An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening

PubMed Central

2017-01-01

DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing. PMID:28199790

An Integrated Microfluidic Processor for DNA-Encoded Combinatorial Library Functional Screening.

PubMed

MacConnell, Andrew B; Price, Alexander K; Paegel, Brian M

2017-03-13

DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits. DNA-encoded compound beads (10-μm diameter) displaying a photocleavable positive control inhibitor pepstatin A were mixed (1920 beads, 729 encoding sequences) with negative control beads (58 000 beads, 1728 encoding sequences) and screened for cathepsin D inhibition using a biochemical enzyme activity assay. The circuit sorted 1518 hit droplets for collection following 18 min incubation over a 240 min analysis. Visual inspection of a subset of droplets (1188 droplets) yielded a 24% false discovery rate (1166 pepstatin A beads; 366 negative control beads). Using template barcoding strategies, it was possible to count hit collection beads (1863) using next-generation sequencing data. Bead-specific barcodes enabled replicate counting, and the false discovery rate was reduced to 2.6% by only considering hit-encoding sequences that were observed on >2 beads. This work represents a complete distributable small molecule discovery platform, from microfluidic miniaturized automation to ultrahigh-throughput hit deconvolution by sequencing.

A pleiotropy-informed Bayesian false discovery rate adapted to a shared control design finds new disease associations from GWAS summary statistics.

PubMed

Liley, James; Wallace, Chris

2015-02-01

Genome-wide association studies (GWAS) have been successful in identifying single nucleotide polymorphisms (SNPs) associated with many traits and diseases. However, at existing sample sizes, these variants explain only part of the estimated heritability. Leverage of GWAS results from related phenotypes may improve detection without the need for larger datasets. The Bayesian conditional false discovery rate (cFDR) constitutes an upper bound on the expected false discovery rate (FDR) across a set of SNPs whose p values for two diseases are both less than two disease-specific thresholds. Calculation of the cFDR requires only summary statistics and have several advantages over traditional GWAS analysis. However, existing methods require distinct control samples between studies. Here, we extend the technique to allow for some or all controls to be shared, increasing applicability. Several different SNP sets can be defined with the same cFDR value, and we show that the expected FDR across the union of these sets may exceed expected FDR in any single set. We describe a procedure to establish an upper bound for the expected FDR among the union of such sets of SNPs. We apply our technique to pairwise analysis of p values from ten autoimmune diseases with variable sharing of controls, enabling discovery of 59 SNP-disease associations which do not reach GWAS significance after genomic control in individual datasets. Most of the SNPs we highlight have previously been confirmed using replication studies or larger GWAS, a useful validation of our technique; we report eight SNP-disease associations across five diseases not previously declared. Our technique extends and strengthens the previous algorithm, and establishes robust limits on the expected FDR. This approach can improve SNP detection in GWAS, and give insight into shared aetiology between phenotypically related conditions.

Bon-EV: an improved multiple testing procedure for controlling false discovery rates.

PubMed

Li, Dongmei; Xie, Zidian; Zand, Martin; Fogg, Thomas; Dye, Timothy

2017-01-03

Stability of multiple testing procedures, defined as the standard deviation of total number of discoveries, can be used as an indicator of variability of multiple testing procedures. Improving stability of multiple testing procedures can help to increase the consistency of findings from replicated experiments. Benjamini-Hochberg's and Storey's q-value procedures are two commonly used multiple testing procedures for controlling false discoveries in genomic studies. Storey's q-value procedure has higher power and lower stability than Benjamini-Hochberg's procedure. To improve upon the stability of Storey's q-value procedure and maintain its high power in genomic data analysis, we propose a new multiple testing procedure, named Bon-EV, to control false discovery rate (FDR) based on Bonferroni's approach. Simulation studies show that our proposed Bon-EV procedure can maintain the high power of the Storey's q-value procedure and also result in better FDR control and higher stability than Storey's q-value procedure for samples of large size(30 in each group) and medium size (15 in each group) for either independent, somewhat correlated, or highly correlated test statistics. When sample size is small (5 in each group), our proposed Bon-EV procedure has performance between the Benjamini-Hochberg procedure and the Storey's q-value procedure. Examples using RNA-Seq data show that the Bon-EV procedure has higher stability than the Storey's q-value procedure while maintaining equivalent power, and higher power than the Benjamini-Hochberg's procedure. For medium or large sample sizes, the Bon-EV procedure has improved FDR control and stability compared with the Storey's q-value procedure and improved power compared with the Benjamini-Hochberg procedure. The Bon-EV multiple testing procedure is available as the BonEV package in R for download at https://CRAN.R-project.org/package=BonEV .

STS-131 Discovery Launch

NASA Image and Video Library

2010-04-04

Contrails are seen as workers leave the Launch Control Center after the launch of the space shuttle Discovery and the start of the STS-131 mission at NASA Kennedy Space Center in Cape Canaveral, Fla. on Monday April 5, 2010. Discovery is carrying a multi-purpose logistics module filled with science racks for the laboratories aboard the station. The mission has three planned spacewalks, with work to include replacing an ammonia tank assembly, retrieving a Japanese experiment from the station’s exterior, and switching out a rate gyro assembly on the station’s truss structure. Photo Credit: (NASA/Bill Ingalls)

STS-131 Discovery Launch

NASA Image and Video Library

2010-04-04

NASA Administrator Charles Bolden looks out the window of Firing Room Four in the Launch Control Center during the launch of the space shuttle Discovery and the start of the STS-131 mission at NASA Kennedy Space Center in Cape Canaveral, Fla. on Monday April 5, 2010. Discovery is carrying a multi-purpose logistics module filled with science racks for the laboratories aboard the station. The mission has three planned spacewalks, with work to include replacing an ammonia tank assembly, retrieving a Japanese experiment from the station’s exterior, and switching out a rate gyro assembly on the station’s truss structure. Photo Credit: (NASA/Bill Ingalls)

4-Hydroxyphenylpyruvate Dioxygenase Inhibitors: From Chemical Biology to Agrochemicals.

PubMed

Ndikuryayo, Ferdinand; Moosavi, Behrooz; Yang, Wen-Chao; Yang, Guang-Fu

2017-10-04

The development of new herbicides is receiving considerable attention to control weed biotypes resistant to current herbicides. Consequently, new enzymes are always desired as targets for herbicide discovery. 4-Hydroxyphenylpyruvate dioxygenase (HPPD, EC 1.13.11.27) is an enzyme engaged in photosynthetic activity and catalyzes the transformation of 4-hydroxyphenylpyruvic acid (HPPA) into homogentisic acid (HGA). HPPD inhibitors constitute a promising area of discovery and development of innovative herbicides with some advantages, including excellent crop selectivity, low application rates, and broad-spectrum weed control. HPPD inhibitors have been investigated for agrochemical interests, and some of them have already been commercialized as herbicides. In this review, we mainly focus on the chemical biology of HPPD, discovery of new potential inhibitors, and strategies for engineering transgenic crops resistant to current HPPD-inhibiting herbicides. The conclusion raises some relevant gaps for future research directions.

STS-131 Discovery Launch

NASA Image and Video Library

2010-04-05

201004050001hq (5 April 2010) --- NASA Administrator Charles Bolden looks out the window of Firing Room Four in the Launch Control Center during the launch of the space shuttle Discovery and the start of the STS-131 mission at NASA Kennedy Space Center in Cape Canaveral, Fla. on April 5, 2010. Discovery is carrying a multi-purpose logistics module filled with science racks for the laboratories aboard the International Space Station. The mission has three planned spacewalks, with work to include replacing an ammonia tank assembly, retrieving a Japanese experiment from the station?s exterior, and switching out a rate gyro assembly on the station?s truss structure. Photo Credit: NASA/Bill Ingalls

Climatic shocks associate with innovation in science and technology.

PubMed

De Dreu, Carsten K W; van Dijk, Mathijs A

2018-01-01

Human history is shaped by landmark discoveries in science and technology. However, across both time and space the rate of innovation is erratic: Periods of relative inertia alternate with bursts of creative science and rapid cascades of technological innovations. While the origins of the rise and fall in rates of discovery and innovation remain poorly understood, they may reflect adaptive responses to exogenously emerging threats and pressures. Here we examined this possibility by fitting annual rates of scientific discovery and technological innovation to climatic variability and its associated economic pressures and resource scarcity. In time-series data from Europe (1500-1900CE), we indeed found that rates of innovation are higher during prolonged periods of cold (versus warm) surface temperature and during the presence (versus absence) of volcanic dust veils. This negative temperature-innovation link was confirmed in annual time-series for France, Germany, and the United Kingdom (1901-1965CE). Combined, across almost 500 years and over 5,000 documented innovations and discoveries, a 0.5°C increase in temperature associates with a sizable 0.30-0.60 standard deviation decrease in innovation. Results were robust to controlling for fluctuations in population size. Furthermore, and consistent with economic theory and micro-level data on group innovation, path analyses revealed that the relation between harsher climatic conditions between 1500-1900CE and more innovation is mediated by climate-induced economic pressures and resource scarcity.

Resampling-Based Empirical Bayes Multiple Testing Procedures for Controlling Generalized Tail Probability and Expected Value Error Rates: Focus on the False Discovery Rate and Simulation Study

PubMed Central

Dudoit, Sandrine; Gilbert, Houston N.; van der Laan, Mark J.

2014-01-01

Summary This article proposes resampling-based empirical Bayes multiple testing procedures for controlling a broad class of Type I error rates, defined as generalized tail probability (gTP) error rates, gTP(q, g) = Pr(g(Vn, Sn) > q), and generalized expected value (gEV) error rates, gEV(g) = E[g(Vn, Sn)], for arbitrary functions g(Vn, Sn) of the numbers of false positives Vn and true positives Sn. Of particular interest are error rates based on the proportion g(Vn, Sn) = Vn/(Vn + Sn) of Type I errors among the rejected hypotheses, such as the false discovery rate (FDR), FDR = E[Vn/(Vn + Sn)]. The proposed procedures offer several advantages over existing methods. They provide Type I error control for general data generating distributions, with arbitrary dependence structures among variables. Gains in power are achieved by deriving rejection regions based on guessed sets of true null hypotheses and null test statistics randomly sampled from joint distributions that account for the dependence structure of the data. The Type I error and power properties of an FDR-controlling version of the resampling-based empirical Bayes approach are investigated and compared to those of widely-used FDR-controlling linear step-up procedures in a simulation study. The Type I error and power trade-off achieved by the empirical Bayes procedures under a variety of testing scenarios allows this approach to be competitive with or outperform the Storey and Tibshirani (2003) linear step-up procedure, as an alternative to the classical Benjamini and Hochberg (1995) procedure. PMID:18932138

New field discovery rates in lower 48 states

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

Woods, T.J.; Hugman, R.; Vidas, H.

1989-03-01

Through 1982, AAPG reported new field discovery rates. In 1985, a paper demonstrated that through 1975 the AAPG survey of new field discoveries had significantly underreported the larger new field discoveries. This presentation updates the new field discovery data reported in that paper and extends the data through the mid-1980s. Regional details of the new field discoveries, including an explicit breakout of discoveries below 15,000 ft, are reported. The extent to which the observed relative stabilization in new field discoveries per wildcat reflects regional shifts in exploration activity is discussed. Finally, the rate of reserve growth reflected in the passagemore » of particular fields through the AAPG field size categories is discussed.« less

cn.FARMS: a latent variable model to detect copy number variations in microarray data with a low false discovery rate.

PubMed

Clevert, Djork-Arné; Mitterecker, Andreas; Mayr, Andreas; Klambauer, Günter; Tuefferd, Marianne; De Bondt, An; Talloen, Willem; Göhlmann, Hinrich; Hochreiter, Sepp

2011-07-01

Cost-effective oligonucleotide genotyping arrays like the Affymetrix SNP 6.0 are still the predominant technique to measure DNA copy number variations (CNVs). However, CNV detection methods for microarrays overestimate both the number and the size of CNV regions and, consequently, suffer from a high false discovery rate (FDR). A high FDR means that many CNVs are wrongly detected and therefore not associated with a disease in a clinical study, though correction for multiple testing takes them into account and thereby decreases the study's discovery power. For controlling the FDR, we propose a probabilistic latent variable model, 'cn.FARMS', which is optimized by a Bayesian maximum a posteriori approach. cn.FARMS controls the FDR through the information gain of the posterior over the prior. The prior represents the null hypothesis of copy number 2 for all samples from which the posterior can only deviate by strong and consistent signals in the data. On HapMap data, cn.FARMS clearly outperformed the two most prevalent methods with respect to sensitivity and FDR. The software cn.FARMS is publicly available as a R package at http://www.bioinf.jku.at/software/cnfarms/cnfarms.html.

Empirical Bayes method for reducing false discovery rates of correlation matrices with block diagonal structure.

PubMed

Pacini, Clare; Ajioka, James W; Micklem, Gos

2017-04-12

Correlation matrices are important in inferring relationships and networks between regulatory or signalling elements in biological systems. With currently available technology sample sizes for experiments are typically small, meaning that these correlations can be difficult to estimate. At a genome-wide scale estimation of correlation matrices can also be computationally demanding. We develop an empirical Bayes approach to improve covariance estimates for gene expression, where we assume the covariance matrix takes a block diagonal form. Our method shows lower false discovery rates than existing methods on simulated data. Applied to a real data set from Bacillus subtilis we demonstrate it's ability to detecting known regulatory units and interactions between them. We demonstrate that, compared to existing methods, our method is able to find significant covariances and also to control false discovery rates, even when the sample size is small (n=10). The method can be used to find potential regulatory networks, and it may also be used as a pre-processing step for methods that calculate, for example, partial correlations, so enabling the inference of the causal and hierarchical structure of the networks.

Climatic shocks associate with innovation in science and technology

PubMed Central

van Dijk, Mathijs A.

2018-01-01

Human history is shaped by landmark discoveries in science and technology. However, across both time and space the rate of innovation is erratic: Periods of relative inertia alternate with bursts of creative science and rapid cascades of technological innovations. While the origins of the rise and fall in rates of discovery and innovation remain poorly understood, they may reflect adaptive responses to exogenously emerging threats and pressures. Here we examined this possibility by fitting annual rates of scientific discovery and technological innovation to climatic variability and its associated economic pressures and resource scarcity. In time-series data from Europe (1500–1900CE), we indeed found that rates of innovation are higher during prolonged periods of cold (versus warm) surface temperature and during the presence (versus absence) of volcanic dust veils. This negative temperature–innovation link was confirmed in annual time-series for France, Germany, and the United Kingdom (1901–1965CE). Combined, across almost 500 years and over 5,000 documented innovations and discoveries, a 0.5°C increase in temperature associates with a sizable 0.30–0.60 standard deviation decrease in innovation. Results were robust to controlling for fluctuations in population size. Furthermore, and consistent with economic theory and micro-level data on group innovation, path analyses revealed that the relation between harsher climatic conditions between 1500–1900CE and more innovation is mediated by climate-induced economic pressures and resource scarcity. PMID:29364910

Phase Transition in a Healthy Human Heart Rate

NASA Astrophysics Data System (ADS)

Kiyono, Ken; Struzik, Zbigniew R.; Aoyagi, Naoko; Togo, Fumiharu; Yamamoto, Yoshiharu

2005-07-01

A healthy human heart rate displays complex fluctuations which share characteristics of physical systems in a critical state. We demonstrate that the human heart rate in healthy individuals undergoes a dramatic breakdown of criticality characteristics, reminiscent of continuous second order phase transitions. By studying the germane determinants, we show that the hallmark of criticality—highly correlated fluctuations—is observed only during usual daily activity, and a breakdown of these characteristics occurs in prolonged, strenuous exercise and sleep. This finding is the first reported discovery of the dynamical phase transition phenomenon in a biological control system and will be a key to understanding the heart rate control system in health and disease.

Optimal selection of markers for validation or replication from genome-wide association studies.

PubMed

Greenwood, Celia M T; Rangrej, Jagadish; Sun, Lei

2007-07-01

With reductions in genotyping costs and the fast pace of improvements in genotyping technology, it is not uncommon for the individuals in a single study to undergo genotyping using several different platforms, where each platform may contain different numbers of markers selected via different criteria. For example, a set of cases and controls may be genotyped at markers in a small set of carefully selected candidate genes, and shortly thereafter, the same cases and controls may be used for a genome-wide single nucleotide polymorphism (SNP) association study. After such initial investigations, often, a subset of "interesting" markers is selected for validation or replication. Specifically, by validation, we refer to the investigation of associations between the selected subset of markers and the disease in independent data. However, it is not obvious how to choose the best set of markers for this validation. There may be a prior expectation that some sets of genotyping data are more likely to contain real associations. For example, it may be more likely for markers in plausible candidate genes to show disease associations than markers in a genome-wide scan. Hence, it would be desirable to select proportionally more markers from the candidate gene set. When a fixed number of markers are selected for validation, we propose an approach for identifying an optimal marker-selection configuration by basing the approach on minimizing the stratified false discovery rate. We illustrate this approach using a case-control study of colorectal cancer from Ontario, Canada, and we show that this approach leads to substantial reductions in the estimated false discovery rates in the Ontario dataset for the selected markers, as well as reductions in the expected false discovery rates for the proposed validation dataset. Copyright 2007 Wiley-Liss, Inc.

Discrete False-Discovery Rate Improves Identification of Differentially Abundant Microbes.

PubMed

Jiang, Lingjing; Amir, Amnon; Morton, James T; Heller, Ruth; Arias-Castro, Ery; Knight, Rob

2017-01-01

Differential abundance testing is a critical task in microbiome studies that is complicated by the sparsity of data matrices. Here we adapt for microbiome studies a solution from the field of gene expression analysis to produce a new method, discrete false-discovery rate (DS-FDR), that greatly improves the power to detect differential taxa by exploiting the discreteness of the data. Additionally, DS-FDR is relatively robust to the number of noninformative features, and thus removes the problem of filtering taxonomy tables by an arbitrary abundance threshold. We show by using a combination of simulations and reanalysis of nine real-world microbiome data sets that this new method outperforms existing methods at the differential abundance testing task, producing a false-discovery rate that is up to threefold more accurate, and halves the number of samples required to find a given difference (thus increasing the efficiency of microbiome experiments considerably). We therefore expect DS-FDR to be widely applied in microbiome studies. IMPORTANCE DS-FDR can achieve higher statistical power to detect significant findings in sparse and noisy microbiome data compared to the commonly used Benjamini-Hochberg procedure and other FDR-controlling procedures.

Search strategy has influenced the discovery rate of human viruses.

PubMed

Rosenberg, Ronald; Johansson, Michael A; Powers, Ann M; Miller, Barry R

2013-08-20

A widely held concern is that the pace of infectious disease emergence has been increasing. We have analyzed the rate of discovery of pathogenic viruses, the preeminent source of newly discovered causes of human disease, from 1897 through 2010. The rate was highest during 1950-1969, after which it moderated. This general picture masks two distinct trends: for arthropod-borne viruses, which comprised 39% of pathogenic viruses, the discovery rate peaked at three per year during 1960-1969, but subsequently fell nearly to zero by 1980; however, the rate of discovery of nonarboviruses remained stable at about two per year from 1950 through 2010. The period of highest arbovirus discovery coincided with a comprehensive program supported by The Rockefeller Foundation of isolating viruses from humans, animals, and arthropod vectors at field stations in Latin America, Africa, and India. The productivity of this strategy illustrates the importance of location, approach, long-term commitment, and sponsorship in the discovery of emerging pathogens.

Genomic prediction unifies animal and plant breeding programs to form platforms for biological discovery.

PubMed

Hickey, John M; Chiurugwi, Tinashe; Mackay, Ian; Powell, Wayne

2017-08-30

The rate of annual yield increases for major staple crops must more than double relative to current levels in order to feed a predicted global population of 9 billion by 2050. Controlled hybridization and selective breeding have been used for centuries to adapt plant and animal species for human use. However, achieving higher, sustainable rates of improvement in yields in various species will require renewed genetic interventions and dramatic improvement of agricultural practices. Genomic prediction of breeding values has the potential to improve selection, reduce costs and provide a platform that unifies breeding approaches, biological discovery, and tools and methods. Here we compare and contrast some animal and plant breeding approaches to make a case for bringing the two together through the application of genomic selection. We propose a strategy for the use of genomic selection as a unifying approach to deliver innovative 'step changes' in the rate of genetic gain at scale.

Control of rRNA transcription in Escherichia coli.

PubMed Central

Condon, C; Squires, C; Squires, C L

1995-01-01

The control of rRNA synthesis in response to both extra- and intracellular signals has been a subject of interest to microbial physiologists for nearly four decades, beginning with the observations that Salmonella typhimurium cells grown on rich medium are larger and contain more RNA than those grown on poor medium. This was followed shortly by the discovery of the stringent response in Escherichia coli, which has continued to be the organism of choice for the study of rRNA synthesis. In this review, we summarize four general areas of E. coli rRNA transcription control: stringent control, growth rate regulation, upstream activation, and anti-termination. We also cite similar mechanisms in other bacteria and eukaryotes. The separation of growth rate-dependent control of rRNA synthesis from stringent control continues to be a subject of controversy. One model holds that the nucleotide ppGpp is the key effector for both mechanisms, while another school holds that it is unlikely that ppGpp or any other single effector is solely responsible for growth rate-dependent control. Recent studies on activation of rRNA synthesis by cis-acting upstream sequences has led to the discovery of a new class of promoters that make contact with RNA polymerase at a third position, called the UP element, in addition to the well-known -10 and -35 regions. Lastly, clues as to the role of antitermination in rRNA operons have begun to appear. Transcription complexes modified at the antiterminator site appear to elongate faster and are resistant to the inhibitory effects of ppGpp during the stringent response. PMID:8531889

False-positive rate determination of protein target discovery using a covalent modification- and mass spectrometry-based proteomics platform.

PubMed

Strickland, Erin C; Geer, M Ariel; Hong, Jiyong; Fitzgerald, Michael C

2014-01-01

Detection and quantitation of protein-ligand binding interactions is important in many areas of biological research. Stability of proteins from rates of oxidation (SPROX) is an energetics-based technique for identifying the proteins targets of ligands in complex biological mixtures. Knowing the false-positive rate of protein target discovery in proteome-wide SPROX experiments is important for the correct interpretation of results. Reported here are the results of a control SPROX experiment in which chemical denaturation data is obtained on the proteins in two samples that originated from the same yeast lysate, as would be done in a typical SPROX experiment except that one sample would be spiked with the test ligand. False-positive rates of 1.2-2.2% and <0.8% are calculated for SPROX experiments using Q-TOF and Orbitrap mass spectrometer systems, respectively. Our results indicate that the false-positive rate is largely determined by random errors associated with the mass spectral analysis of the isobaric mass tag (e.g., iTRAQ®) reporter ions used for peptide quantitation. Our results also suggest that technical replicates can be used to effectively eliminate such false positives that result from this random error, as is demonstrated in a SPROX experiment to identify yeast protein targets of the drug, manassantin A. The impact of ion purity in the tandem mass spectral analyses and of background oxidation on the false-positive rate of protein target discovery using SPROX is also discussed.

A two-step hierarchical hypothesis set testing framework, with applications to gene expression data on ordered categories

PubMed Central

2014-01-01

Background In complex large-scale experiments, in addition to simultaneously considering a large number of features, multiple hypotheses are often being tested for each feature. This leads to a problem of multi-dimensional multiple testing. For example, in gene expression studies over ordered categories (such as time-course or dose-response experiments), interest is often in testing differential expression across several categories for each gene. In this paper, we consider a framework for testing multiple sets of hypothesis, which can be applied to a wide range of problems. Results We adopt the concept of the overall false discovery rate (OFDR) for controlling false discoveries on the hypothesis set level. Based on an existing procedure for identifying differentially expressed gene sets, we discuss a general two-step hierarchical hypothesis set testing procedure, which controls the overall false discovery rate under independence across hypothesis sets. In addition, we discuss the concept of the mixed-directional false discovery rate (mdFDR), and extend the general procedure to enable directional decisions for two-sided alternatives. We applied the framework to the case of microarray time-course/dose-response experiments, and proposed three procedures for testing differential expression and making multiple directional decisions for each gene. Simulation studies confirm the control of the OFDR and mdFDR by the proposed procedures under independence and positive correlations across genes. Simulation results also show that two of our new procedures achieve higher power than previous methods. Finally, the proposed methodology is applied to a microarray dose-response study, to identify 17 β-estradiol sensitive genes in breast cancer cells that are induced at low concentrations. Conclusions The framework we discuss provides a platform for multiple testing procedures covering situations involving two (or potentially more) sources of multiplicity. The framework is easy to use and adaptable to various practical settings that frequently occur in large-scale experiments. Procedures generated from the framework are shown to maintain control of the OFDR and mdFDR, quantities that are especially relevant in the case of multiple hypothesis set testing. The procedures work well in both simulations and real datasets, and are shown to have better power than existing methods. PMID:24731138

Cancer microenvironment, inflammation and cancer stem cells: A hypothesis for a paradigm change and new targets in cancer control

PubMed Central

Blaylock, Russell L.

