OriR. Of note, unlike the large nonstructural protein (Rep78/68 or NS1) of other parvoviruses, HBoV1 NS1 did not specifically bind OriR in vitro, indicating that other viral and cellular components or the oligomerization of NS1 is required for NS1 binding to the OriR. In vivo studies demonstrated that residues responsible for NS1 binding and nicking are within the origin-binding domain. Further analysis identified that the small nonstructural protein NP1 is required for HBoV1 DNA replication at OriR. NP1 and other viral nonstructural proteins (NS1 to NS4) colocalized within the viral DNA replication centers in both OriR-transfected cells and virus-infected cells, highlighting a direct involvement of NP1 in viral DNA replication at OriR. Overall, our study revealed the characteristics of HBoV1 DNA replication at OriR, suggesting novel characteristics of autonomous parvovirus DNA replication. Human bocavirus 1 (HBoV1) causes acute respiratory tract infections in young children. The duplex HBoV1 genome replicates in HEK293 cells and produces progeny virions that are infectious in well-differentiated airway epithelial cells. A recombinant AAV2 vector pseudotyped with an HBoV1 capsid has been developed to efficiently deliver the cystic fibrosis transmembrane conductance regulator gene to human airway epithelia. Here, we identified both cis-acting elements and trans-acting proteins that are required for HBoV1 DNA replication at the right-end hairpin in HEK293 cells. We localized the minimal replication origin, which contains both NS1 nicking and binding sites, to a 46-nucleotide sequence in the right-end hairpin. The identification of these essential elements of HBoV1 DNA replication acting both in cis and in trans will provide guidance to develop antiviral strategies targeting viral DNA replication at the right-end hairpin and to design next-generation recombinant HBoV1 vectors, a promising tool for gene therapy of lung diseases. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

GAPPARD: a computationally efficient method of approximating gap-scale disturbance in vegetation models

NASA Astrophysics Data System (ADS)

Scherstjanoi, M.; Kaplan, J. O.; Thürig, E.; Lischke, H.

2013-09-01

Models of vegetation dynamics that are designed for application at spatial scales larger than individual forest gaps suffer from several limitations. Typically, either a population average approximation is used that results in unrealistic tree allometry and forest stand structure, or models have a high computational demand because they need to simulate both a series of age-based cohorts and a number of replicate patches to account for stochastic gap-scale disturbances. The detail required by the latter method increases the number of calculations by two to three orders of magnitude compared to the less realistic population average approach. In an effort to increase the efficiency of dynamic vegetation models without sacrificing realism, we developed a new method for simulating stand-replacing disturbances that is both accurate and faster than approaches that use replicate patches. The GAPPARD (approximating GAP model results with a Probabilistic Approach to account for stand Replacing Disturbances) method works by postprocessing the output of deterministic, undisturbed simulations of a cohort-based vegetation model by deriving the distribution of patch ages at any point in time on the basis of a disturbance probability. With this distribution, the expected value of any output variable can be calculated from the output values of the deterministic undisturbed run at the time corresponding to the patch age. To account for temporal changes in model forcing (e.g., as a result of climate change), GAPPARD performs a series of deterministic simulations and interpolates between the results in the postprocessing step. We integrated the GAPPARD method in the vegetation model LPJ-GUESS, and evaluated it in a series of simulations along an altitudinal transect of an inner-Alpine valley. We obtained results very similar to the output of the original LPJ-GUESS model that uses 100 replicate patches, but simulation time was reduced by approximately the factor 10. Our new method is therefore highly suited for rapidly approximating LPJ-GUESS results, and provides the opportunity for future studies over large spatial domains, allows easier parameterization of tree species, faster identification of areas of interesting simulation results, and comparisons with large-scale datasets and results of other forest models.

Heritability maps of human face morphology through large-scale automated three-dimensional phenotyping

NASA Astrophysics Data System (ADS)

Tsagkrasoulis, Dimosthenis; Hysi, Pirro; Spector, Tim; Montana, Giovanni

2017-04-01

The human face is a complex trait under strong genetic control, as evidenced by the striking visual similarity between twins. Nevertheless, heritability estimates of facial traits have often been surprisingly low or difficult to replicate. Furthermore, the construction of facial phenotypes that correspond to naturally perceived facial features remains largely a mystery. We present here a large-scale heritability study of face geometry that aims to address these issues. High-resolution, three-dimensional facial models have been acquired on a cohort of 952 twins recruited from the TwinsUK registry, and processed through a novel landmarking workflow, GESSA (Geodesic Ensemble Surface Sampling Algorithm). The algorithm places thousands of landmarks throughout the facial surface and automatically establishes point-wise correspondence across faces. These landmarks enabled us to intuitively characterize facial geometry at a fine level of detail through curvature measurements, yielding accurate heritability maps of the human face (www.heritabilitymaps.info).

The forkhead-like transcription factor (Fhl1p) maintains yeast replicative lifespan by regulating ribonucleotide reductase 1 (RNR1) gene transcription

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tai, Akiko; Kamei, Yuka; Mukai, Yukio

In eukaryotes, numerous genetic factors contribute to the lifespan including metabolic enzymes, signal transducers, and transcription factors. As previously reported, the forkhead-like transcription factor (FHL1) gene was required for yeast replicative lifespan and cell proliferation. To determine how Fhl1p regulates the lifespan, we performed a DNA microarray analysis of a heterozygous diploid strain deleted for FHL1. We discovered numerous Fhl1p-target genes, which were then screened for lifespan-regulating activity. We identified the ribonucleotide reductase (RNR) 1 gene (RNR1) as a regulator of replicative lifespan. RNR1 encodes a large subunit of the RNR complex, which consists of two large (Rnr1p/Rnr3p) and twomore » small (Rnr2p/Rnr4p) subunits. Heterozygous deletion of FHL1 reduced transcription of RNR1 and RNR3, but not RNR2 and RNR4. Chromatin immunoprecipitation showed that Fhl1p binds to the promoter regions of RNR1 and RNR3. Cells harboring an RNR1 deletion or an rnr1-C428A mutation, which abolishes RNR catalytic activity, exhibited a short lifespan. In contrast, cells with a deletion of the other RNR genes had a normal lifespan. Overexpression of RNR1, but not RNR3, restored the lifespan of the heterozygous FHL1 mutant to the wild-type (WT) level. The Δfhl1/FHL1 mutant conferred a decrease in dNTP levels and an increase in hydroxyurea (HU) sensitivity. These findings reveal that Fhl1p regulates RNR1 gene transcription to maintain dNTP levels, thus modulating longevity by protection against replication stress. - Highlights: • Fhl1p regulates replicative lifespan and transcription of RNR large subunit genes. • Rnr1p uniquely acts as a lifespan regulator independent of the RNR complex. • dNTP levels modulate longevity by protection against replication stress.« less

Future of the particle replication in nonwetting templates (PRINT) technology.

PubMed

Xu, Jing; Wong, Dominica H C; Byrne, James D; Chen, Kai; Bowerman, Charles; DeSimone, Joseph M

2013-06-24

Particle replication in nonwetting templates (PRINT) is a continuous, roll-to-roll, high-resolution molding technology which allows the design and synthesis of precisely defined micro- and nanoparticles. This technology adapts the lithographic techniques from the microelectronics industry and marries these with the roll-to-roll processes from the photographic film industry to enable researchers to have unprecedented control over particle size, shape, chemical composition, cargo, modulus, and surface properties. In addition, PRINT is a GMP-compliant (GMP=good manufacturing practice) platform amenable for particle fabrication on a large scale. Herein, we describe some of our most recent work involving the PRINT technology for application in the biomedical and material sciences. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rajbhandari, Samyam; NIkam, Akshay; Lai, Pai-Wei

Tensor contractions represent the most compute-intensive core kernels in ab initio computational quantum chemistry and nuclear physics. Symmetries in these tensor contractions makes them difficult to load balance and scale to large distributed systems. In this paper, we develop an efficient and scalable algorithm to contract symmetric tensors. We introduce a novel approach that avoids data redistribution in contracting symmetric tensors while also avoiding redundant storage and maintaining load balance. We present experimental results on two parallel supercomputers for several symmetric contractions that appear in the CCSD quantum chemistry method. We also present a novel approach to tensor redistribution thatmore » can take advantage of parallel hyperplanes when the initial distribution has replicated dimensions, and use collective broadcast when the final distribution has replicated dimensions, making the algorithm very efficient.« less

Ethanol for a sustainable energy future.

PubMed

Goldemberg, José

2007-02-09

Renewable energy is one of the most efficient ways to achieve sustainable development. Increasing its share in the world matrix will help prolong the existence of fossil fuel reserves, address the threats posed by climate change, and enable better security of the energy supply on a global scale. Most of the "new renewable energy sources" are still undergoing large-scale commercial development, but some technologies are already well established. These include Brazilian sugarcane ethanol, which, after 30 years of production, is a global energy commodity that is fully competitive with motor gasoline and appropriate for replication in many countries.

An Analysis of the Sensitivity of Proteogenomic Mapping of Somatic Mutations and Novel Splicing Events in Cancer.

PubMed

Ruggles, Kelly V; Tang, Zuojian; Wang, Xuya; Grover, Himanshu; Askenazi, Manor; Teubl, Jennifer; Cao, Song; McLellan, Michael D; Clauser, Karl R; Tabb, David L; Mertins, Philipp; Slebos, Robbert; Erdmann-Gilmore, Petra; Li, Shunqiang; Gunawardena, Harsha P; Xie, Ling; Liu, Tao; Zhou, Jian-Ying; Sun, Shisheng; Hoadley, Katherine A; Perou, Charles M; Chen, Xian; Davies, Sherri R; Maher, Christopher A; Kinsinger, Christopher R; Rodland, Karen D; Zhang, Hui; Zhang, Zhen; Ding, Li; Townsend, R Reid; Rodriguez, Henry; Chan, Daniel; Smith, Richard D; Liebler, Daniel C; Carr, Steven A; Payne, Samuel; Ellis, Matthew J; Fenyő, David

2016-03-01

Improvements in mass spectrometry (MS)-based peptide sequencing provide a new opportunity to determine whether polymorphisms, mutations, and splice variants identified in cancer cells are translated. Herein, we apply a proteogenomic data integration tool (QUILTS) to illustrate protein variant discovery using whole genome, whole transcriptome, and global proteome datasets generated from a pair of luminal and basal-like breast-cancer-patient-derived xenografts (PDX). The sensitivity of proteogenomic analysis for singe nucleotide variant (SNV) expression and novel splice junction (NSJ) detection was probed using multiple MS/MS sample process replicates defined here as an independent tandem MS experiment using identical sample material. Despite analysis of over 30 sample process replicates, only about 10% of SNVs (somatic and germline) detected by both DNA and RNA sequencing were observed as peptides. An even smaller proportion of peptides corresponding to NSJ observed by RNA sequencing were detected (<0.1%). Peptides mapping to DNA-detected SNVs without a detectable mRNA transcript were also observed, suggesting that transcriptome coverage was incomplete (∼80%). In contrast to germline variants, somatic variants were less likely to be detected at the peptide level in the basal-like tumor than in the luminal tumor, raising the possibility of differential translation or protein degradation effects. In conclusion, this large-scale proteogenomic integration allowed us to determine the degree to which mutations are translated and identify gaps in sequence coverage, thereby benchmarking current technology and progress toward whole cancer proteome and transcriptome analysis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Internal Wave Apparatus for Copepod Behavior Assays

NASA Astrophysics Data System (ADS)

Jung, S.; Haas, K. A.; Webster, D. R.

2015-11-01

Internal waves are ubiquitous features in coastal marine environments and have been observed to mediate vertical distributions of zooplankton in situ. Internal waves are generated through oscillations of the pycnocline in stratified waters and thereby create fine-scale hydrodynamic cues that copepods and other zooplankton are known to sense, such as fluid density gradients and velocity gradients (quantified as shear deformation rate). The role of copepod behavior in response to cues associated with internal waves is largely unknown. Thus, a coupled quantification of copepod behavior and hydrodynamic cues will provide insight to the bio-physical interaction and the role of biological versus physical forcing in mediating organism distributions. We constructed a laboratory-scale internal wave apparatus to facilitate fine-scale observations of copepod behavior in flows that replicate in situ conditions of internal waves in a two-layer stratification. Three cases are chosen with density jump ranging between 0.75 - 1.5 kg/m3. Analytical analysis of the two-layer system provides guidance of the target forcing frequency to generate a standing internal wave with a single dominate frequency of oscillation. Flow visualization and signal processing of the interface location are used to quantify the wave characteristics. A copepod behavior assay is conducted, and sample trajectories are analyzed to identify copepod response to internal wave structure.

Prospective Large-Scale Field Study Generates Predictive Model Identifying Major Contributors to Colony Losses

PubMed Central

Kielmanowicz, Merav Gleit; Inberg, Alex; Lerner, Inbar Maayan; Golani, Yael; Brown, Nicholas; Turner, Catherine Louise; Hayes, Gerald J. R.; Ballam, Joan M.

2015-01-01

Over the last decade, unusually high losses of colonies have been reported by beekeepers across the USA. Multiple factors such as Varroa destructor, bee viruses, Nosema ceranae, weather, beekeeping practices, nutrition, and pesticides have been shown to contribute to colony losses. Here we describe a large-scale controlled trial, in which different bee pathogens, bee population, and weather conditions across winter were monitored at three locations across the USA. In order to minimize influence of various known contributing factors and their interaction, the hives in the study were not treated with antibiotics or miticides. Additionally, the hives were kept at one location and were not exposed to potential stress factors associated with migration. Our results show that a linear association between load of viruses (DWV or IAPV) in Varroa and bees is present at high Varroa infestation levels (>3 mites per 100 bees). The collection of comprehensive data allowed us to draw a predictive model of colony losses and to show that Varroa destructor, along with bee viruses, mainly DWV replication, contributes to approximately 70% of colony losses. This correlation further supports the claim that insufficient control of the virus-vectoring Varroa mite would result in increased hive loss. The predictive model also indicates that a single factor may not be sufficient to trigger colony losses, whereas a combination of stressors appears to impact hive health. PMID:25875764

A Replication by Any Other Name: A Systematic Review of Replicative Intervention Studies

ERIC Educational Resources Information Center

Cook, Bryan G.; Collins, Lauren W.; Cook, Sara C.; Cook, Lysandra

2016-01-01

Replication research is essential to scientific knowledge. Reviews of replication studies often electronically search for "replicat*" as a textword, which does not identify studies that replicate previous research but do not self-identify as such. We examined whether the 83 intervention studies published in six non-categorical research…

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

PubMed

He, Meian; Xu, Min; Zhang, Ben; Liang, Jun; Chen, Peng; Lee, Jong-Young; Johnson, Todd A; Li, Huaixing; Yang, Xiaobo; Dai, Juncheng; Liang, Liming; Gui, Lixuan; Qi, Qibin; Huang, Jinyan; Li, Yanping; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Cheng, Ching-Yu; Cho, Myeong-Chan; Cho, Yoon Shin; Chu, Minjie; Cui, Bin; Gao, Yu-Tang; Go, Min Jin; Gu, Dongfeng; Gu, Weiqiong; Guo, Huan; Hao, Yongchen; Hong, Jie; Hu, Zhibin; Hu, Yanling; Huang, Jianfeng; Hwang, Joo-Yeon; Ikram, Mohammad Kamran; Jin, Guangfu; Kang, Dae-Hee; Khor, Chiea Chuen; Kim, Bong-Jo; Kim, Hung Tae; Kubo, Michiaki; Lee, Jeannette; Lee, Juyoung; Lee, Nanette R; Li, Ruoying; Li, Jun; Liu, JianJun; Longe, Jirong; Lu, Wei; Lu, Xiangfeng; Miao, Xiaoping; Okada, Yukinori; Ong, Rick Twee-Hee; Qiu, Gaokun; Seielstad, Mark; Sim, Xueling; Song, Huaidong; Takeuchi, Fumihiko; Tanaka, Toshihiro; Taylor, Phil R; Wang, Laiyuan; Wang, Weiqing; Wang, Yiqin; Wu, Chen; Wu, Ying; Xiang, Yong-Bing; Yamamoto, Ken; Yang, Handong; Liao, Ming; Yokota, Mitsuhiro; Young, Terri; Zhang, Xiaomin; Kato, Norihiro; Wang, Qing K; Zheng, Wei; Hu, Frank B; Lin, Dongxin; Shen, Hongbing; Teo, Yik Ying; Mo, Zengnan; Wong, Tien Yin; Lin, Xu; Mohlke, Karen L; Ning, Guang; Tsunoda, Tatsuhiko; Han, Bok-Ghee; Shu, Xiao-Ou; Tai, E Shyong; Wu, Tangchun; Qi, Lu

2015-03-15

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

CLU rs9331888 Polymorphism Contributes to Alzheimer's Disease Susceptibility in Caucasian But Not East Asian Populations.

PubMed

Zhang, Shuyan; Li, Xuling; Ma, Guoda; Jiang, Yongshuai; Liao, Mingzhi; Feng, Rennan; Zhang, Liangcai; Liu, Jiafeng; Wang, Guangyu; Zhao, Bin; Jiang, Qinghua; Li, Keshen; Liu, Guiyou

2016-04-01

Large-scale genome-wide association studies (GWAS) identified three single nucleotide polymorphisms rs11136000, rs2279590, and rs9331888 in CLU gene to be significantly associated with Alzheimer's disease (AD) in Caucasian ancestry. Both rs11136000 and rs2279590 variants were successfully replicated in Asian population. However, previous studies reported either a weak association or no association between rs9331888 polymorphism and AD in Asian population. Here, we searched the PubMed, AlzGene, and Google Scholar databases. We selected 12 independent studies that evaluated the association between the rs9331888 polymorphism and AD using a case-control design. Using an additive model, we did not identify significant heterogeneity among these 12 studies. We observed significant association between rs9331888 polymorphism and AD in pooled populations (P = 2.26E - 07, odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.06-1.14). In subgroup analysis, we did not identify significant heterogeneity in both Asian and Caucasian populations. We identified significant association in Caucasian population (P = 1.67E - 08, OR = 1.13, 95% CI 1.08-1.18) but not in East Asian population (P = 0.49, OR = 1.02, 95% CI 0.96-1.10).

Practical experience from the Office of Adolescent Health's large scale implementation of an evidence-based Teen Pregnancy Prevention Program.

PubMed

Margolis, Amy Lynn; Roper, Allison Yvonne

2014-03-01

After 3 years of experience overseeing the implementation and evaluation of evidence-based teen pregnancy prevention programs in a diversity of populations and settings across the country, the Office of Adolescent Health (OAH) has learned numerous lessons through practical application and new experiences. These lessons and experiences are applicable to those working to implement evidence-based programs on a large scale. The lessons described in this paper focus on what it means for a program to be implementation ready, the role of the program developer in replicating evidence-based programs, the importance of a planning period to ensure quality implementation, the need to define and measure fidelity, and the conditions necessary to support rigorous grantee-level evaluation. Published by Elsevier Inc.

CROSS-DISCIPLINARY PHYSICS AND RELATED AREAS OF SCIENCE AND TECHNOLOGY: Novel Route to Fabrication of Metal-Sandwiched Nanoscale Tapered Structures

NASA Astrophysics Data System (ADS)

Zhang, Yang; Yu, Da-Peng

2009-08-01

Tapered dielectric structures in metal have exhibited extraordinary performance in both surface plasmon polariton (SPP) waveguiding and SPP focusing. This is crucial to plasmonic research and industrial plasmonic device integration. We present a method that facilitates easy fabrication of smooth-surfaced sub-micron tapered structures in large scale simply with electron beam lithography (EBL). When a PMMA layer is spin-coated on previously-EBL-defined PMMA structures, steep edges can be transformed into a declining slope to form tapered PMMA structures, scaled from 10 nm to 1000 nm. Despite the simplicity of our method, patterns with PMMA surface smoothness can be well-positioned and replicated in large numbers, which therefore gives scientists easy access to research on the properties of tapered structures.

An instrument design and sample strategy for measuring soil respiration in the coastal temperate rain forest

NASA Astrophysics Data System (ADS)

Nay, S. M.; D'Amore, D. V.

2009-12-01

The coastal temperate rainforest (CTR) along the northwest coast of North America is a large and complex mosaic of forests and wetlands located on an undulating terrain ranging from sea level to thousands of meters in elevation. This biome stores a dynamic portion of the total carbon stock of North America. The fate of the terrestrial carbon stock is of concern due to the potential for mobilization and export of this store to both the atmosphere as carbon respiration flux and ocean as dissolved organic and inorganic carbon flux. Soil respiration is the largest export vector in the system and must be accurately measured to gain any comprehensive understanding of how carbon moves though this system. Suitable monitoring tools capable of measuring carbon fluxes at small spatial scales are essential for our understanding of carbon dynamics at larger spatial scales within this complex assemblage of ecosystems. We have adapted instrumentation and developed a sampling strategy for optimizing replication of soil respiration measurements to quantify differences among spatially complex landscape units of the CTR. We start with the design of the instrument to ease the technological, ergonomic and financial barriers that technicians encounter in monitoring the efflux of CO2 from the soil. Our sampling strategy optimizes the physical efforts of the field work and manages for the high variation of flux measurements encountered in this difficult environment of rough terrain, dense vegetation and wet climate. Our soil respirometer incorporates an infra-red gas analyzer (LiCor Inc. LI-820) and an 8300 cm3 soil respiration chamber; the device is durable, lightweight, easy to operate and can be built for under $5000 per unit. The modest unit price allows for a multiple unit fleet to be deployed and operated in an intensive field monitoring campaign. We use a large 346 cm2 collar to accommodate as much micro spatial variation as feasible and to facilitate repeated measures for tracking temporal trends. Our collar design minimizes root interference yet provides a highly stable platform for coupling with the respirometer. Meso-scale variability characterized by large down woody debris, wind throw pits and mounds and surface roots is negotiated with by a hexagonal array of seven collars at two meter spacing (sample pod). Landscape scale variability is managed through stratification and replication amongst ecosystem types arrayed across a hydrologic gradient from bogs to forested wetlands to upland forests. Our strategy has allowed us to gather data sets consisting of approximately 1800 total observations with approximately 600 measurements per replication per year. Mean coefficients of variation (CV) at the collar (micro-scale) were approximately 0.67. The pod level mean CV was reduced to approximately 0.29 at the pod (meso-scale). The CV at the vegetation strata were 0.43, 0.18 and 0.21 for bog, forested wetland and upland forest respectively. With temperature and hydrological data we are able to measure and model carbon dynamics in this large and complex environment. The analysis of variability at the three spatial scales has confirmed that our approach is capturing and constraining the variability.

Viewpoint: observations on scaled average bioequivalence.

PubMed

Patterson, Scott D; Jones, Byron

2012-01-01

The two one-sided test procedure (TOST) has been used for average bioequivalence testing since 1992 and is required when marketing new formulations of an approved drug. TOST is known to require comparatively large numbers of subjects to demonstrate bioequivalence for highly variable drugs, defined as those drugs having intra-subject coefficients of variation greater than 30%. However, TOST has been shown to protect public health when multiple generic formulations enter the marketplace following patent expiration. Recently, scaled average bioequivalence (SABE) has been proposed as an alternative statistical analysis procedure for such products by multiple regulatory agencies. SABE testing requires that a three-period partial replicate cross-over or full replicate cross-over design be used. Following a brief summary of SABE analysis methods applied to existing data, we will consider three statistical ramifications of the proposed additional decision rules and the potential impact of implementation of scaled average bioequivalence in the marketplace using simulation. It is found that a constraint being applied is biased, that bias may also result from the common problem of missing data and that the SABE methods allow for much greater changes in exposure when generic-generic switching occurs in the marketplace. Copyright © 2011 John Wiley & Sons, Ltd.

Self-Replication of Localized Vegetation Patches in Scarce Environments

NASA Astrophysics Data System (ADS)

Bordeu, Ignacio; Clerc, Marcel G.; Couteron, Piere; Lefever, René; Tlidi, Mustapha

2016-09-01

Desertification due to climate change and increasing drought periods is a worldwide problem for both ecology and economy. Our ability to understand how vegetation manages to survive and propagate through arid and semiarid ecosystems may be useful in the development of future strategies to prevent desertification, preserve flora—and fauna within—or even make use of scarce resources soils. In this paper, we study a robust phenomena observed in semi-arid ecosystems, by which localized vegetation patches split in a process called self-replication. Localized patches of vegetation are visible in nature at various spatial scales. Even though they have been described in literature, their growth mechanisms remain largely unexplored. Here, we develop an innovative statistical analysis based on real field observations to show that patches may exhibit deformation and splitting. This growth mechanism is opposite to the desertification since it allows to repopulate territories devoid of vegetation. We investigate these aspects by characterizing quantitatively, with a simple mathematical model, a new class of instabilities that lead to the self-replication phenomenon observed.

Failure to replicate the internal structure of Greek-specific thalassemia quality of life instrument in adult thalassemia patients in Sabah.

PubMed

Keowmani, Thamron; Lee, Lily Wong Lee

2016-01-01

To study the validity and reliability of the Malay version of the Specific Thalassemia Quality of Life Instrument (STQOLI) in Sabah's adult thalassemia patients. This cross-sectional study was done at Thalassemia Treatment Centre, Queen Elizabeth Hospital in Sabah, Malaysia. Eighty-two adult thalassemia patients who fulfilled the inclusion and exclusion criteria were conveniently selected for participation in the study. The English version of STQOLI was translated into Malay by using forward and back translations. The content of the questionnaire was validated by the chief hematologist of the hospital. The construct validity of the 40-item questionnaire was assessed by principal component analysis with varimax rotation and the scale reliability was assessed by Cronbach's alpha. The study failed to replicate the internal structure of the Greek STQOLI. Instead, 12 factors have been identified from the exploratory factor analysis, which accounted for 72.2% of the variance. However, only eight factors were interpretable. The factors were iron chelation pump impact, transfusion impact, time spent on treatment and its impact on work and social life, sex life, side effects of treatment, cardiovascular problems, psychology, and iron chelation pill impact. The overall scale reliability was 0.913. This study was unable to replicate the internal structure of the Greek STQOLI in Sabah's adult thalassemia patients. Instead, a new structure has emerged that can be used as a guide to develop a questionnaire specific for adult thalassemia patients in Sabah. Future research should focus on the eight factors identified from this study.

Immunochip Analyses of Epistasis in Rheumatoid Arthritis Confirm Multiple Interactions within MHC and Suggest Novel Non-MHC Epistatic Signals.

PubMed

Wei, Wen-Hua; Loh, Chia-Yin; Worthington, Jane; Eyre, Stephen

2016-05-01

Studying statistical gene-gene interactions (epistasis) has been limited by the difficulties in performance, both statistically and computationally, in large enough sample numbers to gain sufficient power. Three large Immunochip datasets from cohort samples recruited in the United Kingdom, United States, and Sweden with European ancestry were used to examine epistasis in rheumatoid arthritis (RA). A full pairwise search was conducted in the UK cohort using a high-throughput tool and the resultant significant epistatic signals were tested for replication in the United States and Swedish cohorts. A forward selection approach was applied to remove redundant signals, while conditioning on the preidentified additive effects. We detected abundant genome-wide significant (p < 1.0e-13) epistatic signals, all within the MHC region. These signals were reduced substantially, but a proportion remained significant (p < 1.0e-03) in conditional tests. We identified 11 independent epistatic interactions across the entire MHC, each explaining on average 0.12% of the phenotypic variance, nearly all replicated in both replication cohorts. We also identified non-MHC epistatic interactions between RA susceptible loci LOC100506023 and IRF5 with Immunochip-wide significance (p < 1.1e-08) and between 2 neighboring single-nucleotide polymorphism near PTPN22 that were in low linkage disequilibrium with independent interaction (p < 1.0e-05). Both non-MHC epistatic interactions were statistically replicated with a similar interaction pattern in the US cohort only. There are multiple but relatively weak interactions independent of the additive effects in RA and a larger sample number is required to confidently assign additional non-MHC epistasis.

GAPPARD: a computationally efficient method of approximating gap-scale disturbance in vegetation models

NASA Astrophysics Data System (ADS)

Scherstjanoi, M.; Kaplan, J. O.; Thürig, E.; Lischke, H.

2013-02-01

Models of vegetation dynamics that are designed for application at spatial scales larger than individual forest gaps suffer from several limitations. Typically, either a population average approximation is used that results in unrealistic tree allometry and forest stand structure, or models have a high computational demand because they need to simulate both a series of age-based cohorts and a number of replicate patches to account for stochastic gap-scale disturbances. The detail required by the latter method increases the number of calculations by two to three orders of magnitude compared to the less realistic population average approach. In an effort to increase the efficiency of dynamic vegetation models without sacrificing realism, and to explore patterns of spatial scaling in forests, we developed a new method for simulating stand-replacing disturbances that is both accurate and 10-50x faster than approaches that use replicate patches. The GAPPARD (approximating GAP model results with a Probabilistic Approach to account for stand Replacing Disturbances) method works by postprocessing the output of deterministic, undisturbed simulations of a cohort-based vegetation model by deriving the distribution of patch ages at any point in time on the basis of a disturbance probability. With this distribution, the expected value of any output variable can be calculated from the output values of the deterministic undisturbed run at the time corresponding to the patch age. To account for temporal changes in model forcing, e.g., as a result of climate change, GAPPARD performs a series of deterministic simulations and interpolates between the results in the postprocessing step. We integrated the GAPPARD method in the forest models LPJ-GUESS and TreeM-LPJ, and evaluated these in a series of simulations along an altitudinal transect of an inner-alpine valley. With GAPPARD applied to LPJ-GUESS results were insignificantly different from the output of the original model LPJ-GUESS using 100 replicate patches, but simulation time was reduced by approximately the factor 10. Our new method is therefore highly suited rapidly approximating LPJ-GUESS results, and provides the opportunity for future studies over large spatial domains, allows easier parameterization of tree species, faster identification of areas of interesting simulation results, and comparisons with large-scale datasets and forest models.

A large-scale initiative to disseminate an evidence-based drug abuse prevention program in Italy: Lessons learned for practitioners and researchers.

PubMed

Velasco, Veronica; Griffin, Kenneth W; Antichi, Mariella; Celata, Corrado

2015-10-01

Across developed countries, experimentation with alcohol, tobacco, and other drugs often begins in the early adolescent years. Several evidence-based programs have been developed to prevent adolescent substance use. Many of the most rigorously tested and empirically supported prevention programs were initially developed and tested in the United States. Increasingly, these interventions are being adopted for use in Europe and throughout the world. This paper reports on a large-scale comprehensive initiative designed to select, adapt, implement, and sustain an evidence-based drug abuse prevention program in Italy. As part of a large-scale regionally funded collaboration in the Lombardy region of Italy, we report on processes through which a team of stakeholders selected, translated and culturally adapted, planned, implemented and evaluated the Life Skills Training (LST) school-based drug abuse prevention program, an evidence-based intervention developed in the United States. We discuss several challenges and lessons learned and implications for prevention practitioners and researchers attempting to undertake similar international dissemination projects. We review several published conceptual models designed to promote the replication and widespread dissemination of effective programs, and discuss their strengths and limitations in the context of planning and implementing a complex, large-scale real-world dissemination effort. Copyright © 2015 Elsevier Ltd. All rights reserved.

On the cross-cultural replicability of the resilient, undercontrolled, and overcontrolled personality types.

PubMed

Alessandri, Guido; Vecchione, Michele; Donnellan, Brent M; Eisenberg, Nancy; Caprara, Gian Vittorio; Cieciuch, Jan

2014-08-01

Personality types reflect typical configurations of personality attributes within individuals. Over the last 20 years, researchers have identified a set of three replicable personality types: resilient (R), undercontrolled (U), and overcontrolled (O) types. In this study, we examined the cross-cultural replicability of the RUO types in Italy, Poland, Spain, and the United States. Personality types were identified using cluster analyses of Big Five profiles in large samples of college students from Italy (n = 322), the United States (n = 499), Spain (n = 420), and Poland (n = 235). Prior to clustering the profiles, the measurement invariance of the Big Five measure across samples was tested. We found evidence for the RUO types in all four samples. The three-cluster solution showed a better fit over alternative solutions and had a relatively high degree of cross-cultural generalizability. The RUO types are evident in samples from four countries with distinct linguistic and cultural traditions. Results were discussed in light of the importance of considering how traits are organized within individuals for advancing contemporary personality psychology. © 2013 Wiley Periodicals, Inc.

Telomere healing following DNA polymerase arrest-induced breakages is likely the main mechanism generating chromosome 4p terminal deletions.

PubMed

Hannes, Femke; Van Houdt, Jeroen; Quarrell, Oliver W; Poot, Martin; Hochstenbach, Ron; Fryns, Jean-Pierre; Vermeesch, Joris R

2010-12-01

Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear chromosomes against chromosome degradation, fusion, and incomplete replication, those terminal-deleted chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase-mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling-induced chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes. © 2010 Wiley-Liss, Inc.

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

PubMed Central

2011-01-01

Background Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. Methods We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients. Results After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086). Conclusions We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease. PMID:21957892

A Host Susceptibility Gene, DR1, Facilitates Influenza A Virus Replication by Suppressing Host Innate Immunity and Enhancing Viral RNA Replication

PubMed Central

Hsu, Shih-Feng; Su, Wen-Chi; Jeng, King-Song

2015-01-01

ABSTRACT Influenza A virus (IAV) depends on cellular factors to complete its replication cycle; thus, investigation of the factors utilized by IAV may facilitate antiviral drug development. To this end, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNA interference (RNAi) screen. Knockdown (KD) of DR1 resulted in reductions of viral RNA and protein production, demonstrating that DR1 acts as a positive host factor in IAV replication. Genome-wide transcriptomic analysis showed that there was a strong induction of interferon-stimulated gene (ISG) expression after prolonged DR1 KD. We found that beta interferon (IFN-β) was induced by DR1 KD, thereby activating the JAK-STAT pathway to turn on ISG expression, which led to a strong inhibition of IAV replication. This result suggests that DR1 in normal cells suppresses IFN induction, probably to prevent undesired cytokine production, but that this suppression may create a milieu that favors IAV replication once cells are infected. Furthermore, biochemical assays of viral RNA replication showed that DR1 KD suppressed viral RNA replication. We also showed that DR1 associated with all three subunits of the viral RNA-dependent RNA polymerase (RdRp) complex, indicating that DR1 may interact with individual components of the viral RdRp complex to enhance viral RNA replication. Thus, DR1 may be considered a novel host susceptibility gene for IAV replication via a dual mechanism, not only suppressing the host defense to indirectly favor IAV replication but also directly facilitating viral RNA replication. IMPORTANCE Investigations of virus-host interactions involved in influenza A virus (IAV) replication are important for understanding viral pathogenesis and host defenses, which may manipulate influenza virus infection or prevent the emergence of drug resistance caused by a high error rate during viral RNA replication. For this purpose, a cellular transcriptional repressor, DR1, was identified from a genome-wide RNAi screen as a positive regulator in IAV replication. In the current studies, we showed that DR1 suppressed the gene expression of a large set of host innate immunity genes, which indirectly facilitated IAV replication in the event of IAV infection. Besides this scenario, DR1 also directly enhanced the viral RdRp activity, likely through associating with individual components of the viral RdRp complex. Thus, DR1 represents a novel host susceptibility gene for IAV replication via multiple functions, not only suppressing the host defense but also enhancing viral RNA replication. DR1 may be a potential target for drug development against influenza virus infection. PMID:25589657

DNA replication origins—where do we begin?

PubMed Central

Prioleau, Marie-Noëlle; MacAlpine, David M.

2016-01-01

For more than three decades, investigators have sought to identify the precise locations where DNA replication initiates in mammalian genomes. The development of molecular and biochemical approaches to identify start sites of DNA replication (origins) based on the presence of defining and characteristic replication intermediates at specific loci led to the identification of only a handful of mammalian replication origins. The limited number of identified origins prevented a comprehensive and exhaustive search for conserved genomic features that were capable of specifying origins of DNA replication. More recently, the adaptation of origin-mapping assays to genome-wide approaches has led to the identification of tens of thousands of replication origins throughout mammalian genomes, providing an unprecedented opportunity to identify both genetic and epigenetic features that define and regulate their distribution and utilization. Here we summarize recent advances in our understanding of how primary sequence, chromatin environment, and nuclear architecture contribute to the dynamic selection and activation of replication origins across diverse cell types and developmental stages. PMID:27542827

Two interferon-independent double-stranded RNA-induced host defense strategies suppress the common cold virus at warm temperature.

PubMed

Foxman, Ellen F; Storer, James A; Vanaja, Kiran; Levchenko, Andre; Iwasaki, Akiko

2016-07-26

Most strains of rhinovirus (RV), the common cold virus, replicate better at cool temperatures found in the nasal cavity (33-35 °C) than at lung temperature (37 °C). Recent studies found that although 37 °C temperature suppressed RV growth largely by engaging the type 1 IFN response in infected epithelial cells, a significant temperature dependence to viral replication remained in cells devoid of IFN induction or signaling. To gain insight into IFN-independent mechanisms limiting RV replication at 37 °C, we studied RV infection in human bronchial epithelial cells and H1-HeLa cells. During the single replication cycle, RV exhibited temperature-dependent replication in both cell types in the absence of IFN induction. At 37 °C, earlier signs of apoptosis in RV-infected cells were accompanied by reduced virus production. Furthermore, apoptosis of epithelial cells was enhanced at 37 °C in response to diverse stimuli. Dynamic mathematical modeling and B cell lymphoma 2 (BCL2) overexpression revealed that temperature-dependent host cell death could partially account for the temperature-dependent growth observed during RV amplification, but also suggested additional mechanisms of virus control. In search of a redundant antiviral pathway, we identified a role for the RNA-degrading enzyme RNAseL. Simultaneous antagonism of apoptosis and RNAseL increased viral replication and dramatically reduced temperature dependence. These findings reveal two IFN-independent mechanisms active in innate defense against RV, and demonstrate that even in the absence of IFNs, temperature-dependent RV amplification is largely a result of host cell antiviral restriction mechanisms operating more effectively at 37 °C than at 33 °C.

Level and pattern of overstory retention influence rates and forms of tree mortality in mature, coniferous forests of the Pacific Northwest, USA

Treesearch

Lauren S. Urgenson; Charles B. Halpern; Paul D. Anderson

2013-01-01

Mortality of retained trees can compromise the ecological objectives of variable-retention harvest. We used a large-scale experiment replicated at six locations in western Washington and Oregon to examine the influences of retention level (40% vs. 15% of original basal area) and its spatial pattern (aggregated vs.dispersed) on the rate and form of tree mortality for 11...

Visual Network Asymmetry and Default Mode Network Function in ADHD: An fMRI Study

PubMed Central

Hale, T. Sigi; Kane, Andrea M.; Kaminsky, Olivia; Tung, Kelly L.; Wiley, Joshua F.; McGough, James J.; Loo, Sandra K.; Kaplan, Jonas T.

2014-01-01

Background: A growing body of research has identified abnormal visual information processing in attention-deficit hyperactivity disorder (ADHD). In particular, slow processing speed and increased reliance on visuo-perceptual strategies have become evident. Objective: The current study used recently developed fMRI methods to replicate and further examine abnormal rightward biased visual information processing in ADHD and to further characterize the nature of this effect; we tested its association with several large-scale distributed network systems. Method: We examined fMRI BOLD response during letter and location judgment tasks, and directly assessed visual network asymmetry and its association with large-scale networks using both a voxelwise and an averaged signal approach. Results: Initial within-group analyses revealed a pattern of left-lateralized visual cortical activity in controls but right-lateralized visual cortical activity in ADHD children. Direct analyses of visual network asymmetry confirmed atypical rightward bias in ADHD children compared to controls. This ADHD characteristic was atypically associated with reduced activation across several extra-visual networks, including the default mode network (DMN). We also found atypical associations between DMN activation and ADHD subjects’ inattentive symptoms and task performance. Conclusion: The current study demonstrated rightward VNA in ADHD during a simple letter discrimination task. This result adds an important novel consideration to the growing literature identifying abnormal visual processing in ADHD. We postulate that this characteristic reflects greater perceptual engagement of task-extraneous content, and that it may be a basic feature of less efficient top-down task-directed control over visual processing. We additionally argue that abnormal DMN function may contribute to this characteristic. PMID:25076915

Follow-up study identifies two novel susceptibility loci PRKCB and 8p11.21 for systemic lupus erythematosus.

PubMed

Sheng, Yu-Jun; Gao, Jin-Ping; Li, Jian; Han, Jian-Wen; Xu, Qiang; Hu, Wen-Long; Pan, Ting-Meng; Cheng, Yi-Lin; Yu, Ze-Ying; Ni, Cheng; Yao, Sha; He, Cai-Feng; Liu, Yang-Sheng; Li, Yun; Ge, Hong-Mei; Xiao, Feng-Li; Sun, Liang-Dan; Yang, Sen; Zhang, Xue-Jun

2011-04-01

We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants affecting susceptibility to SLE. Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate. Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han [rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal. Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.

Contextual sensitivity in scientific reproducibility

PubMed Central

Van Bavel, Jay J.; Mende-Siedlecki, Peter; Brady, William J.; Reinero, Diego A.

2016-01-01

In recent years, scientists have paid increasing attention to reproducibility. For example, the Reproducibility Project, a large-scale replication attempt of 100 studies published in top psychology journals found that only 39% could be unambiguously reproduced. There is a growing consensus among scientists that the lack of reproducibility in psychology and other fields stems from various methodological factors, including low statistical power, researcher’s degrees of freedom, and an emphasis on publishing surprising positive results. However, there is a contentious debate about the extent to which failures to reproduce certain results might also reflect contextual differences (often termed “hidden moderators”) between the original research and the replication attempt. Although psychologists have found extensive evidence that contextual factors alter behavior, some have argued that context is unlikely to influence the results of direct replications precisely because these studies use the same methods as those used in the original research. To help resolve this debate, we recoded the 100 original studies from the Reproducibility Project on the extent to which the research topic of each study was contextually sensitive. Results suggested that the contextual sensitivity of the research topic was associated with replication success, even after statistically adjusting for several methodological characteristics (e.g., statistical power, effect size). The association between contextual sensitivity and replication success did not differ across psychological subdisciplines. These results suggest that researchers, replicators, and consumers should be mindful of contextual factors that might influence a psychological process. We offer several guidelines for dealing with contextual sensitivity in reproducibility. PMID:27217556

Contextual sensitivity in scientific reproducibility.

PubMed

Van Bavel, Jay J; Mende-Siedlecki, Peter; Brady, William J; Reinero, Diego A

2016-06-07

In recent years, scientists have paid increasing attention to reproducibility. For example, the Reproducibility Project, a large-scale replication attempt of 100 studies published in top psychology journals found that only 39% could be unambiguously reproduced. There is a growing consensus among scientists that the lack of reproducibility in psychology and other fields stems from various methodological factors, including low statistical power, researcher's degrees of freedom, and an emphasis on publishing surprising positive results. However, there is a contentious debate about the extent to which failures to reproduce certain results might also reflect contextual differences (often termed "hidden moderators") between the original research and the replication attempt. Although psychologists have found extensive evidence that contextual factors alter behavior, some have argued that context is unlikely to influence the results of direct replications precisely because these studies use the same methods as those used in the original research. To help resolve this debate, we recoded the 100 original studies from the Reproducibility Project on the extent to which the research topic of each study was contextually sensitive. Results suggested that the contextual sensitivity of the research topic was associated with replication success, even after statistically adjusting for several methodological characteristics (e.g., statistical power, effect size). The association between contextual sensitivity and replication success did not differ across psychological subdisciplines. These results suggest that researchers, replicators, and consumers should be mindful of contextual factors that might influence a psychological process. We offer several guidelines for dealing with contextual sensitivity in reproducibility.

Accelerating advances in continental domain hydrologic modeling

USGS Publications Warehouse

Archfield, Stacey A.; Clark, Martyn; Arheimer, Berit; Hay, Lauren E.; McMillan, Hilary; Kiang, Julie E.; Seibert, Jan; Hakala, Kirsti; Bock, Andrew R.; Wagener, Thorsten; Farmer, William H.; Andreassian, Vazken; Attinger, Sabine; Viglione, Alberto; Knight, Rodney; Markstrom, Steven; Over, Thomas M.

2015-01-01

In the past, hydrologic modeling of surface water resources has mainly focused on simulating the hydrologic cycle at local to regional catchment modeling domains. There now exists a level of maturity among the catchment, global water security, and land surface modeling communities such that these communities are converging toward continental domain hydrologic models. This commentary, written from a catchment hydrology community perspective, provides a review of progress in each community toward this achievement, identifies common challenges the communities face, and details immediate and specific areas in which these communities can mutually benefit one another from the convergence of their research perspectives. Those include: (1) creating new incentives and infrastructure to report and share model inputs, outputs, and parameters in data services and open access, machine-independent formats for model replication or reanalysis; (2) ensuring that hydrologic models have: sufficient complexity to represent the dominant physical processes and adequate representation of anthropogenic impacts on the terrestrial water cycle, a process-based approach to model parameter estimation, and appropriate parameterizations to represent large-scale fluxes and scaling behavior; (3) maintaining a balance between model complexity and data availability as well as uncertainties; and (4) quantifying and communicating significant advancements toward these modeling goals.

Genetic variations in the DNA replication origins of human papillomavirus family correlate with their oncogenic potential.

PubMed

Yilmaz, Gulden; Biswas-Fiss, Esther E; Biswas, Subhasis B

2018-04-01

Human papillomaviruses (HPVs) encompass a large family of viruses that range from benign to highly carcinogenic. The crucial differences between benign and carcinogenic types of HPV remain unknown, except that the two HPV types differ in the frequency of DNA replication. We have systematically analyzed the mechanism of HPV DNA replication initiation in low-risk and high-risk HPVs. Our results demonstrate that HPV-encoded E2 initiator protein and its four binding sites in the replication origin play pivotal roles in determining the destiny of the HPV-infected cell. We have identified strain-specific single nucleotide variations in E2 binding sites found only in the high-risk HPVs. We have demonstrated that these variations result in attenuated formation of the E2-DNA complex. E2 binding to these sites is linked to the activation of the DNA replication origin as well as initiation of DNA replication. Both electrophoretic mobility shift assay and atomic force microscopy studies demonstrated that binding of E2 from either low- or high-risk HPVs with variant binding sequences lacked multimeric E2-DNA complex formation in vitro. These results provided a molecular basis of differential DNA replication in the two types of HPVs and pointed to a correlation with the development of cancer. Copyright © 2017. Published by Elsevier B.V.

Arrays of probes for positional sequencing by hybridization

DOEpatents

Cantor, Charles R [Boston, MA; Prezetakiewiczr, Marek [East Boston, MA; Smith, Cassandra L [Boston, MA; Sano, Takeshi [Waltham, MA

2008-01-15

This invention is directed to methods and reagents useful for sequencing nucleic acid targets utilizing sequencing by hybridization technology comprising probes, arrays of probes and methods whereby sequence information is obtained rapidly and efficiently in discrete packages. That information can be used for the detection, identification, purification and complete or partial sequencing of a particular target nucleic acid. When coupled with a ligation step, these methods can be performed under a single set of hybridization conditions. The invention also relates to the replication of probe arrays and methods for making and replicating arrays of probes which are useful for the large scale manufacture of diagnostic aids used to screen biological samples for specific target sequences. Arrays created using PCR technology may comprise probes with 5'- and/or 3'-overhangs.

Practical and Efficient Searching in Proteomics: A Cross Engine Comparison

PubMed Central

Paulo, Joao A.

2014-01-01

Background Analysis of large datasets produced by mass spectrometry-based proteomics relies on database search algorithms to sequence peptides and identify proteins. Several such scoring methods are available, each based on different statistical foundations and thereby not producing identical results. Here, the aim is to compare peptide and protein identifications using multiple search engines and examine the additional proteins gained by increasing the number of technical replicate analyses. Methods A HeLa whole cell lysate was analyzed on an Orbitrap mass spectrometer for 10 technical replicates. The data were combined and searched using Mascot, SEQUEST, and Andromeda. Comparisons were made of peptide and protein identifications among the search engines. In addition, searches using each engine were performed with incrementing number of technical replicates. Results The number and identity of peptides and proteins differed across search engines. For all three search engines, the differences in proteins identifications were greater than the differences in peptide identifications indicating that the major source of the disparity may be at the protein inference grouping level. The data also revealed that analysis of 2 technical replicates can increase protein identifications by up to 10-15%, while a third replicate results in an additional 4-5%. Conclusions The data emphasize two practical methods of increasing the robustness of mass spectrometry data analysis. The data show that 1) using multiple search engines can expand the number of identified proteins (union) and validate protein identifications (intersection), and 2) analysis of 2 or 3 technical replicates can substantially expand protein identifications. Moreover, information can be extracted from a dataset by performing database searching with different engines and performing technical repeats, which requires no additional sample preparation and effectively utilizes research time and effort. PMID:25346847

Practical and Efficient Searching in Proteomics: A Cross Engine Comparison.

PubMed

Paulo, Joao A

2013-10-01

Analysis of large datasets produced by mass spectrometry-based proteomics relies on database search algorithms to sequence peptides and identify proteins. Several such scoring methods are available, each based on different statistical foundations and thereby not producing identical results. Here, the aim is to compare peptide and protein identifications using multiple search engines and examine the additional proteins gained by increasing the number of technical replicate analyses. A HeLa whole cell lysate was analyzed on an Orbitrap mass spectrometer for 10 technical replicates. The data were combined and searched using Mascot, SEQUEST, and Andromeda. Comparisons were made of peptide and protein identifications among the search engines. In addition, searches using each engine were performed with incrementing number of technical replicates. The number and identity of peptides and proteins differed across search engines. For all three search engines, the differences in proteins identifications were greater than the differences in peptide identifications indicating that the major source of the disparity may be at the protein inference grouping level. The data also revealed that analysis of 2 technical replicates can increase protein identifications by up to 10-15%, while a third replicate results in an additional 4-5%. The data emphasize two practical methods of increasing the robustness of mass spectrometry data analysis. The data show that 1) using multiple search engines can expand the number of identified proteins (union) and validate protein identifications (intersection), and 2) analysis of 2 or 3 technical replicates can substantially expand protein identifications. Moreover, information can be extracted from a dataset by performing database searching with different engines and performing technical repeats, which requires no additional sample preparation and effectively utilizes research time and effort.

Distributed Large Data-Object Environments: End-to-End Performance Analysis of High Speed Distributed Storage Systems in Wide Area ATM Networks

NASA Technical Reports Server (NTRS)

Johnston, William; Tierney, Brian; Lee, Jason; Hoo, Gary; Thompson, Mary

1996-01-01

We have developed and deployed a distributed-parallel storage system (DPSS) in several high speed asynchronous transfer mode (ATM) wide area networks (WAN) testbeds to support several different types of data-intensive applications. Architecturally, the DPSS is a network striped disk array, but is fairly unique in that its implementation allows applications complete freedom to determine optimal data layout, replication and/or coding redundancy strategy, security policy, and dynamic reconfiguration. In conjunction with the DPSS, we have developed a 'top-to-bottom, end-to-end' performance monitoring and analysis methodology that has allowed us to characterize all aspects of the DPSS operating in high speed ATM networks. In particular, we have run a variety of performance monitoring experiments involving the DPSS in the MAGIC testbed, which is a large scale, high speed, ATM network and we describe our experience using the monitoring methodology to identify and correct problems that limit the performance of high speed distributed applications. Finally, the DPSS is part of an overall architecture for using high speed, WAN's for enabling the routine, location independent use of large data-objects. Since this is part of the motivation for a distributed storage system, we describe this architecture.

Genes and abdominal aortic aneurysm.

PubMed

Hinterseher, Irene; Tromp, Gerard; Kuivaniemi, Helena

2011-04-01

Abdominal aortic aneurysm (AAA) is a multifactorial disease with a strong genetic component. Since the first candidate gene studies were published 20 years ago, approximately 100 genetic association studies using single nucleotide polymorphisms (SNPs) in biologically relevant genes have been reported on AAA. These studies investigated SNPs in genes of the extracellular matrix, the cardiovascular system, the immune system, and signaling pathways. Very few studies were large enough to draw firm conclusions and very few results could be replicated in another sample set. The more recent unbiased approaches are family-based DNA linkage studies and genome-wide genetic association studies, which have the potential of identifying the genetic basis for AAA, only when appropriately powered and well-characterized large AAA cohorts are used. SNPs associated with AAA have already been identified in these large multicenter studies. One significant association was of a variant in a gene called contactin-3, which is located on chromosome 3p12.3. However, two follow-up studies could not replicate this association. Two other SNPs, which are located on chromosome 9p21 and 9q33, were replicated in other samples. The two genes with the strongest supporting evidence of contribution to the genetic risk for AAA are the CDKN2BAS gene, also known as ANRIL, which encodes an antisense ribonucleic acid that regulates expression of the cyclin-dependent kinase inhibitors CDKN2A and CDKN2B, and DAB2IP, which encodes an inhibitor of cell growth and survival. Functional studies are now needed to establish the mechanisms by which these genes contribute toward AAA pathogenesis. Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.

Multi-tissue analysis of co-expression networks by higher-order generalized singular value decomposition identifies functionally coherent transcriptional modules.

PubMed

Xiao, Xiaolin; Moreno-Moral, Aida; Rotival, Maxime; Bottolo, Leonardo; Petretto, Enrico

2014-01-01

Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co-expressed heat shock protein (Hsp) and cardiomyopathy genes (Bag3, Cryab, Kras, Emd, Plec), which was significantly replicated using separate failing heart and liver gene expression datasets in humans, thus revealing a conserved functional role for Hsp genes in cardiovascular disease.

Parameter estimation and prediction for the course of a single epidemic outbreak of a plant disease.

PubMed

Kleczkowski, A; Gilligan, C A

2007-10-22

Many epidemics of plant diseases are characterized by large variability among individual outbreaks. However, individual epidemics often follow a well-defined trajectory which is much more predictable in the short term than the ensemble (collection) of potential epidemics. In this paper, we introduce a modelling framework that allows us to deal with individual replicated outbreaks, based upon a Bayesian hierarchical analysis. Information about 'similar' replicate epidemics can be incorporated into a hierarchical model, allowing both ensemble and individual parameters to be estimated. The model is used to analyse the data from a replicated experiment involving spread of Rhizoctonia solani on radish in the presence or absence of a biocontrol agent, Trichoderma viride. The rate of primary (soil-to-plant) infection is found to be the most variable factor determining the final size of epidemics. Breakdown of biological control in some replicates results in high levels of primary infection and increased variability. The model can be used to predict new outbreaks of disease based upon knowledge from a 'library' of previous epidemics and partial information about the current outbreak. We show that forecasting improves significantly with knowledge about the history of a particular epidemic, whereas the precision of hindcasting to identify the past course of the epidemic is largely independent of detailed knowledge of the epidemic trajectory. The results have important consequences for parameter estimation, inference and prediction for emerging epidemic outbreaks.

RAB1A promotes Vaccinia virus replication by facilitating the production of intracellular enveloped virions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pechenick Jowers, Tali; Featherstone, Rebecca J.; Reynolds, Danielle K.

2015-01-15

Vaccinia virus (VACV) is a large double-stranded DNA virus with a complex cytoplasmic replication cycle that exploits numerous cellular proteins. This work characterises the role of a proviral cellular protein, the small GTPase RAB1A, in VACV replication. Using siRNA, we identified RAB1A as required for the production of extracellular enveloped virions (EEVs), but not intracellular mature virions (IMVs). Immunofluorescence and electron microscopy further refined the role of RAB1A as facilitating the wrapping of IMVs to become intracellular enveloped virions (IEVs). This is consistent with the known function of RAB1A in maintenance of ER to Golgi transport. VACV can therefore bemore » added to the growing list of viruses which require RAB1A for optimal replication, highlighting this protein as a broadly proviral host factor. - Highlights: • Characterisation of the role of the small GTPase RAB1A in VACV replication. • RAB1A is not required for production of the primary virion form (IMV). • RAB1A is required for production of processed virion forms (IEVs, CEVs and EEVs). • Consistent with known role of RAB1A in ER to Golgi transport.« less

A Genome-Wide Association Study of Depressive Symptoms

PubMed Central

Cornelis, Marilyn C.; Amin, Najaf; Bakshis, Erin; Baumert, Jens; Ding, Jingzhong; Liu, Yongmei; Marciante, Kristin; Meirelles, Osorio; Nalls, Michael A.; Sun, Yan V.; Vogelzangs, Nicole; Yu, Lei; Bandinelli, Stefania; Benjamin, Emelia J.; Bennett, David A.; Boomsma, Dorret; Cannas, Alessandra; Coker, Laura H.; de Geus, Eco; De Jager, Philip L.; Diez-Roux, Ana V.; Purcell, Shaun; Hu, Frank B.; Rimma, Eric B.; Hunter, David J.; Jensen, Majken K.; Curhan, Gary; Rice, Kenneth; Penman, Alan D.; Rotter, Jerome I.; Sotoodehnia, Nona; Emeny, Rebecca; Eriksson, Johan G.; Evans, Denis A.; Ferrucci, Luigi; Fornage, Myriam; Gudnason, Vilmundur; Hofman, Albert; Illig, Thomas; Kardia, Sharon; Kelly-Hayes, Margaret; Koenen, Karestan; Kraft, Peter; Kuningas, Maris; Massaro, Joseph M.; Melzer, David; Mulas, Antonella; Mulder, Cornelis L.; Murray, Anna; Oostra, Ben A.; Palotie, Aarno; Penninx, Brenda; Petersmann, Astrid; Pilling, Luke C.; Psaty, Bruce; Rawal, Rajesh; Reiman, Eric M.; Schulz, Andrea; Shulman, Joshua M.; Singleton, Andrew B.; Smith, Albert V.; Sutin, Angelina R.; Uitterlinden, André G.; Völzke, Henry; Widen, Elisabeth; Yaffe, Kristine; Zonderman, Alan B.; Cucca, Francesco; Harris, Tamara; Ladwig, Karl-Heinz; Llewellyn, David J.; Räikkönen, Katri; Tanaka, Toshiko

2013-01-01

Background Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms. PMID:23290196

Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs*

PubMed Central

Sun, Qiyu; Qi, Xian; Zhang, Yan; Wu, Xiaodong; Liang, Mifang; Li, Chuan; Li, Dexin; Cardona, Carol J.; Xing, Zheng

2016-01-01

Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little is known about the function of synaptogyrin-2. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with high mortality, caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that the viral nonstructural protein NSs forms inclusion bodies (IBs) that are involved in viral immune evasion, as well as viral RNA replication. In this study, we sought to elucidate the mechanism by which NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and adipose differentiation-related protein (ADRP). Through a high throughput screening, we identified synaptogyrin-2 to be highly up-regulated in response to SFTS bunyavirus (SFTSV) infection and to be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased, and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNA-expressing cells, which correlated with the reduced number of the large IBs restructured from regular lipid droplets. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs to become virus factories for viral RNA replication through its interaction with NSs. These findings unveil the function of synaptogyrin-2 as an enhancer in viral infection. PMID:27226560

Hypothesis-Free Search for Connections between Birth Month and Disease Prevalence in Large, Geographically Varied Cohorts

PubMed Central

Borsi, John P.

2016-01-01

We have sought to replicate and extend the Season-wide Association Study (SeaWAS) of Boland, et al.1 in identifying birth month-disease associations from electronic health records (EHRs). We used methodology similar to that implemented by Boland on three geographically distinct cohorts, for a total of 11.8 million individuals derived from multiple data sources. We were able to identify eleven out of sixteen literature-supported birth month associations as compared to seven of sixteen for SeaWAS. Of the nine novel cardiovascular birth month associations discovered by SeaWAS, we were able to replicate four. None of the novel non-cardiovascular associations discovered by SeaWAS emerged as significant relations in our study. We identified thirty birth month disease associations not previously reported; of those, only six associations were validated in more than one cohort. These results suggest that differences in cohort composition and location can cause consequential variation in results of hypothesis-free searches. PMID:28269826

DNA replication origins-where do we begin?

PubMed

Prioleau, Marie-Noëlle; MacAlpine, David M

2016-08-01

For more than three decades, investigators have sought to identify the precise locations where DNA replication initiates in mammalian genomes. The development of molecular and biochemical approaches to identify start sites of DNA replication (origins) based on the presence of defining and characteristic replication intermediates at specific loci led to the identification of only a handful of mammalian replication origins. The limited number of identified origins prevented a comprehensive and exhaustive search for conserved genomic features that were capable of specifying origins of DNA replication. More recently, the adaptation of origin-mapping assays to genome-wide approaches has led to the identification of tens of thousands of replication origins throughout mammalian genomes, providing an unprecedented opportunity to identify both genetic and epigenetic features that define and regulate their distribution and utilization. Here we summarize recent advances in our understanding of how primary sequence, chromatin environment, and nuclear architecture contribute to the dynamic selection and activation of replication origins across diverse cell types and developmental stages. © 2016 Prioleau and MacAlpine; Published by Cold Spring Harbor Laboratory Press.

Paper-based and web-based intervention modeling experiments identified the same predictors of general practitioners' antibiotic-prescribing behavior.

PubMed

Treweek, Shaun; Bonetti, Debbie; Maclennan, Graeme; Barnett, Karen; Eccles, Martin P; Jones, Claire; Pitts, Nigel B; Ricketts, Ian W; Sullivan, Frank; Weal, Mark; Francis, Jill J

2014-03-01

To evaluate the robustness of the intervention modeling experiment (IME) methodology as a way of developing and testing behavioral change interventions before a full-scale trial by replicating an earlier paper-based IME. Web-based questionnaire and clinical scenario study. General practitioners across Scotland were invited to complete the questionnaire and scenarios, which were then used to identify predictors of antibiotic-prescribing behavior. These predictors were compared with the predictors identified in an earlier paper-based IME and used to develop a new intervention. Two hundred seventy general practitioners completed the questionnaires and scenarios. The constructs that predicted simulated behavior and intention were attitude, perceived behavioral control, risk perception/anticipated consequences, and self-efficacy, which match the targets identified in the earlier paper-based IME. The choice of persuasive communication as an intervention in the earlier IME was also confirmed. Additionally, a new intervention, an action plan, was developed. A web-based IME replicated the findings of an earlier paper-based IME, which provides confidence in the IME methodology. The interventions will now be evaluated in the next stage of the IME, a web-based randomized controlled trial. Copyright © 2014 Elsevier Inc. All rights reserved.

Conceptual design and analysis of a dynamic scale model of the Space Station Freedom

NASA Technical Reports Server (NTRS)

Davis, D. A.; Gronet, M. J.; Tan, M. K.; Thorne, J.

1994-01-01

This report documents the conceptual design study performed to evaluate design options for a subscale dynamic test model which could be used to investigate the expected on-orbit structural dynamic characteristics of the Space Station Freedom early build configurations. The baseline option was a 'near-replica' model of the SSF SC-7 pre-integrated truss configuration. The approach used to develop conceptual design options involved three sets of studies: evaluation of the full-scale design and analysis databases, conducting scale factor trade studies, and performing design sensitivity studies. The scale factor trade study was conducted to develop a fundamental understanding of the key scaling parameters that drive design, performance and cost of a SSF dynamic scale model. Four scale model options were estimated: 1/4, 1/5, 1/7, and 1/10 scale. Prototype hardware was fabricated to assess producibility issues. Based on the results of the study, a 1/4-scale size is recommended based on the increased model fidelity associated with a larger scale factor. A design sensitivity study was performed to identify critical hardware component properties that drive dynamic performance. A total of 118 component properties were identified which require high-fidelity replication. Lower fidelity dynamic similarity scaling can be used for non-critical components.

Spatial synchrony of local populations has increased in association with the recent Northern Hemisphere climate trend.

PubMed

Post, Eric; Forchhammer, Mads C

2004-06-22

According to ecological theory, populations whose dynamics are entrained by environmental correlation face increased extinction risk as environmental conditions become more synchronized spatially. This prediction is highly relevant to the study of ecological consequences of climate change. Recent empirical studies have indicated, for example, that large-scale climate synchronizes trophic interactions and population dynamics over broad spatial scales in freshwater and terrestrial systems. Here, we present an analysis of century-scale, spatially replicated data on local weather and the population dynamics of caribou in Greenland. Our results indicate that spatial autocorrelation in local weather has increased with large-scale climatic warming. This increase in spatial synchrony of environmental conditions has been matched, in turn, by an increase in the spatial synchrony of local caribou populations toward the end of the 20th century. Our results indicate that spatial synchrony in environmental conditions and the populations influenced by them are highly variable through time and can increase with climatic warming. We suggest that if future warming can increase population synchrony, it may also increase extinction risk.

A genome-scale map of expression for a mouse brain section obtained using voxelation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chin, Mark H.; Geng, Alex B.; Khan, Arshad H.

Gene expression signatures in the mammalian brain hold the key to understanding neural development and neurological diseases. We have reconstructed 2- dimensional images of gene expression for 20,000 genes in a coronal slice of the mouse brain at the level of the striatum by using microarrays in combination with voxelation at a resolution of 1 mm3. Good reliability of the microarray results were confirmed using multiple replicates, subsequent quantitative RT-PCR voxelation, mass spectrometry voxelation and publicly available in situ hybridization data. Known and novel genes were identified with expression patterns localized to defined substructures within the brain. In addition, genesmore » with unexpected patterns were identified and cluster analysis identified a set of genes with a gradient of dorsal/ventral expression not restricted to known anatomical boundaries. The genome-scale maps of gene expression obtained using voxelation will be a valuable tool for the neuroscience community.« less

Morpho peleides butterfly wing imprints as structural colour stamp.

PubMed

Zobl, Sigrid; Salvenmoser, Willi; Schwerte, Thorsten; Gebeshuber, Ille C; Schreiner, Manfred

2016-02-02

This study presents the replication of a color-causing nanostructure based on the upper laminae of numerous cover scales of Morpho peleides butterfly wings and obtained solely by imprinting their upper-wing surfaces. Our results indicate that a simple casting technique using a novel integrated release agent can obtain a large positive replica using negative imprints via Polyvinylsiloxane. The developed method is low-tech and high-yield and is thus substantially easier and less expensive than previous methods. The microstructures were investigated with light microscopy, the nanostructures with both scanning and transmission electron microscopy, and the reflections with UV visible spectrometry. The influence of the release agent and the quality of the master stamp were determined by comparing measurements of the cover-scale sizes and their chromaticity values obtained by their images and with their positive imprints. The master stamp provided multiple positive replicas up to 3 cm(2) in just 1 h with structural coloration effects visible to the naked eye. Thus, the developed method proves the accuracy of the replicated nanostructure and its potential industrial application as a color-producing nanostamp.

Genome-wide association implicates numerous genes and pleiotropy underlying ecological trait variation in natural populations of Populus trichocarpa

DOE Office of Scientific and Technical Information (OSTI.GOV)

McKown, Athena; Klapste, Jaroslav; Guy, Robert

2014-01-01

To uncover the genetic basis of phenotypic trait variation, we used 448 unrelated wild accessions of black cottonwood (Populus trichocarpa Torr. & Gray) from natural populations throughout western North America. Extensive information from large-scale trait phenotyping (with spatial and temporal replications within a common garden) and genotyping (with a 34K Populus SNP array) of all accessions were used for gene discovery in a genome-wide association study (GWAS).

Responding to the Event Deluge

NASA Technical Reports Server (NTRS)

Williams, Roy D.; Barthelmy, Scott D.; Denny, Robert B.; Graham, Matthew J.; Swinbank, John

2012-01-01

We present the VOEventNet infrastructure for large-scale rapid follow-up of astronomical events, including selection, annotation, machine intelligence, and coordination of observations. The VOEvent.standard is central to this vision, with distributed and replicated services rather than centralized facilities. We also describe some of the event brokers, services, and software that .are connected to the network. These technologies will become more important in the coming years, with new event streams from Gaia, LOF AR, LIGO, LSST, and many others

Single Molecule Analysis of Replicated DNA Reveals the Usage of Multiple KSHV Genome Regions for Latent Replication

PubMed Central

Verma, Subhash C.; Lu, Jie; Cai, Qiliang; Kosiyatrakul, Settapong; McDowell, Maria E.; Schildkraut, Carl L.; Robertson, Erle S.

2011-01-01

Kaposi's sarcoma associated herpesvirus (KSHV), an etiologic agent of Kaposi's sarcoma, Body Cavity Based Lymphoma and Multicentric Castleman's Disease, establishes lifelong latency in infected cells. The KSHV genome tethers to the host chromosome with the help of a latency associated nuclear antigen (LANA). Additionally, LANA supports replication of the latent origins within the terminal repeats by recruiting cellular factors. Our previous studies identified and characterized another latent origin, which supported the replication of plasmids ex-vivo without LANA expression in trans. Therefore identification of an additional origin site prompted us to analyze the entire KSHV genome for replication initiation sites using single molecule analysis of replicated DNA (SMARD). Our results showed that replication of DNA can initiate throughout the KSHV genome and the usage of these regions is not conserved in two different KSHV strains investigated. SMARD also showed that the utilization of multiple replication initiation sites occurs across large regions of the genome rather than a specified sequence. The replication origin of the terminal repeats showed only a slight preference for their usage indicating that LANA dependent origin at the terminal repeats (TR) plays only a limited role in genome duplication. Furthermore, we performed chromatin immunoprecipitation for ORC2 and MCM3, which are part of the pre-replication initiation complex to determine the genomic sites where these proteins accumulate, to provide further characterization of potential replication initiation sites on the KSHV genome. The ChIP data confirmed accumulation of these pre-RC proteins at multiple genomic sites in a cell cycle dependent manner. Our data also show that both the frequency and the sites of replication initiation vary within the two KSHV genomes studied here, suggesting that initiation of replication is likely to be affected by the genomic context rather than the DNA sequences. PMID:22072974

Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq)

PubMed Central

Langley, Alexander R.; Gräf, Stefan; Smith, James C.; Krude, Torsten

2016-01-01

Next-generation sequencing has enabled the genome-wide identification of human DNA replication origins. However, different approaches to mapping replication origins, namely (i) sequencing isolated small nascent DNA strands (SNS-seq); (ii) sequencing replication bubbles (bubble-seq) and (iii) sequencing Okazaki fragments (OK-seq), show only limited concordance. To address this controversy, we describe here an independent high-resolution origin mapping technique that we call initiation site sequencing (ini-seq). In this approach, newly replicated DNA is directly labelled with digoxigenin-dUTP near the sites of its initiation in a cell-free system. The labelled DNA is then immunoprecipitated and genomic locations are determined by DNA sequencing. Using this technique we identify >25,000 discrete origin sites at sub-kilobase resolution on the human genome, with high concordance between biological replicates. Most activated origins identified by ini-seq are found at transcriptional start sites and contain G-quadruplex (G4) motifs. They tend to cluster in early-replicating domains, providing a correlation between early replication timing and local density of activated origins. Origins identified by ini-seq show highest concordance with sites identified by SNS-seq, followed by OK-seq and bubble-seq. Furthermore, germline origins identified by positive nucleotide distribution skew jumps overlap with origins identified by ini-seq and OK-seq more frequently and more specifically than do sites identified by either SNS-seq or bubble-seq. PMID:27587586

Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq).

PubMed

Langley, Alexander R; Gräf, Stefan; Smith, James C; Krude, Torsten

2016-12-01

Next-generation sequencing has enabled the genome-wide identification of human DNA replication origins. However, different approaches to mapping replication origins, namely (i) sequencing isolated small nascent DNA strands (SNS-seq); (ii) sequencing replication bubbles (bubble-seq) and (iii) sequencing Okazaki fragments (OK-seq), show only limited concordance. To address this controversy, we describe here an independent high-resolution origin mapping technique that we call initiation site sequencing (ini-seq). In this approach, newly replicated DNA is directly labelled with digoxigenin-dUTP near the sites of its initiation in a cell-free system. The labelled DNA is then immunoprecipitated and genomic locations are determined by DNA sequencing. Using this technique we identify >25,000 discrete origin sites at sub-kilobase resolution on the human genome, with high concordance between biological replicates. Most activated origins identified by ini-seq are found at transcriptional start sites and contain G-quadruplex (G4) motifs. They tend to cluster in early-replicating domains, providing a correlation between early replication timing and local density of activated origins. Origins identified by ini-seq show highest concordance with sites identified by SNS-seq, followed by OK-seq and bubble-seq. Furthermore, germline origins identified by positive nucleotide distribution skew jumps overlap with origins identified by ini-seq and OK-seq more frequently and more specifically than do sites identified by either SNS-seq or bubble-seq. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

An evaluation of semi-automated methods for collecting ecosystem-level data in temperate marine systems.

PubMed

Griffin, Kingsley J; Hedge, Luke H; González-Rivero, Manuel; Hoegh-Guldberg, Ove I; Johnston, Emma L

2017-07-01

Historically, marine ecologists have lacked efficient tools that are capable of capturing detailed species distribution data over large areas. Emerging technologies such as high-resolution imaging and associated machine-learning image-scoring software are providing new tools to map species over large areas in the ocean. Here, we combine a novel diver propulsion vehicle (DPV) imaging system with free-to-use machine-learning software to semi-automatically generate dense and widespread abundance records of a habitat-forming algae over ~5,000 m 2 of temperate reef. We employ replicable spatial techniques to test the effectiveness of traditional diver-based sampling, and better understand the distribution and spatial arrangement of one key algal species. We found that the effectiveness of a traditional survey depended on the level of spatial structuring, and generally 10-20 transects (50 × 1 m) were required to obtain reliable results. This represents 2-20 times greater replication than have been collected in previous studies. Furthermore, we demonstrate the usefulness of fine-resolution distribution modeling for understanding patterns in canopy algae cover at multiple spatial scales, and discuss applications to other marine habitats. Our analyses demonstrate that semi-automated methods of data gathering and processing provide more accurate results than traditional methods for describing habitat structure at seascape scales, and therefore represent vastly improved techniques for understanding and managing marine seascapes.

Subsurface to substrate: dual-scale micro/nanofluidic networks for investigating transport anomalies in tight porous media.

PubMed

Kelly, Shaina A; Torres-Verdín, Carlos; Balhoff, Matthew T

2016-08-07

Micro/nanofluidic experiments in synthetic representations of tight porous media, often referred to as "reservoir-on-a-chip" devices, are an emerging approach to researching anomalous fluid transport trends in energy-bearing and fluid-sequestering geologic porous media. We detail, for the first time, the construction of dual-scale micro/nanofluidic devices that are relatively large-scale, two-dimensional network representations of granular and fractured nanoporous media. The fabrication scheme used in the development of the networks on quartz substrates (master patterns) is facile and replicable: transmission electron microscopy (TEM) grids with lacey carbon support film were used as shadow masks in thermal evaporation/deposition and reactive ion etch (RIE) was used for hardmask pattern transfer. The reported nanoscale network geometries are heterogeneous and composed of hydraulically resistive paths (throats) meeting at junctures (pores) to mimic the low topological connectivity of nanoporous sedimentary rocks such as shale. The geometry also includes homogenous microscale grid patterns that border the nanoscale networks and represent microfracture pathways. Master patterns were successfully replicated with a sequence of polydimethylsiloxane (PDMS) and Norland Optical Adhesive (NOA) 63 polymers. The functionality of the fabricated quartz and polymer nanofluidic devices was validated with aqueous imbibition experiments and differential interference contrast microscopy. These dual-scale fluidic devices are promising predictive tools for hypothesis testing and calibration against bulk fluid measurements in tight geologic, biologic, and synthetic porous material of similar dual-scale pore structure. Applications to shale/mudrock transport studies in particular are focused on herein.

Prediction of Suicide: A Replication Study

ERIC Educational Resources Information Center

Farberow, Norman L.; MacKinnon, Douglas

1975-01-01

A replication study was conducted to retest the validity of the Neuropsychiatric Hospital Suicide Potential Scale. Fifty four patients who had committed suicide and fifty who had not were the population studied to test, if possible, the limits of prediction the scale can attain by judging the behavior of these patients. (DEP)

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits.

PubMed

Kim, Young Jin; Go, Min Jin; Hu, Cheng; Hong, Chang Bum; Kim, Yun Kyoung; Lee, Ji Young; Hwang, Joo-Yeon; Oh, Ji Hee; Kim, Dong-Joon; Kim, Nam Hee; Kim, Soeui; Hong, Eun Jung; Kim, Ji-Hyun; Min, Haesook; Kim, Yeonjung; Zhang, Rong; Jia, Weiping; Okada, Yukinori; Takahashi, Atsushi; Kubo, Michiaki; Tanaka, Toshihiro; Kamatani, Naoyuki; Matsuda, Koichi; Park, Taesung; Oh, Bermseok; Kimm, Kuchan; Kang, Daehee; Shin, Chol; Cho, Nam H; Kim, Hyung-Lae; Han, Bok-Ghee; Lee, Jong-Young; Cho, Yoon Shin

2011-09-11

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

A Replication of the Internal Validity Structure of Three Major Teaching Rating Scales

ERIC Educational Resources Information Center

Peters, Scott J.; Pereira, Nielsen

2017-01-01

Even as the importance of replication research has become more widely understood, the field of gifted education is almost completely devoid of replication studies. An area in which replication is a particular problem is in student identification research, since instrument validity is a necessary prerequisite for any sound psychometric decision. To…

Global genomics and proteomics approaches to identify host factors as targets to induce resistance against Tomato bushy stunt virus.

PubMed

Nagy, Peter D; Pogany, Judit

2010-01-01

The success of RNA viruses as pathogens of plants, animals, and humans depends on their ability to reprogram the host cell metabolism to support the viral infection cycle and to suppress host defense mechanisms. Plus-strand (+)RNA viruses have limited coding potential necessitating that they co-opt an unknown number of host factors to facilitate their replication in host cells. Global genomics and proteomics approaches performed with Tomato bushy stunt virus (TBSV) and yeast (Saccharomyces cerevisiae) as a model host have led to the identification of 250 host factors affecting TBSV RNA replication and recombination or bound to the viral replicase, replication proteins, or the viral RNA. The roles of a dozen host factors involved in various steps of the replication process have been validated in yeast as well as a plant host. Altogether, the large number of host factors identified and the great variety of cellular functions performed by these factors indicate the existence of a truly complex interaction between TBSV and the host cell. This review summarizes the advantages of using a simple plant virus and yeast as a model host to advance our understanding of virus-host interactions at the molecular and cellular levels. The knowledge of host factors gained can potentially be used to inhibit virus replication via gene silencing, expression of dominant negative mutants, or design of specific chemical inhibitors leading to novel specific or broad-range resistance and antiviral tools against (+)RNA plant viruses. Copyright © 2010 Elsevier Inc. All rights reserved.

Narcissism and belief in the paranormal.

PubMed

Roe, Chris A; Morgan, Claire L

2002-04-01

The present study was designed to assess whether the relationship between narcissistic personality and paranormal belief identified by Tobacyk and Mitchell earlier could be replicated with a general population and to see whether the effect could be found with a narrower definition of paranormal beliefs that focuses only on belief in psychic phenomena. 75 participants completed the Narcissistic Personality Inventory and two measures of paranormal belief, the Paranormal Belief Scale and the Australian Sheep-Goat Scale. There was no correlation between narcissism and Paranormal Belief Scale scores, but narcissism and Australian Sheep-Goat Scale scores were significantly positively correlated. Of the three subscales to the Australian Sheep-Goat measure, scores for narcissism correlated with belief in ESP and PK but not in Life after death. These relationships were interpreted in terms of need for control.

Pathways for scaling up public health interventions.

PubMed

Indig, Devon; Lee, Karen; Grunseit, Anne; Milat, Andrew; Bauman, Adrian

2017-08-01

To achieve population-wide health improvement, public health interventions found effective in selected samples need to be 'scaled up' and implemented more widely. The pathways through which interventions are scaled up are not well characterised. The aim of this paper is to identify examples of public health interventions which have been scaled up and to develop a conceptual framework which quantifies and describes this process. A multi-stage international literature search was undertaken to identify examples of public health interventions in high income countries that have been scaled up or implemented at scale. Initial abstract review identified articles which met all the criteria of being a: 1) public health intervention; 2) chronic disease prevention focus; 3) program delivered at a wide geographical scale (state, national or international). Interventions were reviewed and coded into a conceptual framework pathway to document their scaling up process. For each program, an in-depth review of the identified articles was undertaken along with a broad internet based search to determine the outcomes of the dissemination process. A conceptual framework of scaling up pathways was developed that involved four stages (development, efficacy testing, real world trial and dissemination) to which the 40 programs were mapped. The search identified 40 public health interventions that showed evidence of being scaled up. Four pathways were identified to capture the different scaling up trajectories taken which included: 'Type I - Comprehensive' (55%) which passed through all four stages, 'Type II - Efficacy omitters' (5%) which did not conduct efficacy testing, 'Type III - Trial omitters' (25%) which did not conduct a real world trial, and 'Type IV - At scale dissemination' (15%) which skipped both efficacy testing and a real world trial. This is the first study to classify and quantify the potential pathways through which public health interventions in high income countries are scaled up to reach the broader population. Mapping these pathways not only demonstrates the different trajectories that occur in scaling up public health interventions, but also allows the variation across scaling up pathways to be classified. The policy and practice determinants leading to each pathway remain for future study, especially to identify the conditions under which efficacy and replication stages are missing.

Nurse Family Partnership: Comparing Costs per Family in Randomized Trials Versus Scale-Up.

PubMed

Miller, Ted R; Hendrie, Delia

2015-12-01

The literature that addresses cost differences between randomized trials and full-scale replications is quite sparse. This paper examines how costs differed among three randomized trials and six statewide scale-ups of nurse family partnership (NFP) intensive home visitation to low income first-time mothers. A literature review provided data on pertinent trials. At our request, six well-established programs reported their total expenditures. We adjusted the costs to national prices based on mean hourly wages for registered nurses and then inflated them to 2010 dollars. A centralized data system provided utilization. Replications had fewer home visits per family than trials (25 vs. 31, p = .05), lower costs per client ($8860 vs. $12,398, p = .01), and lower costs per visit ($354 vs. $400, p = .30). Sample size limited the significance of these differences. In this type of labor intensive program, costs probably were lower in scale-up than in randomized trials. Key cost drivers were attrition and the stable caseload size possible in an ongoing program. Our estimates reveal a wide variation in cost per visit across six state programs, which suggests that those planning replications should not expect a simple rule to guide cost estimations for scale-ups. Nevertheless, NFP replications probably achieved some economies of scale.

Beyond the usual suspects: a multidimensional genetic exploration of infant attachment disorganization and security.

PubMed

Pappa, Irene; Szekely, Eszter; Mileva-Seitz, Viara R; Luijk, Maartje P C M; Bakermans-Kranenburg, Marian J; van IJzendoorn, Marinus H; Tiemeier, Henning

2015-01-01

Although the environmental influences on infant attachment disorganization and security are well-studied, little is known about their heritability. Candidate gene studies have shown small, often non-replicable effects. In this study, we gathered the largest sample (N = 657) of ethnically homogenous, 14-month-old children with both observed attachment and genome-wide data. First, we used a Genome-Wide Association Study (GWAS) approach to identify single nucleotide polymorphisms (SNPs) associated with attachment disorganization and security. Second, we annotated them into genes (Versatile Gene-based Association Study) and functional pathways. Our analyses provide evidence of novel genes (HDAC1, ZNF675, BSCD1) and pathways (synaptic transmission, cation transport) associated with attachment disorganization. Similar analyses identified a novel gene (BECN1) but no distinct pathways associated with attachment security. The results of this first extensive, exploratory study on the molecular-genetic basis of infant attachment await replication in large, independent samples.

Symmetry of interactions rules in incompletely connected random replicator ecosystems.

PubMed

Kärenlampi, Petri P

2014-06-01

The evolution of an incompletely connected system of species with speciation and extinction is investigated in terms of random replicators. It is found that evolving random replicator systems with speciation do become large and complex, depending on speciation parameters. Antisymmetric interactions result in large systems, whereas systems with symmetric interactions remain small. A co-dominating feature is within-species interaction pressure: large within-species interaction increases species diversity. Average fitness evolves in all systems, however symmetry and connectivity evolve in small systems only. Newcomers get extinct almost immediately in symmetric systems. The distribution in species lifetimes is determined for antisymmetric systems. The replicator systems investigated do not show any sign of self-organized criticality. The generalized Lotka-Volterra system is shown to be a tedious way of implementing the replicator system.

Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation.

PubMed

Dillinger, Stefan; Straub, Tobias; Németh, Attila

2017-01-01

Mammalian chromosomes are organized in structural and functional domains of 0.1-10 Mb, which are characterized by high self-association frequencies in the nuclear space and different contact probabilities with nuclear sub-compartments. They exhibit distinct chromatin modification patterns, gene expression levels and replication timing. Recently, nucleolus-associated chromosomal domains (NADs) have been discovered, yet their precise genomic organization and dynamics are still largely unknown. Here, we use nucleolus genomics and single-cell experiments to address these questions in human embryonic fibroblasts during replicative senescence. Genome-wide mapping reveals 1,646 NADs in proliferating cells, which cover about 38% of the annotated human genome. They are mainly heterochromatic and correlate with late replicating loci. Using Hi-C data analysis, we show that interactions of NADs dominate interphase chromosome contacts in the 10-50 Mb distance range. Interestingly, only minute changes in nucleolar association are observed upon senescence. These spatial rearrangements in subdomains smaller than 100 kb are accompanied with local transcriptional changes. In contrast, large centromeric and pericentromeric satellite repeat clusters extensively dissociate from nucleoli in senescent cells. Accordingly, H3K9me3-marked heterochromatin gets remodelled at the perinucleolar space as revealed by immunofluorescence analyses. Collectively, this study identifies connections between the nucleolus, 3D genome structure, and cellular aging at the level of interphase chromosome organization.

Nucleolus association of chromosomal domains is largely maintained in cellular senescence despite massive nuclear reorganisation

PubMed Central

Dillinger, Stefan

2017-01-01

Mammalian chromosomes are organized in structural and functional domains of 0.1–10 Mb, which are characterized by high self-association frequencies in the nuclear space and different contact probabilities with nuclear sub-compartments. They exhibit distinct chromatin modification patterns, gene expression levels and replication timing. Recently, nucleolus-associated chromosomal domains (NADs) have been discovered, yet their precise genomic organization and dynamics are still largely unknown. Here, we use nucleolus genomics and single-cell experiments to address these questions in human embryonic fibroblasts during replicative senescence. Genome-wide mapping reveals 1,646 NADs in proliferating cells, which cover about 38% of the annotated human genome. They are mainly heterochromatic and correlate with late replicating loci. Using Hi-C data analysis, we show that interactions of NADs dominate interphase chromosome contacts in the 10–50 Mb distance range. Interestingly, only minute changes in nucleolar association are observed upon senescence. These spatial rearrangements in subdomains smaller than 100 kb are accompanied with local transcriptional changes. In contrast, large centromeric and pericentromeric satellite repeat clusters extensively dissociate from nucleoli in senescent cells. Accordingly, H3K9me3-marked heterochromatin gets remodelled at the perinucleolar space as revealed by immunofluorescence analyses. Collectively, this study identifies connections between the nucleolus, 3D genome structure, and cellular aging at the level of interphase chromosome organization. PMID:28575119

National study of public spending for mental retardation and developmental disabilities.