2015-01-01

Since President Nixon officially declared a war on cancer with the National Cancer Act, billions of dollars have been spent on research in hopes of finding a cure for cancer. Recent reviews have pointed out that over the ensuing 42 years, cancer death rates have barely changed for the major cancers. Recently, several researchers have questioned the prevailing cancer paradigm based on recent discoveries concerning the mechanism of carcinogenesis and the origins of cancer. Over the past decade we have learned a great deal concerning both of these central issues. Cell signaling has taken center stage, particularly as regards the links between chronic inflammation and cancer development. It is now evident that the common factor among a great number of carcinogenic agents is activation of genes controlling inflammation cell-signaling pathways and that these signals control all aspects of the cancer process. Of these pathways, the most important and common to all cancers is the NFκB and STAT3 pathways. The second discovery of critical importance is that mutated stem cells appear to be in charge of the cancer process. Most chemotherapy agents and radiotherapy kill daughter cells of the cancer stem cell, many of which are not tumorigenic themselves. Most cancer stem cells are completely resistant to conventional treatments, which explain dormancy and the poor cure rate with metastatic tumors. A growing number of studies are finding that several polyphenol extracts can kill cancer stem cells as well as daughter cells and can enhance the effectiveness and safety of conventional treatments. These new discoveries provide the clinician with a whole new set of targets for cancer control and cure. PMID:26097771

Efficacy of bait supplements for improving the rate of discovery of bait stations in the field by formosan subterranean termites (Isoptera: Rhinotermitidae).

PubMed

Cornelius, Mary L; Lyn, Margaret; Williams, Kelley S; Lovisa, Mary P; De Lucca, Anthony J; Lax, Alan R

2009-06-01

Field tests of four different bait supplements were conducted in City Park, New Orleans, LA. The four bait supplements tested included two different formulations of decayed material, a sports drink, and the combination of an application of an aqueous solution of Summon Preferred Food Source disks with the disk itself. Although all the bait supplements in this study resulted in a slightly greater number of treated stations discovered compared with control stations, only the application of the aqueous solution combined with the disk caused a significant increase in the number of stations discovered by termites. This treatment resulted in a significantly greater rate of discovery of treated stations versus control stations after only 14 d in the field. Termites were able to discover six times as many treated as control stations after 14 d, 9 times as many after 28 d, and 12 times as many after 42 d. These findings provide evidence that the diffusion of an aqueous solution into the soil underneath monitoring stations significantly decreased the length of time required for termites to infest stations.

Multiple hypotheses testing based on ordered p values--a historical survey with applications to medical research.

PubMed

Hommel, Gerhard; Bretz, Frank; Maurer, Willi

2011-07-01

Global tests and multiple test procedures are often based on ordered p values. Such procedures are available for arbitrary dependence structures as well as for specific dependence assumptions of the test statistics. Most of these procedures have been considered as global tests. Multiple test procedures can be obtained by applying the closure principle in order to control the familywise error rate, or by using the false discovery rate as a criterion for type I error rate control. We provide an overview and present examples showing the importance of these procedures in medical research. Finally, we discuss modifications when different weights for the hypotheses of interest are chosen.

Enhancing the detection of barcoded reads in high throughput DNA sequencing data by controlling the false discovery rate.

PubMed

Buschmann, Tilo; Zhang, Rong; Brash, Douglas E; Bystrykh, Leonid V

2014-08-07

DNA barcodes are short unique sequences used to label DNA or RNA-derived samples in multiplexed deep sequencing experiments. During the demultiplexing step, barcodes must be detected and their position identified. In some cases (e.g., with PacBio SMRT), the position of the barcode and DNA context is not well defined. Many reads start inside the genomic insert so that adjacent primers might be missed. The matter is further complicated by coincidental similarities between barcode sequences and reference DNA. Therefore, a robust strategy is required in order to detect barcoded reads and avoid a large number of false positives or negatives.For mass inference problems such as this one, false discovery rate (FDR) methods are powerful and balanced solutions. Since existing FDR methods cannot be applied to this particular problem, we present an adapted FDR method that is suitable for the detection of barcoded reads as well as suggest possible improvements. In our analysis, barcode sequences showed high rates of coincidental similarities with the Mus musculus reference DNA. This problem became more acute when the length of the barcode sequence decreased and the number of barcodes in the set increased. The method presented in this paper controls the tail area-based false discovery rate to distinguish between barcoded and unbarcoded reads. This method helps to establish the highest acceptable minimal distance between reads and barcode sequences. In a proof of concept experiment we correctly detected barcodes in 83% of the reads with a precision of 89%. Sensitivity improved to 99% at 99% precision when the adjacent primer sequence was incorporated in the analysis. The analysis was further improved using a paired end strategy. Following an analysis of the data for sequence variants induced in the Atp1a1 gene of C57BL/6 murine melanocytes by ultraviolet light and conferring resistance to ouabain, we found no evidence of cross-contamination of DNA material between samples. Our method offers a proper quantitative treatment of the problem of detecting barcoded reads in a noisy sequencing environment. It is based on the false discovery rate statistics that allows a proper trade-off between sensitivity and precision to be chosen.

Characterizing the Joint Effect of Diverse Test-Statistic Correlation Structures and Effect Size on False Discovery Rates in a Multiple-Comparison Study of Many Outcome Measures

NASA Technical Reports Server (NTRS)

Feiveson, Alan H.; Ploutz-Snyder, Robert; Fiedler, James

2011-01-01

In their 2009 Annals of Statistics paper, Gavrilov, Benjamini, and Sarkar report the results of a simulation assessing the robustness of their adaptive step-down procedure (GBS) for controlling the false discovery rate (FDR) when normally distributed test statistics are serially correlated. In this study we extend the investigation to the case of multiple comparisons involving correlated non-central t-statistics, in particular when several treatments or time periods are being compared to a control in a repeated-measures design with many dependent outcome measures. In addition, we consider several dependence structures other than serial correlation and illustrate how the FDR depends on the interaction between effect size and the type of correlation structure as indexed by Foerstner s distance metric from an identity. The relationship between the correlation matrix R of the original dependent variables and R, the correlation matrix of associated t-statistics is also studied. In general R depends not only on R, but also on sample size and the signed effect sizes for the multiple comparisons.

Palomar Planet-Crossing Asteroid Survey (PCAS): Recent discovery rate

NASA Technical Reports Server (NTRS)

Helin, Eleanor F.

1992-01-01

The discovery rate of Near-Earth Asteroids (NEA's) has increased significantly in the last decade. As greater numbers of NEA's are discovered, worldwide interest has grown leading to new programs. With the introduction of CCD telescopes throughout the world, an increase of 1-2 orders of magnitude in the discovery rate can be anticipated. Nevertheless, it will take several decades of dedicated searching to accomplish a 95 percent completeness, even for large objects.

The Production of 3D Tumor Spheroids for Cancer Drug Discovery

PubMed Central

Sant, Shilpa; Johnston, Paul A.

2017-01-01

New cancer drug approval rates are ≤ 5% despite significant investments in cancer research, drug discovery and development. One strategy to improve the rate of success of new cancer drugs transitioning into the clinic would be to more closely align the cellular models used in the early lead discovery with pre-clinical animal models and patient tumors. For solid tumors, this would mandate the development and implementation of three dimensional (3D) in vitro tumor models that more accurately recapitulate human solid tumor architecture and biology. Recent advances in tissue engineering and regenerative medicine have provided new techniques for 3D spheroid generation and a variety of in vitro 3D cancer models are being explored for cancer drug discovery. Although homogeneous assay methods and high content imaging approaches to assess tumor spheroid morphology, growth and viability have been developed, the implementation of 3D models in HTS remains challenging due to reasons that we discuss in this review. Perhaps the biggest obstacle to achieve acceptable HTS assay performance metrics occurs in 3D tumor models that produce spheroids with highly variable morphologies and/or sizes. We highlight two methods that produce uniform size-controlled 3D multicellular tumor spheroids that are compatible with cancer drug research and HTS; tumor spheroids formed in ultra-low attachment microplates, or in polyethylene glycol dimethacrylate hydrogel microwell arrays. PMID:28647083

Quantitative assessment of hit detection and confirmation in single and duplicate high-throughput screenings.

PubMed

Wu, Zhijin; Liu, Dongmei; Sui, Yunxia

2008-02-01

The process of identifying active targets (hits) in high-throughput screening (HTS) usually involves 2 steps: first, removing or adjusting for systematic variation in the measurement process so that extreme values represent strong biological activity instead of systematic biases such as plate effect or edge effect and, second, choosing a meaningful cutoff on the calculated statistic to declare positive compounds. Both false-positive and false-negative errors are inevitable in this process. Common control or estimation of error rates is often based on an assumption of normal distribution of the noise. The error rates in hit detection, especially false-negative rates, are hard to verify because in most assays, only compounds selected in primary screening are followed up in confirmation experiments. In this article, the authors take advantage of a quantitative HTS experiment in which all compounds are tested 42 times over a wide range of 14 concentrations so true positives can be found through a dose-response curve. Using the activity status defined by dose curve, the authors analyzed the effect of various data-processing procedures on the sensitivity and specificity of hit detection, the control of error rate, and hit confirmation. A new summary score is proposed and demonstrated to perform well in hit detection and useful in confirmation rate estimation. In general, adjusting for positional effects is beneficial, but a robust test can prevent overadjustment. Error rates estimated based on normal assumption do not agree with actual error rates, for the tails of noise distribution deviate from normal distribution. However, false discovery rate based on empirically estimated null distribution is very close to observed false discovery proportion.

A critique of the molecular target-based drug discovery paradigm based on principles of metabolic control: advantages of pathway-based discovery.

PubMed

Hellerstein, Marc K

2008-01-01

Contemporary drug discovery and development (DDD) is dominated by a molecular target-based paradigm. Molecular targets that are potentially important in disease are physically characterized; chemical entities that interact with these targets are identified by ex vivo high-throughput screening assays, and optimized lead compounds enter testing as drugs. Contrary to highly publicized claims, the ascendance of this approach has in fact resulted in the lowest rate of new drug approvals in a generation. The primary explanation for low rates of new drugs is attrition, or the failure of candidates identified by molecular target-based methods to advance successfully through the DDD process. In this essay, I advance the thesis that this failure was predictable, based on modern principles of metabolic control that have emerged and been applied most forcefully in the field of metabolic engineering. These principles, such as the robustness of flux distributions, address connectivity relationships in complex metabolic networks and make it unlikely a priori that modulating most molecular targets will have predictable, beneficial functional outcomes. These same principles also suggest, however, that unexpected therapeutic actions will be common for agents that have any effect (i.e., that complexity can be exploited therapeutically). A potential operational solution (pathway-based DDD), based on observability rather than predictability, is described, focusing on emergent properties of key metabolic pathways in vivo. Recent examples of pathway-based DDD are described. In summary, the molecular target-based DDD paradigm is built on a naïve and misleading model of biologic control and is not heuristically adequate for advancing the mission of modern therapeutics. New approaches that take account of and are built on principles described by metabolic engineers are needed for the next generation of DDD.

The Paradox of Equipoise: The Principle That Drives and Limits Therapeutic Discoveries in Clinical Research

PubMed Central

Djulbegovic, Benjamin

2009-01-01

Background Progress in clinical medicine relies on the willingness of patients to take part in experimental clinical trials, particularly randomized controlled trials (RCTs). Before agreeing to enroll in clinical trials, patients require guarantees that they will not knowingly be harmed and will have the best possible chances of receiving the most favorable treatments. This guarantee is provided by the acknowledgment of uncertainty (equipoise), which removes ethical dilemmas and makes it easier for patients to enroll in clinical trials. Methods Since the design of clinical trials is mostly affected by clinical equipoise, the “clinical equipoise hypothesis” has been postulated. If the uncertainty requirement holds, this means that investigators cannot predict what they are going to discover in any individual trial that they undertake. In some instances, new treatments will be superior to standard treatments, while in others, standard treatments will be superior to experimental treatments, and in still others, no difference will be detected between new and standard treatments. It is hypothesized that there must be a relationship between the overall pattern of treatment successes and the uncertainties that RCTs are designed to address. Results An analysis of published trials shows that the results cannot be predicted at the level of individual trials. However, the results also indicate that the overall pattern of discovery of treatment success across a series of trials is predictable and is consistent with clinical equipoise hypothesis. The analysis shows that we can discover no more than 25% to 50% of successful treatments when they are tested in RCTs. The analysis also indicates that this discovery rate is optimal in helping to preserve the clinical trial system; a high discovery rate (eg, a 90% to 100% probability of success) is neither feasible nor desirable since under these circumstances, neither the patient nor the researcher has an interest in randomization. This in turn would halt the RCT system as we know it. Conclusions The “principle or law of clinical discovery” described herein predicts the efficiency of the current system of RCTs at generating discoveries of new treatments. The principle is derived from the requirement for uncertainty or equipoise as a precondition for RCTs, the precept that paradoxically drives discoveries of new treatments while limiting the proportion and rate of new therapeutic discoveries. PMID:19910921

Functional Brain Connectome and Its Relation to Hoehn and Yahr Stage in Parkinson Disease.

PubMed

Suo, Xueling; Lei, Du; Li, Nannan; Cheng, Lan; Chen, Fuqin; Wang, Meiyun; Kemp, Graham J; Peng, Rong; Gong, Qiyong

2017-12-01

Purpose To use resting-state functional magnetic resonance (MR) imaging and graph theory approaches to investigate the brain functional connectome and its potential relation to disease severity in Parkinson disease (PD). Materials and Methods This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 153 right-handed patients with PD and 81 healthy control participants recruited who were matched for age, sex, and handedness to undergo a 3-T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Nonparametric permutation tests were used to compare topologic properties, and their relationship to disease severity was assessed. Results The functional connectome in PD showed abnormalities at the global level (ie, decrease in clustering coefficient, global efficiency, and local efficiency, and increase in characteristic path length) and at the nodal level (decreased nodal centralities in the sensorimotor cortex, default mode, and temporal-occipital regions; P < .001, false discovery rate corrected). Further, the nodal centralities in left postcentral gyrus and left superior temporal gyrus correlated negatively with Unified Parkinson's Disease Rating Scale III score (P = .038, false discovery rate corrected, r = -0.198; and P = .009, false discovery rate corrected, r = -0.270, respectively) and decreased with increasing Hoehn and Yahr stage in patients with PD. Conclusion The configurations of brain functional connectome in patients with PD were perturbed and correlated with disease severity, notably with those responsible for motor functions. These results provide topologic insights into understanding the neural functional changes in relation to disease severity of PD. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on September 11, 2017.

Early detection surveillance for an emerging plant pathogen: a rule of thumb to predict prevalence at first discovery.

PubMed

Parnell, S; Gottwald, T R; Cunniffe, N J; Alonso Chavez, V; van den Bosch, F

2015-09-07

Emerging plant pathogens are a significant problem for conservation and food security. Surveillance is often instigated in an attempt to detect an invading epidemic before it gets out of control. Yet in practice many epidemics are not discovered until already at a high prevalence, partly due to a lack of quantitative understanding of how surveillance effort and the dynamics of an invading epidemic relate. We test a simple rule of thumb to determine, for a surveillance programme taking a fixed number of samples at regular intervals, the distribution of the prevalence an epidemic will have reached on first discovery (discovery-prevalence) and its expectation E(q*). We show that E(q*) = r/(N/Δ), i.e. simply the rate of epidemic growth divided by the rate of sampling; where r is the epidemic growth rate, N is the sample size and Δ is the time between sampling rounds. We demonstrate the robustness of this rule of thumb using spatio-temporal epidemic models as well as data from real epidemics. Our work supports the view that, for the purposes of early detection surveillance, simple models can provide useful insights in apparently complex systems. The insight can inform decisions on surveillance resource allocation in plant health and has potential applicability to invasive species generally. © 2015 The Author(s).

Early detection surveillance for an emerging plant pathogen: a rule of thumb to predict prevalence at first discovery

PubMed Central

Parnell, S.; Gottwald, T. R.; Cunniffe, N. J.; Alonso Chavez, V.; van den Bosch, F.

2015-01-01

Emerging plant pathogens are a significant problem for conservation and food security. Surveillance is often instigated in an attempt to detect an invading epidemic before it gets out of control. Yet in practice many epidemics are not discovered until already at a high prevalence, partly due to a lack of quantitative understanding of how surveillance effort and the dynamics of an invading epidemic relate. We test a simple rule of thumb to determine, for a surveillance programme taking a fixed number of samples at regular intervals, the distribution of the prevalence an epidemic will have reached on first discovery (discovery-prevalence) and its expectation E(q*). We show that E(q*) = r/(N/Δ), i.e. simply the rate of epidemic growth divided by the rate of sampling; where r is the epidemic growth rate, N is the sample size and Δ is the time between sampling rounds. We demonstrate the robustness of this rule of thumb using spatio-temporal epidemic models as well as data from real epidemics. Our work supports the view that, for the purposes of early detection surveillance, simple models can provide useful insights in apparently complex systems. The insight can inform decisions on surveillance resource allocation in plant health and has potential applicability to invasive species generally. PMID:26336177

Comparative genetics of longevity and cancer: insights from long-lived rodents

PubMed Central

Gorbunova, Vera; Seluanov, Andrei; Zhang, Zhengdong; Gladyshev, Vadim N.; Vijg, Jan

2015-01-01

Mammals have evolved a dramatic diversity of aging rates. Within the single order of Rodentia maximum lifespans differ from four years in mice to 32 years in naked mole rats. Cancer rates also differ significantly, from cancer-prone mice to virtually cancer-proof naked and blind mole rats. Recent progress in rodent comparative biology, in combination with the emergence of whole genome sequence information, has opened opportunities for the discovery of genetic factors controlling longevity and cancer susceptibility. PMID:24981598

From crystal to compound: structure-based antimalarial drug discovery.

PubMed

Drinkwater, Nyssa; McGowan, Sheena

2014-08-01

Despite a century of control and eradication campaigns, malaria remains one of the world's most devastating diseases. Our once-powerful therapeutic weapons are losing the war against the Plasmodium parasite, whose ability to rapidly develop and spread drug resistance hamper past and present malaria-control efforts. Finding new and effective treatments for malaria is now a top global health priority, fuelling an increase in funding and promoting open-source collaborations between researchers and pharmaceutical consortia around the world. The result of this is rapid advances in drug discovery approaches and technologies, with three major methods for antimalarial drug development emerging: (i) chemistry-based, (ii) target-based, and (iii) cell-based. Common to all three of these approaches is the unique ability of structural biology to inform and accelerate drug development. Where possible, SBDD (structure-based drug discovery) is a foundation for antimalarial drug development programmes, and has been invaluable to the development of a number of current pre-clinical and clinical candidates. However, as we expand our understanding of the malarial life cycle and mechanisms of resistance development, SBDD as a field must continue to evolve in order to develop compounds that adhere to the ideal characteristics for novel antimalarial therapeutics and to avoid high attrition rates pre- and post-clinic. In the present review, we aim to examine the contribution that SBDD has made to current antimalarial drug development efforts, covering hit discovery to lead optimization and prevention of parasite resistance. Finally, the potential for structural biology, particularly high-throughput structural genomics programmes, to identify future targets for drug discovery are discussed.

Conserved Non-Coding Sequences are Associated with Rates of mRNA Decay in Arabidopsis.

PubMed

Spangler, Jacob B; Feltus, Frank Alex

2013-01-01

Steady-state mRNA levels are tightly regulated through a combination of transcriptional and post-transcriptional control mechanisms. The discovery of cis-acting DNA elements that encode these control mechanisms is of high importance. We have investigated the influence of conserved non-coding sequences (CNSs), DNA patterns retained after an ancient whole genome duplication event, on the breadth of gene expression and the rates of mRNA decay in Arabidopsis thaliana. The absence of CNSs near α duplicate genes was associated with a decrease in breadth of gene expression and slower mRNA decay rates while the presence CNSs near α duplicates was associated with an increase in breadth of gene expression and faster mRNA decay rates. The observed difference in mRNA decay rate was fastest in genes with CNSs in both non-transcribed and transcribed regions, albeit through an unknown mechanism. This study supports the notion that some Arabidopsis CNSs regulate the steady-state mRNA levels through post-transcriptional control mechanisms and that CNSs also play a role in controlling the breadth of gene expression.

Conserved Non-Coding Sequences are Associated with Rates of mRNA Decay in Arabidopsis

PubMed Central

Spangler, Jacob B.; Feltus, Frank Alex

2013-01-01

Steady-state mRNA levels are tightly regulated through a combination of transcriptional and post-transcriptional control mechanisms. The discovery of cis-acting DNA elements that encode these control mechanisms is of high importance. We have investigated the influence of conserved non-coding sequences (CNSs), DNA patterns retained after an ancient whole genome duplication event, on the breadth of gene expression and the rates of mRNA decay in Arabidopsis thaliana. The absence of CNSs near α duplicate genes was associated with a decrease in breadth of gene expression and slower mRNA decay rates while the presence CNSs near α duplicates was associated with an increase in breadth of gene expression and faster mRNA decay rates. The observed difference in mRNA decay rate was fastest in genes with CNSs in both non-transcribed and transcribed regions, albeit through an unknown mechanism. This study supports the notion that some Arabidopsis CNSs regulate the steady-state mRNA levels through post-transcriptional control mechanisms and that CNSs also play a role in controlling the breadth of gene expression. PMID:23675377

Long-term trends in oil and gas discovery rates in lower 48 United States

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

Woods, T.J.

1985-09-01

The Gas Research Institute (GRI), in association with Energy and Environmental Analysis, Inc. (EEA), has developed a data base characterizing the discovered oil and gas fields in the lower 48 United States. The number of fields in this data base reported to have been discovered since 1947 substantially exceeds the count presented in the AAPG survey of new-field discoveries since 1947. The greatest relative difference between the field counts is for fields larger than 10 million bbl of oil equivalent (BOE) (AAPG Class C fields or larger). Two factors contribute to the difference in reported discoveries by field size. First,more » the AAPG survey does not capture all new-field discoveries, particularly in the offshore. Second, the AAPG survey does not update field sizes past 6 years after the field discovery date. Because of reserve appreciation to discovered fields, discovery-trend data based on field-size data should be used with caution, particularly when field-size estimates have not been updated for a substantial period of time. Based on the GRI/EEA data base, the major decline in the discovery rates of large, new oil and gas fields in the lower 48 United States appears to have ended by the early 1960s. Since then, discovery rates seem to have improved. Thus, the outlook for future discoveries of large fields may be much better than previously believed.« less

Dual transcriptional-translational cascade permits cellular level tuneable expression control

PubMed Central

Morra, Rosa; Shankar, Jayendra; Robinson, Christopher J.; Halliwell, Samantha; Butler, Lisa; Upton, Mathew; Hay, Sam; Micklefield, Jason; Dixon, Neil

2016-01-01

The ability to induce gene expression in a small molecule dependent manner has led to many applications in target discovery, functional elucidation and bio-production. To date these applications have relied on a limited set of protein-based control mechanisms operating at the level of transcription initiation. The discovery, design and reengineering of riboswitches offer an alternative means by which to control gene expression. Here we report the development and characterization of a novel tunable recombinant expression system, termed RiboTite, which operates at both the transcriptional and translational level. Using standard inducible promoters and orthogonal riboswitches, a multi-layered modular genetic control circuit was developed to control the expression of both bacteriophage T7 RNA polymerase and recombinant gene(s) of interest. The system was benchmarked against a number of commonly used E. coli expression systems, and shows tight basal control, precise analogue tunability of gene expression at the cellular level, dose-dependent regulation of protein production rates over extended growth periods and enhanced cell viability. This novel system expands the number of E. coli expression systems for use in recombinant protein production and represents a major performance enhancement over and above the most widely used expression systems. PMID:26405200

Accounting for control mislabeling in case-control biomarker studies.

PubMed

Rantalainen, Mattias; Holmes, Chris C

2011-12-02

In biomarker discovery studies, uncertainty associated with case and control labels is often overlooked. By omitting to take into account label uncertainty, model parameters and the predictive risk can become biased, sometimes severely. The most common situation is when the control set contains an unknown number of undiagnosed, or future, cases. This has a marked impact in situations where the model needs to be well-calibrated, e.g., when the prediction performance of a biomarker panel is evaluated. Failing to account for class label uncertainty may lead to underestimation of classification performance and bias in parameter estimates. This can further impact on meta-analysis for combining evidence from multiple studies. Using a simulation study, we outline how conventional statistical models can be modified to address class label uncertainty leading to well-calibrated prediction performance estimates and reduced bias in meta-analysis. We focus on the problem of mislabeled control subjects in case-control studies, i.e., when some of the control subjects are undiagnosed cases, although the procedures we report are generic. The uncertainty in control status is a particular situation common in biomarker discovery studies in the context of genomic and molecular epidemiology, where control subjects are commonly sampled from the general population with an established expected disease incidence rate.

Clinical Development of Gamitrinib, a Novel Mitochondrial-Targeted Small Molecule Hsp90 Inhibitor

DTIC Science & Technology

2015-09-01

Group 2 and Group 3 animals examined at the end of the 7-repeated doses was comparable to those in control Group 1 animals (Figure 2). (7) Despite... posttest (for more than two- group comparisons) using a GraphPad software package (Prism 6.0) for Windows. Data are expressed as mean ± SD or mean ± SEM...Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: A practical and powerful approach to multiple testing. J R Stat Soc Series B Stat

Near-Earth asteroid discovery rate review

NASA Technical Reports Server (NTRS)

Helin, Eleanor F.

1991-01-01

Fifteen to twenty years ago the discovery of 1 or 2 Near Earth Asteroids (NEAs) per year was typical from one systematic search program, Palomar Planet Crossing Asteroid Survey (PCAS), and the incidental discovery from a variety of other astronomical program. Sky coverage and magnitude were both limited by slower emulsions, requiring longer exposures. The 1970's sky coverage of 15,000 to 25,000 sq. deg. per year led to about 1 NEA discovery every 13,000 sq. deg. Looking at the years from 1987 through 1990, it was found that by comparing 1987/1988 and 1989/1990, the world discovery rate of NEAs went from 20 to 43. More specifically, PCAS' results when grouped into the two year periods, show an increase from 5 discoveries in the 1st period to 20 in the 2nd period, a fourfold increase. Also, the discoveries went from representing about 25 pct. of the world total to about 50 pct. of discoveries worldwide. The surge of discoveries enjoyed by PCAS in particular is attributed to new fine grain sensitive emulsions, film hypering, more uniformity in the quality of the photograph, more equitable scheduling, better weather, and coordination of efforts. The maximum discoveries seem to have been attained at Palomar Schmidt.

[The problem of small "n" and big "P" in neuropsycho-pharmacology, or how to keep the rate of false discoveries under control].

PubMed

Petschner, Péter; Bagdy, György; Tóthfalusi, Laszló

2015-03-01

One of the characteristics of many methods used in neuropsychopharmacology is that a large number of parameters (P) are measured in relatively few subjects (n). Functional magnetic resonance imaging, electroencephalography (EEG) and genomic studies are typical examples. For example one microarray chip can contain thousands of probes. Therefore, in studies using microarray chips, P may be several thousand-fold larger than n. Statistical analysis of such studies is a challenging task and they are refereed to in the statistical literature such as the small "n" big "P" problem. The problem has many facets including the controversies associated with multiple hypothesis testing. A typical scenario in this context is, when two or more groups are compared by the individual attributes. If the increased classification error due to the multiple testing is neglected, then several highly significant differences will be discovered. But in reality, some of these significant differences are coincidental, not reproducible findings. Several methods were proposed to solve this problem. In this review we discuss two of the proposed solutions, algorithms to compare sets and statistical hypothesis tests controlling the false discovery rate.

Coordinate based random effect size meta-analysis of neuroimaging studies.

PubMed

Tench, C R; Tanasescu, Radu; Constantinescu, C S; Auer, D P; Cottam, W J

2017-06-01

Low power in neuroimaging studies can make them difficult to interpret, and Coordinate based meta-analysis (CBMA) may go some way to mitigating this issue. CBMA has been used in many analyses to detect where published functional MRI or voxel-based morphometry studies testing similar hypotheses report significant summary results (coordinates) consistently. Only the reported coordinates and possibly t statistics are analysed, and statistical significance of clusters is determined by coordinate density. Here a method of performing coordinate based random effect size meta-analysis and meta-regression is introduced. The algorithm (ClusterZ) analyses both coordinates and reported t statistic or Z score, standardised by the number of subjects. Statistical significance is determined not by coordinate density, but by a random effects meta-analyses of reported effects performed cluster-wise using standard statistical methods and taking account of censoring inherent in the published summary results. Type 1 error control is achieved using the false cluster discovery rate (FCDR), which is based on the false discovery rate. This controls both the family wise error rate under the null hypothesis that coordinates are randomly drawn from a standard stereotaxic space, and the proportion of significant clusters that are expected under the null. Such control is necessary to avoid propagating and even amplifying the very issues motivating the meta-analysis in the first place. ClusterZ is demonstrated on both numerically simulated data and on real data from reports of grey matter loss in multiple sclerosis (MS) and syndromes suggestive of MS, and of painful stimulus in healthy controls. The software implementation is available to download and use freely. Copyright © 2017 Elsevier Inc. All rights reserved.

Discovery of a polystyrene binding peptide isolated from phage display library and its application in peptide immobilization.

PubMed

Qiang, Xu; Sun, Keyong; Xing, Lijun; Xu, Yifeng; Wang, Hong; Zhou, Zhengpin; Zhang, Juan; Zhang, Fang; Caliskan, Bilgen; Wang, Min; Qiu, Zheng

2017-06-01

Phage peptide display is a powerful technique for discovery of various target-specific ligands. However, target-unrelated peptides can often be obtained and cause ambiguous results. Peptide PB-TUP has been isolated repeatedly in our laboratory on different targets and we conducted a research on PB-TUP phage to investigate their binding properties and rate of propagation. ELISA and phage recovery assay demonstrated that PB-TUP phage had a significant superior affinity to polystyrene solid surface compared with control phage clones. In this study, some incidental bindings are excluded like blocking agents and non-specific binding of secondary antibodies. Propagation rate assays of the selected phage clones showed that the growth rate of PB-TUP phage was not superior to the control phages. Furthermore, the binding of PB-TUB to polystyrene was concentration dependent and varied with solution pH. Molecular modeling revealed that stable structures of α-helix and β-turn may contribute to the binding of PB-TUP to polystyrene plate. The PB-TUP sequence was fused to the N-terminus of peptide P2 and the fusion peptide significantly increased the binding affinity to polystyrene. The fusion peptide also enhanced the cell adhesion ability of peptide P2 with human umbilical vein endothelial cell (HUVEC). The addition of the polystyrene binding peptide provided a convenient method for peptide immobilization.

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease.

PubMed

Yokoyama, Jennifer S; Wang, Yunpeng; Schork, Andrew J; Thompson, Wesley K; Karch, Celeste M; Cruchaga, Carlos; McEvoy, Linda K; Witoelar, Aree; Chen, Chi-Hua; Holland, Dominic; Brewer, James B; Franke, Andre; Dillon, William P; Wilson, David M; Mukherjee, Pratik; Hess, Christopher P; Miller, Zachary; Bonham, Luke W; Shen, Jeffrey; Rabinovici, Gil D; Rosen, Howard J; Miller, Bruce L; Hyman, Bradley T; Schellenberg, Gerard D; Karlsen, Tom H; Andreassen, Ole A; Dale, Anders M; Desikan, Rahul S

2016-06-01

Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies. To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD. In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer's Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer's Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer's Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10-5 for AD, and 6.03 × 10-15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10-6 for AD, and 6.57 × 10-5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer's Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10-10; IPMK: β [SE], -0.096 [0.013]; P = 7.57 × 10-13). Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression.

Association Between Genetic Traits for Immune-Mediated Diseases and Alzheimer Disease

PubMed Central

Yokoyama, Jennifer S.; Wang, Yunpeng; Schork, Andrew J.; Thompson, Wesley K.; Karch, Celeste M.; Cruchaga, Carlos; McEvoy, Linda K.; Witoelar, Aree; Chen, Chi-Hua; Holland, Dominic; Brewer, James B.; Franke, Andre; Dillon, William P.; Wilson, David M.; Mukherjee, Pratik; Hess, Christopher P.; Miller, Zachary; Bonham, Luke W.; Shen, Jeffrey; Rabinovici, Gil D.; Rosen, Howard J.; Miller, Bruce L.; Hyman, Bradley T.; Schellenberg, Gerard D.; Karlsen, Tom H.; Andreassen, Ole A.; Dale, Anders M.; Desikan, Rahul S.

2016-01-01

IMPORTANCE Late-onset Alzheimer disease (AD), the most common form of dementia, places a large burden on families and society. Although epidemiological and clinical evidence suggests a relationship between inflammation and AD, their relationship is not well understood and could have implications for treatment and prevention strategies. OBJECTIVE To determine whether a subset of genes involved with increased risk of inflammation are also associated with increased risk for AD. DESIGN, SETTING, AND PARTICIPANTS In a genetic epidemiology study conducted in July 2015, we systematically investigated genetic overlap between AD (International Genomics of Alzheimer’s Project stage 1) and Crohn disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, and psoriasis using summary data from genome-wide association studies at multiple academic clinical research centers. P values and odds ratios from genome-wide association studies of more than 100 000 individuals were from previous comparisons of patients vs respective control cohorts. Diagnosis for each disorder was previously established for the parent study using consensus criteria. MAIN OUTCOMES AND MEASURES The primary outcome was the pleiotropic (conjunction) false discovery rate P value. Follow-up for candidate variants included neuritic plaque and neurofibrillary tangle pathology; longitudinal Alzheimer’s Disease Assessment Scale cognitive subscale scores as a measure of cognitive dysfunction (Alzheimer’s Disease Neuroimaging Initiative); and gene expression in AD vs control brains (Gene Expression Omnibus data). RESULTS Eight single-nucleotide polymorphisms (false discovery rate P < .05) were associated with both AD and immune-mediated diseases. Of these, rs2516049 (closest gene HLA-DRB5; conjunction false discovery rate P = .04 for AD and psoriasis, 5.37 × 10−5 for AD, and 6.03 × 10−15 for psoriasis) and rs12570088 (closest gene IPMK; conjunction false discovery rate P = .009 for AD and Crohn disease, P = 5.73 × 10−6 for AD, and 6.57 × 10−5 for Crohn disease) demonstrated the same direction of allelic effect between AD and the immune-mediated diseases. Both rs2516049 and rs12570088 were significantly associated with neurofibrillary tangle pathology (P = .01352 and .03151, respectively); rs2516049 additionally correlated with longitudinal decline on Alzheimer’s Disease Assessment Scale cognitive subscale scores (β [SE], 0.405 [0.190]; P = .03). Regarding gene expression, HLA-DRA and IPMK transcript expression was significantly altered in AD brains compared with control brains (HLA-DRA: β [SE], 0.155 [0.024]; P = 1.97 × 10−10; IPMK: β [SE], −0.096 [0.013]; P = 7.57 × 10−13). CONCLUSIONS AND RELEVANCE Our findings demonstrate genetic overlap between AD and immune-mediated diseases and suggest that immune system processes influence AD pathogenesis and progression. PMID:27088644

Characterization of a Genomic Signature of Pregnancy in the Breast

PubMed Central

Belitskaya-Lévy, Ilana; Zeleniuch-Jacquotte, Anne; Russo, Jose; Russo, Irma H.; Bordás, Pal; Åhman, Janet; Afanasyeva, Yelena; Johansson, Robert; Lenner, Per; Li, Xiaochun; de Cicco, Ricardo López; Peri, Suraj; Ross, Eric; Russo, Patricia A.; Santucci-Pereira, Julia; Sheriff, Fathima S.; Slifker, Michael; Hallmans, Göran; Toniolo, Paolo; Arslan, Alan A.

2012-01-01

The objective of the current study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts; scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression and significance analysis for microarrays were used to identify statistically significant differences in expression of genes. The False Discovery Rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at a FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell cycle control, adhesion and differentiation. The results provide persuasive evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer. PMID:21622728

Forecasting petroleum discoveries in sparsely drilled areas: Nigeria and the North Sea

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

Attanasi, E.D.; Root, D.H.

1988-10-01

Decline function methods for projecting future discoveries generally capture the crowding effects of wildcat wells on the discovery rate. However, these methods do not accommodate easily situations where exploration areas and horizons are expanding. In this paper, a method is presented that uses a mapping algorithm for separating these often countervailing influences. The method is applied to Nigeria and the North Sea. For an amount of future drilling equivalent to past drilling (825 wildcat wells), future discoveries (in resources found) for Nigeria are expected to decline by 68% per well but still amount to 8.5 billion barrels of oil equivalentmore » (BOE). Similarly, for the total North Sea for an equivalent amount and mix among areas of past drilling (1322 wildcat wells), future discoveries are expected to amount to 17.9 billion BOE, whereas the average discovery rate per well is expected to decline by 71%.« less

Forecasting petroleum discoveries in sparsely drilled areas: Nigeria and the North Sea

USGS Publications Warehouse

Attanasi, E.D.; Root, D.H.

1988-01-01

Decline function methods for projecting future discoveries generally capture the crowding effects of wildcat wells on the discovery rate. However, these methods do not accommodate easily situations where exploration areas and horizons are expanding. In this paper, a method is presented that uses a mapping algorithm for separating these often countervailing influences. The method is applied to Nigeria and the North Sea. For an amount of future drilling equivalent to past drilling (825 wildcat wells), future discoveries (in resources found) for Nigeria are expected to decline by 68% per well but still amount to 8.5 billion barrels of oil equivalent (BOE). Similarly, for the total North Sea for an equivalent amount and mix among areas of past drilling (1322 wildcat wells), future discoveries are expected to amount to 17.9 billion BOE, whereas the average discovery rate per well is expected to decline by 71%. ?? 1988 International Association for Mathematical Geology.

28 CFR 76.21 - Discovery.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

28 CFR 76.21 - Discovery.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

28 CFR 76.21 - Discovery.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

28 CFR 76.21 - Discovery.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 28 Judicial Administration 2 2011-07-01 2011-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

28 CFR 76.21 - Discovery.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 28 Judicial Administration 2 2010-07-01 2010-07-01 false Discovery. 76.21 Section 76.21 Judicial... POSSESSION OF CERTAIN CONTROLLED SUBSTANCES § 76.21 Discovery. (a) Scope. Discovery under this part covers... as a general guide for discovery practices in proceedings before the Judge. However, unless otherwise...

Mass univariate analysis of event-related brain potentials/fields I: a critical tutorial review.

PubMed

Groppe, David M; Urbach, Thomas P; Kutas, Marta

2011-12-01

Event-related potentials (ERPs) and magnetic fields (ERFs) are typically analyzed via ANOVAs on mean activity in a priori windows. Advances in computing power and statistics have produced an alternative, mass univariate analyses consisting of thousands of statistical tests and powerful corrections for multiple comparisons. Such analyses are most useful when one has little a priori knowledge of effect locations or latencies, and for delineating effect boundaries. Mass univariate analyses complement and, at times, obviate traditional analyses. Here we review this approach as applied to ERP/ERF data and four methods for multiple comparison correction: strong control of the familywise error rate (FWER) via permutation tests, weak control of FWER via cluster-based permutation tests, false discovery rate control, and control of the generalized FWER. We end with recommendations for their use and introduce free MATLAB software for their implementation. Copyright © 2011 Society for Psychophysiological Research.

FDR-controlled metabolite annotation for high-resolution imaging mass spectrometry.

PubMed

Palmer, Andrew; Phapale, Prasad; Chernyavsky, Ilya; Lavigne, Regis; Fay, Dominik; Tarasov, Artem; Kovalev, Vitaly; Fuchser, Jens; Nikolenko, Sergey; Pineau, Charles; Becker, Michael; Alexandrov, Theodore

2017-01-01

High-mass-resolution imaging mass spectrometry promises to localize hundreds of metabolites in tissues, cell cultures, and agar plates with cellular resolution, but it is hampered by the lack of bioinformatics tools for automated metabolite identification. We report pySM, a framework for false discovery rate (FDR)-controlled metabolite annotation at the level of the molecular sum formula, for high-mass-resolution imaging mass spectrometry (https://github.com/alexandrovteam/pySM). We introduce a metabolite-signal match score and a target-decoy FDR estimate for spatial metabolomics.

Analysis of the rate of wildcat drilling and deposit discovery

USGS Publications Warehouse

Drew, L.J.

1975-01-01

The rate at which petroleum deposits were discovered during a 16-yr period (1957-72) was examined in relation to changes in a suite of economic and physical variables. The study area encompasses 11,000 mi2 and is located on the eastern flank of the Powder River Basin. A two-stage multiple-regression model was used as a basis for this analysis. The variables employed in this model were: (1) the yearly wildcat drilling rate, (2) a measure of the extent of the physical exhaustion of the resource base of the region, (3) a proxy for the discovery expectation of the exploration operators active in the region, (4) an exploration price/cost ratio, and (5) the expected depths of the exploration targets sought. The rate at which wildcat wells were drilled was strongly correlated with the discovery expectation of the exploration operators. Small additional variations in the wildcat drilling rate were explained by the price/cost ratio and target-depth variables. The number of deposits discovered each year was highly dependent on the wildcat drilling rate, but the aggregate quantity of petroleum discovered each year was independent of the wildcat drilling rate. The independence between these last two variables is a consequence of the cyclical behavior of the exploration play mechanism. Although the discovery success ratio declined sharply during the initial phases of the two exploration plays which developed in the study area, a learning effect occurred whereby the discovery success ratio improved steadily with the passage of time during both exploration plays. ?? 1975 Plenum Publishing Corporation.

Toward a Quantitative Theory of Intellectual Discovery (Especially in Physics).

ERIC Educational Resources Information Center

Fowler, Richard G.

1987-01-01

Studies time intervals in a list of critical ideas in physics. Infers that the rate of growth of ideas has been proportional to the totality of known ideas multiplied by the totality of people in the world. Indicates that the rate of discovery in physics has been decreasing. (CW)

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

Shen, M.; Vermeulen, R.; Rajaraman, P.

The high incidence of lung cancer in Xuanwei County, China has been attributed to exposure to indoor smoky coal emissions that contain polycyclic aromatic hydrocarbons (PAHs). The inflammatory response induced by coal smoke components may promote lung tumor development. We studied the association between single nucleotide polymorphisms (SNPs) in genes involved in innate immunity and lung cancer risk in a population-based case-control study (122 cases and 122 controls) in Xuanwei. A total of 1,360 tag SNPs in 149 gene regions were included in the analysis. FCER2 rs7249320 was the most significant SNP (OR: 0.30; 95% Cl: 0.16-0.55; P: 0.0001; falsemore » discovery rate value, 0.13) for variant carriers. The gene regions ALOX12B/ALOX15B and KLK2 were associated with increased lung cancer risk globally (false discovery rate value < 0.15). In addition, there were positive interactions between KLK15 rs3745523 and smoky coal use (OR: 9.40; P-interaction = 0.07) and between FCER2 rs7249320 and KLK2 rs2739476 (OR: 10.77; P-interaction = 0.003). Our results suggest that genetic polymorphisms in innate immunity genes may play a role in the genesis of lung cancer caused by PAH-containing coal smoke. Integrin/receptor and complement pathways as well as IgE regulation are particularly noteworthy.« less

Specificity control for read alignments using an artificial reference genome-guided false discovery rate.

PubMed

Giese, Sven H; Zickmann, Franziska; Renard, Bernhard Y

2014-01-01

Accurate estimation, comparison and evaluation of read mapping error rates is a crucial step in the processing of next-generation sequencing data, as further analysis steps and interpretation assume the correctness of the mapping results. Current approaches are either focused on sensitivity estimation and thereby disregard specificity or are based on read simulations. Although continuously improving, read simulations are still prone to introduce a bias into the mapping error quantitation and cannot capture all characteristics of an individual dataset. We introduce ARDEN (artificial reference driven estimation of false positives in next-generation sequencing data), a novel benchmark method that estimates error rates of read mappers based on real experimental reads, using an additionally generated artificial reference genome. It allows a dataset-specific computation of error rates and the construction of a receiver operating characteristic curve. Thereby, it can be used for optimization of parameters for read mappers, selection of read mappers for a specific problem or for filtering alignments based on quality estimation. The use of ARDEN is demonstrated in a general read mapper comparison, a parameter optimization for one read mapper and an application example in single-nucleotide polymorphism discovery with a significant reduction in the number of false positive identifications. The ARDEN source code is freely available at http://sourceforge.net/projects/arden/.

Child Predictors of Learning to Control Variables via Instruction or Self-Discovery

ERIC Educational Resources Information Center

Wagensveld, Barbara; Segers, Eliane; Kleemans, Tijs; Verhoeven, Ludo

2015-01-01

We examined the role child factors on the acquisition and transfer of learning the control of variables strategy (CVS) via instruction or self-discovery. Seventy-six fourth graders and 43 sixth graders were randomly assigned to a group receiving direct CVS instruction or a discovery learning group. Prior to the intervention, cognitive, scientific,…

MSblender: A probabilistic approach for integrating peptide identifications from multiple database search engines.

PubMed

Kwon, Taejoon; Choi, Hyungwon; Vogel, Christine; Nesvizhskii, Alexey I; Marcotte, Edward M

2011-07-01

Shotgun proteomics using mass spectrometry is a powerful method for protein identification but suffers limited sensitivity in complex samples. Integrating peptide identifications from multiple database search engines is a promising strategy to increase the number of peptide identifications and reduce the volume of unassigned tandem mass spectra. Existing methods pool statistical significance scores such as p-values or posterior probabilities of peptide-spectrum matches (PSMs) from multiple search engines after high scoring peptides have been assigned to spectra, but these methods lack reliable control of identification error rates as data are integrated from different search engines. We developed a statistically coherent method for integrative analysis, termed MSblender. MSblender converts raw search scores from search engines into a probability score for every possible PSM and properly accounts for the correlation between search scores. The method reliably estimates false discovery rates and identifies more PSMs than any single search engine at the same false discovery rate. Increased identifications increment spectral counts for most proteins and allow quantification of proteins that would not have been quantified by individual search engines. We also demonstrate that enhanced quantification contributes to improve sensitivity in differential expression analyses.

MSblender: a probabilistic approach for integrating peptide identifications from multiple database search engines

PubMed Central

Kwon, Taejoon; Choi, Hyungwon; Vogel, Christine; Nesvizhskii, Alexey I.; Marcotte, Edward M.

2011-01-01

Shotgun proteomics using mass spectrometry is a powerful method for protein identification but suffers limited sensitivity in complex samples. Integrating peptide identifications from multiple database search engines is a promising strategy to increase the number of peptide identifications and reduce the volume of unassigned tandem mass spectra. Existing methods pool statistical significance scores such as p-values or posterior probabilities of peptide-spectrum matches (PSMs) from multiple search engines after high scoring peptides have been assigned to spectra, but these methods lack reliable control of identification error rates as data are integrated from different search engines. We developed a statistically coherent method for integrative analysis, termed MSblender. MSblender converts raw search scores from search engines into a probability score for all possible PSMs and properly accounts for the correlation between search scores. The method reliably estimates false discovery rates and identifies more PSMs than any single search engine at the same false discovery rate. Increased identifications increment spectral counts for all detected proteins and allow quantification of proteins that would not have been quantified by individual search engines. We also demonstrate that enhanced quantification contributes to improve sensitivity in differential expression analyses. PMID:21488652

Alzheimer's Disease Sequencing Project discovery and replication criteria for cases and controls: Data from a community-based prospective cohort study with autopsy follow-up.