PubMed

Braddock, D; Hemp, R; Fujiura, G

1987-09-01

Results of a nationwide study of public mental retardation/developmental disabilities (MR/DD) spending in the states during Fiscal Years 1977 through 1986 were summarized. Trends identified included: (a) continuing growth in spending for community services, (b) contraction of total spending for institutional operations, and (c) predominance of ICF/MR support in large (16+ beds) congregate care settings. Periodic replication of the study was recommended as was additional research to identify the political and economic determinants of state MR/DD spending.

Multilength Scale Patterning of Functional Layers by Roll-to-Roll Ultraviolet-Light-Assisted Nanoimprint Lithography.

PubMed

Leitgeb, Markus; Nees, Dieter; Ruttloff, Stephan; Palfinger, Ursula; Götz, Johannes; Liska, Robert; Belegratis, Maria R; Stadlober, Barbara

2016-05-24

Top-down fabrication of nanostructures with high throughput is still a challenge. We demonstrate the fast (>10 m/min) and continuous fabrication of multilength scale structures by roll-to-roll UV-nanoimprint lithography on a 250 mm wide web. The large-area nanopatterning is enabled by a multicomponent UV-curable resist system (JRcure) with viscous, mechanical, and surface properties that are tunable over a wide range to either allow for usage as polymer stamp material or as imprint resist. The adjustable elasticity and surface chemistry of the resist system enable multistep self-replication of structured resist layers. Decisive for defect-free UV-nanoimprinting in roll-to-roll is the minimization of the surface energies of stamp and resist, and the stepwise reduction of the stiffness from one layer to the next is essential for optimizing the reproduction fidelity especially for nanoscale features. Accordingly, we demonstrate the continuous replication of 3D nanostructures and the high-throughput fabrication of multilength scale resist structures resulting in flexible polyethylenetherephtalate film rolls with superhydrophobic properties. Moreover, a water-soluble UV-imprint resist (JRlift) is introduced that enables residue-free nanoimprinting in roll-to-roll. Thereby we could demonstrate high-throughput fabrication of metallic patterns with only 200 nm line width.

Copy Number Variation Is a Fundamental Aspect of the Placental Genome

PubMed Central

Hannibal, Roberta L.; Chuong, Edward B.; Rivera-Mulia, Juan Carlos; Gilbert, David M.; Valouev, Anton; Baker, Julie C.

2014-01-01

Discovery of lineage-specific somatic copy number variation (CNV) in mammals has led to debate over whether CNVs are mutations that propagate disease or whether they are a normal, and even essential, aspect of cell biology. We show that 1,000N polyploid trophoblast giant cells (TGCs) of the mouse placenta contain 47 regions, totaling 138 Megabases, where genomic copies are underrepresented (UR). UR domains originate from a subset of late-replicating heterochromatic regions containing gene deserts and genes involved in cell adhesion and neurogenesis. While lineage-specific CNVs have been identified in mammalian cells, classically in the immune system where V(D)J recombination occurs, we demonstrate that CNVs form during gestation in the placenta by an underreplication mechanism, not by recombination nor deletion. Our results reveal that large scale CNVs are a normal feature of the mammalian placental genome, which are regulated systematically during embryogenesis and are propagated by a mechanism of underreplication. PMID:24785991

Test aspects of the JPL Viterbi decoder

NASA Technical Reports Server (NTRS)

Breuer, M. A.

1989-01-01

The generation of test vectors and design-for-test aspects of the Jet Propulsion Laboratory (JPL) Very Large Scale Integration (VLSI) Viterbi decoder chip is discussed. Each processor integrated circuit (IC) contains over 20,000 gates. To achieve a high degree of testability, a scan architecture is employed. The logic has been partitioned so that very few test vectors are required to test the entire chip. In addition, since several blocks of logic are replicated numerous times on this chip, test vectors need only be generated for each block, rather than for the entire circuit. These unique blocks of logic have been identified and test sets generated for them. The approach employed for testing was to use pseudo-exhaustive test vectors whenever feasible. That is, each cone of logid is tested exhaustively. Using this approach, no detailed logic design or fault model is required. All faults which modify the function of a block of combinational logic are detected, such as all irredundant single and multiple stuck-at faults.

Phosphorylation at the Homotypic Interface Regulates Nucleoprotein Oligomerization and Assembly of the Influenza Virus Replication Machinery

PubMed Central

Mondal, Arindam; Potts, Gregory K.; Dawson, Anthony R.; Coon, Joshua J.; Mehle, Andrew

2015-01-01

Negative-sense RNA viruses assemble large ribonucleoprotein (RNP) complexes that direct replication and transcription of the viral genome. Influenza virus RNPs contain the polymerase, genomic RNA and multiple copies of nucleoprotein (NP). During RNP assembly, monomeric NP oligomerizes along the length of the genomic RNA. Regulated assembly of the RNP is essential for virus replication, but how NP is maintained as a monomer that subsequently oligomerizes to form RNPs is poorly understood. Here we elucidate a mechanism whereby NP phosphorylation regulates oligomerization. We identified new evolutionarily conserved phosphorylation sites on NP and demonstrated that phosphorylation of NP decreased formation of higher-order complexes. Two phosphorylation sites were located on opposite sides of the NP:NP interface. In both influenza A and B virus, mutating or mimicking phosphorylation at these residues blocked homotypic interactions and drove NP towards a monomeric form. Highlighting the central role of this process during infection, these mutations impaired RNP formation, polymerase activity and virus replication. Thus, dynamic phosphorylation of NP regulates RNP assembly and modulates progression through the viral life cycle. PMID:25867750

Managing conflict between large carnivores and livestock.

PubMed

van Eeden, Lily M; Crowther, Mathew S; Dickman, Chris R; Macdonald, David W; Ripple, William J; Ritchie, Euan G; Newsome, Thomas M

2018-02-01

Large carnivores are persecuted globally because they threaten human industries and livelihoods. How this conflict is managed has consequences for the conservation of large carnivores and biodiversity more broadly. Mitigating human-predator conflict should be evidence-based and accommodate people's values while protecting carnivores. Despite much research into human and large-carnivore coexistence strategies, there have been few attempts to document the success of conflict-mitigation strategies on a global scale. We conducted a meta-analysis of global research on conflict mitigation related to large carnivores and humans. We focused on conflicts that arise from the threat large carnivores pose to livestock. We first used structured and unstructured searching to identify replicated studies that used before-after or control-impact design to measure change in livestock loss as a result of implementing a management intervention. We then extracted relevant data from these studies to calculate an overall effect size for each intervention type. Research effort and focus varied among continents and aligned with the histories and cultures that shaped livestock production and attitudes toward carnivores. Livestock guardian animals most effectively reduced livestock losses. Lethal control was the second most effective control, although its success varied the most, and guardian animals and lethal control did not differ significantly. Financial incentives have promoted tolerance of large carnivores in some settings and reduced retaliatory killings. We suggest coexistence strategies be location-specific, incorporate cultural values and environmental conditions, and be designed such that return on financial investment can be evaluated. Improved monitoring of mitigation measures is urgently required to promote effective evidence-based policy. © 2017 Society for Conservation Biology.

Psychometric properties of the Sexual Excitation/Sexual Inhibition Inventory for Women and Men (SESII-W/M) and the Sexual Excitation Scales/Sexual Inhibition Scales short form (SIS/SES-SF) in a population-based sample in Germany

PubMed Central

Scholten, Saskia; Margraf, Jürgen

2018-01-01

The Sexual Excitation Sexual/Inhibition Inventory for Women and Men (SESII-W/M) and the Sexual Excitation Scales/Sexual Inhibition Scales short form (SIS/SES-SF) are two self-report questionnaires for assessing sexual excitation (SE) and sexual inhibition (SI). According to the dual control model of sexual response, SE and SI differ between individuals and influence the occurrence of sexual arousal in given situations. Extreme levels of SE and SI are postulated to be associated with sexual difficulties or risky sexual behaviors. The present study was designed to assess the psychometric properties of the German versions of both questionnaires utilizing a large population-based sample of 2,708 participants (Mage = 51.19, SD = 14.03). Overall, psychometric evaluation of the two instruments yielded good convergent and discriminant validity and mediocre to good internal consistency. The original 30-item version of the SESII-W/M did not show a sufficient model fit. For a 24-item version of the SESII-W/M partial strong measurement invariance across gender, and strong measurement invariance across relationship status, age, and educational levels were established. The original structure (14 items, 3 factors) of the SIS/SES-SF was not replicated. However, a 4-factor model including 13 items showed a good model fit and strong measurement invariance across the before-mentioned participant groups. For both questionnaires, partial strong measurement invariance with the original American versions of the scales was found. As some factors showed unsatisfactory internal consistency and the factor structure of the original scales could not be replicated, scores on several SE- and SI-factors should be interpreted with caution. However, most analyses indicated sufficient psychometric quality of the German SESII-W/M and SIS/SES-SF and their use can be recommended in German-speaking samples. More research with diverse samples (i.e., different sexual orientations, individuals with sexual difficulties) is needed to ensure the replicability of the factor solutions presented in this study. PMID:29529045

Viral DNA Replication Orientation and hnRNPs Regulate Transcription of the Human Papillomavirus 18 Late Promoter.

PubMed

Wang, Xiaohong; Liu, Haibin; Ge, Hui; Ajiro, Masahiko; Sharma, Nishi R; Meyers, Craig; Morozov, Pavel; Tuschl, Thomas; Klar, Amar; Court, Donald; Zheng, Zhi-Ming

2017-05-30

The life cycle of human papillomaviruses (HPVs) is tightly linked to keratinocyte differentiation. Although expression of viral early genes is initiated immediately upon virus infection of undifferentiated basal cells, viral DNA amplification and late gene expression occur only in the mid to upper strata of the keratinocytes undergoing terminal differentiation. In this report, we show that the relative activity of HPV18 TATA-less late promoter P 811 depends on its orientation relative to that of the origin (Ori) of viral DNA replication and is sensitive to the eukaryotic DNA polymerase inhibitor aphidicolin. Additionally, transfected 70-nucleotide (nt)-long single-strand DNA oligonucleotides that are homologous to the region near Ori induce late promoter activity. We also found that promoter activation in raft cultures leads to production of the late promoter-associated, sense-strand transcription initiation RNAs (tiRNAs) and splice-site small RNAs (spliRNAs). Finally, a cis -acting AAGTATGCA core element that functions as a repressor to the promoter was identified. This element interacts with hnRNP D0B and hnRNP A/B factors. Point mutations in the core prevented binding of hnRNPs and increased the promoter activity. Confirming this result, knocking down the expression of both hnRNPs in keratinocytes led to increased promoter activity. Taking the data together, our study revealed the mechanism of how the HPV18 late promoter is regulated by DNA replication and host factors. IMPORTANCE It has been known for decades that the activity of viral late promoters is associated with viral DNA replication among almost all DNA viruses. However, the mechanism of how DNA replication activates the viral late promoter and what components of the replication machinery are involved remain largely unknown. In this study, we characterized the P 811 promoter region of HPV18 and demonstrated that its activation depends on the orientation of DNA replication. Using single-stranded oligonucleotides targeting the replication fork on either leading or lagging strands, we showed that viral lagging-strand replication activates the promoter. We also identified a transcriptional repressor element located upstream of the promoter transcription start site which interacts with cellular proteins hnRNP D0B and hnRNP A/B and modulates the late promoter activity. This is the first report on how DNA replication activates a viral late promoter. Copyright © 2017 Wang et al.

Identification of the BCAR1-CFDP1-TMEM170A locus as a determinant of carotid intima-media thickness and coronary artery disease risk.

PubMed

Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J; Ohrvik, John; Zabaneh, Delilah; Shah, Sonia; Veglia, Fabrizio; Fava, Cristiano; Kavousi, Maryam; McLachlan, Stela; Kivimäki, Mika; Bolton, Jennifer L; Folkersen, Lasse; Gigante, Bruna; Leander, Karin; Vikström, Max; Larsson, Malin; Silveira, Angela; Deanfield, John; Voight, Benjamin F; Fontanillas, Pierre; Sabater-Lleal, Maria; Colombo, Gualtiero I; Kumari, Meena; Langenberg, Claudia; Wareham, Nick J; Uitterlinden, André G; Gabrielsen, Anders; Hedin, Ulf; Franco-Cereceda, Anders; Nyyssönen, Kristiina; Rauramaa, Rainer; Tuomainen, Tomi-Pekka; Savonen, Kai; Smit, Andries J; Giral, Philippe; Mannarino, Elmo; Robertson, Christine M; Talmud, Philippa J; Hedblad, Bo; Hofman, Albert; Erdmann, Jeanette; Reilly, Muredach P; O'Donnell, Christopher J; Farrall, Martin; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Syvänen, Ann-Christine; Hansson, Göran K; Eriksson, Per; Samani, Nilesh J; Watkins, Hugh; Price, Jacqueline F; Hingorani, Aroon D; Melander, Olle; Witteman, Jacqueline C M; Baldassarre, Damiano; Tremoli, Elena; de Faire, Ulf; Humphries, Steve E; Hamsten, Anders

2012-12-01

Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMT(mean), IMT(max), and IMT(mean-max)), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11,590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75 × 10(-7) for IMT(max); replication P=7.24×10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53 × 10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83 × 10(-4), n=82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent.

Meta-replication reveals nonstationarity in multi-scale habitat selection of Mexican Spotted Owl

Treesearch

Ho Yi Wan; Kevin McGarigal; Joseph L. Ganey; Valentin Lauret; Brad C. Timm; Samuel A. Cushman

2017-01-01

Anthropogenic environmental changes are leading to habitat loss and degradation, driving many species to extinction. In this context, habitat models become increasingly important for effective species management and conservation. However, most habitat studies lack replicated study areas and do not properly address the role of nonstationarity and spatial scales in...

Self-Replication of Localized Vegetation Patches in Scarce Environments

PubMed Central

Bordeu, Ignacio; Clerc, Marcel G.; Couteron, Piere; Lefever, René; Tlidi, Mustapha

2016-01-01

Desertification due to climate change and increasing drought periods is a worldwide problem for both ecology and economy. Our ability to understand how vegetation manages to survive and propagate through arid and semiarid ecosystems may be useful in the development of future strategies to prevent desertification, preserve flora—and fauna within—or even make use of scarce resources soils. In this paper, we study a robust phenomena observed in semi-arid ecosystems, by which localized vegetation patches split in a process called self-replication. Localized patches of vegetation are visible in nature at various spatial scales. Even though they have been described in literature, their growth mechanisms remain largely unexplored. Here, we develop an innovative statistical analysis based on real field observations to show that patches may exhibit deformation and splitting. This growth mechanism is opposite to the desertification since it allows to repopulate territories devoid of vegetation. We investigate these aspects by characterizing quantitatively, with a simple mathematical model, a new class of instabilities that lead to the self-replication phenomenon observed. PMID:27650430

Falsifiability is not optional.

PubMed

LeBel, Etienne P; Berger, Derek; Campbell, Lorne; Loving, Timothy J

2017-08-01

Finkel, Eastwick, and Reis (2016; FER2016) argued the post-2011 methodological reform movement has focused narrowly on replicability, neglecting other essential goals of research. We agree multiple scientific goals are essential, but argue, however, a more fine-grained language, conceptualization, and approach to replication is needed to accomplish these goals. Replication is the general empirical mechanism for testing and falsifying theory. Sufficiently methodologically similar replications, also known as direct replications, test the basic existence of phenomena and ensure cumulative progress is possible a priori. In contrast, increasingly methodologically dissimilar replications, also known as conceptual replications, test the relevance of auxiliary hypotheses (e.g., manipulation and measurement issues, contextual factors) required to productively investigate validity and generalizability. Without prioritizing replicability, a field is not empirically falsifiable. We also disagree with FER2016's position that "bigger samples are generally better, but . . . that very large samples could have the downside of commandeering resources that would have been better invested in other studies" (abstract). We identify problematic assumptions involved in FER2016's modifications of our original research-economic model, and present an improved model that quantifies when (and whether) it is reasonable to worry that increasing statistical power will engender potential trade-offs. Sufficiently powering studies (i.e., >80%) maximizes both research efficiency and confidence in the literature (research quality). Given that we are in agreement with FER2016 on all key open science points, we are eager to start seeing the accelerated rate of cumulative knowledge development of social psychological phenomena such a sufficiently transparent, powered, and falsifiable approach will generate. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Biological evolution of replicator systems: towards a quantitative approach.

PubMed

Martin, Osmel; Horvath, J E

2013-04-01

The aim of this work is to study the features of a simple replicator chemical model of the relation between kinetic stability and entropy production under the action of external perturbations. We quantitatively explore the different paths leading to evolution in a toy model where two independent replicators compete for the same substrate. To do that, the same scenario described originally by Pross (J Phys Org Chem 17:312-316, 2004) is revised and new criteria to define the kinetic stability are proposed. Our results suggest that fast replicator populations are continually favored by the effects of strong stochastic environmental fluctuations capable to determine the global population, the former assumed to be the only acting evolution force. We demonstrate that the process is continually driven by strong perturbations only, and that population crashes may be useful proxies for these catastrophic environmental fluctuations. As expected, such behavior is particularly enhanced under very large scale perturbations, suggesting a likely dynamical footprint in the recovery patterns of new species after mass extinction events in the Earth's geological past. Furthermore, the hypothesis that natural selection always favors the faster processes may give theoretical support to different studies that claim the applicability of maximum principles like the Maximum Metabolic Flux (MMF) or Maximum Entropy Productions Principle (MEPP), seen as the main goal of biological evolution.

Biological Evolution of Replicator Systems: Towards a Quantitative Approach

NASA Astrophysics Data System (ADS)

Martin, Osmel; Horvath, J. E.

2013-04-01

The aim of this work is to study the features of a simple replicator chemical model of the relation between kinetic stability and entropy production under the action of external perturbations. We quantitatively explore the different paths leading to evolution in a toy model where two independent replicators compete for the same substrate. To do that, the same scenario described originally by Pross (J Phys Org Chem 17:312-316, 2004) is revised and new criteria to define the kinetic stability are proposed. Our results suggest that fast replicator populations are continually favored by the effects of strong stochastic environmental fluctuations capable to determine the global population, the former assumed to be the only acting evolution force. We demonstrate that the process is continually driven by strong perturbations only, and that population crashes may be useful proxies for these catastrophic environmental fluctuations. As expected, such behavior is particularly enhanced under very large scale perturbations, suggesting a likely dynamical footprint in the recovery patterns of new species after mass extinction events in the Earth's geological past. Furthermore, the hypothesis that natural selection always favors the faster processes may give theoretical support to different studies that claim the applicability of maximum principles like the Maximum Metabolic Flux (MMF) or Maximum Entropy Productions Principle (MEPP), seen as the main goal of biological evolution.

Bacterial community changes in an industrial algae production system.

PubMed

Fulbright, Scott P; Robbins-Pianka, Adam; Berg-Lyons, Donna; Knight, Rob; Reardon, Kenneth F; Chisholm, Stephen T

2018-04-01

While microalgae are a promising feedstock for production of fuels and other chemicals, a challenge for the algal bioproducts industry is obtaining consistent, robust algae growth. Algal cultures include complex bacterial communities and can be difficult to manage because specific bacteria can promote or reduce algae growth. To overcome bacterial contamination, algae growers may use closed photobioreactors designed to reduce the number of contaminant organisms. Even with closed systems, bacteria are known to enter and cohabitate, but little is known about these communities. Therefore, the richness, structure, and composition of bacterial communities were characterized in closed photobioreactor cultivations of Nannochloropsis salina in F/2 medium at different scales, across nine months spanning late summer-early spring, and during a sequence of serially inoculated cultivations. Using 16S rRNA sequence data from 275 samples, bacterial communities in small, medium, and large cultures were shown to be significantly different. Larger systems contained richer bacterial communities compared to smaller systems. Relationships between bacterial communities and algae growth were complex. On one hand, blooms of a specific bacterial type were observed in three abnormal, poorly performing replicate cultivations, while on the other, notable changes in the bacterial community structures were observed in a series of serial large-scale batch cultivations that had similar growth rates. Bacteria common to the majority of samples were identified, including a single OTU within the class Saprospirae that was found in all samples. This study contributes important information for crop protection in algae systems, and demonstrates the complex ecosystems that need to be understood for consistent, successful industrial algae cultivation. This is the first study to profile bacterial communities during the scale-up process of industrial algae systems.

Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.

PubMed

Husain, Muhammad I; Chaudhry, Imran B; Husain, Nusrat; Khoso, Ameer B; Rahman, Raza R; Hamirani, Munir M; Hodsoll, John; Qurashi, Inti; Deakin, John Fw; Young, Allan H

2017-09-01

Evidence suggests that anti-inflammatory medication may be effective in the treatment of depressive symptoms. In this study, we aimed to investigate whether minocycline added to treatment as usual (TAU) for 3 months in patients with treatment-resistant depression will lead to an improvement in depressive symptoms. Multi-site, 12-week, double-blind, placebo-controlled, pilot trial of minocycline added to TAU for patients suffering from DSM-5 major depressive disorder, whose current episode has failed to respond to at least two antidepressants. The primary outcome measure was mean change in Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 12. Secondary measures were the Clinical Global Impression scale (CGI), Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder scale (GAD-7) and EuroQoL (EQ-5D) quality-of-life questionnaire. Side-effect checklists were also used. Minocycline was started at 100 mg once daily (OD) and increased to 200 mg after 2 weeks. A total of 41 participants were randomised, with 21 in the minocycline group and 20 in the placebo group. A large decrease in HAMD scores was observed in the minocycline group compared to the placebo group (standardised effect size (ES) -1.21, p < 0.001). CGI scores in the minocycline group also showed a large improvement compared with placebo (odds ratio (OR): 17.6, p < 0.001). PHQ-9, GAD-7 and EQ-5D total showed more moderate improvements (ES ~ 0.4-0.5). The findings indicate that adjunctive minocycline leads to improvement in symptoms of treatment-resistant depression. However, our findings require replication in a larger sample. ClinicalTrials.gov identifier: NCT02263872, registered October 2014.

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function

PubMed Central

Wild, Philipp S.; Felix, Janine F.; Schillert, Arne; Chen, Ming-Huei; Leening, Maarten J.G.; Völker, Uwe; Großmann, Vera; Brody, Jennifer A.; Irvin, Marguerite R.; Shah, Sanjiv J.; Pramana, Setia; Lieb, Wolfgang; Schmidt, Reinhold; Stanton, Alice V.; Malzahn, Dörthe; Lyytikäinen, Leo-Pekka; Tiller, Daniel; Smith, J. Gustav; Di Tullio, Marco R.; Musani, Solomon K.; Morrison, Alanna C.; Pers, Tune H.; Morley, Michael; Kleber, Marcus E.; Aragam, Jayashri; Bis, Joshua C.; Bisping, Egbert; Broeckel, Ulrich; Cheng, Susan; Deckers, Jaap W.; Del Greco M, Fabiola; Edelmann, Frank; Fornage, Myriam; Franke, Lude; Friedrich, Nele; Harris, Tamara B.; Hofer, Edith; Hofman, Albert; Huang, Jie; Hughes, Alun D.; Kähönen, Mika; investigators, KNHI; Kruppa, Jochen; Lackner, Karl J.; Lannfelt, Lars; Laskowski, Rafael; Launer, Lenore J.; Lindgren, Cecilia M.; Loley, Christina; Mayet, Jamil; Medenwald, Daniel; Morris, Andrew P.; Müller, Christian; Müller-Nurasyid, Martina; Nappo, Stefania; Nilsson, Peter M.; Nuding, Sebastian; Nutile, Teresa; Peters, Annette; Pfeufer, Arne; Pietzner, Diana; Pramstaller, Peter P.; Raitakari, Olli T.; Rice, Kenneth M.; Rotter, Jerome I.; Ruohonen, Saku T.; Sacco, Ralph L.; Samdarshi, Tandaw E.; Sharp, Andrew S.P.; Shields, Denis C.; Sorice, Rossella; Sotoodehnia, Nona; Stricker, Bruno H.; Surendran, Praveen; Töglhofer, Anna M.; Uitterlinden, André G.; Völzke, Henry; Ziegler, Andreas; Münzel, Thomas; März, Winfried; Cappola, Thomas P.; Hirschhorn, Joel N.; Mitchell, Gary F.; Smith, Nicholas L.; Fox, Ervin R.; Dueker, Nicole D.; Jaddoe, Vincent W.V.; Melander, Olle; Lehtimäki, Terho; Ciullo, Marina; Hicks, Andrew A.; Lind, Lars; Gudnason, Vilmundur; Pieske, Burkert; Barron, Anthony J.; Zweiker, Robert; Schunkert, Heribert; Ingelsson, Erik; Liu, Kiang; Arnett, Donna K.; Psaty, Bruce M.; Blankenberg, Stefan; Larson, Martin G.; Felix, Stephan B.; Franco, Oscar H.; Zeller, Tanja; Vasan, Ramachandran S.; Dörr, Marcus

2017-01-01

BACKGROUND. Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function. METHODS. A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function. RESULTS. The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue. CONCLUSION. The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies. FUNDING. For detailed information per study, see Acknowledgments. PMID:28394258

Multiscale analysis of replication technique efficiency for 3D roughness characterization of manufactured surfaces

NASA Astrophysics Data System (ADS)

Jolivet, S.; Mezghani, S.; El Mansori, M.

2016-09-01

The replication of topography has been generally restricted to optimizing material processing technologies in terms of statistical and single-scale features such as roughness. By contrast, manufactured surface topography is highly complex, irregular, and multiscale. In this work, we have demonstrated the use of multiscale analysis on replicates of surface finish to assess the precise control of the finished replica. Five commercial resins used for surface replication were compared. The topography of five standard surfaces representative of common finishing processes were acquired both directly and by a replication technique. Then, they were characterized using the ISO 25178 standard and multiscale decomposition based on a continuous wavelet transform, to compare the roughness transfer quality at different scales. Additionally, atomic force microscope force modulation mode was used in order to compare the resins’ stiffness properties. The results showed that less stiff resins are able to replicate the surface finish along a larger wavelength band. The method was then tested for non-destructive quality control of automotive gear tooth surfaces.

Comparison of Wechsler Memory Scale-Fourth Edition (WMS-IV) and Third Edition (WMS-III) dimensional structures: improved ability to evaluate auditory and visual constructs.

PubMed

Hoelzle, James B; Nelson, Nathaniel W; Smith, Clifford A

2011-03-01

Dimensional structures underlying the Wechsler Memory Scale-Fourth Edition (WMS-IV) and Wechsler Memory Scale-Third Edition (WMS-III) were compared to determine whether the revised measure has a more coherent and clinically relevant factor structure. Principal component analyses were conducted in normative samples reported in the respective technical manuals. Empirically supported procedures guided retention of dimensions. An invariant two-dimensional WMS-IV structure reflecting constructs of auditory learning/memory and visual attention/memory (C1 = .97; C2 = .96) is more theoretically coherent than the replicable, heterogeneous WMS-III dimension (C1 = .97). This research suggests that the WMS-IV may have greater utility in identifying lateralized memory dysfunction.

Enhancing multiple-point geostatistical modeling: 1. Graph theory and pattern adjustment

NASA Astrophysics Data System (ADS)

Tahmasebi, Pejman; Sahimi, Muhammad

2016-03-01

In recent years, higher-order geostatistical methods have been used for modeling of a wide variety of large-scale porous media, such as groundwater aquifers and oil reservoirs. Their popularity stems from their ability to account for qualitative data and the great flexibility that they offer for conditioning the models to hard (quantitative) data, which endow them with the capability for generating realistic realizations of porous formations with very complex channels, as well as features that are mainly a barrier to fluid flow. One group of such models consists of pattern-based methods that use a set of data points for generating stochastic realizations by which the large-scale structure and highly-connected features are reproduced accurately. The cross correlation-based simulation (CCSIM) algorithm, proposed previously by the authors, is a member of this group that has been shown to be capable of simulating multimillion cell models in a matter of a few CPU seconds. The method is, however, sensitive to pattern's specifications, such as boundaries and the number of replicates. In this paper the original CCSIM algorithm is reconsidered and two significant improvements are proposed for accurately reproducing large-scale patterns of heterogeneities in porous media. First, an effective boundary-correction method based on the graph theory is presented by which one identifies the optimal cutting path/surface for removing the patchiness and discontinuities in the realization of a porous medium. Next, a new pattern adjustment method is proposed that automatically transfers the features in a pattern to one that seamlessly matches the surrounding patterns. The original CCSIM algorithm is then combined with the two methods and is tested using various complex two- and three-dimensional examples. It should, however, be emphasized that the methods that we propose in this paper are applicable to other pattern-based geostatistical simulation methods.

Salience network-based classification and prediction of symptom severity in children with autism.

PubMed

Uddin, Lucina Q; Supekar, Kaustubh; Lynch, Charles J; Khouzam, Amirah; Phillips, Jennifer; Feinstein, Carl; Ryali, Srikanth; Menon, Vinod

2013-08-01

Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual's salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

Salience Network–Based Classification and Prediction of Symptom Severity in Children With Autism

PubMed Central

Uddin, Lucina Q.; Supekar, Kaustubh; Lynch, Charles J.; Khouzam, Amirah; Phillips, Jennifer; Feinstein, Carl; Ryali, Srikanth; Menon, Vinod

2014-01-01

IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individual’s salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen–level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD. PMID:23803651

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Junghyun; Gangwon, Jo; Jaehoon, Jung

Applications written solely in OpenCL or CUDA cannot execute on a cluster as a whole. Most previous approaches that extend these programming models to clusters are based on a common idea: designating a centralized host node and coordinating the other nodes with the host for computation. However, the centralized host node is a serious performance bottleneck when the number of nodes is large. In this paper, we propose a scalable and distributed OpenCL framework called SnuCL-D for large-scale clusters. SnuCL-D's remote device virtualization provides an OpenCL application with an illusion that all compute devices in a cluster are confined inmore » a single node. To reduce the amount of control-message and data communication between nodes, SnuCL-D replicates the OpenCL host program execution and data in each node. We also propose a new OpenCL host API function and a queueing optimization technique that significantly reduce the overhead incurred by the previous centralized approaches. To show the effectiveness of SnuCL-D, we evaluate SnuCL-D with a microbenchmark and eleven benchmark applications on a large-scale CPU cluster and a medium-scale GPU cluster.« less

Synaptogyrin-2 Promotes Replication of a Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs.

PubMed

Sun, Qiyu; Qi, Xian; Zhang, Yan; Wu, Xiaodong; Liang, Mifang; Li, Chuan; Li, Dexin; Cardona, Carol J; Xing, Zheng

2016-07-29

Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little is known about the function of synaptogyrin-2. Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with high mortality, caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that the viral nonstructural protein NSs forms inclusion bodies (IBs) that are involved in viral immune evasion, as well as viral RNA replication. In this study, we sought to elucidate the mechanism by which NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and adipose differentiation-related protein (ADRP). Through a high throughput screening, we identified synaptogyrin-2 to be highly up-regulated in response to SFTS bunyavirus (SFTSV) infection and to be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased, and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNA-expressing cells, which correlated with the reduced number of the large IBs restructured from regular lipid droplets. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs to become virus factories for viral RNA replication through its interaction with NSs. These findings unveil the function of synaptogyrin-2 as an enhancer in viral infection. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The prevalence of terraced treescapes in analyses of phylogenetic data sets.

PubMed

Dobrin, Barbara H; Zwickl, Derrick J; Sanderson, Michael J

2018-04-04

The pattern of data availability in a phylogenetic data set may lead to the formation of terraces, collections of equally optimal trees. Terraces can arise in tree space if trees are scored with parsimony or with partitioned, edge-unlinked maximum likelihood. Theory predicts that terraces can be large, but their prevalence in contemporary data sets has never been surveyed. We selected 26 data sets and phylogenetic trees reported in recent literature and investigated the terraces to which the trees would belong, under a common set of inference assumptions. We examined terrace size as a function of the sampling properties of the data sets, including taxon coverage density (the proportion of taxon-by-gene positions with any data present) and a measure of gene sampling "sufficiency". We evaluated each data set in relation to the theoretical minimum gene sampling depth needed to reduce terrace size to a single tree, and explored the impact of the terraces found in replicate trees in bootstrap methods. Terraces were identified in nearly all data sets with taxon coverage densities < 0.90. They were not found, however, in high-coverage-density (i.e., ≥ 0.94) transcriptomic and genomic data sets. The terraces could be very large, and size varied inversely with taxon coverage density and with gene sampling sufficiency. Few data sets achieved a theoretical minimum gene sampling depth needed to reduce terrace size to a single tree. Terraces found during bootstrap resampling reduced overall support. If certain inference assumptions apply, trees estimated from empirical data sets often belong to large terraces of equally optimal trees. Terrace size correlates to data set sampling properties. Data sets seldom include enough genes to reduce terrace size to one tree. When bootstrap replicate trees lie on a terrace, statistical support for phylogenetic hypotheses may be reduced. Although some of the published analyses surveyed were conducted with edge-linked inference models (which do not induce terraces), unlinked models have been used and advocated. The present study describes the potential impact of that inference assumption on phylogenetic inference in the context of the kinds of multigene data sets now widely assembled for large-scale tree construction.

Replication profile of Saccharomyces cerevisiae chromosome VI.

PubMed

Friedman, K L; Brewer, B J; Fangman, W L

1997-11-01

An understanding of the replication programme at the genome level will require the identification and characterization of origins of replication through large, contiguous regions of DNA. As a step toward this goal, origin efficiencies and replication times were determined for 10 ARSs spanning most of the 270 kilobase (kb) chromosome VI of Saccharomyces cerevisiae. Chromosome VI shows a wide variation in the percentage of cell cycles in which different replication origins are utilized. Most of the origins are activated in only a fraction of cells, suggesting that the pattern of origin usage on chromosome VI varies greatly within the cell population. The replication times of fragments containing chromosome VI origins show a temporal pattern that has been recognized on other chromosomes--the telomeres replicate late in S phase, while the central region of the chromosome replicates early. As demonstrated here for chromosome VI, analysis of the direction of replication fork movement along a chromosome and determination of replication time by measuring a period of hemimethylation may provide an efficient means of surveying origin activity over large regions of the genome.

Identifying Cancer Driver Genes Using Replication-Incompetent Retroviral Vectors

PubMed Central

Bii, Victor M.; Trobridge, Grant D.

2016-01-01

Identifying novel genes that drive tumor metastasis and drug resistance has significant potential to improve patient outcomes. High-throughput sequencing approaches have identified cancer genes, but distinguishing driver genes from passengers remains challenging. Insertional mutagenesis screens using replication-incompetent retroviral vectors have emerged as a powerful tool to identify cancer genes. Unlike replicating retroviruses and transposons, replication-incompetent retroviral vectors lack additional mutagenesis events that can complicate the identification of driver mutations from passenger mutations. They can also be used for almost any human cancer due to the broad tropism of the vectors. Replication-incompetent retroviral vectors have the ability to dysregulate nearby cancer genes via several mechanisms including enhancer-mediated activation of gene promoters. The integrated provirus acts as a unique molecular tag for nearby candidate driver genes which can be rapidly identified using well established methods that utilize next generation sequencing and bioinformatics programs. Recently, retroviral vector screens have been used to efficiently identify candidate driver genes in prostate, breast, liver and pancreatic cancers. Validated driver genes can be potential therapeutic targets and biomarkers. In this review, we describe the emergence of retroviral insertional mutagenesis screens using replication-incompetent retroviral vectors as a novel tool to identify cancer driver genes in different cancer types. PMID:27792127

Computational identification of obligatorily autocatalytic replicators embedded in metabolic networks

PubMed Central

Kun, Ádám; Papp, Balázs; Szathmáry, Eörs

2008-01-01

Background If chemical A is necessary for the synthesis of more chemical A, then A has the power of replication (such systems are known as autocatalytic systems). We provide the first systems-level analysis searching for small-molecular autocatalytic components in the metabolisms of diverse organisms, including an inferred minimal metabolism. Results We find that intermediary metabolism is invariably autocatalytic for ATP. Furthermore, we provide evidence for the existence of additional, organism-specific autocatalytic metabolites in the forms of coenzymes (NAD+, coenzyme A, tetrahydrofolate, quinones) and sugars. Although the enzymatic reactions of a number of autocatalytic cycles are present in most of the studied organisms, they display obligatorily autocatalytic behavior in a few networks only, hence demonstrating the need for a systems-level approach to identify metabolic replicators embedded in large networks. Conclusion Metabolic replicators are apparently common and potentially both universal and ancestral: without their presence, kick-starting metabolic networks is impossible, even if all enzymes and genes are present in the same cell. Identification of metabolic replicators is also important for attempts to create synthetic cells, as some of these autocatalytic molecules will presumably be needed to be added to the system as, by definition, the system cannot synthesize them without their initial presence. PMID:18331628

ISG15 Functions as an Interferon-Mediated Antiviral Effector Early in the Murine Norovirus Life Cycle

PubMed Central

Rodriguez, Marisela R.; Monte, Kristen; Thackray, Larissa B.

2014-01-01

ABSTRACT Human noroviruses (HuNoV) are the leading cause of nonbacterial gastroenteritis worldwide. Similar to HuNoV, murine noroviruses (MNV) are enteric pathogens spread via the fecal-oral route and have been isolated from numerous mouse facilities worldwide. Type I and type II interferons (IFN) restrict MNV-1 replication; however, the antiviral effectors impacting MNV-1 downstream of IFN signaling are largely unknown. Studies using dendritic cells, macrophages, and mice deficient in free and conjugated forms of interferon-stimulated gene 15 (ISG15) revealed that ISG15 conjugation contributes to protection against MNV-1 both in vitro and in vivo. ISG15 inhibited a step early in the viral life cycle upstream of viral genome transcription. Directly transfecting MNV-1 RNA into IFN-stimulated mouse embryonic fibroblasts (MEFs) and bone marrow-derived dendritic cells (BMDC) lacking ISG15 conjugates bypassed the antiviral activity of ISG15, further suggesting that ISG15 conjugates restrict the MNV-1 life cycle at the viral entry/uncoating step. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of early stages of MNV-1 replication. IMPORTANCE Type I IFNs are important in controlling murine norovirus 1 (MNV-1) infections; however, the proteins induced by IFNs that restrict viral growth are largely unknown. This report reveals that interferon-stimulated gene 15 (ISG15) mitigates MNV-1 replication both in vitro and in vivo. In addition, it shows that ISG15 inhibits MNV-1 replication by targeting an early step in the viral life cycle, MNV-1 entry and/or uncoating. These results identify ISG15 as the first type I IFN effector regulating MNV-1 infection both in vitro and in vivo and for the first time implicate the ISG15 pathway in the regulation of viral entry/uncoating. PMID:24899198

CONSIDERATIONS FOR A REGULATORY FRAMEWORK FOR LARGE-SCALE GEOLOGIC SEQUESTRATION OF CARBON DIOXIDE: A NORTH AMERICAN PERSPECTIVE

EPA Science Inventory

Large scale geologic sequestration (GS) of carbon dioxide poses a novel set of challenges for regulators. This paper focuses on the unique needs of large scale GS projects in light of the existing regulatory regimes in the United States and Canada and identifies several differen...

Vaccinia Virus C9 Ankyrin Repeat/F-Box Protein Is a Newly Identified Antagonist of the Type I Interferon-Induced Antiviral State.

PubMed

Liu, Ruikang; Moss, Bernard

2018-05-01

Type I interferons (IFNs) induce expression of more than 300 cellular genes that provide protection against viruses and other pathogens. For survival, viruses evolved defenses to prevent the IFN response or counteract the IFN-induced antiviral state. However, because viruses and cells coevolved, the dynamic relationship between virus and host is difficult to discern. In the present study, we demonstrated that vaccinia virus with a large deletion near the left end of the genome had a diminished ability to replicate in cells that had been pretreated with beta interferon (IFN-β), suggesting that one or more of the missing 17 open reading frames (ORFs) encode an antagonist of the IFN-induced antiviral state. By systematically deleting groups of ORFs and then individual ORFs, the C9L gene was shown to be required for IFN resistance. Replication of the C9L deletion mutant (vΔC9) was impaired in human cells that had been pretreated with IFN-β. Expression of viral early genes occurred, but subsequent events, including genome uncoating, genome replication, and postreplicative gene expression, were inhibited. Expression of the C9 protein occurred prior to genome replication, consistent with an early role in counteracting the IFN-induced antiviral state. C9 contains six ankyrin repeat motifs and a near C-terminal F-box. Mass spectrometry and immunoblotting identified host proteins that copurified with a functional epitope-tagged C9. The most abundant proteins were components of the SCF (CUL1, SKP1, F-box) and signalosome/deneddylation complexes, which interact with each other, suggesting a possible role in proteolysis of one or more interferon-induced proteins. IMPORTANCE Poxviruses comprise a family of large DNA viruses that replicate in the cytoplasm of vertebrate and insect hosts and cause human and zoonotic diseases. In most cases the primary infection is moderated by innate immune defenses. Vertebrates, including fish, amphibians, reptiles, birds, and mammals, all produce type I interferon homologs. In humans, interferon stimulates the synthesis of more than 300 proteins thought to have roles in host defense. Conversely, viruses have evolved means to thwart the host defenses. We are attempting to deconstruct the established virus-host relationship in order to better understand the molecular mechanisms involved. In the present study, we identified a vaccinia virus gene that prevents interferon-mediated inhibition of very early stages of viral replication and is conserved in orthopoxviruses. The viral protein was shown to interact with host proteins involved in proteolysis, suggesting that vaccinia virus may subvert the cellular apparatus for its own defense. Copyright © 2018 American Society for Microbiology.

Multi-atlas learner fusion: An efficient segmentation approach for large-scale data.

PubMed

Asman, Andrew J; Huo, Yuankai; Plassard, Andrew J; Landman, Bennett A

2015-12-01

We propose multi-atlas learner fusion (MLF), a framework for rapidly and accurately replicating the highly accurate, yet computationally expensive, multi-atlas segmentation framework based on fusing local learners. In the largest whole-brain multi-atlas study yet reported, multi-atlas segmentations are estimated for a training set of 3464 MR brain images. Using these multi-atlas estimates we (1) estimate a low-dimensional representation for selecting locally appropriate example images, and (2) build AdaBoost learners that map a weak initial segmentation to the multi-atlas segmentation result. Thus, to segment a new target image we project the image into the low-dimensional space, construct a weak initial segmentation, and fuse the trained, locally selected, learners. The MLF framework cuts the runtime on a modern computer from 36 h down to 3-8 min - a 270× speedup - by completely bypassing the need for deformable atlas-target registrations. Additionally, we (1) describe a technique for optimizing the weak initial segmentation and the AdaBoost learning parameters, (2) quantify the ability to replicate the multi-atlas result with mean accuracies approaching the multi-atlas intra-subject reproducibility on a testing set of 380 images, (3) demonstrate significant increases in the reproducibility of intra-subject segmentations when compared to a state-of-the-art multi-atlas framework on a separate reproducibility dataset, (4) show that under the MLF framework the large-scale data model significantly improve the segmentation over the small-scale model under the MLF framework, and (5) indicate that the MLF framework has comparable performance as state-of-the-art multi-atlas segmentation algorithms without using non-local information. Copyright © 2015 Elsevier B.V. All rights reserved.

Recombination-dependent replication and gene conversion homogenize repeat sequences and diversify plastid genome structure.

PubMed

Ruhlman, Tracey A; Zhang, Jin; Blazier, John C; Sabir, Jamal S M; Jansen, Robert K

2017-04-01

There is a misinterpretation in the literature regarding the variable orientation of the small single copy region of plastid genomes (plastomes). The common phenomenon of small and large single copy inversion, hypothesized to occur through intramolecular recombination between inverted repeats (IR) in a circular, single unit-genome, in fact, more likely occurs through recombination-dependent replication (RDR) of linear plastome templates. If RDR can be primed through both intra- and intermolecular recombination, then this mechanism could not only create inversion isomers of so-called single copy regions, but also an array of alternative sequence arrangements. We used Illumina paired-end and PacBio single-molecule real-time (SMRT) sequences to characterize repeat structure in the plastome of Monsonia emarginata (Geraniaceae). We used OrgConv and inspected nucleotide alignments to infer ancestral nucleotides and identify gene conversion among repeats and mapped long (>1 kb) SMRT reads against the unit-genome assembly to identify alternative sequence arrangements. Although M. emarginata lacks the canonical IR, we found that large repeats (>1 kilobase; kb) represent ∼22% of the plastome nucleotide content. Among the largest repeats (>2 kb), we identified GC-biased gene conversion and mapping filtered, long SMRT reads to the M. emarginata unit-genome assembly revealed alternative, substoichiometric sequence arrangements. We offer a model based on RDR and gene conversion between long repeated sequences in the M. emarginata plastome and provide support that both intra-and intermolecular recombination between large repeats, particularly in repeat-rich plastomes, varies unit-genome structure while homogenizing the nucleotide sequence of repeats. © 2017 Botanical Society of America.

Copying of holograms by spot scanning approach.

PubMed

Okui, Makoto; Wakunami, Koki; Oi, Ryutaro; Ichihashi, Yasuyuki; Jackin, Boaz Jessie; Yamamoto, Kenji

2018-05-20

To replicate holograms, contact copying has conventionally been used. In this approach, a photosensitive material is fixed together with a master hologram and illuminated with a coherent beam. This method is simple and enables high-quality copies; however, it requires a large optical setup for large-area holograms. In this paper, we present a new method of replicating holograms that uses a relatively compact optical system even for the replication of large holograms. A small laser spot that irradiates only part of the hologram is used to reproduce the hologram by scanning the spot over the whole area of the hologram. We report on the results of experiments carried out to confirm the copy quality, along with a guide to design scanning conditions. The results show the potential effectiveness of the large-area hologram replication technology using a relatively compact apparatus.

Characterization and improvement of RNA-Seq precision in quantitative transcript expression profiling.

PubMed

Łabaj, Paweł P; Leparc, Germán G; Linggi, Bryan E; Markillie, Lye Meng; Wiley, H Steven; Kreil, David P

2011-07-01

Measurement precision determines the power of any analysis to reliably identify significant signals, such as in screens for differential expression, independent of whether the experimental design incorporates replicates or not. With the compilation of large-scale RNA-Seq datasets with technical replicate samples, however, we can now, for the first time, perform a systematic analysis of the precision of expression level estimates from massively parallel sequencing technology. This then allows considerations for its improvement by computational or experimental means. We report on a comprehensive study of target identification and measurement precision, including their dependence on transcript expression levels, read depth and other parameters. In particular, an impressive recall of 84% of the estimated true transcript population could be achieved with 331 million 50 bp reads, with diminishing returns from longer read lengths and even less gains from increased sequencing depths. Most of the measurement power (75%) is spent on only 7% of the known transcriptome, however, making less strongly expressed transcripts harder to measure. Consequently, <30% of all transcripts could be quantified reliably with a relative error<20%. Based on established tools, we then introduce a new approach for mapping and analysing sequencing reads that yields substantially improved performance in gene expression profiling, increasing the number of transcripts that can reliably be quantified to over 40%. Extrapolations to higher sequencing depths highlight the need for efficient complementary steps. In discussion we outline possible experimental and computational strategies for further improvements in quantification precision. rnaseq10@boku.ac.at

A SELEX-Screened Aptamer of Human Hepatitis B Virus RNA Encapsidation Signal Suppresses Viral Replication

PubMed Central

Feng, Hui; Beck, Jürgen; Nassal, Michael; Hu, Kang-hong

2011-01-01

Background The specific interaction between hepatitis B virus (HBV) polymerase (P protein) and the ε RNA stem-loop on pregenomic (pg) RNA is crucial for viral replication. It triggers both pgRNA packaging and reverse transcription and thus represents an attractive antiviral target. RNA decoys mimicking ε in P protein binding but not supporting replication might represent novel HBV inhibitors. However, because generation of recombinant enzymatically active HBV polymerase is notoriously difficult, such decoys have as yet not been identified. Methodology/Principal Findings Here we used a SELEX approach, based on a new in vitro reconstitution system exploiting a recombinant truncated HBV P protein (miniP), to identify potential ε decoys in two large ε RNA pools with randomized upper stem. Selection of strongly P protein binding RNAs correlated with an unexpected strong enrichment of A residues. Two aptamers, S6 and S9, displayed particularly high affinity and specificity for miniP in vitro, yet did not support viral replication when part of a complete HBV genome. Introducing S9 RNA into transiently HBV producing HepG2 cells strongly suppressed pgRNA packaging and DNA synthesis, indicating the S9 RNA can indeed act as an ε decoy that competitively inhibits P protein binding to the authentic ε signal on pgRNA. Conclusions/Significance This study demonstrates the first successful identification of human HBV ε aptamers by an in vitro SELEX approach. Effective suppression of HBV replication by the S9 aptamer provides proof-of-principle for the ability of ε decoy RNAs to interfere with viral P-ε complex formation and suggests that S9-like RNAs may further be developed into useful therapeutics against chronic hepatitis B. PMID:22125633

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism

PubMed Central

Reynolds, John J; Bicknell, Louise S; Carroll, Paula; Higgs, Martin R; Shaheen, Ranad; Murray, Jennie E; Papadopoulos, Dimitrios K; Leitch, Andrea; Murina, Olga; Tarnauskaitė, Žygimantė; Wessel, Sarah R; Zlatanou, Anastasia; Vernet, Audrey; von Kriegsheim, Alex; Mottram, Rachel MA; Logan, Clare V; Bye, Hannah; Li, Yun; Brean, Alexander; Maddirevula, Sateesh; Challis, Rachel C; Skouloudaki, Kassiani; Almoisheer, Agaadir; Alsaif, Hessa S; Amar, Ariella; Prescott, Natalie J; Bober, Michael B; Duker, Angela; Faqeih, Eissa; Seidahmed, Mohammed Zain; Al Tala, Saeed; Alswaid, Abdulrahman; Ahmed, Saleem; Al-Aama, Jumana Yousuf; Altmüller, Janine; Al Balwi, Mohammed; Brady, Angela F; Chessa, Luciana; Cox, Helen; Fischetto, Rita; Heller, Raoul; Henderson, Bertram D; Hobson, Emma; Nürnberg, Peter; Percin, E Ferda; Peron, Angela; Spaccini, Luigina; Quigley, Alan J; Thakur, Seema; Wise, Carol A; Yoon, Grace; Alnemer, Maha; Tomancak, Pavel; Yigit, Gökhan; Taylor, A Malcolm R; Reijns, Martin AM; Simpson, Michael A; Cortez, David; Alkuraya, Fowzan S; Mathew, Christopher G; Jackson, Andrew P; Stewart, Grant S

2017-01-01

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication, and protect, repair and restart damaged forks. Here we identify DONSON as a novel fork protection factor, and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilises forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATR-dependent signalling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity, and potentiating chromosomal instability. Hypomorphic mutations substantially reduce DONSON protein levels and impair fork stability in patient cells, consistent with defective DNA replication underlying the disease phenotype. In summary, we identify mutations in DONSON as a common cause of microcephalic dwarfism, and establish DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability. PMID:28191891

An integrated workflow to assess technical and biological variability of cell population frequencies in human peripheral blood by flow cytometry

PubMed Central

Burel, Julie G.; Qian, Yu; Arlehamn, Cecilia Lindestam; Weiskopf, Daniela; Zapardiel-Gonzalo, Jose; Taplitz, Randy; Gilman, Robert H.; Saito, Mayuko; de Silva, Aruna D.; Vijayanand, Pandurangan; Scheuermann, Richard H.; Sette, Alessandro; Peters, Bjoern

2016-01-01

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. Here, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intra-individual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high inter-individual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naïve T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these co-variates in immune profiling studies. Finally, we exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies. PMID:28069807

An Integrated Workflow To Assess Technical and Biological Variability of Cell Population Frequencies in Human Peripheral Blood by Flow Cytometry.

PubMed

Burel, Julie G; Qian, Yu; Lindestam Arlehamn, Cecilia; Weiskopf, Daniela; Zapardiel-Gonzalo, Jose; Taplitz, Randy; Gilman, Robert H; Saito, Mayuko; de Silva, Aruna D; Vijayanand, Pandurangan; Scheuermann, Richard H; Sette, Alessandro; Peters, Bjoern

2017-02-15

In the context of large-scale human system immunology studies, controlling for technical and biological variability is crucial to ensure that experimental data support research conclusions. In this study, we report on a universal workflow to evaluate both technical and biological variation in multiparameter flow cytometry, applied to the development of a 10-color panel to identify all major cell populations and T cell subsets in cryopreserved PBMC. Replicate runs from a control donation and comparison of different gating strategies assessed the technical variability associated with each cell population and permitted the calculation of a quality control score. Applying our panel to a large collection of PBMC samples, we found that most cell populations showed low intraindividual variability over time. In contrast, certain subpopulations such as CD56 T cells and Temra CD4 T cells were associated with high interindividual variability. Age but not gender had a significant effect on the frequency of several populations, with a drastic decrease in naive T cells observed in older donors. Ethnicity also influenced a significant proportion of immune cell population frequencies, emphasizing the need to account for these covariates in immune profiling studies. We also exemplify the usefulness of our workflow by identifying a novel cell-subset signature of latent tuberculosis infection. Thus, our study provides a universal workflow to establish and evaluate any flow cytometry panel in systems immunology studies. Copyright © 2017 by The American Association of Immunologists, Inc.

Nuclear Architecture Organized by Rif1 Underpins the Replication-Timing Program

PubMed Central

Foti, Rossana; Gnan, Stefano; Cornacchia, Daniela; Dileep, Vishnu; Bulut-Karslioglu, Aydan; Diehl, Sarah; Buness, Andreas; Klein, Felix A.; Huber, Wolfgang; Johnstone, Ewan; Loos, Remco; Bertone, Paul; Gilbert, David M.; Manke, Thomas; Jenuwein, Thomas; Buonomo, Sara C.B.

2016-01-01

Summary DNA replication is temporally and spatially organized in all eukaryotes, yet the molecular control and biological function of the replication-timing program are unclear. Rif1 is required for normal genome-wide regulation of replication timing, but its molecular function is poorly understood. Here we show that in mouse embryonic stem cells, Rif1 coats late-replicating domains and, with Lamin B1, identifies most of the late-replicating genome. Rif1 is an essential determinant of replication timing of non-Lamin B1-bound late domains. We further demonstrate that Rif1 defines and restricts the interactions between replication-timing domains during the G1 phase, thereby revealing a function of Rif1 as organizer of nuclear architecture. Rif1 loss affects both number and replication-timing specificity of the interactions between replication-timing domains. In addition, during the S phase, Rif1 ensures that replication of interacting domains is temporally coordinated. In summary, our study identifies Rif1 as the molecular link between nuclear architecture and replication-timing establishment in mammals. PMID:26725008

Analytic Complexity and Challenges in Identifying Mixtures of Exposures Associated with Phenotypes in the Exposome Era.

PubMed

Patel, Chirag J

2017-01-01

Mixtures, or combinations and interactions between multiple environmental exposures, are hypothesized to be causally linked with disease and health-related phenotypes. Established and emerging molecular measurement technologies to assay the exposome , the comprehensive battery of exposures encountered from birth to death, promise a new way of identifying mixtures in disease in the epidemiological setting. In this opinion, we describe the analytic complexity and challenges in identifying mixtures associated with phenotype and disease. Existing and emerging machine-learning methods and data analytic approaches (e.g., "environment-wide association studies" [EWASs]), as well as large cohorts may enhance possibilities to identify mixtures of correlated exposures associated with phenotypes; however, the analytic complexity of identifying mixtures is immense. If the exposome concept is realized, new analytical methods and large sample sizes will be required to ascertain how mixtures are associated with disease. The author recommends documenting prevalent correlated exposures and replicated main effects prior to identifying mixtures.

Composting in small laboratory pilots: Performance and reproducibility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lashermes, G.; Barriuso, E.; Le Villio-Poitrenaud, M.

2012-02-15

Highlights: Black-Right-Pointing-Pointer We design an innovative small-scale composting device including six 4-l reactors. Black-Right-Pointing-Pointer We investigate the performance and reproducibility of composting on a small scale. Black-Right-Pointing-Pointer Thermophilic conditions are established by self-heating in all replicates. Black-Right-Pointing-Pointer Biochemical transformations, organic matter losses and stabilisation are realistic. Black-Right-Pointing-Pointer The organic matter evolution exhibits good reproducibility for all six replicates. - Abstract: Small-scale reactors (<10 l) have been employed in composting research, but few attempts have assessed the performance of composting considering the transformations of organic matter. Moreover, composting at small scales is often performed by imposing a fixed temperature, thus creatingmore » artificial conditions, and the reproducibility of composting has rarely been reported. The objectives of this study are to design an innovative small-scale composting device safeguarding self-heating to drive the composting process and to assess the performance and reproducibility of composting in small-scale pilots. The experimental setup included six 4-l reactors used for composting a mixture of sewage sludge and green wastes. The performance of the process was assessed by monitoring the temperature, O{sub 2} consumption and CO{sub 2} emissions, and characterising the biochemical evolution of organic matter. A good reproducibility was found for the six replicates with coefficients of variation for all parameters generally lower than 19%. An intense self-heating ensured the existence of a spontaneous thermophilic phase in all reactors. The average loss of total organic matter (TOM) was 46% of the initial content. Compared to the initial mixture, the hot water soluble fraction decreased by 62%, the hemicellulose-like fraction by 68%, the cellulose-like fraction by 50% and the lignin-like fractions by 12% in the final compost. The TOM losses, compost stabilisation and evolution of the biochemical fractions were similar to observed in large reactors or on-site experiments, excluding the lignin degradation, which was less important than in full-scale systems. The reproducibility of the process and the quality of the final compost make it possible to propose the use of this experimental device for research requiring a mass reduction of the initial composted waste mixtures.« less

Reopening Openness to Experience: A Network Analysis of Four Openness to Experience Inventories.

PubMed

Christensen, Alexander P; Cotter, Katherine N; Silvia, Paul J

2018-05-10

Openness to Experience is a complex trait, the taxonomic structure of which has been widely debated. Previous research has provided greater clarity of its lower order structure by synthesizing facets across several scales related to Openness to Experience. In this study, we take a finer grained approach by investigating the item-level relations of four Openness to Experience inventories (Big Five Aspects Scale, HEXACO-100, NEO PI-3, and Woo et al.'s Openness to Experience Inventory), using a network science approach, which allowed items to form an emergent taxonomy of facets and aspects. Our results (N = 802) identified 10 distinct facets (variety-seeking, aesthetic appreciation, intellectual curiosity, diversity, openness to emotions, fantasy, imaginative, self-assessed intelligence, intellectual interests, and nontraditionalism) that largely replicate previous findings as well as three higher order aspects: two that are commonly found in the literature (intellect and experiencing; i.e., openness), and one novel aspect (open-mindedness). In addition, we demonstrate that each Openness to Experience inventory offers a unique conceptualization of the trait, and that some inventories provide broader coverage of the network space than others. Our findings establish a broader consensus of Openness to Experience at the aspect and facet level, which has important implications for researchers and the Openness to Experience inventories they use.

Identification of common variants associated with human hippocampal and intracranial volumes.

PubMed

Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias; Hibar, Derrek P; Senstad, Rudy E; Winkler, Anderson M; Toro, Roberto; Appel, Katja; Bartecek, Richard; Bergmann, Ørjan; Bernard, Manon; Brown, Andrew A; Cannon, Dara M; Chakravarty, M Mallar; Christoforou, Andrea; Domin, Martin; Grimm, Oliver; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hottenga, Jouke-Jan; Langan, Camilla; Lopez, Lorna M; Hansell, Narelle K; Hwang, Kristy S; Kim, Sungeun; Laje, Gonzalo; Lee, Phil H; Liu, Xinmin; Loth, Eva; Lourdusamy, Anbarasu; Mattingsdal, Morten; Mohnke, Sebastian; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; O'Brien, Carol; Papmeyer, Martina; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rijpkema, Mark; Risacher, Shannon L; Roddey, J Cooper; Rose, Emma J; Ryten, Mina; Shen, Li; Sprooten, Emma; Strengman, Eric; Teumer, Alexander; Trabzuni, Daniah; Turner, Jessica; van Eijk, Kristel; van Erp, Theo G M; van Tol, Marie-Jose; Wittfeld, Katharina; Wolf, Christiane; Woudstra, Saskia; Aleman, Andre; Alhusaini, Saud; Almasy, Laura; Binder, Elisabeth B; Brohawn, David G; Cantor, Rita M; Carless, Melanie A; Corvin, Aiden; Czisch, Michael; Curran, Joanne E; Davies, Gail; de Almeida, Marcio A A; Delanty, Norman; Depondt, Chantal; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fagerness, Jesen; Fox, Peter T; Freimer, Nelson B; Gill, Michael; Göring, Harald H H; Hagler, Donald J; Hoehn, David; Holsboer, Florian; Hoogman, Martine; Hosten, Norbert; Jahanshad, Neda; Johnson, Matthew P; Kasperaviciute, Dalia; Kent, Jack W; Kochunov, Peter; Lancaster, Jack L; Lawrie, Stephen M; Liewald, David C; Mandl, René; Matarin, Mar; Mattheisen, Manuel; Meisenzahl, Eva; Melle, Ingrid; Moses, Eric K; Mühleisen, Thomas W; Nauck, Matthias; Nöthen, Markus M; Olvera, Rene L; Pandolfo, Massimo; Pike, G Bruce; Puls, Ralf; Reinvang, Ivar; Rentería, Miguel E; Rietschel, Marcella; Roffman, Joshua L; Royle, Natalie A; Rujescu, Dan; Savitz, Jonathan; Schnack, Hugo G; Schnell, Knut; Seiferth, Nina; Smith, Colin; Steen, Vidar M; Valdés Hernández, Maria C; Van den Heuvel, Martijn; van der Wee, Nic J; Van Haren, Neeltje E M; Veltman, Joris A; Völzke, Henry; Walker, Robert; Westlye, Lars T; Whelan, Christopher D; Agartz, Ingrid; Boomsma, Dorret I; Cavalleri, Gianpiero L; Dale, Anders M; Djurovic, Srdjan; Drevets, Wayne C; Hagoort, Peter; Hall, Jeremy; Heinz, Andreas; Jack, Clifford R; Foroud, Tatiana M; Le Hellard, Stephanie; Macciardi, Fabio; Montgomery, Grant W; Poline, Jean Baptiste; Porteous, David J; Sisodiya, Sanjay M; Starr, John M; Sussmann, Jessika; Toga, Arthur W; Veltman, Dick J; Walter, Henrik; Weiner, Michael W; Bis, Joshua C; Ikram, M Arfan; Smith, Albert V; Gudnason, Vilmundur; Tzourio, Christophe; Vernooij, Meike W; Launer, Lenore J; DeCarli, Charles; Seshadri, Sudha; Andreassen, Ole A; Apostolova, Liana G; Bastin, Mark E; Blangero, John; Brunner, Han G; Buckner, Randy L; Cichon, Sven; Coppola, Giovanni; de Zubicaray, Greig I; Deary, Ian J; Donohoe, Gary; de Geus, Eco J C; Espeseth, Thomas; Fernández, Guillén; Glahn, David C; Grabe, Hans J; Hardy, John; Hulshoff Pol, Hilleke E; Jenkinson, Mark; Kahn, René S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meyer-Lindenberg, Andreas; Morris, Derek W; Müller-Myhsok, Bertram; Nichols, Thomas E; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W; Potkin, Steven G; Sämann, Philipp G; Saykin, Andrew J; Schumann, Gunter; Smoller, Jordan W; Wardlaw, Joanna M; Weale, Michael E; Martin, Nicholas G; Franke, Barbara; Wright, Margaret J; Thompson, Paul M

2012-04-15

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer's disease and is reduced in schizophrenia, major depression and mesial temporal lobe epilepsy. Whereas many brain imaging phenotypes are highly heritable, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10(-7)).

The obesity-risk variant of FTO is inversely related with the So-Eum constitutional type: genome-wide association and replication analyses.

PubMed

Cha, Seongwon; Yu, Hyunjoo; Park, Ah Yeon; Oh, Soo A; Kim, Jong Yeol

2015-04-15

Body constitutional types described in the traditional Korean medicine system, Sasang constitutional medicine, are heritable, as has been revealed by twin and family studies. Thus, individuals with the same constitution type usually have similar pathophysiological and psychological traits. In several recent genome-wide association (GWA) analyses performed to identify constitution-associated variants, the association signals were not replicated due to small sample size and dissimilar, non-objective methods for classification of the constitutional types. We conducted GWA analysis and followed replication analysis in two large populations (5,490 subjects: 3,810 subjects at discovery stage and 1,680 subjects at replication stage) to identify the replicable constitution-associated variants, wherein subjects with the highest tertile of constitution probability values versus the reference with the lowest tertile of the values obtained from a recently developed constitution analysis tool were compared. We found that the obesity-risk variant in intron 1 of the fat mass and obesity-associated (FTO) gene was replicably inversely associated with the So-Eum (SE) type, characterized by reduced appetite, slim body, and cautious personality (rs7193144 in combined samples: odds ratio = 0.729, p = 1.47 × 10(-7)), and substantial association signal remained after controlling for body mass index (BMI). In contrast, the association of the variant with the Tae-Eum type, characterized by high body mass, disappeared after controlling BMI. In summary, the obesity-risk variant in FTO intron 1 was inversely associated with the SE type, independent of BMI, which corresponded well with the characteristics of the SE type, such as the lowest body mass and lowest susceptibility to metabolic disorders among the constitutional types. Therefore, the obesity-risk variant of FTO associated with body mass increase might be involved in the determination of body constitution type.

Microscopy-based Assays for High-throughput Screening of Host Factors Involved in Brucella Infection of Hela Cells.

PubMed

Casanova, Alain; Low, Shyan H; Emmenlauer, Mario; Conde-Alvarez, Raquel; Salcedo, Suzana P; Gorvel, Jean-Pierre; Dehio, Christoph

2016-08-05

Brucella species are facultative intracellular pathogens that infect animals as their natural hosts. Transmission to humans is most commonly caused by direct contact with infected animals or by ingestion of contaminated food and can lead to severe chronic infections. Brucella can invade professional and non-professional phagocytic cells and replicates within endoplasmic reticulum (ER)-derived vacuoles. The host factors required for Brucella entry into host cells, avoidance of lysosomal degradation, and replication in the ER-like compartment remain largely unknown. Here we describe two assays to identify host factors involved in Brucella entry and replication in HeLa cells. The protocols describe the use of RNA interference, while alternative screening methods could be applied. The assays are based on the detection of fluorescently labeled bacteria in fluorescently labeled host cells using automated wide-field microscopy. The fluorescent images are analyzed using a standardized image analysis pipeline in CellProfiler which allows single cell-based infection scoring. In the endpoint assay, intracellular replication is measured two days after infection. This allows bacteria to traffic to their replicative niche where proliferation is initiated around 12 hr after bacterial entry. Brucella which have successfully established an intracellular niche will thus have strongly proliferated inside host cells. Since intracellular bacteria will greatly outnumber individual extracellular or intracellular non-replicative bacteria, a strain constitutively expressing GFP can be used. The strong GFP signal is then used to identify infected cells. In contrast, for the entry assay it is essential to differentiate between intracellular and extracellular bacteria. Here, a strain encoding for a tetracycline-inducible GFP is used. Induction of GFP with simultaneous inactivation of extracellular bacteria by gentamicin enables the differentiation between intracellular and extracellular bacteria based on the GFP signal, with only intracellular bacteria being able to express GFP. This allows the robust detection of single intracellular bacteria before intracellular proliferation is initiated.

Prehospital Acute Stroke Severity Scale to Predict Large Artery Occlusion: Design and Comparison With Other Scales.

PubMed

Hastrup, Sidsel; Damgaard, Dorte; Johnsen, Søren Paaske; Andersen, Grethe

2016-07-01

We designed and validated a simple prehospital stroke scale to identify emergent large vessel occlusion (ELVO) in patients with acute ischemic stroke and compared the scale to other published scales for prediction of ELVO. A national historical test cohort of 3127 patients with information on intracranial vessel status (angiography) before reperfusion therapy was identified. National Institutes of Health Stroke Scale (NIHSS) items with the highest predictive value of occlusion of a large intracranial artery were identified, and the most optimal combination meeting predefined criteria to ensure usefulness in the prehospital phase was determined. The predictive performance of Prehospital Acute Stroke Severity (PASS) scale was compared with other published scales for ELVO. The PASS scale was composed of 3 NIHSS scores: level of consciousness (month/age), gaze palsy/deviation, and arm weakness. In derivation of PASS 2/3 of the test cohort was used and showed accuracy (area under the curve) of 0.76 for detecting large arterial occlusion. Optimal cut point ≥2 abnormal scores showed: sensitivity=0.66 (95% CI, 0.62-0.69), specificity=0.83 (0.81-0.85), and area under the curve=0.74 (0.72-0.76). Validation on 1/3 of the test cohort showed similar performance. Patients with a large artery occlusion on angiography with PASS ≥2 had a median NIHSS score of 17 (interquartile range=6) as opposed to PASS <2 with a median NIHSS score of 6 (interquartile range=5). The PASS scale showed equal performance although more simple when compared with other scales predicting ELVO. The PASS scale is simple and has promising accuracy for prediction of ELVO in the field. © 2016 American Heart Association, Inc.

Genomic predictors of the maximal O2 uptake response to standardized exercise training programs

PubMed Central

Sarzynski, Mark A.; Rice, Treva K.; Kraus, William E.; Church, Timothy S.; Sung, Yun Ju; Rao, D. C.; Rankinen, Tuomo

2011-01-01

Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O2 uptake (V̇o2max) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genome-wide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in V̇o2max Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 × 10−4. Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in V̇o2max trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their V̇o2max by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ∼6% of the training response of V̇o2max. The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDM1); glutamate receptor, ionotropic, N-methyl-d-aspartate 3A (GRIN3A); K+ channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ∼68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in V̇o2max in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of V̇o2max to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted. PMID:21183627

The Status of Large-Scale Assessment in the Pacific Region. REL Technical Brief. REL 2008-No. 003

ERIC Educational Resources Information Center

Ryan, Jennifer; Keir, Scott

2008-01-01

This technical brief describes the large-scale assessment measures and practices used in the jurisdictions served by the Pacific Regional Educational Laboratory. The need for effective large-scale assessment was identified as a major priority for improving student achievement in the Pacific Region jurisdictions: American Samoa, Guam, Hawaii, the…

Large-scale chromosome folding versus genomic DNA sequences: A discrete double Fourier transform technique.

PubMed

Chechetkin, V R; Lobzin, V V

2017-08-07

Using state-of-the-art techniques combining imaging methods and high-throughput genomic mapping tools leaded to the significant progress in detailing chromosome architecture of various organisms. However, a gap still remains between the rapidly growing structural data on the chromosome folding and the large-scale genome organization. Could a part of information on the chromosome folding be obtained directly from underlying genomic DNA sequences abundantly stored in the databanks? To answer this question, we developed an original discrete double Fourier transform (DDFT). DDFT serves for the detection of large-scale genome regularities associated with domains/units at the different levels of hierarchical chromosome folding. The method is versatile and can be applied to both genomic DNA sequences and corresponding physico-chemical parameters such as base-pairing free energy. The latter characteristic is closely related to the replication and transcription and can also be used for the assessment of temperature or supercoiling effects on the chromosome folding. We tested the method on the genome of E. coli K-12 and found good correspondence with the annotated domains/units established experimentally. As a brief illustration of further abilities of DDFT, the study of large-scale genome organization for bacteriophage PHIX174 and bacterium Caulobacter crescentus was also added. The combined experimental, modeling, and bioinformatic DDFT analysis should yield more complete knowledge on the chromosome architecture and genome organization. Copyright © 2017 Elsevier Ltd. All rights reserved.

Production and characterization of vaccines based on flaviviruses defective in replication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mason, Peter W.; Department of Pathology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019; Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1019

2006-08-01

To develop new vaccine candidates for flavivirus infections, we have engineered two flaviviruses, yellow fever virus (YFV) and West Nile virus (WNV), that are deficient in replication. These defective pseudoinfectious viruses (PIVs) lack a functional copy of the capsid (C) gene in their genomes and are incapable of causing spreading infection upon infection of cells both in vivo and in vitro. However, they produce extracellular E protein in form of secreted subviral particles (SVPs) that are known to be an effective immunogen. PIVs can be efficiently propagated in trans-complementing cell lines making high levels of C or all three viralmore » structural proteins. PIVs derived from YFV and WNV, demonstrated very high safety and immunization produced high levels of neutralizing antibodies and protective immune response. Such defective flaviviruses can be produced in large scale under low biocontainment conditions and should be useful for diagnostic or vaccine applications.« less

Cellulase producing microorganism ATCC 55702

DOEpatents

Dees, H. Craig

1997-01-01

Bacteria which produce large amounts of cellulase--containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualifies for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques.

Cellulase-containing cell-free fermentate produced from microorganism ATCC 55702

DOEpatents

Dees, H. Craig

1997-12-16

Bacteria which produce large amounts of cellulase-containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques.

Cellulase producing microorganism ATCC 55702

DOEpatents

Dees, H.C.

1997-12-30

Bacteria which produce large amounts of cellulase--containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualifies for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques. 5 figs.

Unprecedented large inverted repeats at the replication terminus of circular bacterial chromosomes suggest a novel mode of chromosome rescue

PubMed Central

El Kafsi, Hela; Loux, Valentin; Mariadassou, Mahendra; Blin, Camille; Chiapello, Hélène; Abraham, Anne-Laure; Maguin, Emmanuelle; van de Guchte, Maarten

2017-01-01

The first Lactobacillus delbrueckii ssp. bulgaricus genome sequence revealed the presence of a very large inverted repeat (IR), a DNA sequence arrangement which thus far seemed inconceivable in a non-manipulated circular bacterial chromosome, at the replication terminus. This intriguing observation prompted us to investigate if similar IRs could be found in other bacteria. IRs with sizes varying from 38 to 76 kbp were found at the replication terminus of all 5 L. delbrueckii ssp. bulgaricus chromosomes analysed, but in none of 1373 other chromosomes. They represent the first naturally occurring very large IRs detected in circular bacterial genomes. A comparison of the L. bulgaricus replication terminus regions and the corresponding regions without IR in 5 L. delbrueckii ssp. lactis genomes leads us to propose a model for the formation and evolution of the IRs. The DNA sequence data are consistent with a novel model of chromosome rescue after premature replication termination or irreversible chromosome damage near the replication terminus, involving mechanisms analogous to those proposed in the formation of very large IRs in human cancer cells. We postulate that the L. delbrueckii ssp. bulgaricus-specific IRs in different strains derive from a single ancestral IR of at least 93 kbp. PMID:28281695

Reappraisal of known malaria resistance loci in a large multi-centre study

PubMed Central

Rockett, Kirk A.; Clarke, Geraldine M.; Fitzpatrick, Kathryn; Hubbart, Christina; Jeffreys, Anna E.; Rowlands, Kate; Craik, Rachel; Jallow, Muminatou; Conway, David J.; Bojang, Kalifa A.; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio; Toure, Ousmane; Thera, Mahamadou A.; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Mangano, Valentina D.; Bougouma, Edith C.; Sirima, Sodiomon B.; Modiano, David; Amenga-Etego, Lucas N.; Ghansah, Anita; Koram, Kwadwo A.; Wilson, Michael D.; Enimil, Anthony; Evans, Jennifer; Amodu, Olukemi; Olaniyan, Subulade; Apinjoh, Tobias; Mugri, Regina; Ndi, Andre; Ndila, Carolyne M.; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N.; Manjurano, Alphaxard; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh; Nyirongo, Vysaul; Kachala, David; Molyneux, Malcolm; Dunstan, Sarah J.; Phu, Nguyen Hoan; Ngoc Quyen, Nguyen Thi; Thai, Cao Quang; Hien, Tran Tinh; Manning, Laurens; Laman, Moses; Siba, Peter; Karunajeewa, Harin; Allen, Steve; Allen, Angela; Davis, Timothy M. E.; Michon, Pascal; Mueller, Ivo; Green, Angie; Molloy, Sile; Johnson, Kimberly J.; Kerasidou, Angeliki; Cornelius, Victoria; Hart, Lee; Vanderwal, Aaron; SanJoaquin, Miguel; Band, Gavin; Le, Si Quang; Pirinen, Matti; Sepúlveda, Nuno; Spencer, Chris C.A.; Clark, Taane G.; Agbenyega, Tsiri; Achidi, Eric; Doumbo, Ogobara; Farrar, Jeremy; Marsh, Kevin; Taylor, Terrie; Kwiatkowski, Dominic P.

2015-01-01

Many human genetic associations with resistance to malaria have been reported but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anaemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed. PMID:25261933

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22.

PubMed

Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh; Jung, Jae U; Gao, Shou-Jiang

2018-02-15

The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application. IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application. Copyright © 2018 American Society for Microbiology.

Identification of a high-efficiency baculovirus DNA replication origin that functions in insect and mammalian cells.

PubMed

Wu, Yueh-Lung; Wu, Carol-P; Huang, Yu-Hui; Huang, Sheng-Ping; Lo, Huei-Ru; Chang, Hao-Shuo; Lin, Pi-Hsiu; Wu, Ming-Cheng; Chang, Chia-Jung; Chao, Yu-Chan

2014-11-01

The p143 gene from Autographa californica multinucleocapsid nucleopolyhedrovirus (AcMNPV) has been found to increase the expression of luciferase, which is driven by the polyhedrin gene promoter, in a plasmid with virus coinfection. Further study indicated that this is due to the presence of a replication origin (ori) in the coding region of this gene. Transient DNA replication assays showed that a specific fragment of the p143 coding sequence, p143-3, underwent virus-dependent DNA replication in Spodoptera frugiperda IPLB-Sf-21 (Sf-21) cells. Deletion analysis of the p143-3 fragment showed that subfragment p143-3.2a contained the essential sequence of this putative ori. Sequence analysis of this region revealed a unique distribution of imperfect palindromes with high AT contents. No sequence homology or similarity between p143-3.2a and any other known ori was detected, suggesting that it is a novel baculovirus ori. Further study showed that the p143-3.2a ori can replicate more efficiently in infected Sf-21 cells than baculovirus homologous regions (hrs), the major baculovirus ori, or non-hr oris during virus replication. Previously, hr on its own was unable to replicate in mammalian cells, and for mammalian viral oris, viral proteins are generally required for their proper replication in host cells. However, the p143-3.2a ori was, surprisingly, found to function as an efficient ori in mammalian cells without the need for any viral proteins. We conclude that p143 contains a unique sequence that can function as an ori to enhance gene expression in not only insect cells but also mammalian cells. Baculovirus DNA replication relies on both hr and non-hr oris; however, so far very little is known about the latter oris. Here we have identified a new non-hr ori, the p143 ori, which resides in the coding region of p143. By developing a novel DNA replication-enhanced reporter system, we have identified and located the core region required for the p143 ori. This ori contains a large number of imperfect inverted repeats and is the most active ori in the viral genome during virus infection in insect cells. We also found that it is a unique ori that can replicate in mammalian cells without the assistance of baculovirus gene products. The identification of this ori should contribute to a better understanding of baculovirus DNA replication. Also, this ori is very useful in assisting with gene expression in mammalian cells. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

PubMed Central

Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K.; Li, Changwei; Schwander, Karen; Richard, Melissa A.; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M.; Bielak, Lawrence F.; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P.; Horimoto, Andrea R. V. R.; Lohman, Kurt K.; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert V.; Wojczynski, Mary K.; Alver, Maris; Boissel, Mathilde; Cai, Qiuyin; Divers, Jasmin; Gao, Chuan; Goel, Anuj; Harris, Sarah E.; He, Meian; Hsu, Fang-Chi; Jackson, Anne U.; Kähönen, Mika; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Luan, Jian'an; Nolte, Ilja M.; Padmanabhan, Sandosh; Robino, Antonietta; Scott, Robert A.; Sofer, Tamar; Stančáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O.; Varga, Tibor V.; Vitart, Veronique; Wang, Yajuan; Warren, Helen R.; Wen, Wanqing; Yanek, Lisa R.; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Arking, Dan E.; Aung, Tin; Boerwinkle, Eric; Borecki, Ingrid; Broeckel, Ulrich; Brown, Morris; Brumat, Marco; Burke, Gregory L.; Chakravarti, Aravinda; Charumathi, Sabanayagam; Ida Chen, Yii-Der; Connell, John M.; Correa, Adolfo; de las Fuentes, Lisa; de Mutsert, Renée; de Silva, H. Janaka; Deng, Xuan; Ding, Jingzhong; Duan, Qing; Eaton, Charles B.; Ehret, Georg; Eppinga, Ruben N.; Faul, Jessica D.; Felix, Stephan B.; Forouhi, Nita G.; Forrester, Terrence; Franco, Oscar H.; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gigante, Bruna; Gu, C. Charles; Gu, Dongfeng; Hagenaars, Saskia P.; Hallmans, Göran; Harris, Tamara B.; He, Jiang; Heng, Chew-Kiat; Hirata, Makoto; Howard, Barbara V.; Ikram, M. Arfan; John, Ulrich; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O.; Koh, Woon-Puay; Krieger, José E.; Kritchevsky, Stephen B.; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lehne, Benjamin; Lewis, Cora E.; Li, Yize; Lin, Shiow; Liu, Jianjun; Liu, Jingmin; Loh, Marie; Louie, Tin; Mägi, Reedik; McKenzie, Colin A.; Meitinger, Thomas; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L.; Momozawa, Yukihide; Nalls, Mike A.; Nelson, Christopher P.; Sotoodehnia, Nona; Norris, Jill M.; O'Connell, Jeff R.; Palmer, Nicholette D.; Perls, Thomas; Pedersen, Nancy L.; Peters, Annette; Peyser, Patricia A.; Poulter, Neil; Raffel, Leslie J.; Raitakari, Olli T.; Roll, Kathryn; Rose, Lynda M.; Rosendaal, Frits R.; Rotter, Jerome I.; Schmidt, Carsten O.; Schreiner, Pamela J.; Schupf, Nicole; Scott, William R.; Shi, Yuan; Sidney, Stephen; Sims, Mario; Sitlani, Colleen M.; Smith, Jennifer A.; Snieder, Harold; Starr, John M.; Strauch, Konstantin; Stringham, Heather M.; Tan, Nicholas Y. Q.; Tang, Hua; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Turner, Stephen T.; Uitterlinden, André G.; Vollenweider, Peter; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Williams, Christine; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B.; Becker, Diane M.; Boehnke, Michael; Bowden, Donald W.; Chambers, John C.; Deary, Ian J.; Esko, Tõnu; Farrall, Martin; Franks, Paul W.; Freedman, Barry I.; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S.; Kutalik, Zoltán; Laakso, Markku; Laurie, Cathy C.; Leander, Karin; Lehtimäki, Terho; Study, Lifelines Cohort; Magnusson, Patrik K. E.; Oldehinkel, Albertine J.; Penninx, Brenda W. J. H.; Polasek, Ozren; Porteous, David J.; Rauramaa, Rainer; Samani, Nilesh J.; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E.; Watkins, Hugh; Weir, David R.; Wickremasinghe, Ananda R.; Wu, Tangchun; Zheng, Wei; Bouchard, Claude; Christensen, Kaare; Evans, Michele K.; Gudnason, Vilmundur; Horta, Bernardo L.; Kardia, Sharon L. R.; Liu, Yongmei; Pereira, Alexandre C.; Psaty, Bruce M.; Ridker, Paul M.; van Dam, Rob M.; Gauderman, W. James; Zhu, Xiaofeng; Mook-Kanamori, Dennis O.; Fornage, Myriam; Rotimi, Charles N.; Cupples, L. Adrienne; Kelly, Tanika N.; Fox, Ervin R.; Hayward, Caroline; van Duijn, Cornelia M.; Tai, E Shyong; Wong, Tien Yin; Kooperberg, Charles; Palmas, Walter; Morrison, Alanna C.; Caulfield, Mark J.; Munroe, Patricia B.; Rao, Dabeeru C.; Province, Michael A.; Levy, Daniel

2018-01-01

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension. PMID:29912962

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

PubMed

Feitosa, Mary F; Kraja, Aldi T; Chasman, Daniel I; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Bentley, Amy R; Brown, Michael R; Schwander, Karen; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P; Horimoto, Andrea R V R; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Wojczynski, Mary K; Alver, Maris; Boissel, Mathilde; Cai, Qiuyin; Campbell, Archie; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; He, Meian; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Luan, Jian'an; Matoba, Nana; Nolte, Ilja M; Padmanabhan, Sandosh; Riaz, Muhammad; Rueedi, Rico; Robino, Antonietta; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; Stančáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Vitart, Veronique; Wang, Yajuan; Ware, Erin B; Warren, Helen R; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Boerwinkle, Eric; Borecki, Ingrid; Broeckel, Ulrich; Brown, Morris; Brumat, Marco; Burke, Gregory L; Canouil, Mickaël; Chakravarti, Aravinda; Charumathi, Sabanayagam; Ida Chen, Yii-Der; Connell, John M; Correa, Adolfo; de Las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Deng, Xuan; Ding, Jingzhong; Duan, Qing; Eaton, Charles B; Ehret, Georg; Eppinga, Ruben N; Evangelou, Evangelos; Faul, Jessica D; Felix, Stephan B; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gigante, Bruna; Gu, C Charles; Gu, Dongfeng; Hagenaars, Saskia P; Hallmans, Göran; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Howard, Barbara V; Ikram, M Arfan; John, Ulrich; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Krieger, José E; Kritchevsky, Stephen B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lin, Shiow; Liu, Jianjun; Liu, Jingmin; Loh, Marie; Louie, Tin; Mägi, Reedik; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Momozawa, Yukihide; Nalls, Mike A; Nelson, Christopher P; Sotoodehnia, Nona; Norris, Jill M; O'Connell, Jeff R; Palmer, Nicholette D; Perls, Thomas; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Roll, Kathryn; Rose, Lynda M; Rosendaal, Frits R; Rotter, Jerome I; Schmidt, Carsten O; Schreiner, Pamela J; Schupf, Nicole; Scott, William R; Sever, Peter S; Shi, Yuan; Sidney, Stephen; Sims, Mario; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Stringham, Heather M; Tan, Nicholas Y Q; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Turner, Stephen T; Uitterlinden, André G; Vollenweider, Peter; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Williams, Christine; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Jonas, Jost Bruno; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Kutalik, Zoltán; Laakso, Markku; Laurie, Cathy C; Leander, Karin; Lehtimäki, Terho; Study, Lifelines Cohort; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Polasek, Ozren; Porteous, David J; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Bouchard, Claude; Christensen, Kaare; Evans, Michele K; Gudnason, Vilmundur; Horta, Bernardo L; Kardia, Sharon L R; Liu, Yongmei; Pereira, Alexandre C; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Gauderman, W James; Zhu, Xiaofeng; Mook-Kanamori, Dennis O; Fornage, Myriam; Rotimi, Charles N; Cupples, L Adrienne; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Kooperberg, Charles; Palmas, Walter; Rice, Kenneth; Morrison, Alanna C; Elliott, Paul; Caulfield, Mark J; Munroe, Patricia B; Rao, Dabeeru C; Province, Michael A; Levy, Daniel

2018-01-01

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Validity of the Male Depression Risk Scale in a representative Canadian sample: sensitivity and specificity in identifying men with recent suicide attempt.