PubMed

Crane, Paul K; Foroud, Tatiana; Montine, Thomas J; Larson, Eric B

2017-12-01

The Alzheimer's Disease Sequencing Project (ADSP) used different criteria for assigning case and control status from the discovery and replication phases of the project. We considered data from a community-based prospective cohort study with autopsy follow-up where participants could be categorized as case, control, or neither by both definitions and compared the two sets of criteria. We used data from the Adult Changes in Thought (ACT) study including Diagnostic and Statistical Manual-IV criteria for dementia status, McKhann et al. criteria for clinical Alzheimer's disease, and Braak and Consortium to Establish a Registry for AD findings on neurofibrillary tangles and neuritic plaques to categorize the 621 ACT participants of European ancestry who died and came to autopsy. We applied ADSP discovery and replication definitions to identify controls, cases, and people who were neither controls nor cases. There was some agreement between the discovery and replication definitions. Major areas of discrepancy included the finding that only 40% of the discovery sample controls had sufficiently low levels of neurofibrillary tangles and neuritic plaques to be considered controls by the replication criteria and the finding that 16% of the replication phase cases were diagnosed with non-AD dementia during life and thus were excluded as cases for the discovery phase. These findings should inform interpretation of genetic association findings from the ADSP. Differences in genetic association findings between the two phases of the study may reflect these different phenotype definitions from the discovery and replication phase of the ADSP. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

SFC/MS in drug discovery at Pfizer, La Jolla

NASA Astrophysics Data System (ADS)

Bolaños, Ben; Greig, Michael; Ventura, Manuel; Farrell, William; Aurigemma, Christine M.; Li, Haitao; Quenzer, Terri L.; Tivel, Kathleen; Bylund, Jessica M. R.; Tran, Phuong; Pham, Catherine; Phillipson, Doug

2004-11-01

We report the use of supercritical fluid chromatography/mass spectrometry (SFC/MS) for numerous applications in drug discovery at Pfizer, La Jolla. Namely, SFC/MS has been heavily relied upon for analysis and purification of a diverse set of compounds from the in-house chemical library. Supporting high-speed SFC/MS quality control of the purified compounds is made possible at high flow rate SFC along with time-of-flight mass detection. The flexibility of SFC/MS systems has been extended with the integration of an atmospheric pressure photoionization source (APPI) for use with more non-polar compounds and enhancements in signal to noise. Further SFC/MS applications of note include chiral analysis for purification and assessment of enantiomers and SFC/MS analysis of difficult to separate hydrophobic peptides.

Integration of epigenetic game theory and developmental principles. Reply to comments on ;Epigenetic game theory: How to compute the epigenetic control of maternal-to-zygotic transition;

NASA Astrophysics Data System (ADS)

Wang, Qian; Gosik, Kirk; Xing, Sujuan; Jiang, Libo; Sun, Lidan; Chinchilli, Vernon M.; Wu, Rongling

2017-03-01

In its recent issue, Science published breaking global health news, regarding the discovery of pronounced differences of fetal growth rate between countries, even if the mothers of babies were equally given the optimal circumstances [1]. This discovery by a large team of obstetric and gynecological researchers from multiple countries [2] changes a previous view from a large project called INTERGROWTH-21st, which claims that growth trajectories of unborn babies follow a similar form between countries [3]. This new finding provides evidence of the important role of genetic and epigenetic variants (differing between ethnic groups) in determining fetal growth, a process that is generally believed to be affected predominantly by nutrition and socioeconomic status [4].

The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.

PubMed

Castaldi, Peter J; Cho, Michael H; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lomas, David A; Anderson, Wayne; Beaty, Terri H; Hokanson, John E; Crapo, James D; Laird, Nan; Silverman, Edwin K

2011-12-01

Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

Dynamics and Control of Tethered Satellite Formations for the Purpose of Space-Based Remote Sensing

DTIC Science & Technology

2006-08-01

remote sensing mission. Energy dissipation is found to have an adverse effect on foundational rigid body (Likins-Pringle) equilibria. It is shown that a continuously earth-facing equilibrium condition for a fixed-length tethered system does not exist since the spin rate required for the proper precession would not be high enough to maintain tether tension. The range of required spin rates for steady-spin motion is numerically defined here, but none of these conditions can meet the continuously earth-facing criteria. Of particular note is the discovery that applying certain

Underbody Blast Models of TBI Caused by Hyper-Acceleration and Secondary Head Impact

DTIC Science & Technology

2016-02-01

discovery rate (FDR), which controls for the expected proportion of false rejected hypotheses. ANOVA was performed to evaluate the significance in gene...acceleration/deceleration11,27 and blast4,13 have also been designed for the purpose of evaluating coup-contrecoup and blast wave energies potentially... evaluation of different angles/ locations of the projectile impact to the surface of the rat head. Finally, pilot studies were conducted to provide further

Growth and photosynthetic responses of wheat plants grown in space

NASA Technical Reports Server (NTRS)

Tripathy, B. C.; Brown, C. S.; Levine, H. G.; Krikorian, A. D.

1996-01-01

Growth and photosynthesis of wheat (Triticum aestivum L. cv Super Dwarf) plants grown onboard the space shuttle Discovery for 10 d were examined. Compared to ground control plants, the shoot fresh weight of space-grown seedlings decreased by 25%. Postflight measurements of the O2 evolution/photosynthetic photon flux density response curves of leaf samples revealed that the CO2-saturated photosynthetic rate at saturating light intensities in space-grown plants declined 25% relative to the rate in ground control plants. The relative quantum yield of CO2-saturated photosynthetic O2 evolution measured at limiting light intensities was not significantly affected. In space-grown plants, the light compensation point of the leaves increased by 33%, which likely was due to an increase (27%) in leaf dark-respiration rates. Related experiments with thylakoids isolated from space-grown plants showed that the light-saturated photosynthetic electron transport rate from H2O through photosystems II and I was reduced by 28%. These results demonstrate that photosynthetic functions are affected by the microgravity environment.

Low-z Type Ia Supernova Calibration

NASA Astrophysics Data System (ADS)

Hamuy, Mario

The discovery of acceleration and dark energy in 1998 arguably constitutes one of the most revolutionary discoveries in astrophysics in recent years. This paradigm shift was possible thanks to one of the most traditional cosmological tests: the redshift-distance relation between galaxies. This discovery was based on a differential measurement of the expansion rate of the universe: the current one provided by nearby (low-z) type Ia supernovae and the one in the past measured from distant (high-z) supernovae. This paper focuses on the first part of this journey: the calibration of the type Ia supernova luminosities and the local expansion rate of the universe, which was made possible thanks to the introduction of digital CCD (charge-coupled device) digital photometry. The new technology permitted us in the early 1990s to convert supernovae as precise tools to measure extragalactic distances through two key surveys: (1) the "Tololo Supernova Program" which made possible the critical discovery of the "peak luminosity-decline rate" relation for type Ia supernovae, the key underlying idea today behind precise cosmology from supernovae, and (2) the Calán/Tololo project which provided the low - z type Ia supernova sample for the discovery of acceleration.

Progressive calibration and averaging for tandem mass spectrometry statistical confidence estimation: Why settle for a single decoy?

PubMed Central

Keich, Uri; Noble, William Stafford

2017-01-01

Estimating the false discovery rate (FDR) among a list of tandem mass spectrum identifications is mostly done through target-decoy competition (TDC). Here we offer two new methods that can use an arbitrarily small number of additional randomly drawn decoy databases to improve TDC. Specifically, “Partial Calibration” utilizes a new meta-scoring scheme that allows us to gradually benefit from the increase in the number of identifications calibration yields and “Averaged TDC” (a-TDC) reduces the liberal bias of TDC for small FDR values and its variability throughout. Combining a-TDC with “Progressive Calibration” (PC), which attempts to find the “right” number of decoys required for calibration we see substantial impact in real datasets: when analyzing the Plasmodium falciparum data it typically yields almost the entire 17% increase in discoveries that “full calibration” yields (at FDR level 0.05) using 60 times fewer decoys. Our methods are further validated using a novel realistic simulation scheme and importantly, they apply more generally to the problem of controlling the FDR among discoveries from searching an incomplete database. PMID:29326989

PERSONAL AND CIRCUMSTANTIAL FACTORS INFLUENCING THE ACT OF DISCOVERY.

ERIC Educational Resources Information Center

OSTRANDER, EDWARD R.

HOW STUDENTS SAY THEY LEARN WAS INVESTIGATED. INTERVIEWS WITH A RANDOM SAMPLE OF 74 WOMEN STUDENTS POSED QUESTIONS ABOUT THE NATURE, FREQUENCY, PATTERNS, AND CIRCUMSTANCES UNDER WHICH ACTS OF DISCOVERY TAKE PLACE IN THE ACADEMIC SETTING. STUDENTS WERE ASSIGNED DISCOVERY RATINGS BASED ON READINGS OF TYPESCRIPTS. EACH STUDENT WAS CLASSIFIED AND…

Differential DNA methylation patterns of polycystic ovarian syndrome in whole blood of Chinese women.

PubMed

Li, Shuxia; Zhu, Dongyi; Duan, Hongmei; Ren, Anran; Glintborg, Dorte; Andersen, Marianne; Skov, Vibe; Thomassen, Mads; Kruse, Torben; Tan, Qihua

2017-03-28

As a universally common endocrinopathy in women of reproductive age, the polycystic ovarian syndrome is characterized by composite clinical phenotypes reflecting the contributions of reproductive impact of ovarian dysfunction and metabolic abnormalities with widely varying symptoms resulting from interference of the genome with the environment through integrative biological mechanisms including epigenetics. We have performed a genome-wide DNA methylation analysis on polycystic ovarian syndrome and identified a substantial number of genomic sites differentially methylated in the whole blood of PCOS patients and healthy controls (52 sites, false discovery rate < 0.05 and corresponding p value < 5.68e-06), highly consistently replicating biological pathways extensively implicated in immunity and immunity-related inflammatory disorders (false discovery rate < 0.05) that were reportedly regulated in the DNA methylome from ovarian tissue under PCOS condition. Most importantly, our genome-wide profiling focusing on PCOS patients revealed a large number of DNA methylation sites and their enriched functional pathways significantly associated with diverse clinical features (levels of prolactin, estradiol, progesterone and menstrual cycle) that could serve as novel molecular basis of the clinical heterogeneity observed in PCOS women.

21 CFR 1301.74 - Other security controls for non-practitioners; narcotic treatment programs and compounders for...

Code of Federal Regulations, 2011 CFR

2011-04-01

... controlled substances within one business day of discovery of the theft or loss. The supplier is responsible... selected pursuant to paragraph (e) of this section, within one business day of discovery of such theft or... of business; (2) The specific controlled substances lost; (3) Whether the loss of the controlled...

21 CFR 1301.74 - Other security controls for non-practitioners; narcotic treatment programs and compounders for...

Code of Federal Regulations, 2010 CFR

2010-04-01

... controlled substances within one business day of discovery of the theft or loss. The supplier is responsible... selected pursuant to paragraph (e) of this section, within one business day of discovery of such theft or... of business; (2) The specific controlled substances lost; (3) Whether the loss of the controlled...

40 CFR 209.22 - Other discovery.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 26 2013-07-01 2013-07-01 false Other discovery. 209.22 Section 209.22... Orders Issued Under Section 11(d) of the Noise Control Act § 209.22 Other discovery. (a) Further discovery under this section shall be undertaken only upon order of the administrative law judge or upon...

40 CFR 209.22 - Other discovery.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 25 2014-07-01 2014-07-01 false Other discovery. 209.22 Section 209.22... Orders Issued Under Section 11(d) of the Noise Control Act § 209.22 Other discovery. (a) Further discovery under this section shall be undertaken only upon order of the administrative law judge or upon...

40 CFR 209.22 - Other discovery.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 25 2011-07-01 2011-07-01 false Other discovery. 209.22 Section 209.22... Orders Issued Under Section 11(d) of the Noise Control Act § 209.22 Other discovery. (a) Further discovery under this section shall be undertaken only upon order of the administrative law judge or upon...

40 CFR 209.22 - Other discovery.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 24 2010-07-01 2010-07-01 false Other discovery. 209.22 Section 209.22... Orders Issued Under Section 11(d) of the Noise Control Act § 209.22 Other discovery. (a) Further discovery under this section shall be undertaken only upon order of the administrative law judge or upon...

Discovery of Host Factors and Pathways Utilized in Hantaviral Infection

DTIC Science & Technology

2016-09-01

AWARD NUMBER: W81XWH-14-1-0204 TITLE: Discovery of Host Factors and Pathways Utilized in Hantaviral Infection PRINCIPAL INVESTIGATOR: Paul...Aug 2016 4. TITLE AND SUBTITLE Discovery of Host Factors and Pathways Utilized in Hantaviral Infection 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c...after significance values were calculated and corrected for false discovery rate. The top hit is ATP6V0A1, a gene encoding a subunit of a vacuolar

Evaluating the Importance of the Carotid Chemoreceptors in Controlling Breathing during Exercise in Man

PubMed Central

Parkes, M. J.

2013-01-01

Only the carotid chemoreceptors stimulate breathing during hypoxia in Man. They are also ideally located to warn if the brain's oxygen supply falls, or if hypercapnia occurs. Since their discovery ~80 years ago stimulation, ablation, and recording experiments still leave 3 substantial difficulties in establishing how important the carotid chemoreceptors are in controlling breathing during exercise in Man: (i) they are in the wrong location to measure metabolic rate (but are ideally located to measure any mismatch), (ii) they receive no known signal during exercise linking them with metabolic rate and no overt mismatch signals occur and (iii) their denervation in Man fails to prevent breathing matching metabolic rate in exercise. New research is needed to enable recording from carotid chemoreceptors in Man to establish whether there is any factor that rises with metabolic rate and greatly increases carotid chemoreceptor activity during exercise. Available evidence so far in Man indicates that carotid chemoreceptors are either one of two mechanisms that explain breathing matching metabolic rate or have no importance. We still lack key experimental evidence to distinguish between these two possibilities. PMID:24236297

BinQuasi: a peak detection method for ChIP-sequencing data with biological replicates.

PubMed

Goren, Emily; Liu, Peng; Wang, Chao; Wang, Chong

2018-04-19

ChIP-seq experiments that are aimed at detecting DNA-protein interactions require biological replication to draw inferential conclusions, however there is no current consensus on how to analyze ChIP-seq data with biological replicates. Very few methodologies exist for the joint analysis of replicated ChIP-seq data, with approaches ranging from combining the results of analyzing replicates individually to joint modeling of all replicates. Combining the results of individual replicates analyzed separately can lead to reduced peak classification performance compared to joint modeling. Currently available methods for joint analysis may fail to control the false discovery rate at the nominal level. We propose BinQuasi, a peak caller for replicated ChIP-seq data, that jointly models biological replicates using a generalized linear model framework and employs a one-sided quasi-likelihood ratio test to detect peaks. When applied to simulated data and real datasets, BinQuasi performs favorably compared to existing methods, including better control of false discovery rate than existing joint modeling approaches. BinQuasi offers a flexible approach to joint modeling of replicated ChIP-seq data which is preferable to combining the results of replicates analyzed individually. Source code is freely available for download at https://cran.r-project.org/package=BinQuasi, implemented in R. pliu@iastate.edu or egoren@iastate.edu. Supplementary material is available at Bioinformatics online.

Best (but oft-forgotten) practices: the multiple problems of multiplicity-whether and how to correct for many statistical tests.

PubMed

Streiner, David L

2015-10-01

Testing many null hypotheses in a single study results in an increased probability of detecting a significant finding just by chance (the problem of multiplicity). Debates have raged over many years with regard to whether to correct for multiplicity and, if so, how it should be done. This article first discusses how multiple tests lead to an inflation of the α level, then explores the following different contexts in which multiplicity arises: testing for baseline differences in various types of studies, having >1 outcome variable, conducting statistical tests that produce >1 P value, taking multiple "peeks" at the data, and unplanned, post hoc analyses (i.e., "data dredging," "fishing expeditions," or "P-hacking"). It then discusses some of the methods that have been proposed for correcting for multiplicity, including single-step procedures (e.g., Bonferroni); multistep procedures, such as those of Holm, Hochberg, and Šidák; false discovery rate control; and resampling approaches. Note that these various approaches describe different aspects and are not necessarily mutually exclusive. For example, resampling methods could be used to control the false discovery rate or the family-wise error rate (as defined later in this article). However, the use of one of these approaches presupposes that we should correct for multiplicity, which is not universally accepted, and the article presents the arguments for and against such "correction." The final section brings together these threads and presents suggestions with regard to when it makes sense to apply the corrections and how to do so. © 2015 American Society for Nutrition.

Integrated Proteomic Pipeline Using Multiple Search Engines for a Proteogenomic Study with a Controlled Protein False Discovery Rate.

PubMed

Park, Gun Wook; Hwang, Heeyoun; Kim, Kwang Hoe; Lee, Ju Yeon; Lee, Hyun Kyoung; Park, Ji Yeong; Ji, Eun Sun; Park, Sung-Kyu Robin; Yates, John R; Kwon, Kyung-Hoon; Park, Young Mok; Lee, Hyoung-Joo; Paik, Young-Ki; Kim, Jin Young; Yoo, Jong Shin

2016-11-04

In the Chromosome-Centric Human Proteome Project (C-HPP), false-positive identification by peptide spectrum matches (PSMs) after database searches is a major issue for proteogenomic studies using liquid-chromatography and mass-spectrometry-based large proteomic profiling. Here we developed a simple strategy for protein identification, with a controlled false discovery rate (FDR) at the protein level, using an integrated proteomic pipeline (IPP) that consists of four engrailed steps as follows. First, using three different search engines, SEQUEST, MASCOT, and MS-GF+, individual proteomic searches were performed against the neXtProt database. Second, the search results from the PSMs were combined using statistical evaluation tools including DTASelect and Percolator. Third, the peptide search scores were converted into E-scores normalized using an in-house program. Last, ProteinInferencer was used to filter the proteins containing two or more peptides with a controlled FDR of 1.0% at the protein level. Finally, we compared the performance of the IPP to a conventional proteomic pipeline (CPP) for protein identification using a controlled FDR of <1% at the protein level. Using the IPP, a total of 5756 proteins (vs 4453 using the CPP) including 477 alternative splicing variants (vs 182 using the CPP) were identified from human hippocampal tissue. In addition, a total of 10 missing proteins (vs 7 using the CPP) were identified with two or more unique peptides, and their tryptic peptides were validated using MS/MS spectral pattern from a repository database or their corresponding synthetic peptides. This study shows that the IPP effectively improved the identification of proteins, including alternative splicing variants and missing proteins, in human hippocampal tissues for the C-HPP. All RAW files used in this study were deposited in ProteomeXchange (PXD000395).

False discovery rate control incorporating phylogenetic tree increases detection power in microbiome-wide multiple testing.

PubMed

Xiao, Jian; Cao, Hongyuan; Chen, Jun

2017-09-15

Next generation sequencing technologies have enabled the study of the human microbiome through direct sequencing of microbial DNA, resulting in an enormous amount of microbiome sequencing data. One unique characteristic of microbiome data is the phylogenetic tree that relates all the bacterial species. Closely related bacterial species have a tendency to exhibit a similar relationship with the environment or disease. Thus, incorporating the phylogenetic tree information can potentially improve the detection power for microbiome-wide association studies, where hundreds or thousands of tests are conducted simultaneously to identify bacterial species associated with a phenotype of interest. Despite much progress in multiple testing procedures such as false discovery rate (FDR) control, methods that take into account the phylogenetic tree are largely limited. We propose a new FDR control procedure that incorporates the prior structure information and apply it to microbiome data. The proposed procedure is based on a hierarchical model, where a structure-based prior distribution is designed to utilize the phylogenetic tree. By borrowing information from neighboring bacterial species, we are able to improve the statistical power of detecting associated bacterial species while controlling the FDR at desired levels. When the phylogenetic tree is mis-specified or non-informative, our procedure achieves a similar power as traditional procedures that do not take into account the tree structure. We demonstrate the performance of our method through extensive simulations and real microbiome datasets. We identified far more alcohol-drinking associated bacterial species than traditional methods. R package StructFDR is available from CRAN. chen.jun2@mayo.edu. Supplementary data are available at Bioinformatics online. © The Author (2017). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Spacewatch search for near-Earth asteroids

NASA Technical Reports Server (NTRS)

Gehreis, Tom

1991-01-01

The objective of the Spacewatch Program is to develop new techniques for the discovery of near-earth asteroids and to prove the efficiency of the techniques. Extensive experience was obtained with the 0.91-m Spacewatch Telescope on Kitt Peak that now has the largest CCD detector in the world: a Tektronix 2048 x 2048 with 27-micron pixel size. During the past year, software and hardware for optimizing the discovery of near-earth asteroids were installed. As a result, automatic detection of objects that move with rates between 0.1 and 4 degrees per day has become routine since September 1990. Apparently, one or two near-earth asteroids are discovered per month, on average. The follow up is with astrometry over as long an arc as the geometry and faintness of the object allow, typically three months following the discovery observations. During the second half of 1990, replacing the 0.91-m mirror with a larger one, to increase the discovery rate, was considered. Studies and planning for this switch are proposed for funding during the coming year. It was also proposed that the Spacewatch Telescope be turned on the sky, instead of having the drive turned off, in order to increase the rate of discoveries by perhaps a factor of two.

An effect size filter improves the reproducibility in spectral counting-based comparative proteomics.

PubMed

Gregori, Josep; Villarreal, Laura; Sánchez, Alex; Baselga, José; Villanueva, Josep

2013-12-16

The microarray community has shown that the low reproducibility observed in gene expression-based biomarker discovery studies is partially due to relying solely on p-values to get the lists of differentially expressed genes. Their conclusions recommended complementing the p-value cutoff with the use of effect-size criteria. The aim of this work was to evaluate the influence of such an effect-size filter on spectral counting-based comparative proteomic analysis. The results proved that the filter increased the number of true positives and decreased the number of false positives and the false discovery rate of the dataset. These results were confirmed by simulation experiments where the effect size filter was used to evaluate systematically variable fractions of differentially expressed proteins. Our results suggest that relaxing the p-value cut-off followed by a post-test filter based on effect size and signal level thresholds can increase the reproducibility of statistical results obtained in comparative proteomic analysis. Based on our work, we recommend using a filter consisting of a minimum absolute log2 fold change of 0.8 and a minimum signal of 2-4 SpC on the most abundant condition for the general practice of comparative proteomics. The implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of the results obtained among independent laboratories and MS platforms. Quality control analysis of microarray-based gene expression studies pointed out that the low reproducibility observed in the lists of differentially expressed genes could be partially attributed to the fact that these lists are generated relying solely on p-values. Our study has established that the implementation of an effect size post-test filter improves the statistical results of spectral count-based quantitative proteomics. The results proved that the filter increased the number of true positives whereas decreased the false positives and the false discovery rate of the datasets. The results presented here prove that a post-test filter applying a reasonable effect size and signal level thresholds helps to increase the reproducibility of statistical results in comparative proteomic analysis. Furthermore, the implementation of feature filtering approaches could improve proteomic biomarker discovery initiatives by increasing the reproducibility of results obtained among independent laboratories and MS platforms. This article is part of a Special Issue entitled: Standardization and Quality Control in Proteomics. Copyright © 2013 Elsevier B.V. All rights reserved.

DNA repair variants and breast cancer risk.