PubMed

Rice, Simon M; Ogrodniczuk, John S; Kealy, David; Seidler, Zac E; Dhillon, Haryana M; Oliffe, John L

2017-12-22

Clinical practice and literature has supported the existence of a phenotypic sub-type of depression in men. While a number of self-report rating scales have been developed in order to empirically test the male depression construct, psychometric validation of these scales is limited. To confirm the psychometric properties of the multidimensional Male Depression Risk Scale (MDRS-22) and to develop clinical cut-off scores for the MDRS-22. Data were obtained from an online sample of 1000 Canadian men (median age (M) = 49.63, standard deviation (SD) = 14.60). Confirmatory factor analysis (CFA) was used to replicate the established six-factor model of the MDRS-22. Psychometric values of the MDRS subscales were comparable to the widely used Patient Health Questionnaire-9. CFA model fit indices indicated adequate model fit for the six-factor MDRS-22 model. ROC curve analysis indicated the MDRS-22 was effective for identifying those with a recent (previous four-weeks) suicide attempt (area under curve (AUC) values = 0.837). The MDRS-22 cut-off identified proportionally more (84.62%) cases of recent suicide attempt relative to the PHQ-9 moderate range (53.85%). The MDRS-22 is the first male-sensitive depression scale to be psychometrically validated using CFA techniques in independent and cross-nation samples. Additional studies should identify differential item functioning and evaluate cross-cultural effects.

Multi-agent based control of large-scale complex systems employing distributed dynamic inference engine

NASA Astrophysics Data System (ADS)

Zhang, Daili

Increasing societal demand for automation has led to considerable efforts to control large-scale complex systems, especially in the area of autonomous intelligent control methods. The control system of a large-scale complex system needs to satisfy four system level requirements: robustness, flexibility, reusability, and scalability. Corresponding to the four system level requirements, there arise four major challenges. First, it is difficult to get accurate and complete information. Second, the system may be physically highly distributed. Third, the system evolves very quickly. Fourth, emergent global behaviors of the system can be caused by small disturbances at the component level. The Multi-Agent Based Control (MABC) method as an implementation of distributed intelligent control has been the focus of research since the 1970s, in an effort to solve the above-mentioned problems in controlling large-scale complex systems. However, to the author's best knowledge, all MABC systems for large-scale complex systems with significant uncertainties are problem-specific and thus difficult to extend to other domains or larger systems. This situation is partly due to the control architecture of multiple agents being determined by agent to agent coupling and interaction mechanisms. Therefore, the research objective of this dissertation is to develop a comprehensive, generalized framework for the control system design of general large-scale complex systems with significant uncertainties, with the focus on distributed control architecture design and distributed inference engine design. A Hybrid Multi-Agent Based Control (HyMABC) architecture is proposed by combining hierarchical control architecture and module control architecture with logical replication rings. First, it decomposes a complex system hierarchically; second, it combines the components in the same level as a module, and then designs common interfaces for all of the components in the same module; third, replications are made for critical agents and are organized into logical rings. This architecture maintains clear guidelines for complexity decomposition and also increases the robustness of the whole system. Multiple Sectioned Dynamic Bayesian Networks (MSDBNs) as a distributed dynamic probabilistic inference engine, can be embedded into the control architecture to handle uncertainties of general large-scale complex systems. MSDBNs decomposes a large knowledge-based system into many agents. Each agent holds its partial perspective of a large problem domain by representing its knowledge as a Dynamic Bayesian Network (DBN). Each agent accesses local evidence from its corresponding local sensors and communicates with other agents through finite message passing. If the distributed agents can be organized into a tree structure, satisfying the running intersection property and d-sep set requirements, globally consistent inferences are achievable in a distributed way. By using different frequencies for local DBN agent belief updating and global system belief updating, it balances the communication cost with the global consistency of inferences. In this dissertation, a fully factorized Boyen-Koller (BK) approximation algorithm is used for local DBN agent belief updating, and the static Junction Forest Linkage Tree (JFLT) algorithm is used for global system belief updating. MSDBNs assume a static structure and a stable communication network for the whole system. However, for a real system, sub-Bayesian networks as nodes could be lost, and the communication network could be shut down due to partial damage in the system. Therefore, on-line and automatic MSDBNs structure formation is necessary for making robust state estimations and increasing survivability of the whole system. A Distributed Spanning Tree Optimization (DSTO) algorithm, a Distributed D-Sep Set Satisfaction (DDSSS) algorithm, and a Distributed Running Intersection Satisfaction (DRIS) algorithm are proposed in this dissertation. Combining these three distributed algorithms and a Distributed Belief Propagation (DBP) algorithm in MSDBNs makes state estimations robust to partial damage in the whole system. Combining the distributed control architecture design and the distributed inference engine design leads to a process of control system design for a general large-scale complex system. As applications of the proposed methodology, the control system design of a simplified ship chilled water system and a notional ship chilled water system have been demonstrated step by step. Simulation results not only show that the proposed methodology gives a clear guideline for control system design for general large-scale complex systems with dynamic and uncertain environment, but also indicate that the combination of MSDBNs and HyMABC can provide excellent performance for controlling general large-scale complex systems.

Identification of new protein interactions between dengue fever virus and its hosts, human and mosquito.

PubMed

Mairiang, Dumrong; Zhang, Huamei; Sodja, Ann; Murali, Thilakam; Suriyaphol, Prapat; Malasit, Prida; Limjindaporn, Thawornchai; Finley, Russell L

2013-01-01

The four divergent serotypes of dengue virus are the causative agents of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. About two-fifths of the world's population live in areas where dengue is prevalent, and thousands of deaths are caused by the viruses every year. Dengue virus is transmitted from one person to another primarily by the yellow fever mosquito, Aedes aegypti. Recent studies have begun to define how the dengue viral proteins interact with host proteins to mediate viral replication and pathogenesis. A combined analysis of these studies, however, suggests that many virus-host protein interactions remain to be identified, especially for the mosquito host. In this study, we used high-throughput yeast two-hybrid screening to identify mosquito and human proteins that physically interact with dengue proteins. We tested each identified host protein against the proteins from all four serotypes of dengue to identify interactions that are conserved across serotypes. We further confirmed many of the interactions using co-affinity purification assays. As in other large-scale screens, we identified some previously detected interactions and many new ones, moving us closer to a complete host - dengue protein interactome. To help summarize and prioritize the data for further study, we combined our interactions with other published data and identified a subset of the host-dengue interactions that are now supported by multiple forms of evidence. These data should be useful for understanding the interplay between dengue and its hosts and may provide candidates for drug targets and vector control strategies.

Identification of New Protein Interactions between Dengue Fever Virus and Its Hosts, Human and Mosquito

PubMed Central

Mairiang, Dumrong; Zhang, Huamei; Sodja, Ann; Murali, Thilakam; Suriyaphol, Prapat; Malasit, Prida; Limjindaporn, Thawornchai; Finley, Russell L.

2013-01-01

The four divergent serotypes of dengue virus are the causative agents of dengue fever, dengue hemorrhagic fever and dengue shock syndrome. About two-fifths of the world's population live in areas where dengue is prevalent, and thousands of deaths are caused by the viruses every year. Dengue virus is transmitted from one person to another primarily by the yellow fever mosquito, Aedes aegypti. Recent studies have begun to define how the dengue viral proteins interact with host proteins to mediate viral replication and pathogenesis. A combined analysis of these studies, however, suggests that many virus-host protein interactions remain to be identified, especially for the mosquito host. In this study, we used high-throughput yeast two-hybrid screening to identify mosquito and human proteins that physically interact with dengue proteins. We tested each identified host protein against the proteins from all four serotypes of dengue to identify interactions that are conserved across serotypes. We further confirmed many of the interactions using co-affinity purification assays. As in other large-scale screens, we identified some previously detected interactions and many new ones, moving us closer to a complete host – dengue protein interactome. To help summarize and prioritize the data for further study, we combined our interactions with other published data and identified a subset of the host-dengue interactions that are now supported by multiple forms of evidence. These data should be useful for understanding the interplay between dengue and its hosts and may provide candidates for drug targets and vector control strategies. PMID:23326450

Identifying sites of replication initiation in yeast chromosomes: looking for origins in all the right places.

PubMed

van Brabant, A J; Hunt, S Y; Fangman, W L; Brewer, B J

1998-06-01

DNA fragments that contain an active origin of replication generate bubble-shaped replication intermediates with diverging forks. We describe two methods that use two-dimensional (2-D) agarose gel electrophoresis along with DNA sequence information to identify replication origins in natural and artificial Saccharomyces cerevisiae chromosomes. The first method uses 2-D gels of overlapping DNA fragments to locate an active chromosomal replication origin within a region known to confer autonomous replication on a plasmid. A variant form of 2-D gels can be used to determine the direction of fork movement, and the second method uses this technique to find restriction fragments that are replicated by diverging forks, indicating that a bidirectional replication origin is located between the two fragments. Either of these two methods can be applied to the analysis of any genomic region for which there is DNA sequence information or an adequate restriction map.

DDB1 Stimulates Viral Transcription of Hepatitis B Virus via HBx-Independent Mechanisms.

PubMed

Kim, Woohyun; Lee, Sooyoung; Son, Yeongnam; Ko, Chunkyu; Ryu, Wang-Shick

2016-11-01

HBx, a small regulatory protein of hepatitis B virus (HBV), augments viral DNA replication by stimulating viral transcription. Among numerous reported HBx-binding proteins, DDB1 has drawn attention, because DDB1 acts as a substrate receptor of the Cul4-DDB1 ubiquitin E3 ligase. Previous work reported that the DDB1-HBx interaction is indispensable for HBx-stimulated viral DNA replication, suggesting that the Cul4-DDB1 ubiquitin E3 ligase might target cellular restriction factors for ubiquitination and proteasomal degradation. To gain further insight into the DDB1-HBx interaction, we generated HBx mutants deficient for DDB1 binding (i.e., R96A, L98A, and G99A) and examined whether they support HBx-stimulated viral DNA replication. In contrast to data from previous reports, our results showed that the HBx mutants deficient for DDB1 binding supported viral DNA replication to nearly wild-type levels, revealing that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, we found that DDB1 directly stimulates viral transcription regardless of HBx expression. Through an HBV infection study, importantly, we demonstrated that DDB1 stimulates viral transcription from covalently closed circular DNA, a physiological template for viral transcription. Overall, we concluded that DDB1 stimulates viral transcription via a mechanism that does not involve an interaction with HBx. DDB1 constitutes a cullin-based ubiquitin E3 ligase, where DDB1 serves as an adaptor linking the cullin scaffold to the substrate receptor. Previous findings that the DDB1-binding ability of HBx is essential for HBx-stimulated viral DNA replication led to the hypothesis that HBx could downregulate host restriction factors that limit HBV replication through the cullin ubiquitin E3 ligase that requires the DDB1-HBx interaction. Consistent with this hypothesis, recent work identified Smc5/6 as a host restriction factor that is regulated by the viral cullin ubiquitin E3 ligase. In contrast, here we found that the DDB1-HBx interaction is largely dispensable for HBx-stimulated viral DNA replication. Instead, our results clearly showed that DDB1, regardless of HBx expression, enhances viral transcription. Overall, besides its role in the viral cullin ubiquitin E3 ligase, DDB1 itself stimulates viral transcription via HBx-independent mechanisms. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Cross-lingual neighborhood effects in generalized lexical decision and natural reading.

PubMed

Dirix, Nicolas; Cop, Uschi; Drieghe, Denis; Duyck, Wouter

2017-06-01

The present study assessed intra- and cross-lingual neighborhood effects, using both a generalized lexical decision task and an analysis of a large-scale bilingual eye-tracking corpus (Cop, Dirix, Drieghe, & Duyck, 2016). Using new neighborhood density and frequency measures, the general lexical decision task yielded an inhibitory cross-lingual neighborhood density effect on reading times of second language words, replicating van Heuven, Dijkstra, and Grainger (1998). Reaction times for native language words were not influenced by neighborhood density or frequency but error rates showed cross-lingual neighborhood effects depending on target word frequency. The large-scale eye movement corpus confirmed effects of cross-lingual neighborhood on natural reading, even though participants were reading a novel in a unilingual context. Especially second language reading and to a lesser extent native language reading were influenced by lexical candidates from the nontarget language, although these effects in natural reading were largely facilitatory. These results offer strong and direct support for bilingual word recognition models that assume language-independent lexical access. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

How many bootstrap replicates are necessary?

PubMed

Pattengale, Nicholas D; Alipour, Masoud; Bininda-Emonds, Olaf R P; Moret, Bernard M E; Stamatakis, Alexandros

2010-03-01

Phylogenetic bootstrapping (BS) is a standard technique for inferring confidence values on phylogenetic trees that is based on reconstructing many trees from minor variations of the input data, trees called replicates. BS is used with all phylogenetic reconstruction approaches, but we focus here on one of the most popular, maximum likelihood (ML). Because ML inference is so computationally demanding, it has proved too expensive to date to assess the impact of the number of replicates used in BS on the relative accuracy of the support values. For the same reason, a rather small number (typically 100) of BS replicates are computed in real-world studies. Stamatakis et al. recently introduced a BS algorithm that is 1 to 2 orders of magnitude faster than previous techniques, while yielding qualitatively comparable support values, making an experimental study possible. In this article, we propose stopping criteria--that is, thresholds computed at runtime to determine when enough replicates have been generated--and we report on the first large-scale experimental study to assess the effect of the number of replicates on the quality of support values, including the performance of our proposed criteria. We run our tests on 17 diverse real-world DNA--single-gene as well as multi-gene--datasets, which include 125-2,554 taxa. We find that our stopping criteria typically stop computations after 100-500 replicates (although the most conservative criterion may continue for several thousand replicates) while producing support values that correlate at better than 99.5% with the reference values on the best ML trees. Significantly, we also find that the stopping criteria can recommend very different numbers of replicates for different datasets of comparable sizes. Our results are thus twofold: (i) they give the first experimental assessment of the effect of the number of BS replicates on the quality of support values returned through BS, and (ii) they validate our proposals for stopping criteria. Practitioners will no longer have to enter a guess nor worry about the quality of support values; moreover, with most counts of replicates in the 100-500 range, robust BS under ML inference becomes computationally practical for most datasets. The complete test suite is available at http://lcbb.epfl.ch/BS.tar.bz2, and BS with our stopping criteria is included in the latest release of RAxML v7.2.5, available at http://wwwkramer.in.tum.de/exelixis/software.html.

Identification of novel inhibitors of non-replicating Mycobacterium tuberculosis using a carbon starvation model

PubMed Central

Grant, Sarah Schmidt; Kawate, Tomohiko; Nag, Partha P.; Silvis, Melanie R.; Gordon, Katherine; Stanley, Sarah A.; Kazyanskaya, Ed; Nietupski, Ray; Golas, Aaron; Fitzgerald, Michael; Cho, Sanghyun; Franzblau, Scott G.; Hung, Deborah T.

2013-01-01

During Mycobacterium tuberculosis infection, a population of bacteria is thought to exist in a non-replicating state, refractory to antibiotics, which may contribute to the need for prolonged antibiotic therapy. The identification of inhibitors of the non-replicating state provides tools that can be used to probe this hypothesis and the physiology of this state. The development of such inhibitors also has the potential to shorten the duration of antibiotic therapy required. Here we describe the development of a novel non-replicating assay amenable to high-throughput chemical screening coupled with secondary assays that use carbon starvation as the in vitro model. Together these assays identify compounds with activity against replicating and non-replicating M. tuberculosis as well as compounds that inhibit the transition from non-replicating to replicating stages of growth. Using these assays we successfully screened over 300,000 compounds and identified 786 inhibitors of non-replicating M. tuberculosis. In order to understand the relationship among different non-replicating models, we teste 52 of these molecules in a hypoxia model and four different chemical scaffolds in a stochastic persist model and a streptomycin dependent model. We found that compounds display varying levels of activity in different models for the non-replicating state, suggesting important differences in bacterial physiology between models. Therefore, chemical tools identified in this assay may be useful for determining the relevance of different non-replicating in vitro models to in vivo M. tuberculosis infection. Given our current limited understanding, molecules that are active across multiple models may represent more promising candidates for further development. PMID:23898841

Enterovirus 71 infection of human airway organoids reveals VP1-145 as a viral infectivity determinant.

PubMed

van der Sanden, Sabine M G; Sachs, Norman; Koekkoek, Sylvie M; Koen, Gerrit; Pajkrt, Dasja; Clevers, Hans; Wolthers, Katja C

2018-05-09

Human enteroviruses frequently cause severe diseases in children. Human enteroviruses are transmitted via the fecal-oral route and respiratory droplets, and primary replication occurs in the gastro-intestinal and respiratory tracts; however, how enteroviruses infect these sites is largely unknown. Human intestinal organoids have recently proven to be valuable tools for studying enterovirus-host interactions in the intestinal tract. In this study, we demonstrated the susceptibility of a newly developed human airway organoid model for enterovirus 71 (EV71) infection. We showed for the first time in a human physiological model that EV71 replication kinetics are strain-dependent. A glutamine at position 145 of the VP1 capsid protein was identified as a key determinant of infectivity, and residues VP1-98K and VP1-104D were identified as potential infectivity markers. The results from this study provide new insights into EV71 infectivity in the human airway epithelia and demonstrate the value of organoid technology for virus research.

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

PubMed

Reynolds, John J; Bicknell, Louise S; Carroll, Paula; Higgs, Martin R; Shaheen, Ranad; Murray, Jennie E; Papadopoulos, Dimitrios K; Leitch, Andrea; Murina, Olga; Tarnauskaitė, Žygimantė; Wessel, Sarah R; Zlatanou, Anastasia; Vernet, Audrey; von Kriegsheim, Alex; Mottram, Rachel M A; Logan, Clare V; Bye, Hannah; Li, Yun; Brean, Alexander; Maddirevula, Sateesh; Challis, Rachel C; Skouloudaki, Kassiani; Almoisheer, Agaadir; Alsaif, Hessa S; Amar, Ariella; Prescott, Natalie J; Bober, Michael B; Duker, Angela; Faqeih, Eissa; Seidahmed, Mohammed Zain; Al Tala, Saeed; Alswaid, Abdulrahman; Ahmed, Saleem; Al-Aama, Jumana Yousuf; Altmüller, Janine; Al Balwi, Mohammed; Brady, Angela F; Chessa, Luciana; Cox, Helen; Fischetto, Rita; Heller, Raoul; Henderson, Bertram D; Hobson, Emma; Nürnberg, Peter; Percin, E Ferda; Peron, Angela; Spaccini, Luigina; Quigley, Alan J; Thakur, Seema; Wise, Carol A; Yoon, Grace; Alnemer, Maha; Tomancak, Pavel; Yigit, Gökhan; Taylor, A Malcolm R; Reijns, Martin A M; Simpson, Michael A; Cortez, David; Alkuraya, Fowzan S; Mathew, Christopher G; Jackson, Andrew P; Stewart, Grant S

2017-04-01

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.

Universal Batch Steganalysis

DTIC Science & Technology

2014-06-30

steganalysis) in large-scale datasets such as might be obtained by monitoring a corporate network or social network. Identifying guilty actors...guilty’ user (of steganalysis) in large-scale datasets such as might be obtained by monitoring a corporate network or social network. Identifying guilty...floating point operations (1 TFLOPs) for a 1 megapixel image. We designed a new implementation using Compute Unified Device Architecture (CUDA) on NVIDIA

Measuring suicidality using the personality assessment inventory: a convergent validity study with federal inmates.

PubMed

Patry, Marc W; Magaletta, Philip R

2015-02-01

Although numerous studies have examined the psychometric properties and clinical utility of the Personality Assessment Inventory in correctional contexts, only two studies to date have specifically focused on suicide ideation. This article examines the convergent validity of the Suicide Ideation Scale and the Suicide Potential Index on the Personality Assessment Inventory in a large, nontreatment sample of male and female federal inmates (N = 1,120). The data indicated robust validity support for both the Suicide Ideation Scale and Suicide Potential Index, which were each correlated with a broad group of validity indices representing multiple assessment modalities. Recommendations for future research to build upon these findings through replication and extension are made. © The Author(s) 2014.

Repeated count surveys help standardize multi-agency estimates of American Oystercatcher (Haematopus palliatus) abundance

USGS Publications Warehouse

Hostetter, Nathan J.; Gardner, Beth; Schweitzer, Sara H.; Boettcher, Ruth; Wilke, Alexandra L.; Addison, Lindsay; Swilling, William R.; Pollock, Kenneth H.; Simons, Theodore R.

2015-01-01

The extensive breeding range of many shorebird species can make integration of survey data problematic at regional spatial scales. We evaluated the effectiveness of standardized repeated count surveys coordinated across 8 agencies to estimate the abundance of American Oystercatcher (Haematopus palliatus) breeding pairs in the southeastern United States. Breeding season surveys were conducted across coastal North Carolina (90 plots) and the Eastern Shore of Virginia (3 plots). Plots were visited on 1–5 occasions during April–June 2013. N-mixture models were used to estimate abundance and detection probability in relation to survey date, tide stage, plot size, and plot location (coastal bay vs. barrier island). The estimated abundance of oystercatchers in the surveyed area was 1,048 individuals (95% credible interval: 851–1,408) and 470 pairs (384–637), substantially higher than estimates that did not account for detection probability (maximum counts of 674 individuals and 316 pairs). Detection probability was influenced by a quadratic function of survey date, and increased from mid-April (~0.60) to mid-May (~0.80), then remained relatively constant through June. Detection probability was also higher during high tide than during low, rising, or falling tides. Abundance estimates from N-mixture models were validated at 13 plots by exhaustive productivity studies (2–5 surveys wk−1). Intensive productivity studies identified 78 breeding pairs across 13 productivity plots while the N-mixture model abundance estimate was 74 pairs (62–119) using only 1–5 replicated surveys season−1. Our results indicate that standardized replicated count surveys coordinated across multiple agencies and conducted during a relatively short time window (closure assumption) provide tremendous potential to meet both agency-level (e.g., state) and regional-level (e.g., flyway) objectives in large-scale shorebird monitoring programs.

The reliability of continuous brain responses during naturalistic listening to music.

PubMed

Burunat, Iballa; Toiviainen, Petri; Alluri, Vinoo; Bogert, Brigitte; Ristaniemi, Tapani; Sams, Mikko; Brattico, Elvira

2016-01-01

Low-level (timbral) and high-level (tonal and rhythmical) musical features during continuous listening to music, studied by functional magnetic resonance imaging (fMRI), have been shown to elicit large-scale responses in cognitive, motor, and limbic brain networks. Using a similar methodological approach and a similar group of participants, we aimed to study the replicability of previous findings. Participants' fMRI responses during continuous listening of a tango Nuevo piece were correlated voxelwise against the time series of a set of perceptually validated musical features computationally extracted from the music. The replicability of previous results and the present study was assessed by two approaches: (a) correlating the respective activation maps, and (b) computing the overlap of active voxels between datasets at variable levels of ranked significance. Activity elicited by timbral features was better replicable than activity elicited by tonal and rhythmical ones. These results indicate more reliable processing mechanisms for low-level musical features as compared to more high-level features. The processing of such high-level features is probably more sensitive to the state and traits of the listeners, as well as of their background in music. Copyright © 2015 Elsevier Inc. All rights reserved.

Genome-Wide Association Study of Cardiac Structure and Systolic Function in African Americans: The Candidate Gene Association Resource (CARe) Study

PubMed Central

Fox, Ervin R.; Musani, Solomon K.; Barbalic, Maja; Lin, Honghuang; Yu, Bing; Ogunyankin, Kofo O.; Smith, Nicholas L.; Kutlar, Abdullah; Glazer, Nicole L.; Post, Wendy S.; Paltoo, Dina N.; Dries, Daniel L.; Farlow, Deborah N.; Duarte, Christine W.; Kardia, Sharon L.; Meyers, Kristin J.; Sun, Yan V.; Arnett, Donna K.; Patki, Amit A.; Sha, Jin; Cui, Xiangqui; Samdarshi, Tandaw E.; Penman, Alan D.; Bibbins-Domingo, Kirsten; Bůžková, Petra; Benjamin, Emelia J.; Bluemke, David A.; Morrison, Alanna C.; Heiss, Gerardo; Carr, J. Jeffrey; Tracy, Russell P.; Mosley, Thomas H.; Taylor, Herman A.; Psaty, Bruce M.; Heckbert, Susan R.; Cappola, Thomas P.; Vasan, Ramachandran S.

2013-01-01

Background Using data from four community-based cohorts of African Americans (AA), we tested the association between genome-wide markers (SNPs) and cardiac phenotypes in the Candidate-gene Association REsource (CARe) study. Methods and Results Among 6,765 AA, we related age, sex, height and weight-adjusted residuals for nine cardiac phenotypes (assessed by echocardiogram or MRI) to 2.5 million SNPs genotyped using Genome-Wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within cohort genome-wide association analysis was conducted followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10−07). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested look-ups in one consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (p=1.43 × 10−07) for left ventricular mass (LVM); rs7213314 in WIPI1 (p=1.68 × 10−07) for LV internal diastolic diameter (LVIDD); rs1571099 in PPAPDC1A (p= 2.57 × 10−08) for interventricular septal wall thickness (IVST); and rs9530176 in KLF5 (p=4.02 × 10−07) for ejection fraction (EF). Associated variants were enriched in three signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry were confirmed in look-ups in EchoGEN. Conclusions In the largest GWAS of cardiac structure and function to date in AA, we identified 4 genetic loci related to LVM, IVST, LVIDD and EF that reached genome-wide significance. Replication results suggest that these loci may represent unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes. PMID:23275298

IL1RN Coding Variant Is Associated with Lower Risk of Acute Respiratory Distress Syndrome and Increased Plasma IL-1 Receptor Antagonist

PubMed Central

Feng, Rui; Li, Mingyao; Zhao, Yang; Sheu, Chau-Chyun; Tejera, Paula; Gallop, Robert; Bellamy, Scarlett; Rushefski, Melanie; Lanken, Paul N.; Aplenc, Richard; O’Keefe, Grant E.; Wurfel, Mark M.; Christiani, David C.; Christie, Jason D.

2013-01-01

Rationale: Acute respiratory distress syndrome (ARDS) behaves as a complex genetic trait, yet knowledge of genetic susceptibility factors remains incomplete. Objectives: To identify genetic risk variants for ARDS using large scale genotyping. Methods: A multistage genetic association study was conducted of three critically ill populations phenotyped for ARDS. Stage I, a trauma cohort study (n = 224), was genotyped with a 50K gene-centric single-nucleotide polymorphism (SNP) array. We tested SNPs associated with ARDS at P < 5 × 10−4 for replication in stage II, a trauma case–control population (n = 778). SNPs replicating their association in stage II (P < 0.005) were tested in a stage III nested case–control population of mixed subjects in the intensive care unit (n = 2,063). Logistic regression was used to adjust for potential clinical confounders. We performed ELISA to test for an association between ARDS-associated genotype and plasma protein levels. Measurements and Main Results: A total of 12 SNPs met the stage I threshold for an association with ARDS. rs315952 in the IL1RN gene encoding IL-1 receptor antagonist (IL1RA) replicated its association with reduced ARDS risk in stages II (P < 0.004) and III (P < 0.02), and was robust to clinical adjustment (combined odds ratio = 0.81; P = 4.2 × 10−5). Plasma IL1RA level was associated with rs315952C in a subset of critically ill subjects. The effect of rs315952 was independent from the tandem repeat variant in IL1RN. Conclusions: The IL1RN SNP rs315952C is associated with decreased risk of ARDS in three populations with heterogeneous ARDS risk factors, and with increased plasma IL1RA response. IL1RA may attenuate ARDS risk. PMID:23449693

Novel Autism Subtype-Dependent Genetic Variants Are Revealed by Quantitative Trait and Subphenotype Association Analyses of Published GWAS Data

PubMed Central

Hu, Valerie W.; Addington, Anjene; Hyman, Alexander

2011-01-01

The heterogeneity of symptoms associated with autism spectrum disorders (ASDs) has presented a significant challenge to genetic analyses. Even when associations with genetic variants have been identified, it has been difficult to associate them with a specific trait or characteristic of autism. Here, we report that quantitative trait analyses of ASD symptoms combined with case-control association analyses using distinct ASD subphenotypes identified on the basis of symptomatic profiles result in the identification of highly significant associations with 18 novel single nucleotide polymorphisms (SNPs). The symptom categories included deficits in language usage, non-verbal communication, social development, and play skills, as well as insistence on sameness or ritualistic behaviors. Ten of the trait-associated SNPs, or quantitative trait loci (QTL), were associated with more than one subtype, providing partial replication of the identified QTL. Notably, none of the novel SNPs is located within an exonic region, suggesting that these hereditary components of ASDs are more likely related to gene regulatory processes (or gene expression) than to structural or functional changes in gene products. Seven of the QTL reside within intergenic chromosomal regions associated with rare copy number variants that have been previously reported in autistic samples. Pathway analyses of the genes associated with the QTL identified in this study implicate neurological functions and disorders associated with autism pathophysiology. This study underscores the advantage of incorporating both quantitative traits as well as subphenotypes into large-scale genome-wide analyses of complex disorders. PMID:21556359

Replication Study of the Milwaukee Inventory for Subtypes of Trichotillomania–Adult Version in a Clinically Characterized Sample

PubMed Central

Keuthen, Nancy J.; Tung, Esther S.; Woods, Douglas W.; Franklin, Martin E.; Altenburger, Erin M.; Pauls, David L.; Flessner, Christopher A.

2015-01-01

In the present study, we evaluated the Milwaukee Inventory for Subtypes of Trichotillomania–Adult Version (MIST-A) in a replication sample of clinically characterized hair pullers using exploratory factor analysis (EFA; N = 193). EFA eigenvalues and visual inspection of our scree plot revealed a two-factor solution. Factor structure coefficients and internal consistencies suggested a 13-item scale with an 8-item “Intention” scale and a 5-item “Emotion” scale. Both scales displayed good construct and discriminant validity. These findings indicate the need for a revised scale that provides a more refined assessment of pulling phenomenology that can facilitate future treatment advances. PMID:25868534

The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β

PubMed Central

Koag, Myong-Chul; Nam, Kwangho; Lee, Seongmin

2014-01-01

To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β (polβ), we report four crystal structures of polβ complexed with dG•dTTP and dA•dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg2+-bound ground-state structures show that the dA•dCTP-Mg2+ complex adopts an ‘intermediate’ protein conformation while the dG•dTTP-Mg2+ complex adopts an open protein conformation. The Mn2+-bound ‘pre-chemistry-state’ structures show that the dA•dCTP-Mn2+ complex is structurally very similar to the dA•dCTP-Mg2+ complex, whereas the dG•dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson–Crick-like dG•dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that polβ increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, polβ appears to allow only a Watson–Crick-like conformation for purine•pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson–Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of polβ. PMID:25200079

Identifying CpG sites associated with eczema via random forest screening of epigenome-scale DNA methylation.

PubMed

Quraishi, B M; Zhang, H; Everson, T M; Ray, M; Lockett, G A; Holloway, J W; Tetali, S R; Arshad, S H; Kaushal, A; Rezwan, F I; Karmaus, W

2015-01-01

The prevalence of eczema is increasing in industrialized nations. Limited evidence has shown the association of DNA methylation (DNA-M) with eczema. We explored this association at the epigenome-scale to better understand the role of DNA-M. Data from the first generation (F1) of the Isle of Wight (IoW) birth cohort participants and the second generation (F2) were examined in our study. Epigenome-scale DNA methylation of F1 at age 18 years and F2 in cord blood was measured using the Illumina Infinium HumanMethylation450 Beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) in the F1 generation were screened via recursive random forest (RF) for their potential association with eczema at age 18. Functional enrichment and pathway analysis of resulting genes were carried out using DAVID gene functional classification tool. Log-linear models were performed in F1 to corroborate the identified CpGs. Findings in F1 were further replicated in F2. The recursive RF yielded 140 CpGs, 88 of which showed statistically significant associations with eczema at age 18, corroborated by log-linear models after controlling for false discovery rate (FDR) of 0.05. These CpGs were enriched among many biological pathways, including pathways related to creating transcriptional variety and pathways mechanistically linked to eczema such as cadherins, cell adhesion, gap junctions, tight junctions, melanogenesis, and apoptosis. In the F2 generation, about half of the 83 CpGs identified in F1 showed the same direction of association with eczema risk as in F1, of which two CpGs were significantly associated with eczema risk, cg04850479 of the PROZ gene (risk ratio (RR) = 15.1 in F1, 95 % confidence interval (CI) 1.71, 79.5; RR = 6.82 in F2, 95 % CI 1.52, 30.62) and cg01427769 of the NEU1 gene (RR = 0.13 in F1, 95 % CI 0.03, 0.46; RR = 0.09 in F2, 95 % CI 0.03, 0.36). Via epigenome-scaled analyses using recursive RF followed by log-linear models, we identified 88 CpGs associated with eczema in F1, of which 41 were replicated in F2. Several identified CpGs are located within genes in biological pathways relating to skin barrier integrity, which is central to the pathogenesis of eczema. Novel genes associated with eczema risk were identified (e.g., the PROZ and NEU1 genes).

An epigenetic state associated with areas of gene duplication

PubMed Central

Gimelbrant, Alexander A.; Chess, Andrew

2006-01-01

Asynchronous DNA replication is an epigenetically determined feature found in all cases of monoallelic expression, including genomic imprinting, X-inactivation, and random monoallelic expression of autosomal genes such as immunoglobulins and olfactory receptor genes. Most genes of the latter class were identified in experiments focused on genes functioning in the chemosensory and immune systems. We performed an unbiased survey of asynchronous replication in the mouse genome, excluding known asynchronously replicated genes. Fully 10% (eight of 80) of the genes tested exhibited asynchronous replication. A common feature of the newly identified asynchronously replicated areas is their proximity to areas of tandem gene duplication. Testing of other clustered areas supported the idea that such regions are enriched with asynchronously replicated genes. PMID:16687731

Common fragile sites (CFS) and extremely large CFS genes are targets for human papillomavirus integrations and chromosome rearrangements in oropharyngeal squamous cell carcinoma.

PubMed

Gao, Ge; Johnson, Sarah H; Vasmatzis, George; Pauley, Christina E; Tombers, Nicole M; Kasperbauer, Jan L; Smith, David I

2017-01-01

Common fragile sites (CFS) are chromosome regions that are prone to form gaps or breaks in response to DNA replication stress. They are often found as hotspots for sister chromatid exchanges, deletions, and amplifications in different cancers. Many of the CFS regions are found to span genes whose genomic sequence is greater than 1 Mb, some of which have been demonstrated to function as important tumor suppressors. CFS regions are also hotspots for human papillomavirus (HPV) integrations in cervical cancer. We used mate-pair sequencing to examine HPV integration events and chromosomal structural variations in 34 oropharyngeal squamous cell carcinoma (OPSCC). We used endpoint PCR and Sanger sequencing to validate each HPV integration event and found HPV integrations preferentially occurred within CFS regions similar to what is observed in cervical cancer. We also found that many of the chromosomal alterations detected also occurred at or near the cytogenetic location of CFSs. Several large genes were also found to be recurrent targets of rearrangements, independent of HPV integrations, including CSMD1 (2.1Mb), LRP1B (1.9Mb), and LARGE1 (0.7Mb). Sanger sequencing revealed that the nucleotide sequences near to identified junction sites contained repetitive and AT-rich sequences that were shown to have the potential to form stem-loop DNA secondary structures that might stall DNA replication fork progression during replication stress. This could then cause increased instability in these regions which could lead to cancer development in human cells. Our findings suggest that CFSs and some specific large genes appear to play important roles in OPSCC. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Causal inference between bioavailability of heavy metals and environmental factors in a large-scale region.

PubMed

Liu, Yuqiong; Du, Qingyun; Wang, Qi; Yu, Huanyun; Liu, Jianfeng; Tian, Yu; Chang, Chunying; Lei, Jing

2017-07-01

The causation between bioavailability of heavy metals and environmental factors are generally obtained from field experiments at local scales at present, and lack sufficient evidence from large scales. However, inferring causation between bioavailability of heavy metals and environmental factors across large-scale regions is challenging. Because the conventional correlation-based approaches used for causation assessments across large-scale regions, at the expense of actual causation, can result in spurious insights. In this study, a general approach framework, Intervention calculus when the directed acyclic graph (DAG) is absent (IDA) combined with the backdoor criterion (BC), was introduced to identify causation between the bioavailability of heavy metals and the potential environmental factors across large-scale regions. We take the Pearl River Delta (PRD) in China as a case study. The causal structures and effects were identified based on the concentrations of heavy metals (Zn, As, Cu, Hg, Pb, Cr, Ni and Cd) in soil (0-20 cm depth) and vegetable (lettuce) and 40 environmental factors (soil properties, extractable heavy metals and weathering indices) in 94 samples across the PRD. Results show that the bioavailability of heavy metals (Cd, Zn, Cr, Ni and As) was causally influenced by soil properties and soil weathering factors, whereas no causal factor impacted the bioavailability of Cu, Hg and Pb. No latent factor was found between the bioavailability of heavy metals and environmental factors. The causation between the bioavailability of heavy metals and environmental factors at field experiments is consistent with that on a large scale. The IDA combined with the BC provides a powerful tool to identify causation between the bioavailability of heavy metals and environmental factors across large-scale regions. Causal inference in a large system with the dynamic changes has great implications for system-based risk management. Copyright © 2017 Elsevier Ltd. All rights reserved.

Origin-Dependent Inverted-Repeat Amplification: Tests of a Model for Inverted DNA Amplification

PubMed Central

Brewer, Bonita J.; Payen, Celia; Di Rienzi, Sara C.; Higgins, Megan M.; Ong, Giang; Dunham, Maitreya J.; Raghuraman, M. K.

2015-01-01

DNA replication errors are a major driver of evolution—from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test a specific replication-based model to explain the generation of interstitial, inverted triplications. While no genetic information is lost, the novel inversion junctions and increased copy number of the included sequences create the potential for adaptive phenotypes. The model—Origin-Dependent Inverted-Repeat Amplification (ODIRA)—proposes that a replication error at pre-existing short, interrupted, inverted repeats in genomic sequences generates an extrachromosomal, inverted dimeric, autonomously replicating intermediate; subsequent genomic integration of the dimer yields this class of CNV without loss of distal chromosomal sequences. We used a combination of in vitro and in vivo approaches to test the feasibility of the proposed replication error and its downstream consequences on chromosome structure in the yeast Saccharomyces cerevisiae. We show that the proposed replication error—the ligation of leading and lagging nascent strands to create “closed” forks—can occur in vitro at short, interrupted inverted repeats. The removal of molecules with two closed forks results in a hairpin-capped linear duplex that we show replicates in vivo to create an inverted, dimeric plasmid that subsequently integrates into the genome by homologous recombination, creating an inverted triplication. While other models have been proposed to explain inverted triplications and their derivatives, our model can also explain the generation of human, de novo, inverted amplicons that have a 2:1 mixture of sequences from both homologues of a single parent—a feature readily explained by a plasmid intermediate that arises from one homologue and integrates into the other homologue prior to meiosis. Our tests of key features of ODIRA lend support to this mechanism and suggest further avenues of enquiry to unravel the origins of interstitial, inverted CNVs pivotal in human health and evolution. PMID:26700858

Origin-Dependent Inverted-Repeat Amplification: Tests of a Model for Inverted DNA Amplification.

PubMed

Brewer, Bonita J; Payen, Celia; Di Rienzi, Sara C; Higgins, Megan M; Ong, Giang; Dunham, Maitreya J; Raghuraman, M K

2015-12-01

DNA replication errors are a major driver of evolution--from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test a specific replication-based model to explain the generation of interstitial, inverted triplications. While no genetic information is lost, the novel inversion junctions and increased copy number of the included sequences create the potential for adaptive phenotypes. The model--Origin-Dependent Inverted-Repeat Amplification (ODIRA)-proposes that a replication error at pre-existing short, interrupted, inverted repeats in genomic sequences generates an extrachromosomal, inverted dimeric, autonomously replicating intermediate; subsequent genomic integration of the dimer yields this class of CNV without loss of distal chromosomal sequences. We used a combination of in vitro and in vivo approaches to test the feasibility of the proposed replication error and its downstream consequences on chromosome structure in the yeast Saccharomyces cerevisiae. We show that the proposed replication error-the ligation of leading and lagging nascent strands to create "closed" forks-can occur in vitro at short, interrupted inverted repeats. The removal of molecules with two closed forks results in a hairpin-capped linear duplex that we show replicates in vivo to create an inverted, dimeric plasmid that subsequently integrates into the genome by homologous recombination, creating an inverted triplication. While other models have been proposed to explain inverted triplications and their derivatives, our model can also explain the generation of human, de novo, inverted amplicons that have a 2:1 mixture of sequences from both homologues of a single parent--a feature readily explained by a plasmid intermediate that arises from one homologue and integrates into the other homologue prior to meiosis. Our tests of key features of ODIRA lend support to this mechanism and suggest further avenues of enquiry to unravel the origins of interstitial, inverted CNVs pivotal in human health and evolution.

Testing the Replicability of a Successful Care Management Program: Results from a Randomized Trial and Likely Explanations for Why Impacts Did Not Replicate.

PubMed

Peterson, G Greg; Zurovac, Jelena; Brown, Randall S; Coburn, Kenneth D; Markovich, Patricia A; Marcantonio, Sherry A; Clark, William D; Mutti, Anne; Stepanczuk, Cara

2016-12-01

To test whether a care management program could replicate its success in an earlier trial and determine likely explanations for why it did not. Medicare claims and nurse contact data for Medicare fee-for-service beneficiaries with chronic illnesses enrolled in the trial in eastern Pennsylvania (N = 483). A randomized trial with half of enrollees receiving intensive care management services and half receiving usual care. We developed and tested hypotheses for why impacts declined. All outcomes and covariates were derived from claims and the nurse contact data. From 2010 to 2014, the program did not reduce hospitalizations or generate Medicare savings to offset program fees that averaged $260 per beneficiary per month. These estimates are statistically different (p < .05) from the large reductions in hospitalizations and spending in the first trial (2002-2010). The treatment-control differences in the second trial disappeared because the control group's risk-adjusted hospitalization rate improved, not because the treatment group's outcomes worsened. Even if demonstrated in a randomized trial, successful results from one test may not replicate in other settings or time periods. Assessing whether gaps in care that the original program filled exist in other settings can help identify where earlier success is likely to replicate. © Health Research and Educational Trust.

Genome-wide association study identifies three new melanoma susceptibility loci.

PubMed

Barrett, Jennifer H; Iles, Mark M; Harland, Mark; Taylor, John C; Aitken, Joanne F; Andresen, Per Arne; Akslen, Lars A; Armstrong, Bruce K; Avril, Marie-Francoise; Azizi, Esther; Bakker, Bert; Bergman, Wilma; Bianchi-Scarrà, Giovanna; Bressac-de Paillerets, Brigitte; Calista, Donato; Cannon-Albright, Lisa A; Corda, Eve; Cust, Anne E; Dębniak, Tadeusz; Duffy, David; Dunning, Alison M; Easton, Douglas F; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Giles, Graham G; Hansson, Johan; Hocevar, Marko; Höiom, Veronica; Hopper, John L; Ingvar, Christian; Janssen, Bart; Jenkins, Mark A; Jönsson, Göran; Kefford, Richard F; Landi, Giorgio; Landi, Maria Teresa; Lang, Julie; Lubiński, Jan; Mackie, Rona; Malvehy, Josep; Martin, Nicholas G; Molven, Anders; Montgomery, Grant W; van Nieuwpoort, Frans A; Novakovic, Srdjan; Olsson, Håkan; Pastorino, Lorenza; Puig, Susana; Puig-Butille, Joan Anton; Randerson-Moor, Juliette; Snowden, Helen; Tuominen, Rainer; Van Belle, Patricia; van der Stoep, Nienke; Whiteman, David C; Zelenika, Diana; Han, Jiali; Fang, Shenying; Lee, Jeffrey E; Wei, Qingyi; Lathrop, G Mark; Gillanders, Elizabeth M; Brown, Kevin M; Goldstein, Alisa M; Kanetsky, Peter A; Mann, Graham J; Macgregor, Stuart; Elder, David E; Amos, Christopher I; Hayward, Nicholas K; Gruis, Nelleke A; Demenais, Florence; Bishop, Julia A Newton; Bishop, D Timothy

2011-10-09

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Modelling solute dispersion in periodic heterogeneous porous media: Model benchmarking against intermediate scale experiments

NASA Astrophysics Data System (ADS)

Majdalani, Samer; Guinot, Vincent; Delenne, Carole; Gebran, Hicham

2018-06-01

This paper is devoted to theoretical and experimental investigations of solute dispersion in heterogeneous porous media. Dispersion in heterogenous porous media has been reported to be scale-dependent, a likely indication that the proposed dispersion models are incompletely formulated. A high quality experimental data set of breakthrough curves in periodic model heterogeneous porous media is presented. In contrast with most previously published experiments, the present experiments involve numerous replicates. This allows the statistical variability of experimental data to be accounted for. Several models are benchmarked against the data set: the Fickian-based advection-dispersion, mobile-immobile, multirate, multiple region advection dispersion models, and a newly proposed transport model based on pure advection. A salient property of the latter model is that its solutions exhibit a ballistic behaviour for small times, while tending to the Fickian behaviour for large time scales. Model performance is assessed using a novel objective function accounting for the statistical variability of the experimental data set, while putting equal emphasis on both small and large time scale behaviours. Besides being as accurate as the other models, the new purely advective model has the advantages that (i) it does not exhibit the undesirable effects associated with the usual Fickian operator (namely the infinite solute front propagation speed), and (ii) it allows dispersive transport to be simulated on every heterogeneity scale using scale-independent parameters.

Competitive fitness in coronaviruses is not correlated with size or number of double-membrane vesicles under reduced-temperature growth conditions.

PubMed

Al-Mulla, Hawaa M N; Turrell, Lauren; Smith, Nicola M; Payne, Luke; Baliji, Surendranath; Züst, Roland; Thiel, Volker; Baker, Susan C; Siddell, Stuart G; Neuman, Benjamin W

2014-04-01

Positive-stranded viruses synthesize their RNA in membrane-bound organelles, but it is not clear how this benefits the virus or the host. For coronaviruses, these organelles take the form of double-membrane vesicles (DMVs) interconnected by a convoluted membrane network. We used electron microscopy to identify murine coronaviruses with mutations in nsp3 and nsp14 that replicated normally while producing only half the normal amount of DMVs under low-temperature growth conditions. Viruses with mutations in nsp5 and nsp16 produced small DMVs but also replicated normally. Quantitative reverse transcriptase PCR (RT-PCR) confirmed that the most strongly affected of these, the nsp3 mutant, produced more viral RNA than wild-type virus. Competitive growth assays were carried out in both continuous and primary cells to better understand the contribution of DMVs to viral fitness. Surprisingly, several viruses that produced fewer or smaller DMVs showed a higher fitness than wild-type virus at the reduced temperature, suggesting that larger and more numerous DMVs do not necessarily confer a competitive advantage in primary or continuous cell culture. For the first time, this directly demonstrates that replication and organelle formation may be, at least in part, studied separately during infection with positive-stranded RNA virus. IMPORTANCE The viruses that cause severe acute respiratory syndrome (SARS), poliomyelitis, and hepatitis C all replicate in double-membrane vesicles (DMVs). The big question about DMVs is why they exist in the first place. In this study, we looked at thousands of infected cells and identified two coronavirus mutants that made half as many organelles as normal and two others that made typical numbers but smaller organelles. Despite differences in DMV size and number, all four mutants replicated as efficiently as wild-type virus. To better understand the relative importance of replicative organelles, we carried out competitive fitness experiments. None of these viruses was found to be significantly less fit than wild-type, and two were actually fitter in tests in two kinds of cells. This suggests that viruses have evolved to have tremendous plasticity in the ability to form membrane-associated replication complexes and that large and numerous DMVs are not exclusively associated with efficient coronavirus replication.

Quantifying variability in delta experiments

NASA Astrophysics Data System (ADS)

Miller, K. L.; Berg, S. R.; McElroy, B. J.

2017-12-01

Large populations of people and wildlife make their homes on river deltas, therefore it is important to be able to make useful and accurate predictions of how these landforms will change over time. However, making predictions can be a challenge due to inherent variability of the natural system. Furthermore, when we extrapolate results from the laboratory to the field setting, we bring with it random and systematic errors of the experiment. We seek to understand both the intrinsic and experimental variability of river delta systems to help better inform predictions of how these landforms will evolve. We run exact replicates of experiments with steady sediment and water discharge and record delta evolution with overhead time lapse imaging. We measure aspects of topset progradation and channel dynamics and compare these metrics of delta morphology between the 6 replicated experimental runs. We also use data from all experimental runs collectively to build a large dataset to extract statistics of the system properties. We find that although natural variability exists, the processes in the experiments must have outcomes that no longer depend on their initial conditions after some time. Applying these results to the field scale will aid in our ability to make forecasts of how these landforms will progress.

Innovations in oral health: A toolkit for interprofessional education.

PubMed

Dolce, Maria C; Parker, Jessica L; Werrlein, Debra T

2017-05-01

The integration of oral health competencies into non-dental health professions curricula can serve as an effective driver for interprofessional education (IPE). The purpose of this report is to describe a replicable oral-health-driven IPE model and corresponding online toolkit, both of which were developed as part of the Innovations in Oral Health (IOH): Technology, Instruction, Practice, and Service programme at Bouvé College of Health Sciences, Northeastern University, USA. Tooth decay is a largely preventable disease that is connected to overall health and wellness, and it affects the majority of adults and a fifth of children in the United States. To prepare all health professionals to address this problem, the IOH model couples programming from the online resource Smiles for Life: A National Oral Health Curriculum with experiential learning opportunities designed for undergraduate and graduate students that include simulation-learning (technology), hands-on workshops and didactic sessions (instruction), and opportunities for both cooperative education (practice) and community-based learning (service). The IOH Toolkit provides the means for others to replicate portions of the IOH model or to establish a large-scale IPE initiative that will support the creation of an interprofessional workforce-one equipped with oral health competencies and ready for collaborative practice.

The Immersive Virtual Reality Lab: Possibilities for Remote Experimental Manipulations of Autonomic Activity on a Large Scale.

PubMed

Juvrud, Joshua; Gredebäck, Gustaf; Åhs, Fredrik; Lerin, Nils; Nyström, Pär; Kastrati, Granit; Rosén, Jörgen

2018-01-01

There is a need for large-scale remote data collection in a controlled environment, and the in-home availability of virtual reality (VR) and the commercial availability of eye tracking for VR present unique and exciting opportunities for researchers. We propose and provide a proof-of-concept assessment of a robust system for large-scale in-home testing using consumer products that combines psychophysiological measures and VR, here referred to as a Virtual Lab. For the first time, this method is validated by correlating autonomic responses, skin conductance response (SCR), and pupillary dilation, in response to a spider, a beetle, and a ball using commercially available VR. Participants demonstrated greater SCR and pupillary responses to the spider, and the effect was dependent on the proximity of the stimuli to the participant, with a stronger response when the spider was close to the virtual self. We replicated these effects across two experiments and in separate physical room contexts to mimic variability in home environment. Together, these findings demonstrate the utility of pupil dilation as a marker of autonomic arousal and the feasibility to assess this in commercially available VR hardware and support a robust Virtual Lab tool for massive remote testing.

The Immersive Virtual Reality Lab: Possibilities for Remote Experimental Manipulations of Autonomic Activity on a Large Scale

PubMed Central

Juvrud, Joshua; Gredebäck, Gustaf; Åhs, Fredrik; Lerin, Nils; Nyström, Pär; Kastrati, Granit; Rosén, Jörgen

2018-01-01

There is a need for large-scale remote data collection in a controlled environment, and the in-home availability of virtual reality (VR) and the commercial availability of eye tracking for VR present unique and exciting opportunities for researchers. We propose and provide a proof-of-concept assessment of a robust system for large-scale in-home testing using consumer products that combines psychophysiological measures and VR, here referred to as a Virtual Lab. For the first time, this method is validated by correlating autonomic responses, skin conductance response (SCR), and pupillary dilation, in response to a spider, a beetle, and a ball using commercially available VR. Participants demonstrated greater SCR and pupillary responses to the spider, and the effect was dependent on the proximity of the stimuli to the participant, with a stronger response when the spider was close to the virtual self. We replicated these effects across two experiments and in separate physical room contexts to mimic variability in home environment. Together, these findings demonstrate the utility of pupil dilation as a marker of autonomic arousal and the feasibility to assess this in commercially available VR hardware and support a robust Virtual Lab tool for massive remote testing. PMID:29867318

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.

PubMed

van der Harst, Pim; Verweij, Niek

2018-02-02

Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant ( P <5×10 -8 ) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising ( P <0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance ( P <5×10 -8 ) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci ( P <5×10 -8 ) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD. © 2017 The Authors.

Method for identifying subsurface fluid migration and drainage pathways in and among oil and gas reservoirs using 3-D and 4-D seismic imaging

DOEpatents

Anderson, R.N.; Boulanger, A.; Bagdonas, E.P.; Xu, L.; He, W.

1996-12-17

The invention utilizes 3-D and 4-D seismic surveys as a means of deriving information useful in petroleum exploration and reservoir management. The methods use both single seismic surveys (3-D) and multiple seismic surveys separated in time (4-D) of a region of interest to determine large scale migration pathways within sedimentary basins, and fine scale drainage structure and oil-water-gas regions within individual petroleum producing reservoirs. Such structure is identified using pattern recognition tools which define the regions of interest. The 4-D seismic data sets may be used for data completion for large scale structure where time intervals between surveys do not allow for dynamic evolution. The 4-D seismic data sets also may be used to find variations over time of small scale structure within individual reservoirs which may be used to identify petroleum drainage pathways, oil-water-gas regions and, hence, attractive drilling targets. After spatial orientation, and amplitude and frequency matching of the multiple seismic data sets, High Amplitude Event (HAE) regions consistent with the presence of petroleum are identified using seismic attribute analysis. High Amplitude Regions are grown and interconnected to establish plumbing networks on the large scale and reservoir structure on the small scale. Small scale variations over time between seismic surveys within individual reservoirs are identified and used to identify drainage patterns and bypassed petroleum to be recovered. The location of such drainage patterns and bypassed petroleum may be used to site wells. 22 figs.

Method for identifying subsurface fluid migration and drainage pathways in and among oil and gas reservoirs using 3-D and 4-D seismic imaging

DOEpatents

Anderson, Roger N.; Boulanger, Albert; Bagdonas, Edward P.; Xu, Liqing; He, Wei

1996-01-01

The invention utilizes 3-D and 4-D seismic surveys as a means of deriving information useful in petroleum exploration and reservoir management. The methods use both single seismic surveys (3-D) and multiple seismic surveys separated in time (4-D) of a region of interest to determine large scale migration pathways within sedimentary basins, and fine scale drainage structure and oil-water-gas regions within individual petroleum producing reservoirs. Such structure is identified using pattern recognition tools which define the regions of interest. The 4-D seismic data sets may be used for data completion for large scale structure where time intervals between surveys do not allow for dynamic evolution. The 4-D seismic data sets also may be used to find variations over time of small scale structure within individual reservoirs which may be used to identify petroleum drainage pathways, oil-water-gas regions and, hence, attractive drilling targets. After spatial orientation, and amplitude and frequency matching of the multiple seismic data sets, High Amplitude Event (HAE) regions consistent with the presence of petroleum are identified using seismic attribute analysis. High Amplitude Regions are grown and interconnected to establish plumbing networks on the large scale and reservoir structure on the small scale. Small scale variations over time between seismic surveys within individual reservoirs are identified and used to identify drainage patterns and bypassed petroleum to be recovered. The location of such drainage patterns and bypassed petroleum may be used to site wells.

The temporal program of chromosome replication: genomewide replication in clb5{Delta} Saccharomyces cerevisiae.

PubMed

McCune, Heather J; Danielson, Laura S; Alvino, Gina M; Collingwood, David; Delrow, Jeffrey J; Fangman, Walton L; Brewer, Bonita J; Raghuraman, M K

2008-12-01

Temporal regulation of origin activation is widely thought to explain the pattern of early- and late-replicating domains in the Saccharomyces cerevisiae genome. Recently, single-molecule analysis of replication suggested that stochastic processes acting on origins with different probabilities of activation could generate the observed kinetics of replication without requiring an underlying temporal order. To distinguish between these possibilities, we examined a clb5Delta strain, where origin firing is largely limited to the first half of S phase, to ask whether all origins nonspecifically show decreased firing (as expected for disordered firing) or if only some origins ("late" origins) are affected. Approximately half the origins in the mutant genome show delayed replication while the remainder replicate largely on time. The delayed regions can encompass hundreds of kilobases and generally correspond to regions that replicate late in wild-type cells. Kinetic analysis of replication in wild-type cells reveals broad windows of origin firing for both early and late origins. Our results are consistent with a temporal model in which origins can show some heterogeneity in both time and probability of origin firing, but clustering of temporally like origins nevertheless yields a genome that is organized into blocks showing different replication times.

Cluster-cluster aggregation with particle replication and chemotaxy: a simple model for the growth of animal cells in culture

NASA Astrophysics Data System (ADS)

Alves, S. G.; Martins, M. L.

2010-09-01

Aggregation of animal cells in culture comprises a series of motility, collision and adhesion processes of basic relevance for tissue engineering, bioseparations, oncology research and in vitro drug testing. In the present paper, a cluster-cluster aggregation model with stochastic particle replication and chemotactically driven motility is investigated as a model for the growth of animal cells in culture. The focus is on the scaling laws governing the aggregation kinetics. Our simulations reveal that in the absence of chemotaxy the mean cluster size and the total number of clusters scale in time as stretched exponentials dependent on the particle replication rate. Also, the dynamical cluster size distribution functions are represented by a scaling relation in which the scaling function involves a stretched exponential of the time. The introduction of chemoattraction among the particles leads to distribution functions decaying as power laws with exponents that decrease in time. The fractal dimensions and size distributions of the simulated clusters are qualitatively discussed in terms of those determined experimentally for several normal and tumoral cell lines growing in culture. It is shown that particle replication and chemotaxy account for the simplest cluster size distributions of cellular aggregates observed in culture.

The Rights and Responsibility of Test Takers When Large-Scale Testing Is Used for Classroom Assessment

ERIC Educational Resources Information Center

van Barneveld, Christina; Brinson, Karieann

2017-01-01

The purpose of this research was to identify conflicts in the rights and responsibility of Grade 9 test takers when some parts of a large-scale test are marked by teachers and used in the calculation of students' class marks. Data from teachers' questionnaires and students' questionnaires from a 2009-10 administration of a large-scale test of…

Identifying large scale structures at 1 AU using fluctuations and wavelets

NASA Astrophysics Data System (ADS)

Niembro, T.; Lara, A.

2016-12-01

The solar wind (SW) is inhomogeneous and it is dominated for two types of flows: one quasi-stationary and one related to large scale transients (such as coronal mass ejections and co-rotating interaction regions). The SW inhomogeneities can be study as fluctuations characterized by a wide range of length and time scales. We are interested in the study of the characteristic fluctuations caused by large scale transient events. To do so, we define the vector space F with the normalized moving monthly/annual deviations as the orthogonal basis. Then, we compute the norm in this space of the solar wind parameters (velocity, magnetic field, density and temperature) fluctuations using WIND data from August 1992 to August 2015. This norm gives important information about the presence of a large structure disturbance in the solar wind and by applying a wavelet transform to this norm, we are able to determine, without subjectivity, the duration of the compression regions of these large transient structures and, even more, to identify if the structure corresponds to a single or complex (or merged) event. With this method we have automatically detected most of the events identified and published by other authors.

Large Scale Ionospheric Response During March 17, 2013 Geomagnetic Storm: Reanalysis Based on Multiple Satellites Observations and TIEGCM Simulations

NASA Astrophysics Data System (ADS)

Yue, X.; Wang, W.; Schreiner, W. S.; Kuo, Y. H.; Lei, J.; Liu, J.; Burns, A. G.; Zhang, Y.; Zhang, S.

2015-12-01

Based on slant total electron content (TEC) observations made by ~10 satellites and ~450 ground IGS GNSS stations, we constructed a 4-D ionospheric electron density reanalysis during the March 17, 2013 geomagnetic storm. Four main large-scale ionospheric disturbances are identified from reanalysis: (1) The positive storm during the initial phase; (2) The SED (storm enhanced density) structure in both northern and southern hemisphere; (3) The large positive storm in main phase; (4) The significant negative storm in middle and low latitude during recovery phase. We then run the NCAR-TIEGCM model with Heelis electric potential empirical model as polar input. The TIEGCM can reproduce 3 of 4 large-scale structures (except SED) very well. We then further analyzed the altitudinal variations of these large-scale disturbances and found several interesting things, such as the altitude variation of SED, the rotation of positive/negative storm phase with local time. Those structures could not be identified clearly by traditional used data sources, which either has no gloval coverage or no vertical resolution. The drivers such as neutral wind/density and electric field from TIEGCM simulations are also analyzed to self-consistantly explain the identified disturbance features.

Impacts of large herbivorous mammals on bird diversity and abundance in an African savanna.

PubMed

Ogada, D L; Gadd, M E; Ostfeld, R S; Young, T P; Keesing, F

2008-05-01

Large native mammals are declining dramatically in abundance across Africa, with strong impacts on both plant and animal community dynamics. However, the net effects of this large-scale loss in megafauna are poorly understood because responses by several ecologically important groups have not been assessed. We used a large-scale, replicated exclusion experiment in Kenya to investigate the impacts of different guilds of native and domestic large herbivores on the diversity and abundance of birds over a 2-year period. The exclusion of large herbivorous native mammals, including zebras (Equus burchelli), giraffes (Giraffa camelopardalis), elephants (Loxodonta africana), and buffalos (Syncerus caffer), increased the diversity of birds by 30%. Most of this effect was attributable to the absence of elephants and giraffes; these megaherbivores reduced both the canopy area of subdominant woody vegetation and the biomass of ground-dwelling arthropods, and both of these factors were good predictors of the diversity of birds. The canopy area of subdominant trees was positively correlated with the diversity of granivorous birds. The biomass of ground-dwelling arthropods was positively correlated with the diversity of insectivorous birds. Our results suggest that most native large herbivores are compatible with an abundant and diverse bird fauna, as are cattle if they are at a relatively low stocking rate. Future research should focus on determining the spatial arrangements and densities of megaherbivores that will optimize both megaherbivore abundance and bird diversity.

Corridors cause differential seed predation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Orrock, John L.; Damschen, Ellen I.

2005-06-01

Orrock, John, L., and Ellen I. Damschen. 2005. Corridors cause differential seed predation. Ecol. Apps. 15(3):793-798. Abstract. Corridors that connect disjunct populations are heavily debated in conservation, largely because the effects of corridors have rarely been evaluated by replicated, large-scale studies. Using large-scale experimental landscapes, we found that, in addition to documented positive effects, corridors also have negative impacts on bird-dispersed plants by affecting seed predation, and that overall predation is a function of the seeds primary consumer (rodents or arthropods). Both large-seeded Prunus serotina and small-seeded Rubus allegheniensis experienced greater predation in connected patches. However, P. serotina experienced significantlymore » less seed predation compared to R. allegheniensis in unconnected patches, due to decreased impacts of rodent seed predators on this large-seeded species. Viewed in light of previous evidence that corridors have beneficial impacts by increasing pollination and seed dispersal, this work demonstrates that corridors may have both positive and negative effects for the same plant species at different life stages. Moreover, these effects may differentially affect plant species within the same community: seeds primarily consumed by rodents suffer less predation in unconnected patches. By shifting the impact of rodent and arthropod seed predators, corridors constructed for plant conservation could lead to shifts in the seed bank.« less

Single-Cell Analysis of the Impact of Host Cell Heterogeneity on Infection with Foot-and-Mouth Disease Virus.

PubMed

Xin, Xiu; Wang, Hailong; Han, Lingling; Wang, Mingzhen; Fang, Hui; Hao, Yao; Li, Jiadai; Zhang, Hu; Zheng, Congyi; Shen, Chao

2018-05-01

Viral infection and replication are affected by host cell heterogeneity, but the mechanisms underlying the effects remain unclear. Using single-cell analysis, we investigated the effects of host cell heterogeneity, including cell size, inclusion, and cell cycle, on foot-and-mouth disease virus (FMDV) infection (acute and persistent infections) and replication. We detected various viral genome replication levels in FMDV-infected cells. Large cells and cells with a high number of inclusions generated more viral RNA copies and viral protein and a higher proportion of infectious cells than other cells. Additionally, we found that the viral titer was 10- to 100-fold higher in cells in G 2 /M than those in other cell cycle phases and identified a strong correlation between cell size, inclusion, and cell cycle heterogeneity, which all affected the infection and replication of FMDV. Furthermore, we demonstrated that host cell heterogeneity influenced the adsorption of FMDV due to differences in the levels of FMDV integrin receptors expression. Collectively, these results further our understanding of the evolution of a virus in a single host cell. IMPORTANCE It is important to understand how host cell heterogeneity affects viral infection and replication. Using single-cell analysis, we found that viral genome replication levels exhibited dramatic variability in foot-and-mouth disease virus (FMDV)-infected cells. We also found a strong correlation between heterogeneity in cell size, inclusion number, and cell cycle status and that all of these characteristics affect the infection and replication of FMDV. Moreover, we found that host cell heterogeneity influenced the viral adsorption as differences in the levels of FMDV integrin receptors' expression. This study provided new ideas for the studies of correlation between FMDV infection mechanisms and host cells. Copyright © 2018 American Society for Microbiology.

Class I Histone Deacetylase HDAC1 and WRN RECQ Helicase Contribute Additively to Protect Replication Forks upon Hydroxyurea-induced Arrest.

PubMed

Kehrli, Keffy; Phelps, Michael; Lazarchuk, Pavlo; Chen, Eleanor; Monnat, Ray; Sidorova, Julia M

2016-11-18

The WRN helicase/exonuclease is mutated in Werner syndrome of genomic instability and premature aging. WRN-depleted fibroblasts, although remaining largely viable, have a reduced capacity to maintain replication forks active during a transient hydroxyurea-induced arrest. A strand exchange protein, RAD51, is also required for replication fork maintenance, and here we show that recruitment of RAD51 to stalled forks is reduced in the absence of WRN. We performed a siRNA screen for genes that are required for viability of WRN-depleted cells after hydroxyurea treatment, and identified HDAC1, a member of the class I histone deacetylase family. One of the functions of HDAC1, which it performs together with a close homolog HDAC2, is deacetylation of new histone H4 deposited at replication forks. We show that HDAC1 depletion exacerbates defects in fork reactivation and progression after hydroxyurea treatment observed in WRN- or RAD51-deficient cells. The additive WRN, HDAC1 loss-of-function phenotype is also observed with a catalytic mutant of HDAC1; however, it does not correlate with changes in histone H4 deacetylation at replication forks. On the other hand, inhibition of histone deacetylation by an inhibitor specific to HDACs 1-3, CI-994, correlates with increased processing of newly synthesized DNA strands in hydroxyurea-stalled forks. WRN co-precipitates with HDAC1 and HDAC2. Taken together, our findings indicate that WRN interacts with HDACs 1 and 2 to facilitate activity of stalled replication forks under conditions of replication stress. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Association between a variation in the phosphodiesterase 4D gene and bone mineral density.

PubMed

Reneland, Richard H; Mah, Steven; Kammerer, Stefan; Hoyal, Carolyn R; Marnellos, George; Wilson, Scott G; Sambrook, Philip N; Spector, Tim D; Nelson, Matthew R; Braun, Andreas

2005-03-07

Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown. We performed a large-scale association study investigating more than 25,000 single nucleotide polymorphisms (SNPs) located within 16,000 genes. Allele frequencies were estimated in contrasting DNA pools from white females selected for low (<0.87 g/cm2, n = 319) and high (> 1.11 g/cm2, n = 321) BMD at the lumbar spine. Significant findings were verified in two additional sample collections. Based on allele frequency differences between DNA pools and subsequent individual genotyping, one of the candidate loci indicated was the phosphodiesterase 4D (PDE4D) gene region on chromosome 5q12. We subsequently tested the marker SNP, rs1498608, in a second sample of 138 white females with low (<0.91 g/cm2) and 138 females with high (>1.04 g/cm2) lumbar spine BMD. Odds ratios were 1.5 (P = 0.035) in the original sample and 2.1 (P = 0.018) in the replication sample. Association fine mapping with 80 SNPs located within 50 kilobases of the marker SNP identified a 20 kilobase region of association containing exon 6 of PDE4D. In a second, family-based replication sample with a preponderance of females with low BMD, rs1498608 showed an opposite relationship with BMD at different sites (p = 0.00044-0.09). We also replicated the previously reported association of the Ser37Ala polymorphism in BMP2, known to interact biologically with PDE4D, with BMD. This study indicates that variants in the gene encoding PDE4D account for some of the genetic contribution to bone mineral density variation in humans. The contrasting results from different samples indicate that the effect may be context-dependent. PDE4 inhibitors have been shown to increase bone mass in normal and osteopenic mice, but up until now there have been no reports implicating any member of the PDE4 gene family in human osteoporosis.

An Evaluation of Talent 4 . . . : A Programme to Identify Talent and Skills for Prisoners, Disadvantaged, Unemployed, and Vulnerable Groups.

PubMed

McGuire-Snieckus, Rebecca; Caulfield, Laura

2017-11-01

Previous research suggests that the relationship between employment and recidivism is complex, with more support needed to facilitate employability motivation for sustained change. An arts-based programme designed to facilitate vocational self-determinism among prisoners with evidence of impact across three prisons in the United Kingdom was replicated and delivered to 234 prisoners and long-term unemployed participants from six European countries, to explore whether the findings from the previous evaluation would be replicated on a much larger scale. The research presented in this article found that supporting prisoners and the long-term unemployed to articulate employability goals had a positive effect on personal growth as well as understanding of individual strengths and weaknesses with respect to work, employment, problem solving, and thinking styles. Future research might explore the longer term impact on employment and recidivism.

Large-scale purification and crystallization of the endoribonuclease XendoU: troubleshooting with His-tagged proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Renzi, Fabiana; Panetta, Gianna; Vallone, Beatrice

Recombinant His-tagged XendoU, a eukaryotic endoribonuclease, appeared to aggregate in the presence of divalent cations. Monodisperse protein which yielded crystals diffracting to 2.2 Å was obtained by addition of EDTA. XendoU is the first endoribonuclease described in higher eukaryotes as being involved in the endonucleolytic processing of intron-encoded small nucleolar RNAs. It is conserved among eukaryotes and its viral homologue is essential in SARS replication and transcription. The large-scale purification and crystallization of recombinant XendoU are reported. The tendency of the recombinant enzyme to aggregate could be reversed upon the addition of chelating agents (EDTA, imidazole): aggregation is a potentialmore » drawback when purifying and crystallizing His-tagged proteins, which are widely used, especially in high-throughput structural studies. Purified monodisperse XendoU crystallized in two different space groups: trigonal P3{sub 1}21, diffracting to low resolution, and monoclinic C2, diffracting to higher resolution.« less

Body size, skills, and income: evidence from 150,000 teenage siblings.

PubMed

Lundborg, Petter; Nystedt, Paul; Rooth, Dan-Olof

2014-10-01

We provide new evidence on the long-run labor market penalty of teenage overweight and obesity using unique and large-scale data on 150,000 male siblings from the Swedish military enlistment. Our empirical analysis provides four important results. First, we provide the first evidence of a large adult male labor market penalty for being overweight or obese as a teenager. Second, we replicate this result using data from the United States and the United Kingdom. Third, we note a strikingly strong within-family relationship between body size and cognitive skills/noncognitive skills. Fourth, a large part of the estimated body-size penalty reflects lower skill acquisition among overweight and obese teenagers. Taken together, these results reinforce the importance of policy combating early-life obesity in order to reduce healthcare expenditures as well as poverty and inequalities later in life.

Single cell Hi-C reveals cell-to-cell variability in chromosome structure

PubMed Central

Schoenfelder, Stefan; Yaffe, Eitan; Dean, Wendy; Laue, Ernest D.; Tanay, Amos; Fraser, Peter

2013-01-01

Large-scale chromosome structure and spatial nuclear arrangement have been linked to control of gene expression and DNA replication and repair. Genomic techniques based on chromosome conformation capture assess contacts for millions of loci simultaneously, but do so by averaging chromosome conformations from millions of nuclei. Here we introduce single cell Hi-C, combined with genome-wide statistical analysis and structural modeling of single copy X chromosomes, to show that individual chromosomes maintain domain organisation at the megabase scale, but show variable cell-to-cell chromosome territory structures at larger scales. Despite this structural stochasticity, localisation of active gene domains to boundaries of territories is a hallmark of chromosomal conformation. Single cell Hi-C data bridge current gaps between genomics and microscopy studies of chromosomes, demonstrating how modular organisation underlies dynamic chromosome structure, and how this structure is probabilistically linked with genome activity patterns. PMID:24067610

The RNA-binding proteins Zfp36l1 and Zfp36l2 enforce the thymic β-selection checkpoint by limiting DNA damage response signaling and cell cycle progression

PubMed Central

Galloway, Alison; Ahlfors, Helena; Turner, Martin

2016-01-01

The RNA binding proteins Zfp36l1 and Zfp36l2 act redundantly to enforce the β-selection checkpoint during thymopoiesis, yet their molecular targets remain largely unknown. Here, we identify these targets on a genome wide scale in primary mouse thymocytes and show that Zfp36l1/l2 regulate DNA damage response and cell cycle transcripts to ensure proper β-selection. DN3 thymocytes lacking Zfp36l1/l2 share a gene expression profile with post-selected DN3b cells despite the absence of intracellular TCRβ and reduced IL-7 signaling. Our findings show that in addition to controlling the timing of proliferation at β-selection post-transcriptional control by Zfp36l1/l2 limits DNA damage responses which are known to promote thymocyte differentiation. Zfp36l1/l2 therefore act as post-transcriptional safeguards against chromosomal instability and replication stress by integrating pre-TCR and IL-7 signaling with DNA damage and cell cycle control. PMID:27566829

Diversity of Functionally Permissive Sequences in the Receptor-Binding Site of Influenza Hemagglutinin.

PubMed

Wu, Nicholas C; Xie, Jia; Zheng, Tianqing; Nycholat, Corwin M; Grande, Geramie; Paulson, James C; Lerner, Richard A; Wilson, Ian A

2017-06-14

Influenza A virus hemagglutinin (HA) initiates viral entry by engaging host receptor sialylated glycans via its receptor-binding site (RBS). The amino acid sequence of the RBS naturally varies across avian and human influenza virus subtypes and is also evolvable. However, functional sequence diversity in the RBS has not been fully explored. Here, we performed a large-scale mutational analysis of the RBS of A/WSN/33 (H1N1) and A/Hong Kong/1/1968 (H3N2) HAs. Many replication-competent mutants not yet observed in nature were identified, including some that could escape from an RBS-targeted broadly neutralizing antibody. This functional sequence diversity is made possible by pervasive epistasis in the RBS 220-loop and can be buffered by avidity in viral receptor binding. Overall, our study reveals that the HA RBS can accommodate a much greater range of sequence diversity than previously thought, which has significant implications for the complex evolutionary interrelationships between receptor specificity and immune escape. Copyright © 2017 Elsevier Inc. All rights reserved.

A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.

PubMed

Timpson, Nicholas J; Walter, Klaudia; Min, Josine L; Tachmazidou, Ioanna; Malerba, Giovanni; Shin, So-Youn; Chen, Lu; Futema, Marta; Southam, Lorraine; Iotchkova, Valentina; Cocca, Massimiliano; Huang, Jie; Memari, Yasin; McCarthy, Shane; Danecek, Petr; Muddyman, Dawn; Mangino, Massimo; Menni, Cristina; Perry, John R B; Ring, Susan M; Gaye, Amadou; Dedoussis, George; Farmaki, Aliki-Eleni; Burton, Paul; Talmud, Philippa J; Gambaro, Giovanni; Spector, Tim D; Smith, George Davey; Durbin, Richard; Richards, J Brent; Humphries, Steve E; Zeggini, Eleftheria; Soranzo, Nicole

2014-09-16

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

PubMed Central

Steckel, Michael; Molina-Arcas, Miriam; Weigelt, Britta; Marani, Michaela; Warne, Patricia H; Kuznetsov, Hanna; Kelly, Gavin; Saunders, Becky; Howell, Michael; Downward, Julian; Hancock, David C

2012-01-01

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy. PMID:22613949

Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

PubMed Central

van Leeuwen, Elisabeth M; Sabo, Aniko; Bis, Joshua C; Huffman, Jennifer E; Manichaikul, Ani; Smith, Albert V; Feitosa, Mary F; Demissie, Serkalem; Joshi, Peter K; Duan, Qing; Marten, Jonathan; van Klinken, Jan B; Surakka, Ida; Nolte, Ilja M; Zhang, Weihua; Mbarek, Hamdi; Li-Gao, Ruifang; Trompet, Stella; Verweij, Niek; Evangelou, Evangelos; Lyytikäinen, Leo-Pekka; Tayo, Bamidele O; Deelen, Joris; van der Most, Peter J; van der Laan, Sander W; Arking, Dan E; Morrison, Alanna; Dehghan, Abbas; Franco, Oscar H; Hofman, Albert; Rivadeneira, Fernando; Sijbrands, Eric J; Uitterlinden, Andre G; Mychaleckyj, Josyf C; Campbell, Archie; Hocking, Lynne J; Padmanabhan, Sandosh; Brody, Jennifer A; Rice, Kenneth M; White, Charles C; Harris, Tamara; Isaacs, Aaron; Campbell, Harry; Lange, Leslie A; Rudan, Igor; Kolcic, Ivana; Navarro, Pau; Zemunik, Tatijana; Salomaa, Veikko; Kooner, Angad S; Kooner, Jaspal S; Lehne, Benjamin; Scott, William R; Tan, Sian-Tsung; de Geus, Eco J; Milaneschi, Yuri; Penninx, Brenda W J H; Willemsen, Gonneke; de Mutsert, Renée; Ford, Ian; Gansevoort, Ron T; Segura-Lepe, Marcelo P; Raitakari, Olli T; Viikari, Jorma S; Nikus, Kjell; Forrester, Terrence; McKenzie, Colin A; de Craen, Anton J M; de Ruijter, Hester M; Pasterkamp, Gerard; Snieder, Harold; Oldehinkel, Albertine J; Slagboom, P Eline; Cooper, Richard S; Kähönen, Mika; Lehtimäki, Terho; Elliott, Paul; van der Harst, Pim; Jukema, J Wouter; Mook-Kanamori, Dennis O; Boomsma, Dorret I; Chambers, John C; Swertz, Morris; Ripatti, Samuli; Willems van Dijk, Ko; Vitart, Veronique; Polasek, Ozren; Hayward, Caroline; Wilson, James G; Wilson, James F; Gudnason, Vilmundur; Rich, Stephen S; Psaty, Bruce M; Borecki, Ingrid B; Boerwinkle, Eric; Rotter, Jerome I; Cupples, L Adrienne; van Duijn, Cornelia M

2016-01-01

Background So far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels. Methods We used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage. Results Our study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene. Conclusions This study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels. PMID:27036123

Statistical correction of the Winner’s Curse explains replication variability in quantitative trait genome-wide association studies

PubMed Central

Pe’er, Itsik

2017-01-01

Genome-wide association studies (GWAS) have identified hundreds of SNPs responsible for variation in human quantitative traits. However, genome-wide-significant associations often fail to replicate across independent cohorts, in apparent inconsistency with their apparent strong effects in discovery cohorts. This limited success of replication raises pervasive questions about the utility of the GWAS field. We identify all 332 studies of quantitative traits from the NHGRI-EBI GWAS Database with attempted replication. We find that the majority of studies provide insufficient data to evaluate replication rates. The remaining papers replicate significantly worse than expected (p < 10−14), even when adjusting for regression-to-the-mean of effect size between discovery- and replication-cohorts termed the Winner’s Curse (p < 10−16). We show this is due in part to misreporting replication cohort-size as a maximum number, rather than per-locus one. In 39 studies accurately reporting per-locus cohort-size for attempted replication of 707 loci in samples with similar ancestry, replication rate matched expectation (predicted 458, observed 457, p = 0.94). In contrast, ancestry differences between replication and discovery (13 studies, 385 loci) cause the most highly-powered decile of loci to replicate worse than expected, due to difference in linkage disequilibrium. PMID:28715421

Tunable resonance-domain diffraction gratings based on electrostrictive polymers.

PubMed

Axelrod, Ramon; Shacham-Diamand, Yosi; Golub, Michael A

2017-03-01

Critical combination of high diffraction efficiency and large diffraction angles can be delivered by resonance-domain diffractive optics with high aspect ratio and wavelength-scale grating periods. To advance from static to electrically tunable resonance-domain diffraction grating, we resorted to its replication onto 2-5 μm thick P(VDF-TrFE-CFE) electrostrictive ter-polymer membranes. Electromechanical and optical computer simulations provided higher than 90% diffraction efficiency, a large continuous deflection range exceeding 20°, and capabilities for adiabatic spatial modulation of the grating period and slant. A prototype of the tunable resonance-domain diffraction grating was fabricated in a soft-stamp thermal nanoimprinting process, characterized, optically tested, and provided experimental feasibility proof for the tunable sub-micron-period gratings on electrostrictive polymers.

The dispersion and detection patterns of mtDNA-assigned red fox Vulpes vulpes scats in Tasmania are anomalous.

PubMed

Marks, Clive A; Obendorf, David; Pereira, Filipe; Edwards, Ivo; Hall, Graham P

2014-08-01

Models used for resource allocation in eradication programmes must be based on replicated data of known quality and have proven predictive accuracy, or they may provide a false indication of species presence and/or distribution. In the absence of data corroborating the presence of extant foxes Vulpes vulpes in Tasmania, a habitat-specific model based upon mtDNA data (Sarre et al . 2012. Journal Applied Ecology , 50, 459-468) implied that foxes were widespread. Overall, 61 of 9940 (0·6%) surveyed scats were assigned as mtDNA fox positive by the fox eradication programme (FEP). We investigated the spatiotemporal distribution of the 61 mtDNA-assigned fox scats and modelled the probability of replicating scat detection in independent surveys using detection dogs based upon empirically derived probabilities of scat detection success obtained by the FEP using imported fox scats. In a prior mainland study, fox genotypes were recurrently detected in a consecutive four-day pool of scats. In Tasmania, only three contemporaneously collected scat pairs of unknown genotype were detected by the FEP within an area corresponding to a conservatively large mainland fox home range (639 ha) in a decade. Nearest neighbour pairs were widely spaced (mean = 7·0 km; circular area = 153 km 2 ) and generated after a mean of 281 days. The majority of assigned mtDNA positive scats were found in urban and peri-urban environments corresponding to small mainland fox home ranges (30-45 ha) that imply higher scat density and more certain replication. Using the lowest empirically determined scat detection success for dogs, the failure to replicate fox scat detection on 34 of 36 occasions in a large (639 ha) home range is highly improbable ( P  = 0·00001) and suggestive of Type I error. Synthesis and applications . Type I error, which may have various sources, should be considered when scat mtDNA data are few, accumulated over many years, uncorroborated by observations of extant specimens, inadequately replicated in independent surveys within an expected spatiotemporal scale and reported in geographically isolated environments unlikely to have been colonized.

Method of producing a cellulase-containing cell-free fermentate produced from microorganism ATCC 55702

DOEpatents

Dees, H. Craig

1998-01-01

Bacteria which produce large amounts of cellulose-containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques.

Detergent composition comprising a cellulase containing cell-free fermentate produced from microorganism ATCC 55702 or mutant thereof

DOEpatents

Dees, H. Craig

1998-01-01

Bacteria which produce large amounts of a cellulase-containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques.

Cellulase-containing cell-free fermentate produced from microorganism ATCC 55702

DOEpatents

Dees, H.C.

1997-12-16

Bacteria which produce large amounts of cellulase-containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques. 5 figs.

Method of producing a cellulase-containing cell-free fermentate produced from microorganism ATCC 55702

DOEpatents

Dees, H.C.

1998-05-26

Bacteria which produce large amounts of cellulose-containing cell-free fermentate have been identified. The original bacterium (ATCC 55703) was genetically altered using nitrosoguanidine (MNNG) treatment to produce the enhanced cellulase producing bacterium (ATCC 55702), which was identified through replicate plating. ATCC 55702 has improved characteristics and qualities for the degradation of cellulosic waste materials for fuel production, food processing, textile processing, and other industrial applications. ATCC 55702 is an improved bacterial host for genetic manipulations using recombinant DNA techniques, and is less likely to destroy genetic manipulations using standard mutagenesis techniques. 5 figs.

Tools for understanding landscapes: combining large-scale surveys to characterize change. Chapter 9.

Treesearch

W. Keith Moser; Janine Bolliger; Don C. Bragg; Mark H. Hansen; Mark A. Hatfield; Timothy A. Nigh; Lisa A. Schulte

2008-01-01

All landscapes change continuously. Since change is perceived and interpreted through measures of scale, any quantitative analysis of landscapes must identify and describe the spatiotemporal mosaics shaped by large-scale structures and processes. This process is controlled by core influences, or "drivers," that shape the change and affect the outcome...

Inventory of nanotechnology companies in Mexico

NASA Astrophysics Data System (ADS)

Appelbaum, Richard; Zayago Lau, Edgar; Foladori, Guillermo; Parker, Rachel; Vazquez, Laura Liliana Villa; Belmont, Eduardo Robles; Figueroa, Edgar Ramón Arteaga

2016-02-01

This study presents an inventory of 139 nanotechnology companies in Mexico, identifying their geographic distribution, economic sector classification, and position in the nanotechnology value chain. We find that the principal economic sector of nanotechnology-engaged firms involves the manufacture of chemical products, which largely serve as means of production (primary or intermediate materials; instruments and equipment) for industrial processes. The methodology used in this analysis could be replicated in other countries without major modifications.