PubMed

Grundy, Anne; Richardson, Harriet; Schuetz, Johanna M; Burstyn, Igor; Spinelli, John J; Brooks-Wilson, Angela; Aronson, Kristan J

2016-05-01

A functional DNA repair system has been identified as important in the prevention of tumour development. Previous studies have hypothesized that common polymorphisms in DNA repair genes could play a role in breast cancer risk and also identified the potential for interactions between these polymorphisms and established breast cancer risk factors such as physical activity. Associations with breast cancer risk for 99 single nucleotide polymorphisms (SNPs) from genes in ten DNA repair pathways were examined in a case-control study including both Europeans (644 cases, 809 controls) and East Asians (299 cases, 160 controls). Odds ratios in both additive and dominant genetic models were calculated separately for participants of European and East Asian ancestry using multivariate logistic regression. The impact of multiple comparisons was assessed by correcting for the false discovery rate within each DNA repair pathway. Interactions between several breast cancer risk factors and DNA repair SNPs were also evaluated. One SNP (rs3213282) in the gene XRCC1 was associated with an increased risk of breast cancer in the dominant model of inheritance following adjustment for the false discovery rate (P < 0.05), although no associations were observed for other DNA repair SNPs. Interactions of six SNPs in multiple DNA repair pathways with physical activity were evident prior to correction for FDR, following which there was support for only one of the interaction terms (P < 0.05). No consistent associations between variants in DNA repair genes and breast cancer risk or their modification by breast cancer risk factors were observed. © 2016 Wiley Periodicals, Inc.

Milagro Observations of Potential TeV Emitters

NASA Astrophysics Data System (ADS)

Abeysekara, Anushka; Linnemann, James

2012-03-01

We searched for point sources in Milagro sky maps at the locations in four catalogs of potential TeV emitting sources. Our candidates are selected from the Fermi 2FGL pulsars, Fermi 2FGL extragalactic sources, TeVCat extragalactic sources, and from the BL Lac TeV Candidate list published by Costamante and Ghisellini in 2002. The False Discovery Rate (FDR) statistical procedure is used to select the sources. The FDR procedure controls the fraction of false detections. Our results are presented in this talk.

Petroleum-resource appraisal and discovery rate forecasting in partially explored regions

USGS Publications Warehouse

Drew, Lawrence J.; Schuenemeyer, J.H.; Root, David H.; Attanasi, E.D.

1980-01-01

PART A: A model of the discovery process can be used to predict the size distribution of future petroleum discoveries in partially explored basins. The parameters of the model are estimated directly from the historical drilling record, rather than being determined by assumptions or analogies. The model is based on the concept of the area of influence of a drill hole, which states that the area of a basin exhausted by a drill hole varies with the size and shape of targets in the basin and with the density of previously drilled wells. It also uses the concept of discovery efficiency, which measures the rate of discovery within several classes of deposit size. The model was tested using 25 years of historical exploration data (1949-74) from the Denver basin. From the trend in the discovery rate (the number of discoveries per unit area exhausted), the discovery efficiencies in each class of deposit size were estimated. Using pre-1956 discovery and drilling data, the model accurately predicted the size distribution of discoveries for the 1956-74 period. PART B: A stochastic model of the discovery process has been developed to predict, using past drilling and discovery data, the distribution of future petroleum deposits in partially explored basins, and the basic mathematical properties of the model have been established. The model has two exogenous parameters, the efficiency of exploration and the effective basin size. The first parameter is the ratio of the probability that an actual exploratory well will make a discovery to the probability that a randomly sited well will make a discovery. The second parameter, the effective basin size, is the area of that part of the basin in which drillers are willing to site wells. Methods for estimating these parameters from locations of past wells and from the sizes and locations of past discoveries were derived, and the properties of estimators of the parameters were studied by simulation. PART C: This study examines the temporal properties and determinants of petroleum exploration for firms operating in the Denver basin. Expectations associated with the favorability of a specific area are modeled by using distributed lag proxy variables (of previous discoveries) and predictions from a discovery process model. In the second part of the study, a discovery process model is linked with a behavioral well-drilling model in order to predict the supply of new reserves. Results of the study indicate that the positive effects of new discoveries on drilling increase for several periods and then diminish to zero within 2? years after the deposit discovery date. Tests of alternative specifications of the argument of the distributed lag function using alternative minimum size classes of deposits produced little change in the model's explanatory power. This result suggests that, once an exploration play is underway, favorable operator expectations are sustained by the quantity of oil found per time period rather than by the discovery of specific size deposits. When predictions of the value of undiscovered deposits (generated from a discovery process model) were substituted for the expectations variable in models used to explain exploration effort, operator behavior was found to be consistent with these predictions. This result suggests that operators, on the average, were efficiently using information contained in the discovery history of the basin in carrying out their exploration plans. Comparison of the two approaches to modeling unobservable operator expectations indicates that the two models produced very similar results. The integration of the behavioral well-drilling model and discovery process model to predict the additions to reserves per unit time was successful only when the quarterly predictions were aggregated to annual values. The accuracy of the aggregated predictions was also found to be reasonably robust to errors in predictions from the behavioral well-drilling equation.

Oblique view of the Orbiter Discovery from ground level in ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Oblique view of the Orbiter Discovery from ground level in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note that the Forward Reaction Control System Module has been removed from the forward section. The void left behind by the removal of the reaction control system has been sealed with a clear flexible barrier and kept under positive pressure to reduce the contaminant infiltration potential. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

General view of the aft section of the Orbiter Discovery ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

General view of the aft section of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the main engines and Orbiter Maneuvering System/Reaction Control System pods are removed in this photo. The flexible hoses protruding from the starboard aft section are to control temperature, humidity and pressure in the orbiter's void spaces during its down time. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of triflumezopyrim as a potent hopper insecticide1.

PubMed

Zhang, Wenming; Holyoke, Caleb W; Pahutski, Thomas F; Lahm, George P; Barry, James D; Cordova, Daniel; Leighty, Robert M; Singh, Vineet; Vicent, Daniel R; Tong, My-Hanh T; Hughes, Kenneth A; McCann, Stephen F; Henry, Yewande T; Xu, Ming; Briddell, Twyla A

2017-01-01

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program which led to the discovery of triflumezopyrim as a highly potent insecticide controlling various hopper species. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented. Copyright © 2016 Elsevier Ltd. All rights reserved.

Biomaterials and biotechnology: from the discovery of the first angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering.

PubMed

Langer, Robert

2013-09-01

This paper describes the discovery of the first inhibitors of angiogenesis; the discoveries that led to the development of the first biocompatible controlled release systems for macromolecules, and findings that helped to create the field of tissue engineering. In addition, new paradigms for creating biomaterials, early work on nanotechnology in medicine and intelligent drug delivery systems are discussed. Copyright © 2013 Wiley Periodicals, Inc.

Testing inhomogeneous solvation theory in structure-based ligand discovery.

PubMed

Balius, Trent E; Fischer, Marcus; Stein, Reed M; Adler, Thomas B; Nguyen, Crystal N; Cruz, Anthony; Gilson, Michael K; Kurtzman, Tom; Shoichet, Brian K

2017-08-15

Binding-site water is often displaced upon ligand recognition, but is commonly neglected in structure-based ligand discovery. Inhomogeneous solvation theory (IST) has become popular for treating this effect, but it has not been tested in controlled experiments at atomic resolution. To do so, we turned to a grid-based version of this method, GIST, readily implemented in molecular docking. Whereas the term only improves docking modestly in retrospective ligand enrichment, it could be added without disrupting performance. We thus turned to prospective docking of large libraries to investigate GIST's impact on ligand discovery, geometry, and water structure in a model cavity site well-suited to exploring these terms. Although top-ranked docked molecules with and without the GIST term often overlapped, many ligands were meaningfully prioritized or deprioritized; some of these were selected for testing. Experimentally, 13/14 molecules prioritized by GIST did bind, whereas none of the molecules that it deprioritized were observed to bind. Nine crystal complexes were determined. In six, the ligand geometry corresponded to that predicted by GIST, for one of these the pose without the GIST term was wrong, and three crystallographic poses differed from both predictions. Notably, in one structure, an ordered water molecule with a high GIST displacement penalty was observed to stay in place. Inclusion of this water-displacement term can substantially improve the hit rates and ligand geometries from docking screens, although the magnitude of its effects can be small and its impact in drug binding sites merits further controlled studies.

Biomarker Discovery and Verification of Esophageal Squamous Cell Carcinoma Using Integration of SWATH/MRM.

PubMed

Hou, Guixue; Lou, Xiaomin; Sun, Yulin; Xu, Shaohang; Zi, Jin; Wang, Quanhui; Zhou, Baojin; Han, Bo; Wu, Lin; Zhao, Xiaohang; Lin, Liang; Liu, Siqi

2015-09-04

We propose an efficient integration of SWATH with MRM for biomarker discovery and verification when the corresponding ion library is well established. We strictly controlled the false positive rate associated with SWATH MS signals and carefully selected the target peptides coupled with SWATH and MRM. We collected 10 samples of esophageal squamous cell carcinoma (ESCC) tissues paired with tumors and adjacent regions and quantified 1758 unique proteins with FDR 1% at protein level using SWATH, in which 467 proteins were abundance-dependent with ESCC. After carefully evaluating the SWATH MS signals of the up-regulated proteins, we selected 120 proteins for MRM verification. MRM analysis of the pooled and individual esophageal tissues resulted in 116 proteins that exhibited similar abundance response modes to ESCC that were acquired with SWATH. Because the ESCC-related proteins consisted of a high percentile of secreted proteins, we conducted the MRM assay on patient sera that were collected from pre- and postoperation. Of the 116 target proteins, 42 were identified in the ESCC sera, including 11 with lowered abundances postoperation. Coupling SWATH and MRM is thus feasible and efficient for the discovery and verification of cancer-related protein biomarkers.

Multiple Testing of Gene Sets from Gene Ontology: Possibilities and Pitfalls.

PubMed

Meijer, Rosa J; Goeman, Jelle J

2016-09-01

The use of multiple testing procedures in the context of gene-set testing is an important but relatively underexposed topic. If a multiple testing method is used, this is usually a standard familywise error rate (FWER) or false discovery rate (FDR) controlling procedure in which the logical relationships that exist between the different (self-contained) hypotheses are not taken into account. Taking those relationships into account, however, can lead to more powerful variants of existing multiple testing procedures and can make summarizing and interpreting the final results easier. We will show that, from the perspective of interpretation as well as from the perspective of power improvement, FWER controlling methods are more suitable than FDR controlling methods. As an example of a possible power improvement, we suggest a modified version of the popular method by Holm, which we also implemented in the R package cherry. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Modeling inter-signal arrival times for accurate detection of CAN bus signal injection attacks

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

Moore, Michael Roy; Bridges, Robert A; Combs, Frank L

Modern vehicles rely on hundreds of on-board electronic control units (ECUs) communicating over in-vehicle networks. As external interfaces to the car control networks (such as the on-board diagnostic (OBD) port, auxiliary media ports, etc.) become common, and vehicle-to-vehicle / vehicle-to-infrastructure technology is in the near future, the attack surface for vehicles grows, exposing control networks to potentially life-critical attacks. This paper addresses the need for securing the CAN bus by detecting anomalous traffic patterns via unusual refresh rates of certain commands. While previous works have identified signal frequency as an important feature for CAN bus intrusion detection, this paper providesmore » the first such algorithm with experiments on five attack scenarios. Our data-driven anomaly detection algorithm requires only five seconds of training time (on normal data) and achieves true positive / false discovery rates of 0.9998/0.00298, respectively (micro-averaged across the five experimental tests).« less

How to talk about protein‐level false discovery rates in shotgun proteomics

PubMed Central

The, Matthew; Tasnim, Ayesha

2016-01-01

A frequently sought output from a shotgun proteomics experiment is a list of proteins that we believe to have been present in the analyzed sample before proteolytic digestion. The standard technique to control for errors in such lists is to enforce a preset threshold for the false discovery rate (FDR). Many consider protein‐level FDRs a difficult and vague concept, as the measurement entities, spectra, are manifestations of peptides and not proteins. Here, we argue that this confusion is unnecessary and provide a framework on how to think about protein‐level FDRs, starting from its basic principle: the null hypothesis. Specifically, we point out that two competing null hypotheses are used concurrently in today's protein inference methods, which has gone unnoticed by many. Using simulations of a shotgun proteomics experiment, we show how confusing one null hypothesis for the other can lead to serious discrepancies in the FDR. Furthermore, we demonstrate how the same simulations can be used to verify FDR estimates of protein inference methods. In particular, we show that, for a simple protein inference method, decoy models can be used to accurately estimate protein‐level FDRs for both competing null hypotheses. PMID:27503675

Science of the science, drug discovery and artificial neural networks.

PubMed

Patel, Jigneshkumar

2013-03-01

Drug discovery process many times encounters complex problems, which may be difficult to solve by human intelligence. Artificial Neural Networks (ANNs) are one of the Artificial Intelligence (AI) technologies used for solving such complex problems. ANNs are widely used for primary virtual screening of compounds, quantitative structure activity relationship studies, receptor modeling, formulation development, pharmacokinetics and in all other processes involving complex mathematical modeling. Despite having such advanced technologies and enough understanding of biological systems, drug discovery is still a lengthy, expensive, difficult and inefficient process with low rate of new successful therapeutic discovery. In this paper, author has discussed the drug discovery science and ANN from very basic angle, which may be helpful to understand the application of ANN for drug discovery to improve efficiency.

Identifying significant gene‐environment interactions using a combination of screening testing and hierarchical false discovery rate control

PubMed Central

Shen, Li; Saykin, Andrew J.; Williams, Scott M.; Moore, Jason H.

2016-01-01

ABSTRACT Although gene‐environment (G× E) interactions play an important role in many biological systems, detecting these interactions within genome‐wide data can be challenging due to the loss in statistical power incurred by multiple hypothesis correction. To address the challenge of poor power and the limitations of existing multistage methods, we recently developed a screening‐testing approach for G× E interaction detection that combines elastic net penalized regression with joint estimation to support a single omnibus test for the presence of G× E interactions. In our original work on this technique, however, we did not assess type I error control or power and evaluated the method using just a single, small bladder cancer data set. In this paper, we extend the original method in two important directions and provide a more rigorous performance evaluation. First, we introduce a hierarchical false discovery rate approach to formally assess the significance of individual G× E interactions. Second, to support the analysis of truly genome‐wide data sets, we incorporate a score statistic‐based prescreening step to reduce the number of single nucleotide polymorphisms prior to fitting the first stage penalized regression model. To assess the statistical properties of our method, we compare the type I error rate and statistical power of our approach with competing techniques using both simple simulation designs as well as designs based on real disease architectures. Finally, we demonstrate the ability of our approach to identify biologically plausible SNP‐education interactions relative to Alzheimer's disease status using genome‐wide association study data from the Alzheimer's Disease Neuroimaging Initiative (ADNI). PMID:27578615

General view of the flight deck of the orbiter Discovery ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

General view of the flight deck of the orbiter Discovery looking forward and overhead at the overhead instrumentation and control panels. This view was taken at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Serendipity in Cancer Drug Discovery: Rational or Coincidence?

PubMed

Prasad, Sahdeo; Gupta, Subash C; Aggarwal, Bharat B

2016-06-01

Novel drug development leading to final approval by the US FDA can cost as much as two billion dollars. Why the cost of novel drug discovery is so expensive is unclear, but high failure rates at the preclinical and clinical stages are major reasons. Although therapies targeting a given cell signaling pathway or a protein have become prominent in drug discovery, such treatments have done little in preventing or treating any disease alone because most chronic diseases have been found to be multigenic. A review of the discovery of numerous drugs currently being used for various diseases including cancer, diabetes, cardiovascular, pulmonary, and autoimmune diseases indicates that serendipity has played a major role in the discovery. In this review we provide evidence that rational drug discovery and targeted therapies have minimal roles in drug discovery, and that serendipity and coincidence have played and continue to play major roles. The primary focus in this review is on cancer-related drug discovery. Copyright © 2016 Elsevier Ltd. All rights reserved.

STS-114: Discovery Post MMT Briefing

NASA Technical Reports Server (NTRS)

2005-01-01

On flight day 13, Leroy Cain, STS-114 Ascent/Entry Flight Director, discusses the condition of the Space Shuttle Discovery, and the weather outlook for landing. He answers questions from the news media about his feelings about re-entry since the Columbia tragedy, possible new information during re-entry, critical moments in the Mission Control Room during landing, and differences between night landing and day landing. Footage of the Mission Control Room and a talk with Soichi Noguchi in orbit is shown. Also, footage of the truss structure of the International Space Station, Destiny Laboratory, crew cabin of Discovery, and the Orbiter Docking System linked up to forward docking port on Discovery is shown. Eileen Collins and Wendy Lawrence are shown in the flight deck of Discovery. Charles Camarda is also shown in the mid-deck. Downlink television from Discovery shows spacewalk choreographer Andy Thomas with Stephen Robinson and Soichi Noguchi preparing for depressurization and pre-breathing activities that will lead to the opening of the hatch. The installation of a replacement GPS antenna, images of the port wing of Discovery and Canadarm moving with the Orbital Boom Sensor System (OBSS) extension is shown.

Promoter and Terminator Discovery and Engineering.

PubMed

Deaner, Matthew; Alper, Hal S

Control of gene expression is crucial to optimize metabolic pathways and synthetic gene networks. Promoters and terminators are stretches of DNA upstream and downstream (respectively) of genes that control both the rate at which the gene is transcribed and the rate at which mRNA is degraded. As a result, both of these elements control net protein expression from a synthetic construct. Thus, it is highly important to discover and engineer promoters and terminators with desired characteristics. This chapter highlights various approaches taken to catalogue these important synthetic elements. Specifically, early strategies have focused largely on semi-rational techniques such as saturation mutagenesis to diversify native promoters and terminators. Next, in an effort to reduce the length of the synthetic biology design cycle, efforts in the field have turned towards the rational design of synthetic promoters and terminators. In this vein, we cover recently developed methods such as hybrid engineering, high throughput characterization, and thermodynamic modeling which allow finer control in the rational design of novel promoters and terminators. Emphasis is placed on the methodologies used and this chapter showcases the utility of these methods across multiple host organisms.

Effects of enamel sealing on shear bond strength and the adhesive remnant index : Study of three fluoride-releasing adhesives in combination with metal and ceramic brackets.

PubMed

Hofmann, Elisabeth; Elsner, Laura; Hirschfelder, Ursula; Ebert, Thomas; Hanke, Sebastian

2017-01-01

Selected combinations of materials were used to create tooth-adhesive-bracket complexes to evaluate shear bond strength (SBS) and the adhesive remnant index (ARI) with regard to enamel sealing. Four adhesive systems also appropriate for use as enamel sealants were combined with four bracket types, resulting in 16 adhesive-bracket combinations, each of which was tested on 15 permanent bovine incisors. Sealant-adhesives included two recently introduced fluoride-releasing systems (Riva bond LC ® and go! ® ), one established primer (Opal ® Seal™), and one commonly used adhesive as control (Transbond™ XT). Brackets included two metal (discovery ® by Dentaurum and Sprint ® ) and two ceramic (discovery ® pearl and GLAM ® ) systems. After embedding the bovine teeth, bonding the brackets to their surface, and storing the resultant samples as per DIN 13990-2 with modifications, an SBS test was performed by applying the shear force directly at the bracket base in an incisocervical direction. Then the ARI scores were determined. Discovery ®  + Transbond™ XT yielded the highest (47.2 MPa) and GLAM ®  + go! ® the lowest (17.0 MPa) mean SBS values. Significant differences (p < 0.0001) were found between metal and ceramic brackets of the same manufacturers (Dentaurum and Forestadent). Our ratings of the failure modes upon debonding predominantly yielded ARI 0 or 1. The high SBS values and low ARI scores observed with discovery ®  + Transbond XT™ were reflected in a high rate of enamel fracture, which occurred on 11 of the 15 tooth specimens in this group. All sealant-bracket combinations were found to yield levels of SBS adequate for clinical application. SBS values and ARI scores varied significantly depending on which sealant-brackets were used.

Retrospective analysis of natural products provides insights for future discovery trends.

PubMed

Pye, Cameron R; Bertin, Matthew J; Lokey, R Scott; Gerwick, William H; Linington, Roger G

2017-05-30

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties.

Statistical detection of EEG synchrony using empirical bayesian inference.

PubMed

Singh, Archana K; Asoh, Hideki; Takeda, Yuji; Phillips, Steven

2015-01-01

There is growing interest in understanding how the brain utilizes synchronized oscillatory activity to integrate information across functionally connected regions. Computing phase-locking values (PLV) between EEG signals is a popular method for quantifying such synchronizations and elucidating their role in cognitive tasks. However, high-dimensionality in PLV data incurs a serious multiple testing problem. Standard multiple testing methods in neuroimaging research (e.g., false discovery rate, FDR) suffer severe loss of power, because they fail to exploit complex dependence structure between hypotheses that vary in spectral, temporal and spatial dimension. Previously, we showed that a hierarchical FDR and optimal discovery procedures could be effectively applied for PLV analysis to provide better power than FDR. In this article, we revisit the multiple comparison problem from a new Empirical Bayes perspective and propose the application of the local FDR method (locFDR; Efron, 2001) for PLV synchrony analysis to compute FDR as a posterior probability that an observed statistic belongs to a null hypothesis. We demonstrate the application of Efron's Empirical Bayes approach for PLV synchrony analysis for the first time. We use simulations to validate the specificity and sensitivity of locFDR and a real EEG dataset from a visual search study for experimental validation. We also compare locFDR with hierarchical FDR and optimal discovery procedures in both simulation and experimental analyses. Our simulation results showed that the locFDR can effectively control false positives without compromising on the power of PLV synchrony inference. Our results from the application locFDR on experiment data detected more significant discoveries than our previously proposed methods whereas the standard FDR method failed to detect any significant discoveries.

Accelerating the Rate of Astronomical Discovery

NASA Astrophysics Data System (ADS)

Norris, Ray P. Ruggles, Clive L. N.

2010-05-01

Special Session 5 on Accelerating the Rate of Astronomical Discovery addressed a range of potential limits to progress - paradigmatic, technological, organisational, and political - examining each issue both from modern and historical perspectives, and drawing lessons to guide future progress. A number of issues were identified which potentially regulate the flow of discoveries, such as the balance between large strongly-focussed projects and instruments, designed to answer the most fundamental questions confronting us, and the need to maintain a creative environment with room for unorthodox thinkers and bold, high risk, projects. Also important is the need to maintain historical and cultural perspectives, and the need to engage the minds of the most brilliant young people on the planet, regardless of their background, ethnicity, gender, or geography.

SpS5: Accelerating the Rate of Astronomical Discovery

NASA Astrophysics Data System (ADS)

Norris, Ray P.

2010-11-01

Special Session 5 on Accelerating the Rate of Astronomical Discovery addressed a range of potential limits to progress: paradigmatic, technological, organizational, and political. It examined each issue both from modern and historical perspectives, and drew lessons to guide future progress. A number of issues were identified which may regulate the flow of discoveries, such as the balance between large strongly-focussed projects and instruments, designed to answer the most fundamental questions confronting us, and the need to maintain a creative environment with room for unorthodox thinkers and bold, high risk, projects. Also important is the need to maintain historical and cultural perspectives, and the need to engage the minds of the most brilliant young people on the planet, regardless of their background, ethnicity, gender, or geography.

Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

PubMed

Baig, Abdul Mannan

2018-04-25

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatic methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multiple Hypothesis Testing for Experimental Gingivitis Based on Wilcoxon Signed Rank Statistics

PubMed Central

Preisser, John S.; Sen, Pranab K.; Offenbacher, Steven

2011-01-01

Dental research often involves repeated multivariate outcomes on a small number of subjects for which there is interest in identifying outcomes that exhibit change in their levels over time as well as to characterize the nature of that change. In particular, periodontal research often involves the analysis of molecular mediators of inflammation for which multivariate parametric methods are highly sensitive to outliers and deviations from Gaussian assumptions. In such settings, nonparametric methods may be favored over parametric ones. Additionally, there is a need for statistical methods that control an overall error rate for multiple hypothesis testing. We review univariate and multivariate nonparametric hypothesis tests and apply them to longitudinal data to assess changes over time in 31 biomarkers measured from the gingival crevicular fluid in 22 subjects whereby gingivitis was induced by temporarily withholding tooth brushing. To identify biomarkers that can be induced to change, multivariate Wilcoxon signed rank tests for a set of four summary measures based upon area under the curve are applied for each biomarker and compared to their univariate counterparts. Multiple hypothesis testing methods with choice of control of the false discovery rate or strong control of the family-wise error rate are examined. PMID:21984957

Geomorphology: the Shock of the Familiar

NASA Astrophysics Data System (ADS)

Dietrich, W. E.

2008-12-01

Everyone experiences landscapes and has a sense about how they work: water runs down hill, it erodes and carries sediments, and that's about it, right? Introductory earth science text books are uniformly qualitative about the field, and leave one with little sense of wonder, and certainly not "shock". But four shocks occur if one peels away the first impressions. First, landscapes are surprisingly similar: the same forms are repeated in virtually all environments, including under the ocean and on other planets. Second, we lack theory and mechanistic observations to answer many simple first-order questions, e.g. what controls the width of a river, how does rock type control hillslope form and erosion rate, or, is there a topographic signature of life. Third, there are unexpected connections between surface erosion, deep earth processes, and climate. And fourth, the field itself, despite having been a subject of study for well over 100 years, is currently experiencing a revolution of ideas and discoveries through new tools, observatories, centers, journals, books, contributions of researchers from other disciplines, and from a significant hiring of young researchers in geomorphology. Deep messages await discovery in the simple landforms surrounding us.

A laser-deposition approach to compositional-spread discovery of materials on conventional sample sizes

NASA Astrophysics Data System (ADS)

Christen, Hans M.; Ohkubo, Isao; Rouleau, Christopher M.; Jellison, Gerald E., Jr.; Puretzky, Alex A.; Geohegan, David B.; Lowndes, Douglas H.

2005-01-01

Parallel (multi-sample) approaches, such as discrete combinatorial synthesis or continuous compositional-spread (CCS), can significantly increase the rate of materials discovery and process optimization. Here we review our generalized CCS method, based on pulsed-laser deposition, in which the synchronization between laser firing and substrate translation (behind a fixed slit aperture) yields the desired variations of composition and thickness. In situ alloying makes this approach applicable to the non-equilibrium synthesis of metastable phases. Deposition on a heater plate with a controlled spatial temperature variation can additionally be used for growth-temperature-dependence studies. Composition and temperature variations are controlled on length scales large enough to yield sample sizes sufficient for conventional characterization techniques (such as temperature-dependent measurements of resistivity or magnetic properties). This technique has been applied to various experimental studies, and we present here the results for the growth of electro-optic materials (SrxBa1-xNb2O6) and magnetic perovskites (Sr1-xCaxRuO3), and discuss the application to the understanding and optimization of catalysts used in the synthesis of dense forests of carbon nanotubes.

A proteomic approach to understanding the pathogenesis of idiopathic macular hole formation.

PubMed

Zhang, Pingbo; Zhu, Min; Zhao, Yuming; Qian, Jiang; Dufresne, Craig; Turner, Randi; Semba, Richard D; Solomon, Sharon D

2017-01-01

Idiopathic macular holes (IMH) are full-thickness defects of retinal tissue that cause severe vision loss due to disruption of the anatomic fovea. Abnormal vitreous traction is involved in the formation of macular holes. Both glial cells and hyalocytes contribute to epiretinal membrane formation in IMH. In order to gain further insight into the pathophysiology of IMH, we conducted a discovery phase investigation of the vitreous proteome in four patients with macular holes and six controls using one-dimensional gel fractionation and liquid chromatography-tandem mass spectrometry analyses on an Orbitrap Elite mass spectrometer. Of a total of 5912 vitreous proteins, 32 proteins had increased and 39 proteins had decreased expression in IMH compared with controls, using a false discovery rate approach with p value < 0.001 and q value < 0.05. IMH was associated with increased expression of proteins in the complement pathway, α-2-macroglobulin, a major inducer of Müller glial cell migration, fibrinogen, and extracellular matrix proteins, and decreased expression of proteins involved in protein folding and actin filament binding. A proteomic approach revealed proteins and biological pathways that may be involved in the pathogenesis of IMH and could be targeted for future studies.

Tertiary oil discoveries whet explorer interest off Tunisia

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

Long, M.

Prospects for increased Tertiary oil production in the S. Mediterranean have brightened with discoveries off Tunisia, but more evaluation is needed before commercial potential is known. Several groups of U.S. and European companies have tested oil in the relatively unexplored Miocene in the Gulf of Hannamet. These include groups operated by Buttes Resources Tunisia, Elf-Aquitaine Tunisia, and Shell Tunirex. Oil test rates of 1,790 to 1,800 bpd have been reported by the Buttes group in 2 Gulf of Hammamet wells. The initial discovery probably was the first Tertiary oil ever tested in that part of the Mediterranean. The discoveries havemore » helped boost exploratory interest in the northern waters of Tunisia and northeast toward Sicily. There are reports more U.S. and European companies are requesting exploration permits from the government of Tunisia. Companies with permits are planning new exploration for 1978. Probably the most significant discovery to date has been the Buttes group's 1 Jasmine (2 BGH). The group tested high-quality 39.5'-gravity oil at a rate of 1,790 bpd. Test flow was from the Sabri Sand at 6,490 to 6,590 ft. The well was drilled in 458 ft of water.« less

High-throughput discovery of rare human nucleotide polymorphisms by Ecotilling

PubMed Central

Till, Bradley J.; Zerr, Troy; Bowers, Elisabeth; Greene, Elizabeth A.; Comai, Luca; Henikoff, Steven

2006-01-01

Human individuals differ from one another at only ∼0.1% of nucleotide positions, but these single nucleotide differences account for most heritable phenotypic variation. Large-scale efforts to discover and genotype human variation have been limited to common polymorphisms. However, these efforts overlook rare nucleotide changes that may contribute to phenotypic diversity and genetic disorders, including cancer. Thus, there is an increasing need for high-throughput methods to robustly detect rare nucleotide differences. Toward this end, we have adapted the mismatch discovery method known as Ecotilling for the discovery of human single nucleotide polymorphisms. To increase throughput and reduce costs, we developed a universal primer strategy and implemented algorithms for automated band detection. Ecotilling was validated by screening 90 human DNA samples for nucleotide changes in 5 gene targets and by comparing results to public resequencing data. To increase throughput for discovery of rare alleles, we pooled samples 8-fold and found Ecotilling to be efficient relative to resequencing, with a false negative rate of 5% and a false discovery rate of 4%. We identified 28 new rare alleles, including some that are predicted to damage protein function. The detection of rare damaging mutations has implications for models of human disease. PMID:16893952

The development of biomarkers to reduce attrition rate in drug discovery focused on oncology and central nervous system.

PubMed

Safavi, Maliheh; Sabourian, Reyhaneh; Abdollahi, Mohammad

2016-10-01

The task of discovery and development of novel therapeutic agents remains an expensive, uncertain, time-consuming, competitive, and inefficient enterprise. Due to a steady increase in the cost and time of drug development and the considerable amount of resources required, a predictive tool is needed for assessing the safety and efficacy of a new chemical entity. This study is focused on the high attrition rate in discovery and development of oncology and central nervous system (CNS) medicines, because the failure rate of these medicines is higher than others. Some approaches valuable in reducing attrition rates are proposed and the judicious use of biomarkers is discussed. Unlike the significant progress made in identifying and characterizing novel mechanisms of disease processes and targeted therapies, the process of novel drug development is associated with an unacceptably high attrition rate. The application of clinically qualified predictive biomarkers holds great promise for further development of therapeutic targets, improved survival, and ultimately personalized medicine sets for patients. Decisions such as candidate selection, development risks, dose ranging, early proof of concept/principle, and patient stratification are based on the measurements of biologically and/or clinically validated biomarkers.

Two Phase Admission Control for QoS Mobile Ad Hoc Networks

NASA Astrophysics Data System (ADS)

Chen, Chien-Sheng; Su, Yi-Wen; Liu, Wen-Hsiung; Chi, Ching-Lung

In this paper a novel and effective two phase admission control (TPAC) for QoS mobile ad hoc networks is proposed that satisfies the real-time traffic requirements in mobile ad hoc networks. With a limited amount of extra overhead, TPAC can avoid network congestions by a simple and precise admission control which blocks most of the overloading flow-requests in the route discovery process. When compared with previous QoS routing schemes such as QoS-aware routing protocol and CACP protocols, it is shown from system simulations that the proposed scheme can increase the system throughput and reduce both the dropping rate and the end-to-end delay. Therefore, TPAC is surely an effective QoS-guarantee protocol to provide for real-time traffic.

Mississippi State University Center for Air Sea Technology. FY93 and FY 94 Research Program in Navy Ocean Modeling and Prediction

DTIC Science & Technology

1994-09-30

relational versus object oriented DBMS, knowledge discovery, data models, rnetadata, data filtering, clustering techniques, and synthetic data. A secondary...The first was the investigation of Al/ES Lapplications (knowledge discovery, data mining, and clustering ). Here CAST collabo.rated with Dr. Fred Petry...knowledge discovery system based on clustering techniques; implemented an on-line data browser to the DBMS; completed preliminary efforts to apply object

STS-26 Mission Control Center (MCC) activity at JSC

NASA Image and Video Library

1988-10-02

STS026-S-101 (2 Oct 1988) --- Flight controllers in the Johnson Space Center?s mission control center listen to a presentation by the five members of the STS 26 crew on the fourth day of Discovery?s orbital mission. Flight Directors Charles W. Shaw and James M. (Milt) Heflin (in the foreground) and other controllers view a television image of Earth on a screen in the front of the flight control room while each member relates some inner feelings while paying tribute to the Challenger crew.

New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics.

PubMed

Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Ma, Dik-Lung; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

2013-01-01

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is "experience driven," the search for a therapeutically useful synthetic drug, like "looking for a needle in a haystack," is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.

75 FR 22394 - Combined Notice of Filings No. 2

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-28

... 21, 2010. Take notice that the Commission has received the following Natural Gas Pipeline Rate and Refund Report filings: Docket Numbers: RP10-539-001. Applicants: Discovery Gas Transmission LLC. Description: Discovery Gas Transmission, LLC submits Substitute First Revised Sheet 225 et al. to FERC Gas...

Scientific Discoveries: What Is Required for Lasting Impact.

PubMed

Lømo, Terje

2016-01-01

I have been involved in two scientific discoveries of some impact. One is the discovery of long-term potentiation (LTP), the phenomenon that brief, high-frequency impulse activity at synapses in the brain can lead to long-lasting increases in their efficiency of transmission. This finding demonstrated that synapses are plastic, a property thought to be necessary for learning and memory. The other discovery is that nerve-evoked muscle impulse activity, rather than putative trophic factors, controls the properties of muscle fibers. Here I describe how these two discoveries were made, the unexpected difficulties of reproducing the first discovery, and the controversies that followed the second discovery. I discuss why the first discovery took many years to become generally recognized, whereas the second caused an immediate sensation and entered textbooks and major reviews but is now largely forgotten. In the long run, discovering a new phenomenon has greater impact than falsifying a popular hypothesis.

Port side view of the Orbiter Discovery from an elevated ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Port side view of the Orbiter Discovery from an elevated platform in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the ground support hardware known as Strongbacks attached to the payload bay doors, the crew access hatch below the name Discovery on the forward section of the Orbiter and the removed Orbiter Maneuvering System/Reaction Control System pod from the aft (tai) section. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Normalization and microbial differential abundance strategies depend upon data characteristics.

PubMed

Weiss, Sophie; Xu, Zhenjiang Zech; Peddada, Shyamal; Amir, Amnon; Bittinger, Kyle; Gonzalez, Antonio; Lozupone, Catherine; Zaneveld, Jesse R; Vázquez-Baeza, Yoshiki; Birmingham, Amanda; Hyde, Embriette R; Knight, Rob

2017-03-03

Data from 16S ribosomal RNA (rRNA) amplicon sequencing present challenges to ecological and statistical interpretation. In particular, library sizes often vary over several ranges of magnitude, and the data contains many zeros. Although we are typically interested in comparing relative abundance of taxa in the ecosystem of two or more groups, we can only measure the taxon relative abundance in specimens obtained from the ecosystems. Because the comparison of taxon relative abundance in the specimen is not equivalent to the comparison of taxon relative abundance in the ecosystems, this presents a special challenge. Second, because the relative abundance of taxa in the specimen (as well as in the ecosystem) sum to 1, these are compositional data. Because the compositional data are constrained by the simplex (sum to 1) and are not unconstrained in the Euclidean space, many standard methods of analysis are not applicable. Here, we evaluate how these challenges impact the performance of existing normalization methods and differential abundance analyses. Effects on normalization: Most normalization methods enable successful clustering of samples according to biological origin when the groups differ substantially in their overall microbial composition. Rarefying more clearly clusters samples according to biological origin than other normalization techniques do for ordination metrics based on presence or absence. Alternate normalization measures are potentially vulnerable to artifacts due to library size. Effects on differential abundance testing: We build on a previous work to evaluate seven proposed statistical methods using rarefied as well as raw data. Our simulation studies suggest that the false discovery rates of many differential abundance-testing methods are not increased by rarefying itself, although of course rarefying results in a loss of sensitivity due to elimination of a portion of available data. For groups with large (~10×) differences in the average library size, rarefying lowers the false discovery rate. DESeq2, without addition of a constant, increased sensitivity on smaller datasets (<20 samples per group) but tends towards a higher false discovery rate with more samples, very uneven (~10×) library sizes, and/or compositional effects. For drawing inferences regarding taxon abundance in the ecosystem, analysis of composition of microbiomes (ANCOM) is not only very sensitive (for >20 samples per group) but also critically the only method tested that has a good control of false discovery rate. These findings guide which normalization and differential abundance techniques to use based on the data characteristics of a given study.

Retrospective analysis of natural products provides insights for future discovery trends

PubMed Central

Pye, Cameron R.; Bertin, Matthew J.; Lokey, R. Scott; Gerwick, William H.

2017-01-01

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties. PMID:28461474

Academic drug discovery: current status and prospects.

PubMed

Everett, Jeremy R

2015-01-01

The contraction in pharmaceutical drug discovery operations in the past decade has been counter-balanced by a significant rise in the number of academic drug discovery groups. In addition, pharmaceutical companies that used to operate in completely independent, vertically integrated operations for drug discovery, are now collaborating more with each other, and with academic groups. We are in a new era of drug discovery. This review provides an overview of the current status of academic drug discovery groups, their achievements and the challenges they face, together with perspectives on ways to achieve improved outcomes. Academic groups have made important contributions to drug discovery, from its earliest days and continue to do so today. However, modern drug discovery and development is exceedingly complex, and has high failure rates, principally because human biology is complex and poorly understood. Academic drug discovery groups need to play to their strengths and not just copy what has gone before. However, there are lessons to be learnt from the experiences of the industrial drug discoverers and four areas are highlighted for attention: i) increased validation of targets; ii) elimination of false hits from high throughput screening (HTS); iii) increasing the quality of molecular probes; and iv) investing in a high-quality informatics infrastructure.

On the universe's cybernetics duality behavior

NASA Astrophysics Data System (ADS)

Feria, Erlan H.

2015-05-01

Universal cybernetics is the study of control and communications in living and non-living systems. In this paper the universal cybernetics duality principle (UCDP), first identified in control theory in 1978 and expressing a cybernetic duality behavior for our universe, is reviewed. The review is given on the heels of major prizes given to physicists for their use of mathematical dualities in solving intractable problems in physics such as those of cosmology's `dark energy', an area that according to a recent New York Times article has become "a cottage industry in physics today". These dualities are not unlike those of our UCDP that are further enhanced with physical dualities. For instance, in 2008 the UCDP guided us to the derivation of the laws of retention in physics as the space-penalty dual of the laws of motion in physics, including the dark energy thought responsible for the observed increase of the volume of our Universe as it ages. The UCDP has also guided us to the discovery of significant results in other fields such as: 1) in matched processors for quantized control with applications in the modeling of central nervous system (CNS) control mechanisms; 2) in radar designs where the discovery of latency theory, the time-penalty dual of information-theory, has led us to high-performance radar solutions that evade the use of `big data' in the form of SAR imagery of the earth; and 3) in unveiling biological lifespan bounds where the life-expectancy of an organism is sensibly predicted through lingerdynamics, the identified time-penalty dual of thermodynamics, which relates its adult lifespan to either: a. the ratio of its body size to its nutritional consumption rate; or b. its specific heat-capacity; or c. the ratio of its nutritional consumption rate energy to its entropic volume energy, a type of dark energy that is consistent with the observed decrease in the mass density of the organism as it ages.

ON MODEL SELECTION STRATEGIES TO IDENTIFY GENES UNDERLYING BINARY TRAITS USING GENOME-WIDE ASSOCIATION DATA.

PubMed

Wu, Zheyang; Zhao, Hongyu

2012-01-01

For more fruitful discoveries of genetic variants associated with diseases in genome-wide association studies, it is important to know whether joint analysis of multiple markers is more powerful than the commonly used single-marker analysis, especially in the presence of gene-gene interactions. This article provides a statistical framework to rigorously address this question through analytical power calculations for common model search strategies to detect binary trait loci: marginal search, exhaustive search, forward search, and two-stage screening search. Our approach incorporates linkage disequilibrium, random genotypes, and correlations among score test statistics of logistic regressions. We derive analytical results under two power definitions: the power of finding all the associated markers and the power of finding at least one associated marker. We also consider two types of error controls: the discovery number control and the Bonferroni type I error rate control. After demonstrating the accuracy of our analytical results by simulations, we apply them to consider a broad genetic model space to investigate the relative performances of different model search strategies. Our analytical study provides rapid computation as well as insights into the statistical mechanism of capturing genetic signals under different genetic models including gene-gene interactions. Even though we focus on genetic association analysis, our results on the power of model selection procedures are clearly very general and applicable to other studies.

ON MODEL SELECTION STRATEGIES TO IDENTIFY GENES UNDERLYING BINARY TRAITS USING GENOME-WIDE ASSOCIATION DATA

PubMed Central

Wu, Zheyang; Zhao, Hongyu

2013-01-01

For more fruitful discoveries of genetic variants associated with diseases in genome-wide association studies, it is important to know whether joint analysis of multiple markers is more powerful than the commonly used single-marker analysis, especially in the presence of gene-gene interactions. This article provides a statistical framework to rigorously address this question through analytical power calculations for common model search strategies to detect binary trait loci: marginal search, exhaustive search, forward search, and two-stage screening search. Our approach incorporates linkage disequilibrium, random genotypes, and correlations among score test statistics of logistic regressions. We derive analytical results under two power definitions: the power of finding all the associated markers and the power of finding at least one associated marker. We also consider two types of error controls: the discovery number control and the Bonferroni type I error rate control. After demonstrating the accuracy of our analytical results by simulations, we apply them to consider a broad genetic model space to investigate the relative performances of different model search strategies. Our analytical study provides rapid computation as well as insights into the statistical mechanism of capturing genetic signals under different genetic models including gene-gene interactions. Even though we focus on genetic association analysis, our results on the power of model selection procedures are clearly very general and applicable to other studies. PMID:23956610

Genome-Wide Methylation Analyses in Glioblastoma Multiforme

PubMed Central

Lai, Rose K.; Chen, Yanwen; Guan, Xiaowei; Nousome, Darryl; Sharma, Charu; Canoll, Peter; Bruce, Jeffrey; Sloan, Andrew E.; Cortes, Etty; Vonsattel, Jean-Paul; Su, Tao; Delgado-Cruzata, Lissette; Gurvich, Irina; Santella, Regina M.; Ostrom, Quinn; Lee, Annette; Gregersen, Peter; Barnholtz-Sloan, Jill

2014-01-01

Few studies had investigated genome-wide methylation in glioblastoma multiforme (GBM). Our goals were to study differential methylation across the genome in gene promoters using an array-based method, as well as repetitive elements using surrogate global methylation markers. The discovery sample set for this study consisted of 54 GBM from Columbia University and Case Western Reserve University, and 24 brain controls from the New York Brain Bank. We assembled a validation dataset using methylation data of 162 TCGA GBM and 140 brain controls from dbGAP. HumanMethylation27 Analysis Bead-Chips (Illumina) were used to interrogate 26,486 informative CpG sites in both the discovery and validation datasets. Global methylation levels were assessed by analysis of L1 retrotransposon (LINE1), 5 methyl-deoxycytidine (5m-dC) and 5 hydroxylmethyl-deoxycytidine (5hm-dC) in the discovery dataset. We validated a total of 1548 CpG sites (1307 genes) that were differentially methylated in GBM compared to controls. There were more than twice as many hypomethylated genes as hypermethylated ones. Both the discovery and validation datasets found 5 tumor methylation classes. Pathway analyses showed that the top ten pathways in hypomethylated genes were all related to functions of innate and acquired immunities. Among hypermethylated pathways, transcriptional regulatory network in embryonic stem cells was the most significant. In the study of global methylation markers, 5m-dC level was the best discriminant among methylation classes, whereas in survival analyses, high level of LINE1 methylation was an independent, favorable prognostic factor in the discovery dataset. Based on a pathway approach, hypermethylation in genes that control stem cell differentiation were significant, poor prognostic factors of overall survival in both the discovery and validation datasets. Approaches that targeted these methylated genes may be a future therapeutic goal. PMID:24586730

Building high-quality assay libraries for targeted analysis of SWATH MS data.

PubMed

Schubert, Olga T; Gillet, Ludovic C; Collins, Ben C; Navarro, Pedro; Rosenberger, George; Wolski, Witold E; Lam, Henry; Amodei, Dario; Mallick, Parag; MacLean, Brendan; Aebersold, Ruedi

2015-03-01

Targeted proteomics by selected/multiple reaction monitoring (S/MRM) or, on a larger scale, by SWATH (sequential window acquisition of all theoretical spectra) MS (mass spectrometry) typically relies on spectral reference libraries for peptide identification. Quality and coverage of these libraries are therefore of crucial importance for the performance of the methods. Here we present a detailed protocol that has been successfully used to build high-quality, extensive reference libraries supporting targeted proteomics by SWATH MS. We describe each step of the process, including data acquisition by discovery proteomics, assertion of peptide-spectrum matches (PSMs), generation of consensus spectra and compilation of MS coordinates that uniquely define each targeted peptide. Crucial steps such as false discovery rate (FDR) control, retention time normalization and handling of post-translationally modified peptides are detailed. Finally, we show how to use the library to extract SWATH data with the open-source software Skyline. The protocol takes 2-3 d to complete, depending on the extent of the library and the computational resources available.

Effect of Summon Preferred Food Source on feeding, tunneling, and bait station discovery by the formosan subterranean termite (Isoptera: Rhinotermitidae).

PubMed

Cornelius, Mary L; Lax, Alan R

2005-04-01

This study evaluated the effect of Summon Preferred Food Source on feeding, tunneling, and bait station discovery by the Formosan subterranean termite, Coptotermes formosanus Shiraki. Bioassays were conducted to determine whether Summon disks affected the aggregation and feeding behavior of termites and to determine whether the presence of Summon disks caused increased recruitment of termites to wood blocks. When termites encountered the disk, they immediately clustered on top of the disk. Termites were observed aggregating on top of the disk throughout the experiment. Consumption of Summon disks was significantly greater than consumption of cardboard disks in paired choice tests. The presence of a Summon disk on top of a wood block caused a significant increase in consumption of the wood block. Bioassays also were conducted to determine whether water extracts of Summon disks affected termite behavior. Consumption of filter paper disks treated with a water extract of Summon disks was significantly greater than consumption of control filter paper disks. Termites tunneled through sand treated with a water extract of Summon disks faster than they tunneled through untreated sand. In a field test, the rate of infestation of monitoring stations with a Summon disk was 3 times greater than the rate of infestations of stations without a disk.

How to talk about protein-level false discovery rates in shotgun proteomics.