Large-scale Activities Associated with the 2005 Sep. 7th Event

NASA Astrophysics Data System (ADS)

Zong, Weiguo

We present a multi-wavelength study on large-scale activities associated with a significant solar event. On 2005 September 7, a flare classified as bigger than X17 was observed. Combining with Hα 6562.8 ˚, He I 10830 ˚and soft X-ray observations, three large-scale activities were A A found to propagate over a long distance on the solar surface. 1) The first large-scale activity emanated from the flare site, which propagated westward around the solar equator and appeared as sequential brightenings. With MDI longitudinal magnetic field map, the activity was found to propagate along the magnetic network. 2) The second large-scale activity could be well identified both in He I 10830 ˚images and soft X-ray images and appeared as diffuse emission A enhancement propagating away. The activity started later than the first one and was not centric on the flare site. Moreover, a rotation was found along with the bright front propagating away. 3) The third activity was ahead of the second one, which was identified as a "winking" filament. The three activities have different origins, which were seldom observed in one event. Therefore this study is useful to understand the mechanism of large-scale activities on solar surface.

Experimental Replication of an Aeroengine Combustion Instability

NASA Technical Reports Server (NTRS)

Cohen, J. M.; Hibshman, J. R.; Proscia, W.; Rosfjord, T. J.; Wake, B. E.; McVey, J. B.; Lovett, J.; Ondas, M.; DeLaat, J.; Breisacher, K.

2000-01-01

Combustion instabilities in gas turbine engines are most frequently encountered during the late phases of engine development, at which point they are difficult and expensive to fix. The ability to replicate an engine-traceable combustion instability in a laboratory-scale experiment offers the opportunity to economically diagnose the problem (to determine the root cause), and to investigate solutions to the problem, such as active control. The development and validation of active combustion instability control requires that the causal dynamic processes be reproduced in experimental test facilities which can be used as a test bed for control system evaluation. This paper discusses the process through which a laboratory-scale experiment was designed to replicate an instability observed in a developmental engine. The scaling process used physically-based analyses to preserve the relevant geometric, acoustic and thermo-fluid features. The process increases the probability that results achieved in the single-nozzle experiment will be scalable to the engine.

Neonicotinoid clothianidin adversely affects insect immunity and promotes replication of a viral pathogen in honey bees

PubMed Central

Di Prisco, Gennaro; Cavaliere, Valeria; Annoscia, Desiderato; Varricchio, Paola; Caprio, Emilio; Nazzi, Francesco; Gargiulo, Giuseppe; Pennacchio, Francesco

2013-01-01

Large-scale losses of honey bee colonies represent a poorly understood problem of global importance. Both biotic and abiotic factors are involved in this phenomenon that is often associated with high loads of parasites and pathogens. A stronger impact of pathogens in honey bees exposed to neonicotinoid insecticides has been reported, but the causal link between insecticide exposure and the possible immune alteration of honey bees remains elusive. Here, we demonstrate that the neonicotinoid insecticide clothianidin negatively modulates NF-κB immune signaling in insects and adversely affects honey bee antiviral defenses controlled by this transcription factor. We have identified in insects a negative modulator of NF-κB activation, which is a leucine-rich repeat protein. Exposure to clothianidin, by enhancing the transcription of the gene encoding this inhibitor, reduces immune defenses and promotes the replication of the deformed wing virus in honey bees bearing covert infections. This honey bee immunosuppression is similarly induced by a different neonicotinoid, imidacloprid, but not by the organophosphate chlorpyriphos, which does not affect NF-κB signaling. The occurrence at sublethal doses of this insecticide-induced viral proliferation suggests that the studied neonicotinoids might have a negative effect at the field level. Our experiments uncover a further level of regulation of the immune response in insects and set the stage for studies on neural modulation of immunity in animals. Furthermore, this study has implications for the conservation of bees, as it will contribute to the definition of more appropriate guidelines for testing chronic or sublethal effects of pesticides used in agriculture. PMID:24145453

Scaled-model guidelines for formation-flying solar coronagraph missions.

PubMed

Landini, Federico; Romoli, Marco; Baccani, Cristian; Focardi, Mauro; Pancrazzi, Maurizio; Galano, Damien; Kirschner, Volker

2016-02-15

Stray light suppression is the main concern in designing a solar coronagraph. The main contribution to the stray light for an externally occulted space-borne solar coronagraph is the light diffracted by the occulter and scattered by the optics. It is mandatory to carefully evaluate the diffraction generated by an external occulter and the impact that it has on the stray light signal on the focal plane. The scientific need for observations to cover a large portion of the heliosphere with an inner field of view as close as possible to the photospheric limb supports the ambition of launching formation-flying giant solar coronagraphs. Their dimension prevents the possibility of replicating the flight geometry in a clean laboratory environment, and the strong need for a scaled model is thus envisaged. The problem of scaling a coronagraph has already been faced for exoplanets, for a single point source on axis at infinity. We face the problem here by adopting an original approach and by introducing the scaling of the solar disk as an extended source.

Micronuclear DNA of Oxytricha nova contains sequences with autonomously replicating activity in Saccharomyces cerevisiae.

PubMed Central

Colombo, M M; Swanton, M T; Donini, P; Prescott, D M

1984-01-01

Oxytricha nova is a hypotrichous ciliate with micronuclei and macronuclei. Micronuclei, which contain large, chromosomal-sized DNA, are genetically inert but undergo meiosis and exchange during cell mating. Macronuclei, which contain only small, gene-sized DNA molecules, provide all of the nuclear RNA needed to run the cell. After cell mating the macronucleus is derived from a micronucleus, a derivation that includes excision of the genes from chromosomes and elimination of the remaining DNA. The eliminated DNA includes all of the repetitious sequences and approximately 95% of the unique sequences. We cloned large restriction fragments from the micronucleus that confer replication ability on a replication-deficient plasmid in Saccharomyces cerevisiae. Sequences that confer replication ability are called autonomously replicating sequences. The frequency and effectiveness of autonomously replicating sequences in micronuclear DNA are similar to those reported for DNAs of other organisms introduced into yeast cells. Of the 12 micronuclear fragments with autonomously replicating sequence activity, 9 also showed homology to macronuclear DNA, indicating that they contain a macronuclear gene sequence. We conclude from this that autonomously replicating sequence activity is nonrandomly distributed throughout micronuclear DNA and is preferentially associated with those regions of micronuclear DNA that contain genes. Images PMID:6092934

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

PubMed Central

Cukier, Holly N.; Kunkle, Brian W.; Vardarajan, Badri N.; Rolati, Sophie; Hamilton-Nelson, Kara L.; Kohli, Martin A.; Whitehead, Patrice L.; Dombroski, Beth A.; Van Booven, Derek; Lang, Rosalyn; Dykxhoorn, Derek M.; Farrer, Lindsay A.; Cuccaro, Michael L.; Vance, Jeffery M.; Gilbert, John R.; Beecham, Gary W.; Martin, Eden R.; Carney, Regina M.; Mayeux, Richard; Schellenberg, Gerard D.; Byrd, Goldie S.; Haines, Jonathan L.

2016-01-01

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD. PMID:27231719

Identification of common variants associated with human hippocampal and intracranial volumes

PubMed Central

Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias; Hibar, Derrek P; Senstad, Rudy E; Winkler, Anderson M; Toro, Roberto; Appel, Katja; Bartecek, Richard; Bergmann, Ørjan; Bernard, Manon; Brown, Andrew A; Cannon, Dara M; Chakravarty, M Mallar; Christoforou, Andrea; Domin, Martin; Grimm, Oliver; Hollinshead, Marisa; Holmes, Avram J; Homuth, Georg; Hottenga, Jouke-Jan; Langan, Camilla; Lopez, Lorna M; Hansell, Narelle K; Hwang, Kristy S; Kim, Sungeun; Laje, Gonzalo; Lee, Phil H; Liu, Xinmin; Loth, Eva; Lourdusamy, Anbarasu; Mattingsdal, Morten; Mohnke, Sebastian; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; O’Brien, Carol; Papmeyer, Martina; Pütz, Benno; Ramasamy, Adaikalavan; Rasmussen, Jerod; Rijpkema, Mark; Risacher, Shannon L; Roddey, J Cooper; Rose, Emma J; Ryten, Mina; Shen, Li; Sprooten, Emma; Strengman, Eric; Teumer, Alexander; Trabzuni, Daniah; Turner, Jessica; van Eijk, Kristel; van Erp, Theo G M; van Tol, Marie-Jose; Wittfeld, Katharina; Wolf, Christiane; Woudstra, Saskia; Aleman, Andre; Alhusaini, Saud; Almasy, Laura; Binder, Elisabeth B; Brohawn, David G; Cantor, Rita M; Carless, Melanie A; Corvin, Aiden; Czisch, Michael; Curran, Joanne E; Davies, Gail; de Almeida, Marcio A A; Delanty, Norman; Depondt, Chantal; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Fagerness, Jesen; Fox, Peter T; Freimer, Nelson B; Gill, Michael; Göring, Harald H H; Hagler, Donald J; Hoehn, David; Holsboer, Florian; Hoogman, Martine; Hosten, Norbert; Jahanshad, Neda; Johnson, Matthew P; Kasperaviciute, Dalia; Kent, Jack W; Kochunov, Peter; Lancaster, Jack L; Lawrie, Stephen M; Liewald, David C; Mandl, René; Matarin, Mar; Mattheisen, Manuel; Meisenzahl, Eva; Melle, Ingrid; Moses, Eric K; Mühleisen, Thomas W; Nauck, Matthias; Nöthen, Markus M; Olvera, Rene L; Pandolfo, Massimo; Pike, G Bruce; Puls, Ralf; Reinvang, Ivar; Rentería, Miguel E; Rietschel, Marcella; Roffman, Joshua L; Royle, Natalie A; Rujescu, Dan; Savitz, Jonathan; Schnack, Hugo G; Schnell, Knut; Seiferth, Nina; Smith, Colin; Steen, Vidar M; Valdés Hernández, Maria C; Van den Heuvel, Martijn; van der Wee, Nic J; Van Haren, Neeltje E M; Veltman, Joris A; Völzke, Henry; Walker, Robert; Westlye, Lars T; Whelan, Christopher D; Agartz, Ingrid; Boomsma, Dorret I; Cavalleri, Gianpiero L; Dale, Anders M; Djurovic, Srdjan; Drevets, Wayne C; Hagoort, Peter; Hall, Jeremy; Heinz, Andreas; Jack, Clifford R; Foroud, Tatiana M; Le Hellard, Stephanie; Macciardi, Fabio; Montgomery, Grant W; Poline, Jean Baptiste; Porteous, David J; Sisodiya, Sanjay M; Starr, John M; Sussmann, Jessika; Toga, Arthur W; Veltman, Dick J; Walter, Henrik; Weiner, Michael W; Bis, Joshua C; Ikram, M Arfan; Smith, Albert V; Gudnason, Vilmundur; Tzourio, Christophe; Vernooij, Meike W; Launer, Lenore J; DeCarli, Charles; Seshadri, Sudha; Andreassen, Ole A; Apostolova, Liana G; Bastin, Mark E; Blangero, John; Brunner, Han G; Buckner, Randy L; Cichon, Sven; Coppola, Giovanni; de Zubicaray, Greig I; Deary, Ian J; Donohoe, Gary; de Geus, Eco J C; Espeseth, Thomas; Fernández, Guillén; Glahn, David C; Grabe, Hans J; Hardy, John; Hulshoff Pol, Hilleke E; Jenkinson, Mark; Kahn, René S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Meyer-Lindenberg, Andreas; Morris, Derek W; Müller-Myhsok, Bertram; Nichols, Thomas E; Ophoff, Roel A; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W; Potkin, Steven G; Sämann, Philipp G; Saykin, Andrew J; Schumann, Gunter; Smoller, Jordan W; Wardlaw, Joanna M; Weale, Michael E; Martin, Nicholas G; Franke, Barbara; Wright, Margaret J; Thompson, Paul M

2013-01-01

Identifying genetic variants influencing human brain structures may reveal new biological mechanisms underlying cognition and neuropsychiatric illness. The volume of the hippocampus is a biomarker of incipient Alzheimer’s disease1,2 and is reduced in schizophrenia3, major depression4 and mesial temporal lobe epilepsy5. Whereas many brain imaging phenotypes are highly heritable6,7, identifying and replicating genetic influences has been difficult, as small effects and the high costs of magnetic resonance imaging (MRI) have led to underpowered studies. Here we report genome-wide association meta-analyses and replication for mean bilateral hippocampal, total brain and intracranial volumes from a large multinational consortium. The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10−16) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 × 10−12). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 × 10−7). PMID:22504417

Genome-wide association study identifies 74 loci associated with educational attainment

PubMed Central

Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark A.; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans68, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A.L.M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C.M.; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E.R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J.A.; Venturini, Cristina; Vinkhuyzen, Anna A.E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J.F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L.R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W.J.H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I.A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

2016-01-01

Summary Educational attainment (EA) is strongly influenced by social and other environmental factors, but genetic factors are also estimated to account for at least 20% of the variation across individuals1. We report the results of a genome-wide association study (GWAS) for EA that extends our earlier discovery sample1,2 of 101,069 individuals to 293,723 individuals, and a replication in an independent sample of 111,349 individuals from the UK Biobank. We now identify 74 genome-wide significant loci associated with number of years of schooling completed. Single-nucleotide polymorphisms (SNPs) associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioral phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because EA is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric disease. PMID:27225129

Genome-wide association study identifies 74 loci associated with educational attainment.

PubMed

Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

2016-05-26

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Noumeavirus replication relies on a transient remote control of the host nucleus

PubMed Central

Fabre, Elisabeth; Jeudy, Sandra; Santini, Sébastien; Legendre, Matthieu; Trauchessec, Mathieu; Couté, Yohann; Claverie, Jean-Michel; Abergel, Chantal

2017-01-01

Acanthamoeba are infected by a remarkable diversity of large dsDNA viruses, the infectious cycles of which have been characterized using genomics, transcriptomics and electron microscopy. Given their gene content and the persistence of the host nucleus throughout their infectious cycle, the Marseilleviridae were initially assumed to fully replicate in the cytoplasm. Unexpectedly, we find that their virions do not incorporate the virus-encoded transcription machinery, making their replication nucleus-dependent. However, instead of delivering their DNA to the nucleus, the Marseilleviridae initiate their replication by transiently recruiting the nuclear transcription machinery to their cytoplasmic viral factory. The nucleus recovers its integrity after becoming leaky at an early stage. This work highlights the importance of virion proteomic analyses to complement genome sequencing in the elucidation of the replication scheme and evolution of large dsDNA viruses. PMID:28429720

Improving health aid for a better planet: The planning, monitoring and evaluation tool (PLANET).

PubMed

Sridhar, Devi; Car, Josip; Chopra, Mickey; Campbell, Harry; Woods, Ngaire; Rudan, Igor

2015-12-01

International development assistance for health (DAH) quadrupled between 1990 and 2012, from US$ 5.6 billion to US$ 28.1 billion. This generates an increasing need for transparent and replicable tools that could be used to set investment priorities, monitor the distribution of funding in real time, and evaluate the impact of those investments. In this paper we present a methodology that addresses these three challenges. We call this approach PLANET, which stands for planning, monitoring and evaluation tool. Fundamentally, PLANET is based on crowdsourcing approach to obtaining information relevant to deployment of large-scale programs. Information is contributed in real time by a diverse group of participants involved in the program delivery. PLANET relies on real-time information from three levels of participants in large-scale programs: funders, managers and recipients. At each level, information is solicited to assess five key risks that are most relevant to each level of operations. The risks at the level of funders involve systematic neglect of certain areas, focus on donor's interests over that of program recipients, ineffective co-ordination between donors, questionable mechanisms of delivery and excessive loss of funding to "middle men". At the level of managers, the risks are corruption, lack of capacity and/or competence, lack of information and /or communication, undue avoidance of governmental structures / preference to non-governmental organizations and exclusion of local expertise. At the level of primary recipients, the risks are corruption, parallel operations / "verticalization", misalignment with local priorities and lack of community involvement, issues with ethics, equity and/or acceptability, and low likelihood of sustainability beyond the end of the program's implementation. PLANET is intended as an additional tool available to policy-makers to prioritize, monitor and evaluate large-scale development programs. In this, it should complement tools such as LiST (for health care/interventions), EQUIST (for health care/interventions) and CHNRI (for health research), which also rely on information from local experts and on local context to set priorities in a transparent, user-friendly, replicable, quantifiable and specific, algorithmic-like manner.

On identifying relationships between the flood scaling exponent and basin attributes.

PubMed

Medhi, Hemanta; Tripathi, Shivam

2015-07-01

Floods are known to exhibit self-similarity and follow scaling laws that form the basis of regional flood frequency analysis. However, the relationship between basin attributes and the scaling behavior of floods is still not fully understood. Identifying these relationships is essential for drawing connections between hydrological processes in a basin and the flood response of the basin. The existing studies mostly rely on simulation models to draw these connections. This paper proposes a new methodology that draws connections between basin attributes and the flood scaling exponents by using observed data. In the proposed methodology, region-of-influence approach is used to delineate homogeneous regions for each gaging station. Ordinary least squares regression is then applied to estimate flood scaling exponents for each homogeneous region, and finally stepwise regression is used to identify basin attributes that affect flood scaling exponents. The effectiveness of the proposed methodology is tested by applying it to data from river basins in the United States. The results suggest that flood scaling exponent is small for regions having (i) large abstractions from precipitation in the form of large soil moisture storages and high evapotranspiration losses, and (ii) large fractions of overland flow compared to base flow, i.e., regions having fast-responding basins. Analysis of simple scaling and multiscaling of floods showed evidence of simple scaling for regions in which the snowfall dominates the total precipitation.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

PubMed

Iyengar, Sudha K; Sedor, John R; Freedman, Barry I; Kao, W H Linda; Kretzler, Matthias; Keller, Benjamin J; Abboud, Hanna E; Adler, Sharon G; Best, Lyle G; Bowden, Donald W; Burlock, Allison; Chen, Yii-Der Ida; Cole, Shelley A; Comeau, Mary E; Curtis, Jeffrey M; Divers, Jasmin; Drechsler, Christiane; Duggirala, Ravi; Elston, Robert C; Guo, Xiuqing; Huang, Huateng; Hoffmann, Michael Marcus; Howard, Barbara V; Ipp, Eli; Kimmel, Paul L; Klag, Michael J; Knowler, William C; Kohn, Orly F; Leak, Tennille S; Leehey, David J; Li, Man; Malhotra, Alka; März, Winfried; Nair, Viji; Nelson, Robert G; Nicholas, Susanne B; O'Brien, Stephen J; Pahl, Madeleine V; Parekh, Rulan S; Pezzolesi, Marcus G; Rasooly, Rebekah S; Rotimi, Charles N; Rotter, Jerome I; Schelling, Jeffrey R; Seldin, Michael F; Shah, Vallabh O; Smiles, Adam M; Smith, Michael W; Taylor, Kent D; Thameem, Farook; Thornley-Brown, Denyse P; Truitt, Barbara J; Wanner, Christoph; Weil, E Jennifer; Winkler, Cheryl A; Zager, Philip G; Igo, Robert P; Hanson, Robert L; Langefeld, Carl D

2015-08-01

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

PubMed Central

Kretzler, Matthias; Keller, Benjamin J.; Adler, Sharon G.; Best, Lyle G.; Bowden, Donald W.; Burlock, Allison; Chen, Yii-Der Ida; Cole, Shelley A.; Comeau, Mary E.; Curtis, Jeffrey M.; Divers, Jasmin; Drechsler, Christiane; Duggirala, Ravi; Elston, Robert C.; Guo, Xiuqing; Huang, Huateng; Hoffmann, Michael Marcus; Howard, Barbara V.; Ipp, Eli; Kimmel, Paul L.; Klag, Michael J.; Knowler, William C.; Kohn, Orly F.; Leak, Tennille S.; Leehey, David J.; Li, Man; Malhotra, Alka; März, Winfried; Nair, Viji; Nelson, Robert G.; Nicholas, Susanne B.; O’Brien, Stephen J.; Pahl, Madeleine V.; Parekh, Rulan S.; Pezzolesi, Marcus G.; Rasooly, Rebekah S.; Rotimi, Charles N.; Rotter, Jerome I.; Schelling, Jeffrey R.; Seldin, Michael F.; Shah, Vallabh O.; Smiles, Adam M.; Smith, Michael W.; Taylor, Kent D.; Thameem, Farook; Thornley-Brown, Denyse P.; Truitt, Barbara J.; Wanner, Christoph; Weil, E. Jennifer; Winkler, Cheryl A.; Zager, Philip G.; Igo, Robert P.; Hanson, Robert L.; Langefeld, Carl D.

2015-01-01

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD. PMID:26305897

Colorectal cancer-susceptibility single-nucleotide polymorphisms in Korean population.

PubMed

Hong, Sung Noh; Park, Changho; Kim, Jong-Il; Kim, Duk-Hwan; Kim, Hee Cheol; Chang, Dong Kyung; Rhee, Poong-Lyul; Kim, Jae J; Rhee, Jong Chul; Son, Hee Jung; Kim, Young-Ho

2015-05-01

Considering the significant racial and ethnic diversity in genetic variation, it is unclear whether the genome-wide association studies-identified colorectal cancer (CRC)-susceptibility single-nucleotide polymorphisms (SNPs) discovered in European populations are also relevant to the Korean population. However, studies on CRC-susceptibility SNPs in Koreans are limited. To investigate the racial and ethnic diversity of CRC-susceptibility genetic variants, we genotyped for the established European CRC-susceptibility SNPs in 198 CRC cases and 329 controls in Korea. To identify novel genetic variants using genome-wide screening in Korea, Illumina HumanHap 370K/610K BeadChips were performed on 105 CRC patients, and candidate CRC-susceptibility SNPs were selected. Subsequently, genotyping for replication was done in 189 CRC cases and 190 controls. Among the European CRC-susceptibility SNPs, rs4939827 in SMAD7 was associated with a significant decreased risk of Korean CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 0.67 [95% CI, 0.47-0.95]; dominant model, 0.59 [95% CI, 0.39-0.91]). rs4779584 and rs10795668 were associated with CRC risk in females and males, respectively. Among candidate CRC-susceptibility SNPs selected from genome-wide screening, novel SNP, rs17051076, was found to be associated with a significantly increased risk of microsatellite instability-high CRC (age-/gender-adjusted odds ratio [95% confidence interval]: additive model, 4.25 [95% CI, 1.51-11.98]; dominant model, 3.52 [95% CI, 1.13-10.94]) in the replication study. rs4939827, rs4779584, and rs10795668 may contribute to the risk of CRC in the Korean population as well as in European populations. Novel rs17051076 could be associated with microsatellite instability-high CRC in Koreans. These associations support the ethnic diversity of CRC-susceptibility SNPs and should be taken into account in large-scale studies. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Genetic studies of type 2 diabetes in South Asians: a systematic overview.

PubMed

Chowdhury, Ritam; Narayan, Kabayam M Venkat; Zabetian, Azadeh; Raj, Suraja; Tabassum, Rubina

2014-01-01

Diabetes Mellitus, which affects 366 million people worldwide, is a leading cause of mortality, morbidity, and loss of quality of life. South Asians, comprising 24% of the world's population, suffer a large burden of type 2 diabetes. With intriguing risk phenotypes, unique environmental triggers, and potential genetic predisposition, South Asians offer a valuable resource for investigating the pathophysiology of type 2 diabetes. Genomics has proven its potential to underpin some of the etiology of type 2 diabetes by identifying a number of susceptibility genes, but such data are scarce and unclear in South Asians. We present a systematic review of studies on the genetic basis of type 2 diabetes or its complications in South Asians published between 1987-2012, and discuss the findings and limitations of the available data. Of the 91 eligible studies meeting our inclusion criteria, a vast majority included Indian populations, followed by a few in those of Pakistani origin, while other South Asian countries were generally under-represented. Though a large number of studies focused on the replication of findings from genome-wide association studies (GWAS) in European populations, a few studies explored new genes and pathways along with GWAS in South Asians and suggested the potential to unravel population- specific susceptibility genes in this population. We find encouraging improvements in study designs, sample sizes and the numbers of genetic variants investigated over the last five years, which reflect the existing capacity and scope for large-scale genetic studies in South Asians.

Large transcription units unify copy number variants and common fragile sites arising under replication stress.

PubMed

Wilson, Thomas E; Arlt, Martin F; Park, So Hae; Rajendran, Sountharia; Paulsen, Michelle; Ljungman, Mats; Glover, Thomas W

2015-02-01

Copy number variants (CNVs) resulting from genomic deletions and duplications and common fragile sites (CFSs) seen as breaks on metaphase chromosomes are distinct forms of structural chromosome instability precipitated by replication inhibition. Although they share a common induction mechanism, it is not known how CNVs and CFSs are related or why some genomic loci are much more prone to their occurrence. Here we compare large sets of de novo CNVs and CFSs in several experimental cell systems to each other and to overlapping genomic features. We first show that CNV hotpots and CFSs occurred at the same human loci within a given cultured cell line. Bru-seq nascent RNA sequencing further demonstrated that although genomic regions with low CNV frequencies were enriched in transcribed genes, the CNV hotpots that matched CFSs specifically corresponded to the largest active transcription units in both human and mouse cells. Consistently, active transcription units >1 Mb were robust cell-type-specific predictors of induced CNV hotspots and CFS loci. Unlike most transcribed genes, these very large transcription units replicated late and organized deletion and duplication CNVs into their transcribed and flanking regions, respectively, supporting a role for transcription in replication-dependent lesion formation. These results indicate that active large transcription units drive extreme locus- and cell-type-specific genomic instability under replication stress, resulting in both CNVs and CFSs as different manifestations of perturbed replication dynamics. © 2015 Wilson et al.; Published by Cold Spring Harbor Laboratory Press.

Large transcription units unify copy number variants and common fragile sites arising under replication stress

PubMed Central

Park, So Hae; Rajendran, Sountharia; Paulsen, Michelle; Ljungman, Mats; Glover, Thomas W.

2015-01-01

Copy number variants (CNVs) resulting from genomic deletions and duplications and common fragile sites (CFSs) seen as breaks on metaphase chromosomes are distinct forms of structural chromosome instability precipitated by replication inhibition. Although they share a common induction mechanism, it is not known how CNVs and CFSs are related or why some genomic loci are much more prone to their occurrence. Here we compare large sets of de novo CNVs and CFSs in several experimental cell systems to each other and to overlapping genomic features. We first show that CNV hotpots and CFSs occurred at the same human loci within a given cultured cell line. Bru-seq nascent RNA sequencing further demonstrated that although genomic regions with low CNV frequencies were enriched in transcribed genes, the CNV hotpots that matched CFSs specifically corresponded to the largest active transcription units in both human and mouse cells. Consistently, active transcription units >1 Mb were robust cell-type-specific predictors of induced CNV hotspots and CFS loci. Unlike most transcribed genes, these very large transcription units replicated late and organized deletion and duplication CNVs into their transcribed and flanking regions, respectively, supporting a role for transcription in replication-dependent lesion formation. These results indicate that active large transcription units drive extreme locus- and cell-type-specific genomic instability under replication stress, resulting in both CNVs and CFSs as different manifestations of perturbed replication dynamics. PMID:25373142

Protein Kinase LegK2 Is a Type IV Secretion System Effector Involved in Endoplasmic Reticulum Recruitment and Intracellular Replication of Legionella pneumophila ▿

PubMed Central

Hervet, Eva; Charpentier, Xavier; Vianney, Anne; Lazzaroni, Jean-Claude; Gilbert, Christophe; Atlan, Danièle; Doublet, Patricia

2011-01-01

Legionella pneumophila is the etiological agent of Legionnaires' disease. Crucial to the pathogenesis of this intracellular pathogen is its ability to subvert host cell defenses, permitting intracellular replication in specialized vacuoles within host cells. The Dot/Icm type IV secretion system (T4SS), which translocates a large number of bacterial effectors into host cell, is absolutely required for rerouting the Legionella phagosome. Many Legionella effectors display distinctive eukaryotic domains, among which are protein kinase domains. In silico analysis and in vitro phosphorylation assays identified five functional protein kinases, LegK1 to LegK5, encoded by the epidemic L. pneumophila Lens strain. Except for LegK5, the Legionella protein kinases are all T4SS effectors. LegK2 plays a key role in bacterial virulence, as demonstrated by gene inactivation. The legK2 mutant containing vacuoles displays less-efficient recruitment of endoplasmic reticulum markers, which results in delayed intracellular replication. Considering that a kinase-dead substitution mutant of legK2 exhibits the same virulence defects, we highlight here a new molecular mechanism, namely, protein phosphorylation, developed by L. pneumophila to establish a replicative niche and evade host cell defenses. PMID:21321072

Reasons for quitting smoking among low-income African American smokers.

PubMed

McBride, C M; Pollak, K I; Bepler, G; Lyna, P; Lipkus, I M; Samsa, G P

2001-09-01

The psychometric characteristics of the Reasons For Quitting scale (RFQ) were assessed among a sample of African American smokers with low income (N=487). The intrinsic and extrinsic scales and their respective subscales were replicated. As hypothesized, higher levels of motivation were associated significantly, in patterns that supported the measure's construct validity, with advanced stage of readiness to quit smoking, greater perceived vulnerability to health effects of smoking, and greater social support for cessation. On the basis of the present study, the RFQ might best predict short-term cessation among older and female smokers. Refinement of the RFQ is needed to assess intrinsic motivators other than health concerns and to identify salient motivators for young and male smokers.

The Value of Suppressor Effects in Explicating the Construct Validity of Symptom Measures

PubMed Central

Watson, David; Clark, Lee Anna; Chmielewski, Michael; Kotov, Roman

2013-01-01

Suppressor effects are operating when the addition of a predictor increases the predictive power of another variable. We argue that suppressor effects can play a valuable role in explicating the construct validity of symptom measures by bringing into clearer focus opposing elements that are inherent—but largely hidden—in the measure’s overall score. We illustrate this point using theoretically grounded, replicated suppressor effects that have emerged in analyses of the original Inventory of Depression and Anxiety Symptoms (IDAS; Watson et al., 2007) and its expanded second version (IDAS-II; Watson et al., 2012). In Study 1, we demonstrate that the IDAS-II Appetite Gain and Appetite Loss scales contain both (a) a shared distress component that creates a positive correlation between them and (b) a specific symptom component that produces a natural negative association between them (i.e., people who recently have experienced decreased interest in food/loss of appetite are less likely to report a concomitant increase in appetite/weight). In Study 2, we establish that mania scales also contain two distinct elements—namely, high energy/positive emotionality and general distress/dysfunction—that oppose each another in many instances. In both studies, we obtained evidence of suppression effects that were highly robust across different types of respondents (e.g., clinical outpatients, community adults, college students) and using both self-report and interview-based measures. These replicable suppressor effects establish that many homogeneous, unidimensional symptom scales actually contain distinguishable components with distinct—at times, even antagonistic—properties. PMID:23795886

Systems Biology-Based Investigation of Host-Plasmodium Interactions.

PubMed

Smith, Maren L; Styczynski, Mark P

2018-05-18

Malaria is a serious, complex disease caused by parasites of the genus Plasmodium. Plasmodium parasites affect multiple tissues as they evade immune responses, replicate, sexually reproduce, and transmit between vertebrate and invertebrate hosts. The explosion of omics technologies has enabled large-scale collection of Plasmodium infection data, revealing systems-scale patterns, mechanisms of pathogenesis, and the ways that host and pathogen affect each other. Here, we provide an overview of recent efforts using systems biology approaches to study host-Plasmodium interactions and the biological themes that have emerged from these efforts. We discuss some of the challenges in using systems biology for this goal, key research efforts needed to address those issues, and promising future malaria applications of systems biology. Copyright © 2018 Elsevier Ltd. All rights reserved.

Characterization of laser-induced plasmas as a complement to high-explosive large-scale detonations

DOE PAGES

Kimblin, Clare; Trainham, Rusty; Capelle, Gene A.; ...

2017-09-12

Experimental investigations into the characteristics of laser-induced plasmas indicate that LIBS provides a relatively inexpensive and easily replicable laboratory technique to isolate and measure reactions germane to understanding aspects of high-explosive detonations under controlled conditions. Furthermore, we examine spectral signatures and derived physical parameters following laser ablation of aluminum, graphite and laser-sparked air as they relate to those observed following detonation of high explosives and as they relate to shocked air. Laser-induced breakdown spectroscopy (LIBS) reliably correlates reactions involving atomic Al and aluminum monoxide (AlO) with respect to both emission spectra and temperatures, as compared to small- and large-scale high-explosivemore » detonations. Atomic Al and AlO resulting from laser ablation and a cited small-scale study, decay within ~10 -5 s, roughly 100 times faster than the Al and AlO decay rates (~10 -3 s) observed following the large-scale detonation of an Al-encased explosive. Temperatures and species produced in laser-sparked air are compared to those produced with laser ablated graphite in air. With graphite present, CN is dominant relative to N 2 + . Thus, in studies where the height of the ablating laser's focus was altered relative to the surface of the graphite substrate, CN concentration was found to decrease with laser focus below the graphite surface, indicating that laser intensity is a critical factor in the production of CN, via reactive nitrogen.« less

Characterization of laser-induced plasmas as a complement to high-explosive large-scale detonations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kimblin, Clare; Trainham, Rusty; Capelle, Gene A.

Experimental investigations into the characteristics of laser-induced plasmas indicate that LIBS provides a relatively inexpensive and easily replicable laboratory technique to isolate and measure reactions germane to understanding aspects of high-explosive detonations under controlled conditions. Furthermore, we examine spectral signatures and derived physical parameters following laser ablation of aluminum, graphite and laser-sparked air as they relate to those observed following detonation of high explosives and as they relate to shocked air. Laser-induced breakdown spectroscopy (LIBS) reliably correlates reactions involving atomic Al and aluminum monoxide (AlO) with respect to both emission spectra and temperatures, as compared to small- and large-scale high-explosivemore » detonations. Atomic Al and AlO resulting from laser ablation and a cited small-scale study, decay within ~10 -5 s, roughly 100 times faster than the Al and AlO decay rates (~10 -3 s) observed following the large-scale detonation of an Al-encased explosive. Temperatures and species produced in laser-sparked air are compared to those produced with laser ablated graphite in air. With graphite present, CN is dominant relative to N 2 + . Thus, in studies where the height of the ablating laser's focus was altered relative to the surface of the graphite substrate, CN concentration was found to decrease with laser focus below the graphite surface, indicating that laser intensity is a critical factor in the production of CN, via reactive nitrogen.« less

Mass production of bulk artificial nacre with excellent mechanical properties.

PubMed

Gao, Huai-Ling; Chen, Si-Ming; Mao, Li-Bo; Song, Zhao-Qiang; Yao, Hong-Bin; Cölfen, Helmut; Luo, Xi-Sheng; Zhang, Fu; Pan, Zhao; Meng, Yu-Feng; Ni, Yong; Yu, Shu-Hong

2017-08-18

Various methods have been exploited to replicate nacre features into artificial structural materials with impressive structural and mechanical similarity. However, it is still very challenging to produce nacre-mimetics in three-dimensional bulk form, especially for further scale-up. Herein, we demonstrate that large-sized, three-dimensional bulk artificial nacre with comprehensive mimicry of the hierarchical structures and the toughening mechanisms of natural nacre can be facilely fabricated via a bottom-up assembly process based on laminating pre-fabricated two-dimensional nacre-mimetic films. By optimizing the hierarchical architecture from molecular level to macroscopic level, the mechanical performance of the artificial nacre is superior to that of natural nacre and many engineering materials. This bottom-up strategy has no size restriction or fundamental barrier for further scale-up, and can be easily extended to other material systems, opening an avenue for mass production of high-performance bulk nacre-mimetic structural materials in an efficient and cost-effective way for practical applications.Artificial materials that replicate the mechanical properties of nacre represent important structural materials, but are difficult to produce in bulk. Here, the authors exploit the bottom-up assembly of 2D nacre-mimetic films to fabricate 3D bulk artificial nacre with an optimized architecture and excellent mechanical properties.

Lack of association between arterial stiffness and genetic variants by genome-wide association scan.

PubMed

Park, Sungha; Lee, Ji-Young; Kim, Byeong-Keuk; Lee, Sang-Hak; Chang, Hyuk-Jae; Choi, DongHoon; Jang, Yangsoo

2015-01-01

Arterial stiffness is an independent predictor of cardiovascular disease risk. However, whether genetic risk variants are associated with arterial stiffness measures, such as pulse-wave velocity (PWV), is largely unknown. Therefore, we performed a genome-wide association study (GWAS) to identify single-nucleotide polymorphisms (SNPs) associated with PWV in a Korea population. Study participants consisted of 402 patients in the Yonsei cardiovascular genome center cohort. Arterial stiffness was measured as brachial-ankle pulse-wave velocity (baPWV). Genotyping was performed in 402 subjects with the Axiom Genome-Wide ASI 1 Array Plate containing more than 600,000 SNP markers. The findings were tested for replication in independent subjects from a community-based cohort of 1206 individuals, using a Taqman assay to include two candidate SNPs. Associations with PWV were evaluated using an additive genetic model that included age, gender, systolic blood pressure and diastolic blood pressure as covariates. GWAS and replication analyses were conducted using the measured genotype method implemented in PLINK and SAS. We observed two candidate SNPs associated with baPWV in GWAS: rs7271920 (p = 7.15 × 10(-9)) and rs10125157 (p = 8.25 × 10(-7)). However, neither of these was significant in the replication cohort. In summary, we did not identify any common genetic variants associated with baPWV in cardiovascular patients.

Differential replication dynamics for large and small Vibrio chromosomes affect gene dosage, expression and location

PubMed Central

Dryselius, Rikard; Izutsu, Kaori; Honda, Takeshi; Iida, Tetsuya

2008-01-01

Background Replication of bacterial chromosomes increases copy numbers of genes located near origins of replication relative to genes located near termini. Such differential gene dosage depends on replication rate, doubling time and chromosome size. Although little explored, differential gene dosage may influence both gene expression and location. For vibrios, a diverse family of fast growing gammaproteobacteria, gene dosage may be particularly important as they harbor two chromosomes of different size. Results Here we examined replication dynamics and gene dosage effects for the separate chromosomes of three Vibrio species. We also investigated locations for specific gene types within the genome. The results showed consistently larger gene dosage differences for the large chromosome which also initiated replication long before the small. Accordingly, large chromosome gene expression levels were generally higher and showed an influence from gene dosage. This was reflected by a higher abundance of growth essential and growth contributing genes of which many locate near the origin of replication. In contrast, small chromosome gene expression levels were low and appeared independent of gene dosage. Also, species specific genes are highly abundant and an over-representation of genes involved in transcription could explain its gene dosage independent expression. Conclusion Here we establish a link between replication dynamics and differential gene dosage on one hand and gene expression levels and the location of specific gene types on the other. For vibrios, this relationship appears connected to a polarisation of genetic content between its chromosomes, which may both contribute to and be enhanced by an improved adaptive capacity. PMID:19032792

Functional connectivity in replicated urban landscapes in the land snail (Cornu aspersum).

PubMed

Balbi, Manon; Ernoult, Aude; Poli, Pedro; Madec, Luc; Guiller, Annie; Martin, Marie-Claire; Nabucet, Jean; Beaujouan, Véronique; Petit, Eric J

2018-03-01

Urban areas are highly fragmented and thereby exert strong constraints on individual dispersal. Despite this, some species manage to persist in urban areas, such as the garden snail, Cornu aspersum, which is common in cityscapes despite its low mobility. Using landscape genetic approaches, we combined study area replication and multiscale analysis to determine how landscape composition, configuration and connectivity influence snail dispersal across urban areas. At the overall landscape scale, areas with a high percentage of roads decreased genetic differentiation between populations. At the population scale, genetic differentiation was positively linked with building surface, the proportion of borders where wooded patches and roads appeared side by side and the proportion of borders combining wooded patches and other impervious areas. Analyses based on pairwise genetic distances validated the isolation-by-distance and isolation-by-resistance models for this land snail, with an equal fit to least-cost paths and circuit-theory-based models. Each of the 12 landscapes analysed separately yielded specific relations to environmental features, whereas analyses integrating all replicates highlighted general common effects. Our results suggest that urban transport infrastructures facilitate passive snail dispersal. At a local scale, corresponding to active dispersal, unfavourable habitats (wooded and impervious areas) isolate populations. This work upholds the use of replicated landscapes to increase the generalizability of landscape genetics results and shows how multiscale analyses provide insight into scale-dependent processes. © 2018 John Wiley & Sons Ltd.

Identifying correlates of self-stigma in adults who stutter: Further establishing the construct validity of the Self-Stigma of Stuttering Scale (4S).

PubMed

Boyle, Michael P

2015-03-01

This study was set up to further establish the construct validity of the Self-Stigma of Stuttering Scale (4S) by demonstrating its associations with other established scales and replicating its original factor structure and reliability estimates. Web surveys were completed by 354 adults who stutter recruited from Board Certified Specialists in Fluency Disorders, and adult chapters of the National Stuttering Association. Participants completed a series of psychometrically validated scales measuring self-stigma, hope, empowerment, quality of life, social support, anxiety, depression, and self-rated speech disruption. Higher subscale and total stigma scores on the 4S were associated with significantly lower levels of hope, empowerment, quality of life, and social support, and significantly higher levels of anxiety, depression, and self-rated speech disruption. The original factor structure of the 4S was replicated, and reliability estimates of the subscales ranged from adequate to excellent. The findings of this study support the construct validity of the 4S and its use by clinicians and researchers intending to measure the construct of self-stigma in adults who stutter. Readers should be able to: (a) distinguish between the various components of self-stigma; (b) describe how the various components of the self-stigma model relate to hope, empowerment, quality of life, and social support, self-rated speech disruption, anxiety, and depression; (c) summarize the psychometric properties of the Self-Stigma of Stuttering Scale (4S) in terms of reliability, factor structure, and construct validity; (d) discuss how the 4S could be used in research and clinical practice. Copyright © 2015 Elsevier Inc. All rights reserved.

Identification of gaps for implementation science in the HIV prevention, care and treatment cascade; a qualitative study in 19 districts in Uganda.

PubMed

Bajunirwe, Francis; Tumwebaze, Flora; Abongomera, George; Akakimpa, Denis; Kityo, Cissy; Mugyenyi, Peter N

2016-04-14

Over the last 20 years, countries in sub Saharan Africa have made significant strides in the implementation of programs for HIV prevention, care and treatment. Despite, the significant progress made, many targets set by the United Nations have not been met. There remains a large gap between the ideal and what has been achieved. There are several operational issues that may be responsible for this gap, and these need to be addressed in order to achieve the targets. Therefore, the aim of this study was to identify gaps in the HIV prevention, care and treatment cascade, in a large district based HIV implementation program. We aimed to identify gaps that are amenable for evaluation using implementation science, in order to improve the delivery of HIV programs in rural Uganda. We conducted key informant (KI) interviews with 60 district health officers and managers of HIV/AIDS clinics and organizations and 32 focus group discussions with exit clients seeking care and treatment for HIV in the 19 districts. The data analysis process was guided using a framework approach. The recordings were transcribed verbatim. Transcripts were read back and forth and codes generated based on the framework. Nine emerging themes that comprise the gaps were identified and these were referral mechanisms indicating several loop holes, low levels of integration of HIV/TB services, low uptake of services for PMTCT services by pregnant women, low coverage of services for most at risk populations (MARPs), poor HIV coordination structures in the districts, poor continuity in the delivery of pediatric HIV/AIDS services, limited community support for orphans and vulnerable (OVC's), inadequate home based care services and HIV services and support for discordant couples. The themes indicate there are plenty of gaps that need to be covered and have been ignored by current programs. Our study has identified several gaps and suggested several interventions that should be tested before large scale implementation. The implementation of these programs should be adequately evaluated in order to provide field evidence of effectiveness and replicability in similar areas.

Use of a highly sensitive strand-specific quantitative PCR to identify abortive replication in the mouse model of respiratory syncytial virus disease

PubMed Central

2010-01-01

Background The BALB/c mouse is commonly used to study RSV infection and disease. However, despite the many advantages of this well-characterised model, the inoculum is large, viral replication is restricted and only a very small amount of virus can be recovered from infected animals. A key question in this model is the fate of the administered virus. Is replication really being measured or is the model measuring the survival of the virus over time? To answer these questions we developed a highly sensitive strand-specific quantitative PCR (QPCR) able to accurately quantify the amount of RSV replication in the BALB/c mouse lung, allowing characterisation of RSV negative and positive strand RNA dynamics. Results In the mouse lung, no increase in RSV genome was seen above the background of the original inoculum whilst only a limited transient increase (< 1 log) in positive strand, replicative intermediate (RI) RNA occurred. This RNA did however persist at detectable levels for 59 days post infection. As expected, ribavirin therapy reduced levels of infectious virus and RI RNA in the mouse lung. However, whilst Palivizumab therapy was also able to reduce levels of infectious virus, it failed to prevent production of intracellular RI RNA. A comparison of RSV RNA kinetics in human (A549) and mouse (KLN205) cell lines demonstrated that RSV replication was also severely delayed and impaired in vitro in the mouse cells. Conclusions This is the first time that such a sensitive strand-specific QPCR technique has been to the RSV mouse system. We have accurately quantified the restricted and abortive nature of RSV replication in the mouse. Further in vitro studies in human and mouse cells suggest this restricted replication is due at least in part to species-specific host cell-viral interactions. PMID:20860795

Immunochip analysis identifies association of the RAD50/IL13 region with human longevity.

PubMed

Flachsbart, Friederike; Ellinghaus, David; Gentschew, Liljana; Heinsen, Femke-Anouska; Caliebe, Amke; Christiansen, Lene; Nygaard, Marianne; Christensen, Kaare; Blanché, Hélène; Deleuze, Jean-François; Derbois, Céline; Galan, Pilar; Büning, Carsten; Brand, Stephan; Peters, Anette; Strauch, Konstantin; Müller-Nurasyid, Martina; Hoffmann, Per; Nöthen, Markus M; Lieb, Wolfgang; Franke, Andre; Schreiber, Stefan; Nebel, Almut

2016-06-01

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long-lived individuals (LLI) and 8919 younger controls. First, we performed a large-scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune-associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip-wide significant signal (PI mmunochip  = 7.01 × 10(-9) ) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with PI mmunochip  < 5 × 10(-4) for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta-analysis of the combined French and Danish data after adjusting for multiple testing. In a meta-analysis of all three samples, rs2706372 reached a P-value of PI mmunochip+Repl  = 5.42 × 10(-7) (OR = 1.20; 95% CI = 1.12-1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Suspension culture process for H9N2 avian influenza virus (strain Re-2).

PubMed

Wang, Honglin; Guo, Suying; Li, Zhenguang; Xu, Xiaoqin; Shao, Zexiang; Song, Guicai

2017-10-01

H9N2 avian influenza virus has caused huge economic loss for the Chinese poultry industry since it was first identified. Vaccination is frequently used as a control method for the disease. Meanwhile suspension culture has become an important tool for the development of influenza vaccines. To optimize the suspension culture conditions for the avian influenza H9N2 virus (Re-2 strain) in Madin-Darby Canine Kidney (MDCK) cells, we studied the culture conditions for cell growth and proliferation parameters for H9N2 virus replication. MDCK cells were successfully cultured in suspension, from a small scale to industrial levels of production, with passage time and initial cell density being optimized. The influence of pH on the culture process in the reactor has been discussed and the process parameters for industrial production were explored via amplification of the 650L reactor. Subsequently, we cultivated cells at high cell density and harvested high amounts of virus, reaching 10log2 (1:1024). Furthermore an animal experiment was conducted to detect antibody. Compared to the chicken embryo virus vaccine, virus cultured from MDCK suspension cells can produce a higher amount of antibodies. The suspension culture process is simple and cost efficient, thus providing a solid foundation for the realization of large-scale avian influenza vaccine production.

A Kinome-Wide Small Interfering RNA Screen Identifies Proviral and Antiviral Host Factors in Severe Acute Respiratory Syndrome Coronavirus Replication, Including Double-Stranded RNA-Activated Protein Kinase and Early Secretory Pathway Proteins

PubMed Central

de Wilde, Adriaan H.; Wannee, Kazimier F.; Scholte, Florine E. M.; Goeman, Jelle J.; ten Dijke, Peter; Snijder, Eric J.

2015-01-01

ABSTRACT To identify host factors relevant for severe acute respiratory syndrome-coronavirus (SARS-CoV) replication, we performed a small interfering RNA (siRNA) library screen targeting the human kinome. Protein kinases are key regulators of many cellular functions, and the systematic knockdown of their expression should provide a broad perspective on factors and pathways promoting or antagonizing coronavirus replication. In addition to 40 proteins that promote SARS-CoV replication, our study identified 90 factors exhibiting an antiviral effect. Pathway analysis grouped subsets of these factors in specific cellular processes, including the innate immune response and the metabolism of complex lipids, which appear to play a role in SARS-CoV infection. Several factors were selected for in-depth validation in follow-up experiments. In cells depleted for the β2 subunit of the coatomer protein complex (COPB2), the strongest proviral hit, we observed reduced SARS-CoV protein expression and a >2-log reduction in virus yield. Knockdown of the COPB2-related proteins COPB1 and Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) also suggested that COPI-coated vesicles and/or the early secretory pathway are important for SARS-CoV replication. Depletion of the antiviral double-stranded RNA-activated protein kinase (PKR) enhanced virus replication in the primary screen, and validation experiments confirmed increased SARS-CoV protein expression and virus production upon PKR depletion. In addition, cyclin-dependent kinase 6 (CDK6) was identified as a novel antiviral host factor in SARS-CoV replication. The inventory of pro- and antiviral host factors and pathways described here substantiates and expands our understanding of SARS-CoV replication and may contribute to the identification of novel targets for antiviral therapy. IMPORTANCE Replication of all viruses, including SARS-CoV, depends on and is influenced by cellular pathways. Although substantial progress has been made in dissecting the coronavirus replicative cycle, our understanding of the host factors that stimulate (proviral factors) or restrict (antiviral factors) infection remains far from complete. To study the role of host proteins in SARS-CoV infection, we set out to systematically identify kinase-regulated processes that influence virus replication. Protein kinases are key regulators in signal transduction, controlling a wide variety of cellular processes, and many of them are targets of approved drugs and other compounds. Our screen identified a variety of hits and will form the basis for more detailed follow-up studies that should contribute to a better understanding of SARS-CoV replication and coronavirus-host interactions in general. The identified factors could be interesting targets for the development of host-directed antiviral therapy to treat infections with SARS-CoV or other pathogenic coronaviruses. PMID:26041291

Complex, multi-scale small intestinal topography replicated in cellular growth substrates fabricated via chemical vapor deposition of Parylene C.

PubMed

Koppes, Abigail N; Kamath, Megha; Pfluger, Courtney A; Burkey, Daniel D; Dokmeci, Mehmet; Wang, Lin; Carrier, Rebecca L

2016-08-22

Native small intestine possesses distinct multi-scale structures (e.g., crypts, villi) not included in traditional 2D intestinal culture models for drug delivery and regenerative medicine. The known impact of structure on cell function motivates exploration of the influence of intestinal topography on the phenotype of cultured epithelial cells, but the irregular, macro- to submicron-scale features of native intestine are challenging to precisely replicate in cellular growth substrates. Herein, we utilized chemical vapor deposition of Parylene C on decellularized porcine small intestine to create polymeric intestinal replicas containing biomimetic irregular, multi-scale structures. These replicas were used as molds for polydimethylsiloxane (PDMS) growth substrates with macro to submicron intestinal topographical features. Resultant PDMS replicas exhibit multiscale resolution including macro- to micro-scale folds, crypt and villus structures, and submicron-scale features of the underlying basement membrane. After 10 d of human epithelial colorectal cell culture on PDMS substrates, the inclusion of biomimetic topographical features enhanced alkaline phosphatase expression 2.3-fold compared to flat controls, suggesting biomimetic topography is important in induced epithelial differentiation. This work presents a facile, inexpensive method for precisely replicating complex hierarchal features of native tissue, towards a new model for regenerative medicine and drug delivery for intestinal disorders and diseases.

Discovery of the first insect nidovirus, a missing evolutionary link in the emergence of the largest RNA virus genomes.

PubMed

Nga, Phan Thi; Parquet, Maria del Carmen; Lauber, Chris; Parida, Manmohan; Nabeshima, Takeshi; Yu, Fuxun; Thuy, Nguyen Thanh; Inoue, Shingo; Ito, Takashi; Okamoto, Kenta; Ichinose, Akitoyo; Snijder, Eric J; Morita, Kouichi; Gorbalenya, Alexander E

2011-09-01

Nidoviruses with large genomes (26.3-31.7 kb; 'large nidoviruses'), including Coronaviridae and Roniviridae, are the most complex positive-sense single-stranded RNA (ssRNA+) viruses. Based on genome size, they are far separated from all other ssRNA+ viruses (below 19.6 kb), including the distantly related Arteriviridae (12.7-15.7 kb; 'small nidoviruses'). Exceptionally for ssRNA+ viruses, large nidoviruses encode a 3'-5'exoribonuclease (ExoN) that was implicated in controlling RNA replication fidelity. Its acquisition may have given rise to the ancestor of large nidoviruses, a hypothesis for which we here provide evolutionary support using comparative genomics involving the newly discovered first insect-borne nidovirus. This Nam Dinh virus (NDiV), named after a Vietnamese province, was isolated from mosquitoes and is yet to be linked to any pathology. The genome of this enveloped 60-80 nm virus is 20,192 nt and has a nidovirus-like polycistronic organization including two large, partially overlapping open reading frames (ORF) 1a and 1b followed by several smaller 3'-proximal ORFs. Peptide sequencing assigned three virion proteins to ORFs 2a, 2b, and 3, which are expressed from two 3'-coterminal subgenomic RNAs. The NDiV ORF1a/ORF1b frameshifting signal and various replicative proteins were tentatively mapped to canonical positions in the nidovirus genome. They include six nidovirus-wide conserved replicase domains, as well as the ExoN and 2'-O-methyltransferase that are specific to large nidoviruses. NDiV ORF1b also encodes a putative N7-methyltransferase, identified in a subset of large nidoviruses, but not the uridylate-specific endonuclease that - in deviation from the current paradigm - is present exclusively in the currently known vertebrate nidoviruses. Rooted phylogenetic inference by Bayesian and Maximum Likelihood methods indicates that NDiV clusters with roniviruses and that its branch diverged from large nidoviruses early after they split from small nidoviruses. Together these characteristics identify NDiV as the prototype of a new nidovirus family and a missing link in the transition from small to large nidoviruses.

Genetic and neurodevelopmental influences in autistic disorder.

PubMed

Nicolson, Rob; Szatmari, Peter

2003-09-01

In the past, autism was considered to be largely psychogenic. However, research in the last 2 decades indicates that autism is largely caused by genetic factors that lead to abnormal brain development. This article reviews research into the genetic and neurodevelopmental factors underlying autism. We review the findings from genetic and brain-imaging studies of autism over the past 15 years and synthesize these findings as a guide for future research. Genome scans and association studies have suggested potential genomic regions and genes, respectively, that may be involved in the etiology of autism, and there have been some replications of these results. Similarly, the findings that brain volume is exaggerated in autism and corpus callosum size is reduced have also been independently replicated. Unfortunately, studies of other subcortical structures remain inconclusive or contradictory. Overwhelming evidence now supports a neurobiological basis for autism. However, further refinements will be needed to guide future studies, particularly to identify the most informative phenotypes to investigate. Additionally, studies examining the role of genetic factors in the brain abnormalities underlying autism will likely lead to further findings that will enhance our understanding of autism's causes.

Circular replication-associated protein encoding DNA viruses identified in the faecal matter of various animals in New Zealand.

PubMed

Steel, Olivia; Kraberger, Simona; Sikorski, Alyssa; Young, Laura M; Catchpole, Ryan J; Stevens, Aaron J; Ladley, Jenny J; Coray, Dorien S; Stainton, Daisy; Dayaram, Anisha; Julian, Laurel; van Bysterveldt, Katherine; Varsani, Arvind

2016-09-01

In recent years, innovations in molecular techniques and sequencing technologies have resulted in a rapid expansion in the number of known viral sequences, in particular those with circular replication-associated protein (Rep)-encoding single-stranded (CRESS) DNA genomes. CRESS DNA viruses are present in the virome of many ecosystems and are known to infect a wide range of organisms. A large number of the recently identified CRESS DNA viruses cannot be classified into any known viral families, indicating that the current view of CRESS DNA viral sequence space is greatly underestimated. Animal faecal matter has proven to be a particularly useful source for sampling CRESS DNA viruses in an ecosystem, as it is cost-effective and non-invasive. In this study a viral metagenomic approach was used to explore the diversity of CRESS DNA viruses present in the faeces of domesticated and wild animals in New Zealand. Thirty-eight complete CRESS DNA viral genomes and two circular molecules (that may be defective molecules or single components of multicomponent genomes) were identified from forty-nine individual animal faecal samples. Based on shared genome organisations and sequence similarities, eighteen of the isolates were classified as gemycircularviruses and twelve isolates were classified as smacoviruses. The remaining eight isolates lack significant sequence similarity with any members of known CRESS DNA virus groups. This research adds significantly to our knowledge of CRESS DNA viral diversity in New Zealand, emphasising the prevalence of CRESS DNA viruses in nature, and reinforcing the suggestion that a large proportion of CRESS DNA viruses are yet to be identified. Copyright © 2016 Elsevier B.V. All rights reserved.

Psychometrically Improved, Abbreviated Versions of Three Classic Measures of Impulsivity and Self-Control

PubMed Central

Morean, Meghan E.; DeMartini, Kelly S.; Leeman, Robert F.; Pearlson, Godfrey D.; Anticevic, Alan; Krishnan-Sarin, Suchitra; Krystal, John H.; O’Malley, Stephanie S.

2014-01-01

Self-reported impulsivity confers risk factor for substance abuse. However, the psychometric properties of many self-report impulsivity measures have been questioned, thereby undermining the interpretability of study findings using these measures. To better understand these measurement limitations and to suggest a path to assessing self-reported impulsivity with greater psychometric stability, we conducted a comprehensive psychometric evaluation of the Barratt Impulsiveness Scale-11 (BIS-11), the Behavioral Inhibition and Activation Scales (BIS/BAS), and the Brief Self Control Scale (BSCS) using data from 1,449 individuals who participated in substance use research. For each measure, we evaluated: 1) latent factor structure, 2) measurement invariance, 3) test-criterion relationships between the measures, and 4) test-criterion relations with drinking and smoking outcomes. Notably, we could not replicate the originally published latent structure for the BIS, BIS/BAS, or BSCS or any previously published alternative factor structures (English language). Using exploratory and confirmatory factor analysis, we identified psychometrically improved, abbreviated versions of each measure (i.e., 8-item, 2 factor BIS-11 [RMSEA = .06, CFI = .95]; 13-item, 4 factor BIS/BAS [RMSEA = .04, CFI = .96]; 7-item, 2 factor BSCS [RMSEA = .05, CFI = .96]). These versions evidenced: 1) stable, replicable factor structures, 2) scalar measurement invariance, ensuring our ability to make statistically interpretable comparisons across subgroups of interest (e.g., sex, race, drinking/smoking status), and 3) test-criterion relationships with each other and with drinking/smoking. This study provides strong support for using these psychometrically improved impulsivity measures, which improve data quality directly through better scale properties and indirectly through reducing response burden. PMID:24885848

An analysis of variability in the manufacturing of dexosomes: implications for development of an autologous therapy.

PubMed

Patel, Sanjay; Mehta-Damani, Anita; Shu, Helen; Le Pecq, Jean-Bernard

2005-10-20

Dexosomes are nanometer-size vesicles released by dendritic-cells, possessing much of the cellular machinery required to stimulate an immune response (i.e. MHC Class I and II). The ability of patient-derived dexosomes loaded with tumor antigens to elicit anti-tumor activity is currently being evaluated in clinical trials. Unlike conventional biologics, where variability between lots of product arises mostly from the manufacturing process, an autologous product has inherent variability in the starting material due to heterogeneity in the human population. In an effort to assess the variability arising from the dexosome manufacturing process versus the human starting material, 144 dexosome preparations from normal donors (111) and cancer patients (33) from two Phase I clinical trials were analyzed. A large variability in the quantity of dexosomes (measured as the number of MHC Class II molecules) produced between individual lots was observed ( > 50-fold). An analysis of intra-lot variability shows that the manufacturing process introduces relatively little of this variability. To identify the source(s) of variability arising from the human starting material, distributions of the key parameters involved in dexosome production were established, and a model created. Computer simulations using this model were performed, and compared to the actual data observed. The main conclusion from these simulations is that the number of cells collected per individual and the productivity of these cells of are the principal sources of variability in the production of Class II. The approach described here can be extended to other autologous therapies in general to evaluate control of manufacturing processes. Moreover, this analysis of process variability is directly applicable to production at a commercial scale, since the large scale manufacture of autologous products entails an exact process replication rather than scale-up in volume, as is the case with traditional drugs or biologics. Copyright 2005 Wiley Periodicals, Inc.

Social influence and political mobilization: Further evidence from a randomized experiment in the 2012 U.S. presidential election

PubMed Central

Bond, Robert M.; Bakshy, Eytan; Eckles, Dean; Fowler, James H.

2017-01-01

A large-scale experiment during the 2010 U.S. Congressional Election demonstrated a positive effect of an online get-out-the-vote message on real world voting behavior. Here, we report results from a replication of the experiment conducted during the U.S. Presidential Election in 2012. In spite of the fact that get-out-the-vote messages typically yield smaller effects during high-stakes elections due to saturation of mobilization efforts from many sources, a significant increase in voting was again observed. Voting also increased significantly among the close friends of those who received the message to go to the polls, and the total effect on the friends was likely larger than the direct effect, suggesting that understanding social influence effects is potentially even more important than understanding the direct effects of messaging. These results replicate earlier work and they add to growing evidence that online social networks can be instrumental for spreading offline behaviors. PMID:28445476

Social influence and political mobilization: Further evidence from a randomized experiment in the 2012 U.S. presidential election.

PubMed

Jones, Jason J; Bond, Robert M; Bakshy, Eytan; Eckles, Dean; Fowler, James H

2017-01-01

A large-scale experiment during the 2010 U.S. Congressional Election demonstrated a positive effect of an online get-out-the-vote message on real world voting behavior. Here, we report results from a replication of the experiment conducted during the U.S. Presidential Election in 2012. In spite of the fact that get-out-the-vote messages typically yield smaller effects during high-stakes elections due to saturation of mobilization efforts from many sources, a significant increase in voting was again observed. Voting also increased significantly among the close friends of those who received the message to go to the polls, and the total effect on the friends was likely larger than the direct effect, suggesting that understanding social influence effects is potentially even more important than understanding the direct effects of messaging. These results replicate earlier work and they add to growing evidence that online social networks can be instrumental for spreading offline behaviors.

Self-assembled biomimetic antireflection coatings

NASA Astrophysics Data System (ADS)

Linn, Nicholas C.; Sun, Chih-Hung; Jiang, Peng; Jiang, Bin

2007-09-01

The authors report a simple self-assembly technique for fabricating antireflection coatings that mimic antireflective moth eyes. Wafer-scale, nonclose-packed colloidal crystals with remarkable large hexagonal domains are created by a spin-coating technology. The resulting polymer-embedded colloidal crystals exhibit highly ordered surface modulation and can be used directly as templates to cast poly(dimethylsiloxane) (PDMS) molds. Moth-eye antireflection coatings with adjustable reflectivity can then be molded against the PDMS master. The specular reflection of replicated nipple arrays matches the theoretical prediction using a thin-film multilayer model. These biomimetic films may find important technological application in optical coatings and solar cells.

Long Island Solar Farm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anders, R.

2013-05-01

The Long Island Solar Farm (LISF) is a remarkable success story, whereby very different interest groups found a way to capitalize on unusual circumstances to develop a mutually beneficial source of renewable energy. The uniqueness of the circumstances that were necessary to develop the Long Island Solar Farm make it very difficult to replicate. The project is, however, an unparalleled resource for solar energy research, which will greatly inform large-scale PV solar development in the East. Lastly, the LISF is a superb model for the process by which the project developed and the innovation and leadership shown by the differentmore » players.« less

Error-free replicative bypass of (6–4) photoproducts by DNA polymerase ζ in mouse and human cells

PubMed Central

Yoon, Jung-Hoon; Prakash, Louise; Prakash, Satya

2010-01-01

The ultraviolet (UV)-induced (6–4) pyrimidine–pyrimidone photoproduct [(6–4) PP] confers a large structural distortion in DNA. Here we examine in human cells the roles of translesion synthesis (TLS) DNA polymerases (Pols) in promoting replication through a (6–4) TT photoproduct carried on a duplex plasmid where bidirectional replication initiates from an origin of replication. We show that TLS contributes to a large fraction of lesion bypass and that it is mostly error-free. We find that, whereas Pol η and Pol ι provide alternate pathways for mutagenic TLS, surprisingly, Pol ζ functions independently of these Pols and in a predominantly error-free manner. We verify and extend these observations in mouse cells and conclude that, in human cells, TLS during replication can be markedly error-free even opposite a highly distorting DNA lesion. PMID:20080950

The Observations of Redshift Evolution in Large Scale Environments (ORELSE) Survey

NASA Astrophysics Data System (ADS)

Squires, Gordon K.; Lubin, L. M.; Gal, R. R.

2007-05-01

We present the motivation, design, and latest results from the Observations of Redshift Evolution in Large Scale Environments (ORELSE) Survey, a systematic search for structure on scales greater than 10 Mpc around 20 known galaxy clusters at z > 0.6. When complete, the survey will cover nearly 5 square degrees, all targeted at high-density regions, making it complementary and comparable to field surveys such as DEEP2, GOODS, and COSMOS. For the survey, we are using the Large Format Camera on the Palomar 5-m and SuPRIME-Cam on the Subaru 8-m to obtain optical/near-infrared imaging of an approximately 30 arcmin region around previously studied high-redshift clusters. Colors are used to identify likely member galaxies which are targeted for follow-up spectroscopy with the DEep Imaging Multi-Object Spectrograph on the Keck 10-m. This technique has been used to identify successfully the Cl 1604 supercluster at z = 0.9, a large scale structure containing at least eight clusters (Gal & Lubin 2004; Gal, Lubin & Squires 2005). We present the most recent structures to be photometrically and spectroscopically confirmed through this program, discuss the properties of the member galaxies as a function of environment, and describe our planned multi-wavelength (radio, mid-IR, and X-ray) observations of these systems. The goal of this survey is to identify and examine a statistical sample of large scale structures during an active period in the assembly history of the most massive clusters. With such a sample, we can begin to constrain large scale cluster dynamics and determine the effect of the larger environment on galaxy evolution.

Ventilation tube insertion simulation: a literature review and validity assessment of five training models.

PubMed

Mahalingam, S; Awad, Z; Tolley, N S; Khemani, S

2016-08-01

The objective of this study was to identify and investigate the face and content validity of ventilation tube insertion (VTI) training models described in the literature. A review of literature was carried out to identify articles describing VTI simulators. Feasible models were replicated and assessed by a group of experts. Postgraduate simulation centre. Experts were defined as surgeons who had performed at least 100 VTI on patients. Seventeen experts were participated ensuring sufficient statistical power for analysis. A standardised 18-item Likert-scale questionnaire was used. This addressed face validity (realism), global and task-specific content (suitability of the model for teaching) and curriculum recommendation. The search revealed eleven models, of which only five had associated validity data. Five models were found to be feasible to replicate. None of the tested models achieved face or global content validity. Only one model achieved task-specific validity, and hence, there was no agreement on curriculum recommendation. The quality of simulation models is moderate and there is room for improvement. There is a need for new models to be developed or existing ones to be refined in order to construct a more realistic training platform for VTI simulation. © 2015 John Wiley & Sons Ltd.

USP7 is a SUMO deubiquitinase essential for DNA replication.

PubMed

Lecona, Emilio; Rodriguez-Acebes, Sara; Specks, Julia; Lopez-Contreras, Andres J; Ruppen, Isabel; Murga, Matilde; Muñoz, Javier; Mendez, Juan; Fernandez-Capetillo, Oscar

2016-04-01

Post-translational modification of proteins by ubiquitin (Ub) and Ub-like modifiers regulates DNA replication. We have previously shown that chromatin around replisomes is rich in SUMO and poor in Ub, whereas mature chromatin exhibits an opposite pattern. How this SUMO-rich, Ub-poor environment is maintained at sites of DNA replication in mammalian cells remains unexplored. Here we identify USP7 as a replisome-enriched SUMO deubiquitinase that is essential for DNA replication. By acting on SUMO and SUMOylated proteins, USP7 counteracts their ubiquitination. Inhibition or genetic deletion of USP7 leads to the accumulation of Ub on SUMOylated proteins, which are displaced away from replisomes. Our findings provide a model explaining the differential accumulation of SUMO and Ub at replication forks and identify an essential role of USP7 in DNA replication that should be considered in the development of USP7 inhibitors as anticancer agents.

Inferring cortical function in the mouse visual system through large-scale systems neuroscience.

PubMed

Hawrylycz, Michael; Anastassiou, Costas; Arkhipov, Anton; Berg, Jim; Buice, Michael; Cain, Nicholas; Gouwens, Nathan W; Gratiy, Sergey; Iyer, Ramakrishnan; Lee, Jung Hoon; Mihalas, Stefan; Mitelut, Catalin; Olsen, Shawn; Reid, R Clay; Teeter, Corinne; de Vries, Saskia; Waters, Jack; Zeng, Hongkui; Koch, Christof

2016-07-05

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

OpenSHS: Open Smart Home Simulator.

PubMed

Alshammari, Nasser; Alshammari, Talal; Sedky, Mohamed; Champion, Justin; Bauer, Carolin

2017-05-02

This paper develops a new hybrid, open-source, cross-platform 3D smart home simulator, OpenSHS, for dataset generation. OpenSHS offers an opportunity for researchers in the field of the Internet of Things (IoT) and machine learning to test and evaluate their models. Following a hybrid approach, OpenSHS combines advantages from both interactive and model-based approaches. This approach reduces the time and efforts required to generate simulated smart home datasets. We have designed a replication algorithm for extending and expanding a dataset. A small sample dataset produced, by OpenSHS, can be extended without affecting the logical order of the events. The replication provides a solution for generating large representative smart home datasets. We have built an extensible library of smart devices that facilitates the simulation of current and future smart home environments. Our tool divides the dataset generation process into three distinct phases: first design: the researcher designs the initial virtual environment by building the home, importing smart devices and creating contexts; second, simulation: the participant simulates his/her context-specific events; and third, aggregation: the researcher applies the replication algorithm to generate the final dataset. We conducted a study to assess the ease of use of our tool on the System Usability Scale (SUS).

From Hayflick to Walford: the role of T cell replicative senescence in human aging.

PubMed

Effros, Rita B

2004-06-01

The immunologic theory of aging, proposed more than 40 years ago by Roy Walford, suggests that the normal process of aging in man and in animals is pathogenetically related to faulty immunological processes. Since that time, research on immunological aging has undergone extraordinary expansion, leading to new information in areas spanning from molecular biology and cell signaling to large-scale clinical studies. Investigation in this area has also provided unexpected insights into HIV disease, many aspects of which represent accelerated immunological aging. This article describes the initial insights and vision of Roy Walford into one particular facet of human immunological aging, namely, the potential relevance of the well-studied human fibroblast replicative senescence model, initially developed by Leonard Hayflick, to cells of the immune system. Extensive research on T cell senescence in cell culture has now documented changes in vitro that closely mirror alterations occurring during in vivo aging in humans, underscoring the biological significance of T cell replicative senescence. Moreover, the inclusion of high proportions of putatively senescent T cells in the 'immune risk phenotype' that is associated with early mortality in octogenarians provides initial clinical confirmation of both the immunologic theory of aging and the role of the T cell Hayflick Limit in human aging, two areas of gerontological research pioneered by Roy Walford.

COS-7-based model: methodological approach to study John Cunningham virus replication cycle.

PubMed

Prezioso, C; Scribano, D; Rodio, D M; Ambrosi, C; Trancassini, M; Palamara, A T; Pietropaolo, V

2018-02-05

John Cunningham virus (JCV) is a human neurotropic polyomavirus whose replication in the Central Nervous System (SNC) induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV propagation and PML investigation have been severely hampered by the lack of an animal model and cell culture systems to propagate JCV have been very limited in their availability and robustness. We previously confirmed that JCV CY strain efficiently replicated in COS-7 cells as demonstrated by the progressive increase of viral load by quantitative PCR (Q-PCR) during the time of transfection and that archetypal regulatory structure was maintained, although two characteristic point mutations were detected during the viral cycle. This short report is an important extension of our previous efforts in defining our reliable model culture system able to support a productive JCV infection.Supernatants collected from transfected cells have been used to infect freshly seeded COS-7 cell line. An infectious viral progeny was obtained as confirmed by Western blot and immunofluorescence assay. During infection, the archetype regulatory region was conserved.Importantly, in this study we developed an improved culture system to obtain a large scale production of JC virus in order to study the genetic features, the biology and the pathogenic mechanisms of JC virus that induce PML.

OpenSHS: Open Smart Home Simulator

PubMed Central

Alshammari, Nasser; Alshammari, Talal; Sedky, Mohamed; Champion, Justin; Bauer, Carolin

2017-01-01

This paper develops a new hybrid, open-source, cross-platform 3D smart home simulator, OpenSHS, for dataset generation. OpenSHS offers an opportunity for researchers in the field of the Internet of Things (IoT) and machine learning to test and evaluate their models. Following a hybrid approach, OpenSHS combines advantages from both interactive and model-based approaches. This approach reduces the time and efforts required to generate simulated smart home datasets. We have designed a replication algorithm for extending and expanding a dataset. A small sample dataset produced, by OpenSHS, can be extended without affecting the logical order of the events. The replication provides a solution for generating large representative smart home datasets. We have built an extensible library of smart devices that facilitates the simulation of current and future smart home environments. Our tool divides the dataset generation process into three distinct phases: first design: the researcher designs the initial virtual environment by building the home, importing smart devices and creating contexts; second, simulation: the participant simulates his/her context-specific events; and third, aggregation: the researcher applies the replication algorithm to generate the final dataset. We conducted a study to assess the ease of use of our tool on the System Usability Scale (SUS). PMID:28468330

Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type.

PubMed

Green, Elaine K; Di Florio, Arianna; Forty, Liz; Gordon-Smith, Katherine; Grozeva, Detelina; Fraser, Christine; Richards, Alexander L; Moran, Jennifer L; Purcell, Shaun; Sklar, Pamela; Kirov, George; Owen, Michael J; O'Donovan, Michael C; Craddock, Nick; Jones, Lisa; Jones, Ian R

2017-12-01

Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10 -5 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10 -8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder. © 2017 Wiley Periodicals, Inc.

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

PubMed

Wain, Louise V; Vaez, Ahmad; Jansen, Rick; Joehanes, Roby; van der Most, Peter J; Erzurumluoglu, A Mesut; O'Reilly, Paul F; Cabrera, Claudia P; Warren, Helen R; Rose, Lynda M; Verwoert, Germaine C; Hottenga, Jouke-Jan; Strawbridge, Rona J; Esko, Tonu; Arking, Dan E; Hwang, Shih-Jen; Guo, Xiuqing; Kutalik, Zoltan; Trompet, Stella; Shrine, Nick; Teumer, Alexander; Ried, Janina S; Bis, Joshua C; Smith, Albert V; Amin, Najaf; Nolte, Ilja M; Lyytikäinen, Leo-Pekka; Mahajan, Anubha; Wareham, Nicholas J; Hofer, Edith; Joshi, Peter K; Kristiansson, Kati; Traglia, Michela; Havulinna, Aki S; Goel, Anuj; Nalls, Mike A; Sõber, Siim; Vuckovic, Dragana; Luan, Jian'an; Del Greco M, Fabiola; Ayers, Kristin L; Marrugat, Jaume; Ruggiero, Daniela; Lopez, Lorna M; Niiranen, Teemu; Enroth, Stefan; Jackson, Anne U; Nelson, Christopher P; Huffman, Jennifer E; Zhang, Weihua; Marten, Jonathan; Gandin, Ilaria; Harris, Sarah E; Zemunik, Tatijana; Lu, Yingchang; Evangelou, Evangelos; Shah, Nabi; de Borst, Martin H; Mangino, Massimo; Prins, Bram P; Campbell, Archie; Li-Gao, Ruifang; Chauhan, Ganesh; Oldmeadow, Christopher; Abecasis, Gonçalo; Abedi, Maryam; Barbieri, Caterina M; Barnes, Michael R; Batini, Chiara; Beilby, John; Blake, Tineka; Boehnke, Michael; Bottinger, Erwin P; Braund, Peter S; Brown, Morris; Brumat, Marco; Campbell, Harry; Chambers, John C; Cocca, Massimiliano; Collins, Francis; Connell, John; Cordell, Heather J; Damman, Jeffrey J; Davies, Gail; de Geus, Eco J; de Mutsert, Renée; Deelen, Joris; Demirkale, Yusuf; Doney, Alex S F; Dörr, Marcus; Farrall, Martin; Ferreira, Teresa; Frånberg, Mattias; Gao, He; Giedraitis, Vilmantas; Gieger, Christian; Giulianini, Franco; Gow, Alan J; Hamsten, Anders; Harris, Tamara B; Hofman, Albert; Holliday, Elizabeth G; Hui, Jennie; Jarvelin, Marjo-Riitta; Johansson, Åsa; Johnson, Andrew D; Jousilahti, Pekka; Jula, Antti; Kähönen, Mika; Kathiresan, Sekar; Khaw, Kay-Tee; Kolcic, Ivana; Koskinen, Seppo; Langenberg, Claudia; Larson, Marty; Launer, Lenore J; Lehne, Benjamin; Liewald, David C M; Lin, Li; Lind, Lars; Mach, François; Mamasoula, Chrysovalanto; Menni, Cristina; Mifsud, Borbala; Milaneschi, Yuri; Morgan, Anna; Morris, Andrew D; Morrison, Alanna C; Munson, Peter J; Nandakumar, Priyanka; Nguyen, Quang Tri; Nutile, Teresa; Oldehinkel, Albertine J; Oostra, Ben A; Org, Elin; Padmanabhan, Sandosh; Palotie, Aarno; Paré, Guillaume; Pattie, Alison; Penninx, Brenda W J H; Poulter, Neil; Pramstaller, Peter P; Raitakari, Olli T; Ren, Meixia; Rice, Kenneth; Ridker, Paul M; Riese, Harriëtte; Ripatti, Samuli; Robino, Antonietta; Rotter, Jerome I; Rudan, Igor; Saba, Yasaman; Saint Pierre, Aude; Sala, Cinzia F; Sarin, Antti-Pekka; Schmidt, Reinhold; Scott, Rodney; Seelen, Marc A; Shields, Denis C; Siscovick, David; Sorice, Rossella; Stanton, Alice; Stott, David J; Sundström, Johan; Swertz, Morris; Taylor, Kent D; Thom, Simon; Tzoulaki, Ioanna; Tzourio, Christophe; Uitterlinden, André G; Völker, Uwe; Vollenweider, Peter; Wild, Sarah; Willemsen, Gonneke; Wright, Alan F; Yao, Jie; Thériault, Sébastien; Conen, David; Attia, John; Sever, Peter; Debette, Stéphanie; Mook-Kanamori, Dennis O; Zeggini, Eleftheria; Spector, Tim D; van der Harst, Pim; Palmer, Colin N A; Vergnaud, Anne-Claire; Loos, Ruth J F; Polasek, Ozren; Starr, John M; Girotto, Giorgia; Hayward, Caroline; Kooner, Jaspal S; Lindgren, Cecila M; Vitart, Veronique; Samani, Nilesh J; Tuomilehto, Jaakko; Gyllensten, Ulf; Knekt, Paul; Deary, Ian J; Ciullo, Marina; Elosua, Roberto; Keavney, Bernard D; Hicks, Andrew A; Scott, Robert A; Gasparini, Paolo; Laan, Maris; Liu, YongMei; Watkins, Hugh; Hartman, Catharina A; Salomaa, Veikko; Toniolo, Daniela; Perola, Markus; Wilson, James F; Schmidt, Helena; Zhao, Jing Hua; Lehtimäki, Terho; van Duijn, Cornelia M; Gudnason, Vilmundur; Psaty, Bruce M; Peters, Annette; Rettig, Rainer; James, Alan; Jukema, J Wouter; Strachan, David P; Palmas, Walter; Metspalu, Andres; Ingelsson, Erik; Boomsma, Dorret I; Franco, Oscar H; Bochud, Murielle; Newton-Cheh, Christopher; Munroe, Patricia B; Elliott, Paul; Chasman, Daniel I; Chakravarti, Aravinda; Knight, Joanne; Morris, Andrew P; Levy, Daniel; Tobin, Martin D; Snieder, Harold; Caulfield, Mark J; Ehret, Georg B

2017-07-24

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7 , TNXB , LRP12 , LOC283335 , SEPT9 , and AKT2 , and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation. © 2017 American Heart Association, Inc.

Mathematical Modeling of Protein Misfolding Mechanisms in Neurological Diseases: A Historical Overview.

PubMed

Carbonell, Felix; Iturria-Medina, Yasser; Evans, Alan C

2018-01-01

Protein misfolding refers to a process where proteins become structurally abnormal and lose their specific 3-dimensional spatial configuration. The histopathological presence of misfolded protein (MP) aggregates has been associated as the primary evidence of multiple neurological diseases, including Prion diseases, Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease. However, the exact mechanisms of MP aggregation and propagation, as well as their impact in the long-term patient's clinical condition are still not well understood. With this aim, a variety of mathematical models has been proposed for a better insight into the kinetic rate laws that govern the microscopic processes of protein aggregation. Complementary, another class of large-scale models rely on modern molecular imaging techniques for describing the phenomenological effects of MP propagation over the whole brain. Unfortunately, those neuroimaging-based studies do not take full advantage of the tremendous capabilities offered by the chemical kinetics modeling approach. Actually, it has been barely acknowledged that the vast majority of large-scale models have foundations on previous mathematical approaches that describe the chemical kinetics of protein replication and propagation. The purpose of the current manuscript is to present a historical review about the development of mathematical models for describing both microscopic processes that occur during the MP aggregation and large-scale events that characterize the progression of neurodegenerative MP-mediated diseases.

Delayed Effects of a Low-Cost and Large-Scale Summer Reading Intervention on Elementary School Children's Reading Comprehension

ERIC Educational Resources Information Center

Kim, James S.; Guryan, Jonathan; White, Thomas G.; Quinn, David M.; Capotosto, Lauren; Kingston, Helen Chen

2016-01-01

To improve the reading comprehension outcomes of children in high-poverty schools, policymakers need to identify reading interventions that show promise of effectiveness at scale. This study evaluated the effectiveness of a low-cost and large-scale summer reading intervention that provided comprehension lessons at the end of the school year and…

DNA barcoding at riverscape scales: Assessing biodiversity among fishes of the genus Cottus (Teleostei) in northern Rocky Mountain streams

Treesearch

Michael K. Young; Kevin S. McKelvey; Kristine L. Pilgrim; Michael K. Schwartz

2013-01-01

There is growing interest in broad-scale biodiversity assessments that can serve as benchmarks for identifying ecological change. Genetic tools have been used for such assessments for decades, but spatial sampling considerations have largely been ignored. Here, we demonstrate how intensive sampling efforts across a large geographical scale can influence identification...

Genome-wide meta-analyses of stratified depression in Generation Scotland and UK Biobank.

PubMed

Hall, Lynsey S; Adams, Mark J; Arnau-Soler, Aleix; Clarke, Toni-Kim; Howard, David M; Zeng, Yanni; Davies, Gail; Hagenaars, Saskia P; Maria Fernandez-Pujals, Ana; Gibson, Jude; Wigmore, Eleanor M; Boutin, Thibaud S; Hayward, Caroline; Scotland, Generation; Porteous, David J; Deary, Ian J; Thomson, Pippa A; Haley, Chris S; McIntosh, Andrew M

2018-01-10

Few replicable genetic associations for Major Depressive Disorder (MDD) have been identified. Recent studies of MDD have identified common risk variants by using a broader phenotype definition in very large samples, or by reducing phenotypic and ancestral heterogeneity. We sought to ascertain whether it is more informative to maximize the sample size using data from all available cases and controls, or to use a sex or recurrent stratified subset of affected individuals. To test this, we compared heritability estimates, genetic correlation with other traits, variance explained by MDD polygenic score, and variants identified by genome-wide meta-analysis for broad and narrow MDD classifications in two large British cohorts - Generation Scotland and UK Biobank. Genome-wide meta-analysis of MDD in males yielded one genome-wide significant locus on 3p22.3, with three genes in this region (CRTAP, GLB1, and TMPPE) demonstrating a significant association in gene-based tests. Meta-analyzed MDD, recurrent MDD and female MDD yielded equivalent heritability estimates, showed no detectable difference in association with polygenic scores, and were each genetically correlated with six health-correlated traits (neuroticism, depressive symptoms, subjective well-being, MDD, a cross-disorder phenotype and Bipolar Disorder). Whilst stratified GWAS analysis revealed a genome-wide significant locus for male MDD, the lack of independent replication, and the consistent pattern of results in other MDD classifications suggests that phenotypic stratification using recurrence or sex in currently available sample sizes is currently weakly justified. Based upon existing studies and our findings, the strategy of maximizing sample sizes is likely to provide the greater gain.

An index-based framework for assessing patterns and trends in river fragmentation and flow regulation by global dams at multiple scales

NASA Astrophysics Data System (ADS)

Grill, Günther; Lehner, Bernhard; Lumsdon, Alexander E.; MacDonald, Graham K.; Zarfl, Christiane; Reidy Liermann, Catherine

2015-01-01

The global number of dam constructions has increased dramatically over the past six decades and is forecast to continue to rise, particularly in less industrialized regions. Identifying development pathways that can deliver the benefits of new infrastructure while also maintaining healthy and productive river systems is a great challenge that requires understanding the multifaceted impacts of dams at a range of scales. New approaches and advanced methodologies are needed to improve predictions of how future dam construction will affect biodiversity, ecosystem functioning, and fluvial geomorphology worldwide, helping to frame a global strategy to achieve sustainable dam development. Here, we respond to this need by applying a graph-based river routing model to simultaneously assess flow regulation and fragmentation by dams at multiple scales using data at high spatial resolution. We calculated the cumulative impact of a set of 6374 large existing dams and 3377 planned or proposed dams on river connectivity and river flow at basin and subbasin scales by fusing two novel indicators to create a holistic dam impact matrix for the period 1930-2030. Static network descriptors such as basin area or channel length are of limited use in hierarchically nested and dynamic river systems, so we developed the river fragmentation index and the river regulation index, which are based on river volume. These indicators are less sensitive to the effects of network configuration, offering increased comparability among studies with disparate hydrographies as well as across scales. Our results indicate that, on a global basis, 48% of river volume is moderately to severely impacted by either flow regulation, fragmentation, or both. Assuming completion of all dams planned and under construction in our future scenario, this number would nearly double to 93%, largely due to major dam construction in the Amazon Basin. We provide evidence for the importance of considering small to medium sized dams and for the need to include waterfalls to establish a baseline of natural fragmentation. Our versatile framework can serve as a component of river fragmentation and connectivity assessments; as a standardized, easily replicable monitoring framework at global and basin scales; and as part of regional dam planning and management strategies.