PubMed

The, Matthew; Tasnim, Ayesha; Käll, Lukas

2016-09-01

A frequently sought output from a shotgun proteomics experiment is a list of proteins that we believe to have been present in the analyzed sample before proteolytic digestion. The standard technique to control for errors in such lists is to enforce a preset threshold for the false discovery rate (FDR). Many consider protein-level FDRs a difficult and vague concept, as the measurement entities, spectra, are manifestations of peptides and not proteins. Here, we argue that this confusion is unnecessary and provide a framework on how to think about protein-level FDRs, starting from its basic principle: the null hypothesis. Specifically, we point out that two competing null hypotheses are used concurrently in today's protein inference methods, which has gone unnoticed by many. Using simulations of a shotgun proteomics experiment, we show how confusing one null hypothesis for the other can lead to serious discrepancies in the FDR. Furthermore, we demonstrate how the same simulations can be used to verify FDR estimates of protein inference methods. In particular, we show that, for a simple protein inference method, decoy models can be used to accurately estimate protein-level FDRs for both competing null hypotheses. © 2016 The Authors. Proteomics Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Impact of Mandatory Carbon Monoxide Alarms: An Investigation of the Effects on Detection and Poisoning Rates in New York City

PubMed Central

Wheeler-Martin, Katherine; Soghoian, Sari; Manini, Alex F.; Marker, Elizabeth; Stajic, Marina; Prezant, David; Nelson, Lewis S.; Hoffman, Robert S.

2015-01-01

Objectives. We sought to evaluate the impact of New York City’s (NYC’s) 2004 carbon monoxide (CO) alarm legislation on CO incident detection and poisoning rates. Methods. We compared CO poisoning deaths, hospitalizations, exposures reported to Poison Control, and fire department investigations, before and after the law for 2000 to 2010. Use of CO alarms was assessed in the 2009 NYC Community Health Survey. Results. Investigations that found indoor CO levels greater than 9 parts per million increased nearly 7-fold after the law (P < .001). There were nonsignificant decreases in unintentional, nonfire-related CO poisoning hospitalization rates (P = .114) and death rates (P = .216). After we controlled for ambient temperature, the law’s effect on hospitalizations remained nonsignificantly protective (incidence rate ratio = 0.747; 95% confidence interval = 0.520, 1.074). By 2009, 83% of NYC residents reported having CO alarms; only 54% also recently tested or replaced their batteries. Conclusions. Mandating CO alarms significantly increased the detection of potentially hazardous CO levels in NYC homes. Small numbers and detection bias might have limited the discovery of significant decreases in poisoning outcomes. Investigation of individual poisoning circumstances since the law might elucidate remaining gaps in awareness and proper use of CO alarms. PMID:26066948

Design of small-molecule epigenetic modulators

PubMed Central

Pachaiyappan, Boobalan

2013-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735

New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics

PubMed Central

Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

2013-01-01

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development. PMID:23634172

The Effect of Rules and Discovery in the Retention and Retrieval of Braille Inkprint Letter Pairs.

ERIC Educational Resources Information Center

Nagengast, Daniel L.; And Others

The effects of rule knowledge were investigated using Braille inkprint pairs. Both recognition and recall were studied in three groups of subjects: rule knowledge, rule discovery, and no rule. Two hypotheses were tested: (1) that the group exposed to the rule would score better than would a discovery group and a control group; and (2) that all…

A petroleum discovery-rate forecast revisited-The problem of field growth

USGS Publications Warehouse

Drew, L.J.; Schuenemeyer, J.H.

1992-01-01

A forecast of the future rates of discovery of crude oil and natural gas for the 123,027-km2 Miocene/Pliocene trend in the Gulf of Mexico was made in 1980. This forecast was evaluated in 1988 by comparing two sets of data: (1) the actual versus the forecasted number of fields discovered, and (2) the actual versus the forecasted volumes of crude oil and natural gas discovered with the drilling of 1,820 wildcat wells along the trend between January 1, 1977, and December 31, 1985. The forecast specified that this level of drilling would result in the discovery of 217 fields containing 1.78 billion barrels of oil equivalent; however, 238 fields containing 3.57 billion barrels of oil equivalent were actually discovered. This underestimation is attributed to biases introduced by field growth and, to a lesser degree, the artificially low, pre-1970's price of natural gas that prevented many smaller gas fields from being brought into production at the time of their discovery; most of these fields contained less than 50 billion cubic feet of producible natural gas. ?? 1992 Oxford University Press.

Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

PubMed

Benson, Neil

2015-08-01

Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way. Copyright © 2015 Elsevier Ltd. All rights reserved.

Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches

PubMed Central

2013-01-01

Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets. PMID:24015767

In situ click chemistry: a powerful means for lead discovery.

PubMed

Sharpless, K Barry; Manetsch, Roman

2006-11-01

Combinatorial chemistry and parallel synthesis are important and regularly applied tools for lead identification and optimisation, although they are often accompanied by challenges related to the efficiency of library synthesis and the purity of the compound library. In the last decade, novel means of lead discovery approaches have been investigated where the biological target is actively involved in the synthesis of its own inhibitory compound. These fragment-based approaches, also termed target-guided synthesis (TGS), show great promise in lead discovery applications by combining the synthesis and screening of libraries of low molecular weight compounds in a single step. Of all the TGS methods, the kinetically controlled variant is the least well known, but it has the potential to emerge as a reliable lead discovery method. The kinetically controlled TGS approach, termed in situ click chemistry, is discussed in this article.

KSC-2009-2105

NASA Image and Video Library

2009-03-15

CAPE CANAVERAL, Fla. – In Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida, from left, Steve Stich, manager of the Kennedy Orbiter Project Office; John Fraser, with Boeing Co. at the Marshall Space Flight Center; Rick Russell, with the NASA Orbiter Sustaining Engineering Office; and Rene Ortega with Marshall Space Flight Center's Shuttle Propulsion Office, are presented with a plaque for their work on the fuel control valve problem on space shuttle Discovery. The award was presented after the successful launch of Discovery on the STS-119 mission. Liftoff was on time at 7:43 p. m. EDT. The STS-119 mission is the 28th to the space station and Discovery's 36th flight. Discovery will deliver the final pair of power-generating solar array wings and the S6 truss segment. Installation of S6 will signal the station's readiness to house a six-member crew for conducting increased science. Photo credit: NASA/Kim Shiflett

Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

PubMed

Lee, Hye-Seung; Burkhardt, Brant R; McLeod, Wendy; Smith, Susan; Eberhard, Chris; Lynch, Kristian; Hadley, David; Rewers, Marian; Simell, Olli; She, Jin-Xiong; Hagopian, Bill; Lernmark, Ake; Akolkar, Beena; Ziegler, Anette G; Krischer, Jeffrey P

2014-07-01

The Environmental Determinants of Diabetes in the Young planned biomarker discovery studies on longitudinal samples for persistent confirmed islet cell autoantibodies and type 1 diabetes using dietary biomarkers, metabolomics, microbiome/viral metagenomics and gene expression. This article describes the details of planning The Environmental Determinants of Diabetes in the Young biomarker discovery studies using a nested case-control design that was chosen as an alternative to the full cohort analysis. In the frame of a nested case-control design, it guides the choice of matching factors, selection of controls, preparation of external quality control samples and reduction of batch effects along with proper sample allocation. Our design is to reduce potential bias and retain study power while reducing the costs by limiting the numbers of samples requiring laboratory analyses. It also covers two primary end points (the occurrence of diabetes-related autoantibodies and the diagnosis of type 1 diabetes). The resulting list of case-control matched samples for each laboratory was augmented with external quality control samples. Copyright © 2013 John Wiley & Sons, Ltd.

The dark energy survey Y1 supernova search: Survey strategy compared to forecasts and the photometric type Is SN volumetric rate

NASA Astrophysics Data System (ADS)

Fischer, John Arthur

For 70 years, the physics community operated under the assumption that the expansion of the Universe must be slowing due to gravitational attraction. Then, in 1998, two teams of scientists used Type Ia supernovae to discover that cosmic expansion was actually acceler- ating due to a mysterious "dark energy." As a result, Type Ia supernovae have become the most cosmologically important transient events in the last 20 years, with a large amount of effort going into their discovery as well as understanding their progenitor systems. One such probe for understanding Type Ia supernovae is to use rate measurements to de- termine the time delay between star formation and supernova explosion. For the last 30 years, the discovery of individual Type Ia supernova events has been accelerating. How- ever, those discoveries were happening in time-domain surveys that probed only a portion of the redshift range where expansion was impacted by dark energy. The Dark Energy Survey (DES) is the first project in the "next generation" of time-domain surveys that will discovery thousands of Type Ia supernovae out to a redshift of 1.2 (where dark energy be- comes subdominant) and DES will have better systematic uncertainties over that redshift range than any survey to date. In order to gauge the discovery effectiveness of this survey, we will use the first season's 469 photometrically typed supernovee and compare it with simulations in order to update the full survey Type Ia projections from 3500 to 2250. We will then use 165 of the 469 supernovae out to a redshift of 0.6 to measure the supernovae rate both as a function of comoving volume and of the star formation rate as it evolves with redshift. We find the most statistically significant prompt fraction of any survey to date (with a 3.9? prompt fraction detection). We will also reinforce the already existing tension in the measurement of the delayed fraction between high (z > 1.2) and low red- shift rate measurements, where we find no significant evidence of a delayed fraction at all in our photometric sample.

Non-gravitational effects on genus penicillium

NASA Technical Reports Server (NTRS)

Loup, Mackenzie

1995-01-01

In September 1994, Shuttle Orbiter Discovery, STS-64, launched into space. Aboard that shuttle was a payload containing Fungi spores, genus Penicillium. With the over looking help of Dr. Audrey Gabel, Associate Professor of Biology at Black Hills State University, investigations on differing media types began. Basis for this experimentation was to determine if there was any differences between the space exposed spores and control spores. Studies concluded that there were differences and those differences were then recorded. It was hypothesized the spores may have been effected causing differences in growth rate, colony size, depth and margins, coloring, germination, and growth on different media.

Emilio Segrè and Spontaneous Fission

Science.gov Websites

fissioned instead. The discovery of fission led in turn to the discovery of the chain reaction that, if material apart before it had a chance to undergo an efficient chain reaction. The possibility of chain reaction. If a similar rate was found in plutonium, it might rule out the use of that element as

Design of small molecule epigenetic modulators.

PubMed

Pachaiyappan, Boobalan; Woster, Patrick M

2014-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Localized Discovery and Recovery for Query Packet Losses in Wireless Sensor Networks with Distributed Detector Clusters

PubMed Central

Teng, Rui; Leibnitz, Kenji; Miura, Ryu

2013-01-01

An essential application of wireless sensor networks is to successfully respond to user queries. Query packet losses occur in the query dissemination due to wireless communication problems such as interference, multipath fading, packet collisions, etc. The losses of query messages at sensor nodes result in the failure of sensor nodes reporting the requested data. Hence, the reliable and successful dissemination of query messages to sensor nodes is a non-trivial problem. The target of this paper is to enable highly successful query delivery to sensor nodes by localized and energy-efficient discovery, and recovery of query losses. We adopt local and collective cooperation among sensor nodes to increase the success rate of distributed discoveries and recoveries. To enable the scalability in the operations of discoveries and recoveries, we employ a distributed name resolution mechanism at each sensor node to allow sensor nodes to self-detect the correlated queries and query losses, and then efficiently locally respond to the query losses. We prove that the collective discovery of query losses has a high impact on the success of query dissemination and reveal that scalability can be achieved by using the proposed approach. We further study the novel features of the cooperation and competition in the collective recovery at PHY and MAC layers, and show that the appropriate number of detectors can achieve optimal successful recovery rate. We evaluate the proposed approach with both mathematical analyses and computer simulations. The proposed approach enables a high rate of successful delivery of query messages and it results in short route lengths to recover from query losses. The proposed approach is scalable and operates in a fully distributed manner. PMID:23748172

Nonintrusive Flow Rate Determination Through Space Shuttle Water Coolant Loop Floodlight Coldplate

NASA Technical Reports Server (NTRS)

Werlink, Rudolph; Johnson, Harry; Margasahayam, Ravi

1997-01-01

Using a Nonintrusive Flow Measurement System (NFMS), the flow rates through the Space Shuttle water coolant coldplate were determined. The objective of this in situ flow measurement was to prove or disprove a potential block inside the affected coldplate had contributed to a reduced flow rate and the subsequent ice formation on the Space Shuttle Discovery. Flow through the coldplate was originally calculated to be 35 to 38 pounds per hour. This application of ultrasonic technology advanced the envelope of flow measurements through use of 1/4-inch-diameter tubing, which resulted in extremely low flow velocities (5 to 30 pounds per hour). In situ measurements on the orbiters Discovery and Atlantis indicated both vehicles, on the average, experienced similar flow rates through the coldplate (around 25 pounds per hour), but lower rates than the designed flow. Based on the noninvasive checks, further invasive troubleshooting was eliminated. Permanent monitoring using the NFMS was recommended.

Discovery and Classification in Astronomy

NASA Astrophysics Data System (ADS)

Dick, Steven J.

2012-01-01

Three decades after Martin Harwit's pioneering Cosmic Discovery (1981), and following on the recent IAU Symposium "Accelerating the Rate of Astronomical Discovery,” we have revisited the problem of discovery in astronomy, emphasizing new classes of objects. 82 such classes have been identified and analyzed, including 22 in the realm of the planets, 36 in the realm of the stars, and 24 in the realm of the galaxies. We find an extended structure of discovery, consisting of detection, interpretation and understanding, each with its own nuances and a microstructure including conceptual, technological and social roles. This is true with a remarkable degree of consistency over the last 400 years of telescopic astronomy, ranging from Galileo's discovery of satellites, planetary rings and star clusters, to the discovery of quasars and pulsars. Telescopes have served as "engines of discovery” in several ways, ranging from telescope size and sensitivity (planetary nebulae and spiral galaxies), to specialized detectors (TNOs) and the opening of the electromagnetic spectrum for astronomy (pulsars, pulsar planets, and most active galaxies). A few classes (radiation belts, the solar wind and cosmic rays), were initially discovered without the telescope. Classification also plays an important role in discovery. While it might seem that classification marks the end of discovery, or a post-discovery phase, in fact it often marks the beginning, even a pre-discovery phase. Nowhere is this more clearly seen than in the classification of stellar spectra, long before dwarfs, giants and supergiants were known, or their evolutionary sequence recognized. Classification may also be part of a post-discovery phase, as in the MK system of stellar classification, constructed after the discovery of stellar luminosity classes. Some classes are declared rather than discovered, as in the case of gas and ice giant planets, and, infamously, Pluto as a dwarf planet.

How molecular profiling could revolutionize drug discovery.

PubMed

Stoughton, Roland B; Friend, Stephen H

2005-04-01

Information from genomic, proteomic and metabolomic measurements has already benefited target discovery and validation, assessment of efficacy and toxicity of compounds, identification of disease subgroups and the prediction of responses of individual patients. Greater benefits can be expected from the application of these technologies on a significantly larger scale; by simultaneously collecting diverse measurements from the same subjects or cell cultures; by exploiting the steadily improving quantitative accuracy of the technologies; and by interpreting the emerging data in the context of underlying biological models of increasing sophistication. The benefits of applying molecular profiling to drug discovery and development will include much lower failure rates at all stages of the drug development pipeline, faster progression from discovery through to clinical trials and more successful therapies for patient subgroups. Upheavals in existing organizational structures in the current 'conveyor belt' models of drug discovery might be required to take full advantage of these methods.

Can Functional Magnetic Resonance Imaging Improve Success Rates in CNS Drug Discovery?

PubMed Central

Borsook, David; Hargreaves, Richard; Becerra, Lino

2011-01-01

Introduction The bar for developing new treatments for CNS disease is getting progressively higher and fewer novel mechanisms are being discovered, validated and developed. The high costs of drug discovery necessitate early decisions to ensure the best molecules and hypotheses are tested in expensive late stage clinical trials. The discovery of brain imaging biomarkers that can bridge preclinical to clinical CNS drug discovery and provide a ‘language of translation’ affords the opportunity to improve the objectivity of decision-making. Areas Covered This review discusses the benefits, challenges and potential issues of using a science based biomarker strategy to change the paradigm of CNS drug development and increase success rates in the discovery of new medicines. The authors have summarized PubMed and Google Scholar based publication searches to identify recent advances in functional, structural and chemical brain imaging and have discussed how these techniques may be useful in defining CNS disease state and drug effects during drug development. Expert opinion The use of novel brain imaging biomarkers holds the bold promise of making neuroscience drug discovery smarter by increasing the objectivity of decision making thereby improving the probability of success of identifying useful drugs to treat CNS diseases. Functional imaging holds the promise to: (1) define pharmacodynamic markers as an index of target engagement (2) improve translational medicine paradigms to predict efficacy; (3) evaluate CNS efficacy and safety based on brain activation; (4) determine brain activity drug dose-response relationships and (5) provide an objective evaluation of symptom response and disease modification. PMID:21765857

Computational modeling approaches to quantitative structure-binding kinetics relationships in drug discovery.

PubMed

De Benedetti, Pier G; Fanelli, Francesca

2018-03-21

Simple comparative correlation analyses and quantitative structure-kinetics relationship (QSKR) models highlight the interplay of kinetic rates and binding affinity as an essential feature in drug design and discovery. The choice of the molecular series, and their structural variations, used in QSKR modeling is fundamental to understanding the mechanistic implications of ligand and/or drug-target binding and/or unbinding processes. Here, we discuss the implications of linear correlations between kinetic rates and binding affinity constants and the relevance of the computational approaches to QSKR modeling. Copyright © 2018 Elsevier Ltd. All rights reserved.

A broken promise: microbiome differential abundance methods do not control the false discovery rate.

PubMed

Hawinkel, Stijn; Mattiello, Federico; Bijnens, Luc; Thas, Olivier

2017-08-22

High-throughput sequencing technologies allow easy characterization of the human microbiome, but the statistical methods to analyze microbiome data are still in their infancy. Differential abundance methods aim at detecting associations between the abundances of bacterial species and subject grouping factors. The results of such methods are important to identify the microbiome as a prognostic or diagnostic biomarker or to demonstrate efficacy of prodrug or antibiotic drugs. Because of a lack of benchmarking studies in the microbiome field, no consensus exists on the performance of the statistical methods. We have compared a large number of popular methods through extensive parametric and nonparametric simulation as well as real data shuffling algorithms. The results are consistent over the different approaches and all point to an alarming excess of false discoveries. This raises great doubts about the reliability of discoveries in past studies and imperils reproducibility of microbiome experiments. To further improve method benchmarking, we introduce a new simulation tool that allows to generate correlated count data following any univariate count distribution; the correlation structure may be inferred from real data. Most simulation studies discard the correlation between species, but our results indicate that this correlation can negatively affect the performance of statistical methods. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

JSC officials in MCC Bldg 30 monitor STS-26 Discovery, OV-103, activity

NASA Image and Video Library

1988-10-03

JSC officials, laughing, listen to crewmembers' commentary onboard Discovery, Orbiter Vehicle (OV) 103, during STS-26. In the Flight Control Room (FCR) of JSC's Mission Control Center (MCC) Bldg 30 and seated at the Mission Operations Directorate (MOD) console, MOD Director Eugene F. Kranz (foreground), wearing red, white and blue vest, smiles along with JSC Director Aaron Cohen and Flight Crew Operations Deputy Director Henry W. Hartsfield, Jr. (far right).

JSC Officials in MCC Bldg 30 monitor STS-26 Discovery, OV-103, activity

NASA Technical Reports Server (NTRS)

1988-01-01

JSC Officials, laughing, listen to crewmembers' commentary onboard Discovery, Orbiter Vehicle (OV) 103, during STS-26. In the Flight Control Room (FCR) of JSC's Mission Control Center (MCC) Bldg 30 and seated at the Mission Operations Directorate (MOD) console, MOD Director Eugene F. Kranz (foreground), wearing red, white and blue vest, smiles along with JSC Director Aaron Cohen and Flight Crew Operations Deputy Director Henry W. Hartsfield, Jr. (far right).

Group Centric Networking: Large Scale Over the Air Testing of Group Centric Networking

DTIC Science & Technology

2016-11-01

protocol designed to support groups of devices in a local region [4]. It attempts to use the wireless medium to broadcast minimal control information...1) Group Discovery: The goal of the group discovery algo- rithm is to find group nodes without globally flooding control messages. To facilitate this...Large Scale Over-the-Air Testing of Group Centric Networking Logan Mercer, Greg Kuperman, Andrew Hunter, Brian Proulx MIT Lincoln Laboratory

Investigating the Metastability of Clathrate Hydrates for Energy Storage

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

Koh, Carolyn Ann

2014-11-18

Important breakthrough discoveries have been achieved from the DOE award on the key processes controlling the synthesis and structure-property relations of clathrate hydrates, which are critical to the development of clathrate hydrates as energy storage materials. Key achievements include: (i) the discovery of key clathrate hydrate building blocks (stable and metastable) leading to clathrate hydrate nucleation and growth; (ii) development of a rapid clathrate hydrate synthesis route via a seeding mechanism; (iii) synthesis-structure relations of H2 + CH4/CO2 binary hydrates to control thermodynamic requirements for energy storage and sequestration applications; (iv) discovery of a new metastable phase present during clathratemore » hydrate structural transitions. The success of our research to-date is demonstrated by the significant papers we have published in high impact journals, including Science, Angewandte Chemie, J. Am. Chem. Soc. Intellectual Merits of Project Accomplishments: The intellectual merits of the project accomplishments are significant and transformative, in which the fundamental coupled computational and experimental program has provided new and critical understanding on the key processes controlling the nucleation, growth, and thermodynamics of clathrate hydrates containing hydrogen, methane, carbon dioxide, and other guest molecules for energy storage. Key examples of the intellectual merits of the accomplishments include: the first discovery of the nucleation pathways and dominant stable and metastable structures leading to clathrate hydrate formation; the discovery and experimental confirmation of new metastable clathrate hydrate structures; the development of new synthesis methods for controlling clathrate hydrate formation and enclathration of molecular hydrogen. Broader Impacts of Project Accomplishments: The molecular investigations performed in this project on the synthesis (nucleation & growth)-structure-stability relations of clathrate hydrate systems are pivotal in the fundamental understanding of crystalline clathrate hydrates and the discovery of new clathrate hydrate properties and novel materials for a broad spectrum of energy applications, including: energy storage (hydrogen, natural gas); carbon dioxide sequestration; controlling hydrate formation in oil/gas transportation in subsea pipelines. The Project has also enabled the training of undergraduate, graduate and postdoctoral students in computational methods, molecular spectroscopy and diffraction, and measurement methods at extreme conditions of high pressure and low temperature.« less

VARIABLE SELECTION FOR QUALITATIVE INTERACTIONS IN PERSONALIZED MEDICINE WHILE CONTROLLING THE FAMILY-WISE ERROR RATE

PubMed Central

Gunter, Lacey; Zhu, Ji; Murphy, Susan

2012-01-01

For many years, subset analysis has been a popular topic for the biostatistics and clinical trials literature. In more recent years, the discussion has focused on finding subsets of genomes which play a role in the effect of treatment, often referred to as stratified or personalized medicine. Though highly sought after, methods for detecting subsets with altering treatment effects are limited and lacking in power. In this article we discuss variable selection for qualitative interactions with the aim to discover these critical patient subsets. We propose a new technique designed specifically to find these interaction variables among a large set of variables while still controlling for the number of false discoveries. We compare this new method against standard qualitative interaction tests using simulations and give an example of its use on data from a randomized controlled trial for the treatment of depression. PMID:22023676

The Blacklegged Tick, Ixodes scapularis: An Increasing Public Health Concern.

PubMed

Eisen, Rebecca J; Eisen, Lars

2018-04-01

In the United States, the blacklegged tick, Ixodes scapularis, is a vector of seven human pathogens, including those causing Lyme disease, anaplasmosis, babesiosis, Borrelia miyamotoi disease, Powassan virus disease, and ehrlichiosis associated with Ehrlichia muris eauclarensis. In addition to an accelerated rate of discovery of I. scapularis-borne pathogens over the past two decades, the geographic range of the tick, and incidence and range of I. scapularis-borne disease cases, have increased. Despite knowledge of when and where humans are most at risk of exposure to infected ticks, control of I. scapularis-borne diseases remains a challenge. Human vaccines are not available, and we lack solid evidence for other prevention and control methods to reduce human disease. The way forward is discussed. Published by Elsevier Ltd.

Successes in drug discovery and design.

PubMed

2004-04-01

The Society for Medicines Research (SMR) held a one-day meeting on case histories in drug discovery on December 4, 2003, at the National Heart and Lung Institute in London. These meetings have been organized by the SMR biannually for many years, and this latest meeting proved extremely popular, attracting a capacity audience of more than 130 registrants. The purpose of these meetings is educational; they allow those interested in drug discovery to hear key learnings from recent successful drug discovery programs. There was no overall linking theme between the talks, other than each success story has led to the introduction of a new and improved product of therapeutic use. The drug discovery stories covered in the meeting were extremely varied and, put together, they emphasized that each successful story is unique and special. This meeting is also special for the SMR because it presents the "SMR Award for Drug Discovery" in recognition of outstanding achievement and contribution in the area. It should be remembered that drug discovery is an extremely risky business and an extremely costly and complicated process in which the success rate is, at best, low. (c) 2004 Prous Science. All rights reserved.

Strategies for bringing drug delivery tools into discovery.

PubMed

Kwong, Elizabeth; Higgins, John; Templeton, Allen C

2011-06-30

The past decade has yielded a significant body of literature discussing approaches for development and discovery collaboration in the pharmaceutical industry. As a result, collaborations between discovery groups and development scientists have increased considerably. The productivity of pharma companies to deliver new drugs to the market, however, has not increased and development costs continue to rise. Inability to predict clinical and toxicological response underlies the high attrition rate of leads at every step of drug development. A partial solution to this high attrition rate could be provided by better preclinical pharmacokinetics measurements that inform PD response based on key pathways that drive disease progression and therapeutic response. A critical link between these key pharmacology, pharmacokinetics and toxicology studies is the formulation. The challenges in pre-clinical formulation development include limited availability of compounds, rapid turn-around requirements and the frequent un-optimized physical properties of the lead compounds. Despite these challenges, this paper illustrates some successes resulting from close collaboration between formulation scientists and discovery teams. This close collaboration has resulted in development of formulations that meet biopharmaceutical needs from early stage preclinical in vivo model development through toxicity testing and development risk assessment of pre-clinical drug candidates. Published by Elsevier B.V.

Use of nanoscale mechanical stimulation for control and manipulation of cell behaviour.

PubMed

Childs, Peter G; Boyle, Christina A; Pemberton, Gabriel D; Nikukar, Habib; Curtis, Adam S G; Henriquez, Fiona L; Dalby, Matthew J; Reid, Stuart

2016-04-01

The ability to control cell behaviour, cell fate and simulate reliable tissue models in vitro remains a significant challenge yet is crucial for various applications of high throughput screening e.g. drug discovery. Mechanotransduction (the ability of cells to convert mechanical forces in their environment to biochemical signalling) represents an alternative mechanism to attain this control with such studies developing techniques to reproducibly control the mechanical environment in techniques which have potential to be scaled. In this review, the use of techniques such as finite element modelling and precision interferometric measurement are examined to provide context for a novel technique based on nanoscale vibration, also known as "nanokicking". Studies have shown this stimulus to alter cellular responses in both endothelial and mesenchymal stem cells (MSCs), particularly in increased proliferation rate and induced osteogenesis respectively. Endothelial cell lines were exposed to nanoscale vibration amplitudes across a frequency range of 1-100 Hz, and MSCs primarily at 1 kHz. This technique provides significant potential benefits over existing technologies, as cellular responses can be initiated without the use of expensive engineering techniques and/or chemical induction factors. Due to the reproducible and scalable nature of the apparatus it is conceivable that nanokicking could be used for controlling cell behaviour within a wide array of high throughput procedures in the research environment, within drug discovery, and for clinical/therapeutic applications. The results discussed within this article summarise the potential benefits of using nanoscale vibration protocols for controlling cell behaviour. There is a significant need for reliable tissue models within the clinical and pharma industries, and the control of cell behaviour and stem cell differentiation would be highly beneficial. The full potential of this method of controlling cell behaviour has not yet been realised. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

STS-31 Discovery, OV-103, auxiliary power unit 1 (APU-1) controller

NASA Technical Reports Server (NTRS)

1990-01-01

The controller for Discovery's, Orbiter Vehicle (OV) 103's, auxiliary power unit 1 (APU-1) is documented before removal following the launch scrub on 04-10-90. The controller weighs about 15 pounds and controls the speed of the APU. It was flown to the vendor, Sundstrand Corp., Rockford, Illinois, for analysis and testing. Launch of OV-103 on mission STS-31 has been rescheduled for 04-24-90 following the successful replacement of the APU-1 and the recharging of the Hubble Space Telescope's (HST's) nickel-hydrogen batteries. View provided by the Kennedy Space Center (KSC) with alternate KSC number KSC-90PC-663.

KSC-07pd1271

NASA Image and Video Library

2007-05-24

KENNEDY SPACE CENTER, FLA. -- In Space Shuttle Maine Engine Shop, workers get ready to install an engine controller in one of the three main engines (behind them) of the orbiter Discovery. The controller is an electronics package mounted on each space shuttle main engine. It contains two digital computers and the associated electronics to control all main engine components and operations. The controller is attached to the main combustion chamber by shock-mounted fittings. Discovery is the designated orbiter for mission STS-120 to the International Space Station. It will carry a payload that includes the Node 2 module, named Harmony. Launch is targeted for no earlier than Oct. 20. Photo credit: NASA/Cory Huston

KSC-07pd1272

NASA Image and Video Library

2007-05-24

KENNEDY SPACE CENTER, FLA. -- In the Space Shuttle Maine Engine Shop, workers are installing an engine controller in one of the three main engines of the orbiter Discovery. The controller is an electronics package mounted on each space shuttle main engine. It contains two digital computers and the associated electronics to control all main engine components and operations. The controller is attached to the main combustion chamber by shock-mounted fittings. Discovery is the designated orbiter for mission STS-120 to the International Space Station. It will carry a payload that includes the Node 2 module, named Harmony. Launch is targeted for no earlier than Oct. 20. Photo credit: NASA/Cory Huston

KSC-07pd1274

NASA Image and Video Library

2007-05-24

KENNEDY SPACE CENTER, FLA. -- In the Space Shuttle Maine Engine Shop, workers check the installation of an engine controller in one of the three main engines of the orbiter Discovery. The controller is an electronics package mounted on each space shuttle main engine. It contains two digital computers and the associated electronics to control all main engine components and operations. The controller is attached to the main combustion chamber by shock-mounted fittings. Discovery is the designated orbiter for mission STS-120 to the International Space Station. It will carry a payload that includes the Node 2 module, named Harmony. Launch is targeted for no earlier than Oct. 20. Photo credit: NASA/Cory Huston

KSC-07pd1273

NASA Image and Video Library

2007-05-24

KENNEDY SPACE CENTER, FLA. -- In the Space Shuttle Maine Engine Shop, workers are installing an engine controller in one of the three main engines of the orbiter Discovery. The controller is an electronics package mounted on each space shuttle main engine. It contains two digital computers and the associated electronics to control all main engine components and operations. The controller is attached to the main combustion chamber by shock-mounted fittings. Discovery is the designated orbiter for mission STS-120 to the International Space Station. It will carry a payload that includes the Node 2 module, named Harmony. Launch is targeted for no earlier than Oct. 20. Photo credit: NASA/Cory Huston

KSC-07pd1270

NASA Image and Video Library

2007-05-24

KENNEDY SPACE CENTER, FLA. -- In the Space Shuttle Maine Engine Shop, workers get ready to install an engine controller in one of the three main engines of the orbiter Discovery. The controller is an electronics package mounted on each space shuttle main engine. It contains two digital computers and the associated electronics to control all main engine components and operations. The controller is attached to the main combustion chamber by shock-mounted fittings. Discovery is the designated orbiter for mission STS-120 to the International Space Station. It will carry a payload that includes the Node 2 module, named Harmony. Launch is targeted for no earlier than Oct. 20. Photo credit: NASA/Cory Huston

Space Shuttle Discovery Launch

NASA Image and Video Library

2008-05-31

NASA Shuttle Launch Director Michael Leinbach, left, STS-124 Assistant Launch Director Ed Mango, center, and Flow Director for Space Shuttle Discovery Stephanie Stilson clap in the the Launch Control Center after the main engine cut off and successful launch of the Space Shuttle Discovery (STS-124) Saturday, May 31, 2008, at the Kennedy Space Center in Cape Canaveral, Fla. The Shuttle lifted off from launch pad 39A at 5:02 p.m. EDT. Photo Credit: (NASA/Bill Ingalls)

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician moves a switch. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

NASA Image and Video Library

2003-08-27

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician moves a switch. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician turns on a switch. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

NASA Image and Video Library

2003-08-27

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician turns on a switch. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

Compound annotation with real time cellular activity profiles to improve drug discovery.

PubMed

Fang, Ye

2016-01-01

In the past decade, a range of innovative strategies have been developed to improve the productivity of pharmaceutical research and development. In particular, compound annotation, combined with informatics, has provided unprecedented opportunities for drug discovery. In this review, a literature search from 2000 to 2015 was conducted to provide an overview of the compound annotation approaches currently used in drug discovery. Based on this, a framework related to a compound annotation approach using real-time cellular activity profiles for probe, drug, and biology discovery is proposed. Compound annotation with chemical structure, drug-like properties, bioactivities, genome-wide effects, clinical phenotypes, and textural abstracts has received significant attention in early drug discovery. However, these annotations are mostly associated with endpoint results. Advances in assay techniques have made it possible to obtain real-time cellular activity profiles of drug molecules under different phenotypes, so it is possible to generate compound annotation with real-time cellular activity profiles. Combining compound annotation with informatics, such as similarity analysis, presents a good opportunity to improve the rate of discovery of novel drugs and probes, and enhance our understanding of the underlying biology.

The in silico drug discovery toolbox: applications in lead discovery and optimization.

PubMed

Bruno, Agostino; Costantino, Gabriele; Sartori, Luca; Radi, Marco

2017-11-06

Discovery and development of a new drug is a long lasting and expensive journey that takes around 15 years from starting idea to approval and marketing of new medication. Despite the R&D expenditures have been constantly increasing in the last few years, number of new drugs introduced into market has been steadily declining. This is mainly due to preclinical and clinical safety issues, which still represent about 40% of drug discontinuation. From this point of view, it is clear that if we want to increase drug-discovery success rate and reduce costs associated with development of a new drug, a comprehensive evaluation/prediction of potential safety issues should be conducted as soon as possible during early drug discovery phase. In the present review, we will analyse the early steps of drug-discovery pipeline, describing the sequence of steps from disease selection to lead optimization and focusing on the most common in silico tools used to assess attrition risks and build a mitigation plan. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Statistical testing and power analysis for brain-wide association study.

PubMed

Gong, Weikang; Wan, Lin; Lu, Wenlian; Ma, Liang; Cheng, Fan; Cheng, Wei; Grünewald, Stefan; Feng, Jianfeng

2018-04-05

The identification of connexel-wise associations, which involves examining functional connectivities between pairwise voxels across the whole brain, is both statistically and computationally challenging. Although such a connexel-wise methodology has recently been adopted by brain-wide association studies (BWAS) to identify connectivity changes in several mental disorders, such as schizophrenia, autism and depression, the multiple correction and power analysis methods designed specifically for connexel-wise analysis are still lacking. Therefore, we herein report the development of a rigorous statistical framework for connexel-wise significance testing based on the Gaussian random field theory. It includes controlling the family-wise error rate (FWER) of multiple hypothesis testings using topological inference methods, and calculating power and sample size for a connexel-wise study. Our theoretical framework can control the false-positive rate accurately, as validated empirically using two resting-state fMRI datasets. Compared with Bonferroni correction and false discovery rate (FDR), it can reduce false-positive rate and increase statistical power by appropriately utilizing the spatial information of fMRI data. Importantly, our method bypasses the need of non-parametric permutation to correct for multiple comparison, thus, it can efficiently tackle large datasets with high resolution fMRI images. The utility of our method is shown in a case-control study. Our approach can identify altered functional connectivities in a major depression disorder dataset, whereas existing methods fail. A software package is available at https://github.com/weikanggong/BWAS. Copyright © 2018 Elsevier B.V. All rights reserved.

Fragment-based drug discovery and molecular docking in drug design.

PubMed

Wang, Tao; Wu, Mian-Bin; Chen, Zheng-Jie; Chen, Hua; Lin, Jian-Ping; Yang, Li-Rong

2015-01-01

Fragment-based drug discovery (FBDD) has caused a revolution in the process of drug discovery and design, with many FBDD leads being developed into clinical trials or approved in the past few years. Compared with traditional high-throughput screening, it displays obvious advantages such as efficiently covering chemical space, achieving higher hit rates, and so forth. In this review, we focus on the most recent developments of FBDD for improving drug discovery, illustrating the process and the importance of FBDD. In particular, the computational strategies applied in the process of FBDD and molecular-docking programs are highlighted elaborately. In most cases, docking is used for predicting the ligand-receptor interaction modes and hit identification by structurebased virtual screening. The successful cases of typical significance and the hits identified most recently are discussed.

Applying flow chemistry: methods, materials, and multistep synthesis.

PubMed

McQuade, D Tyler; Seeberger, Peter H

2013-07-05

The synthesis of complex molecules requires control over both chemical reactivity and reaction conditions. While reactivity drives the majority of chemical discovery, advances in reaction condition control have accelerated method development/discovery. Recent tools include automated synthesizers and flow reactors. In this Synopsis, we describe how flow reactors have enabled chemical advances in our groups in the areas of single-stage reactions, materials synthesis, and multistep reactions. In each section, we detail the lessons learned and propose future directions.

How music training enhances working memory: a cerebrocerebellar blending mechanism that can lead equally to scientific discovery and therapeutic efficacy in neurological disorders.

PubMed

Vandervert, Larry

2015-01-01

Following in the vein of studies that concluded that music training resulted in plastic changes in Einstein's cerebral cortex, controlled research has shown that music training (1) enhances central executive attentional processes in working memory, and (2) has also been shown to be of significant therapeutic value in neurological disorders. Within this framework of music training-induced enhancement of central executive attentional processes, the purpose of this article is to argue that: (1) The foundational basis of the central executive begins in infancy as attentional control during the establishment of working memory, (2) In accordance with Akshoomoff, Courchesne and Townsend's and Leggio and Molinari's cerebellar sequence detection and prediction models, the rigors of volitional control demands of music training can enhance voluntary manipulation of information in thought and movement, (3) The music training-enhanced blending of cerebellar internal models in working memory as can be experienced as intuition in scientific discovery (as Einstein often indicated) or, equally, as moments of therapeutic advancement toward goals in the development of voluntary control in neurological disorders, and (4) The blending of internal models as in (3) thus provides a mechanism by which music training enhances central executive processes in working memory that can lead to scientific discovery and improved therapeutic outcomes in neurological disorders. Within the framework of Leggio and Molinari's cerebellar sequence detection model, it is determined that intuitive steps forward that occur in both scientific discovery and during therapy in those with neurological disorders operate according to the same mechanism of adaptive error-driven blending of cerebellar internal models. It is concluded that the entire framework of the central executive structure of working memory is a product of the cerebrocerebellar system which can, through the learning of internal models, incorporate the multi-dimensional rigor and volitional-control demands of music training and, thereby, enhance voluntary control. It is further concluded that this cerebrocerebellar view of the music training-induced enhancement of central executive control in working memory provides a needed mechanism to explain both the highest level of scientific discovery and the efficacy of music training in the remediation of neurological impairments.

Genome-Wide Association Study of a Varroa-Specific Defense Behavior in Honeybees (Apis mellifera)

PubMed Central

Spötter, Andreas; Gupta, Pooja; Mayer, Manfred; Reinsch, Norbert

2016-01-01

Honey bees are exposed to many damaging pathogens and parasites. The most devastating is Varroa destructor, which mainly affects the brood. A promising approach for preventing its spread is to breed Varroa-resistant honey bees. One trait that has been shown to provide significant resistance against the Varroa mite is hygienic behavior, which is a behavioral response of honeybee workers to brood diseases in general. Here, we report the use of an Affymetrix 44K SNP array to analyze SNPs associated with detection and uncapping of Varroa-parasitized brood by individual worker bees (Apis mellifera). For this study, 22 000 individually labeled bees were video-monitored and a sample of 122 cases and 122 controls was collected and analyzed to determine the dependence/independence of SNP genotypes from hygienic and nonhygienic behavior on a genome-wide scale. After false-discovery rate correction of the P values, 6 SNP markers had highly significant associations with the trait investigated (α < 0.01). Inspection of the genomic regions around these SNPs led to the discovery of putative candidate genes. PMID:26774061

Breast Cancer: Pros and Cons of Conservative vs Aggressive Management

PubMed Central

Davidson, Arthur T.

1981-01-01

Cancer of the breast is the leading type of cancer in women in the United States (28 percent), and the leading cause of death from cancer in women (20 percent). More than half of the cases of breast cancer can be anticipated to exhibit recurrent disease. Most deaths occur within five years of discovery. There has been a minimum reduction in the mortality rate in the past 35 years. This failure is due to microemboli that spread via both the lymphatic and vascular systems in the early predetection state of the primary lesion. In Stage I and Stage II disease, modified radical mastectomy is the treatment of choice. In Stage III disease, radical mastectomy gives a higher incidence of local control of the disease without an increased chance of survival. Adjuvant chemotherapy offers a definite improvement in survival rates. PMID:7031277

20 Discoveries that Shaped Our Lives: Century of the Sciences.

ERIC Educational Resources Information Center

Judson, Horace Freeland

1984-01-01

Describes (in separate articles) 20 developments in science, technology, and medicine that were made during the twentieth century and had significant impact on society. They include discoveries related to intelligence tests, plastics, aviation, antibiotics, genetics, evolution, birth control, computers, transistors, DNA, lasers, statistics,…

Factors affecting survival of patients in the acute phase of upper cervical spine injuries.

PubMed

Morita, Tomonori; Takebayashi, Tsuneo; Irifune, Hideto; Ohnishi, Hirofumi; Hirayama, Suguru; Yamashita, Toshihiko

2017-04-01

In recent years, on the one hand, the mortality rates of upper cervical spine injuries, such as odontoid fractures, were suggested to be not so high, but on the other hand reported to be significantly high. Furthermore, it has not been well documented the relationship between survival rates and various clinical features in those patients during the acute phase of injury because of few reports. This study aimed to evaluate survival rates and acute-phase clinical features of upper cervical spine injuries. We conducted a retrospective review of all patients who were transported to the advanced emergency medical center and underwent computed tomography of the cervical spine at our hospital between January 2006 and December 2015. We excluded the patients who were discovered in a state of cardiopulmonary arrest (CPA) and could not be resuscitated after transportation. Of the 215 consecutive patients with cervical spine injuries, we examined 40 patients (18.6%) diagnosed with upper cervical spine injury (males, 28; females, 12; median age, 58.5 years). Age, sex, mechanism of injury, degree of paralysis, the level of cervical injury, injury severity score (ISS), and incidence of CPA at discovery were evaluated and compared among patients classified into the survival and mortality groups. The survival rate was 77.5% (31/40 patients). In addition, complete paralysis was observed in 32.5% of patients. The median of ISS was 34.0 points, and 14 patients (35.0%) presented with CPA at discovery. Age, the proportion of patients with complete paralysis, a high ISS, and incidence of CPA at discovery were significantly higher in the mortality group (p = 0.038, p = 0.038, p < 0.001, and p < 0.001, respectively). Elderly people were more likely to experience upper cervical spine injuries, and their mortality rate was significantly higher than that in injured younger people. In addition, complete paralysis, high ISS, a state of CPA at discovery, was significantly higher in the mortality group.

Discovery of Hubble's Law as a Series of Type III Errors

ERIC Educational Resources Information Center

Belenkiy, Ari

2015-01-01

Recently much attention has been paid to the history of the discovery of Hubble's law--the linear relation between the rate of recession of the remote galaxies and distance to them from Earth. Though historians of cosmology now mention several names associated with this law instead of just one, the motivation of each actor of that remarkable…

Sky-plane discovery rates for Near Earth Object discoveries from Pan-STARRS1 - implications for future search strategies

NASA Astrophysics Data System (ADS)

Wainscoat, Richard J.; Chambers, Kenneth C.; Chastel, Serge; Denneau, Larry; Lilly Schunova, Eva; Micheli, Marco; Weryk, Robert J.

2016-10-01

The Pan-STARRS1 telescope has been spending most of its time for the last 2.5 years searching the sky for Near Earth Objects (NEOs). The surveyed area covers the entire northern sky and extends south to -49 degrees declination. Because Pan-STARRS1 has a large field-of-view, it has been able survey large areas of the sky, and we are now able to examine NEO discovery rates relative to ecliptic latitude.Most contemporary searches, including Pan-STARRS1, have been spending large amounts of their observing time during the dark moon period searching for NEOs close to the ecliptic. The rationale for this is that many objects have low inclination, and all objects in orbit around the Sun must cross the ecliptic. New search capabilities are now available, including Pan-STARRS2, and the upgraded camera in Catalina Sky Survey's G96 telescope. These allow NEO searches to be conducted over wider areas of the sky, and to extend further from the ecliptic.We have examined the discovery rates relative to location on the sky for new NEOs from Pan-STARRS1, and find that the new NEO discoveries are less concentrated on the ecliptic than might be expected. This finding also holds for larger objects. The southern sky has proven to be very productive in new NEO discoveries - this is a direct consequence of the major NEO surveys being located in the northern hemisphere.Our preliminary findings suggest that NEO searches should extend to at least 30 degrees from the ecliptic during the more sensitive dark moon period. At least 6,000 deg2 should therefore be searched each lunation. This is possible with the newly augmented NEO search assets, and repeat coverage will be needed in order to recover most of the NEO candidates found. However, weather challenges will likely make full and repeated coverage of such a large area of sky difficult to achieve. Some simple coordination between observing sites will likely lead to improvement in efficiency.

Close up view of the Commander's Seat on the Flight ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close up view of the Commander's Seat on the Flight Deck of the Orbiter Discovery. It appears the Orbiter is in the roll out / launch pad configuration. A protective cover is over the Rotational Hand Controller to protect it during the commander's ingress. Most notable in this view are the Speed Brake/Thrust Controller in the center right in this view and the Translational Hand Controller in the center top of the view. This image was taken at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Adipose tissue transcriptomics and epigenomics in low birthweight men and controls: role of high-fat overfeeding.

PubMed

Gillberg, Linn; Perfilyev, Alexander; Brøns, Charlotte; Thomasen, Martin; Grunnet, Louise G; Volkov, Petr; Rosqvist, Fredrik; Iggman, David; Dahlman, Ingrid; Risérus, Ulf; Rönn, Tina; Nilsson, Emma; Vaag, Allan; Ling, Charlotte

2016-04-01

Individuals who had a low birthweight (LBW) are at an increased risk of insulin resistance and type 2 diabetes when exposed to high-fat overfeeding (HFO). We studied genome-wide mRNA expression and DNA methylation in subcutaneous adipose tissue (SAT) after 5 days of HFO and after a control diet in 40 young men, of whom 16 had LBW. mRNA expression was analysed using Affymetrix Human Gene 1.0 ST arrays and DNA methylation using Illumina 450K BeadChip arrays. We found differential DNA methylation at 53 sites in SAT from LBW vs normal birthweight (NBW) men (false discovery rate <5%), including sites in the FADS2 and CPLX1 genes previously associated with type 2 diabetes. When we used reference-free cell mixture adjustments to potentially adjust for cell composition, 4,323 sites had differential methylation in LBW vs NBW men. However, no differences in SAT gene expression levels were identified between LBW and NBW men. In the combined group of all 40 participants, 3,276 genes (16.5%) were differentially expressed in SAT after HFO (false discovery rate <5%) and there was no difference between LBW men and controls. The most strongly upregulated genes were ELOVL6, FADS2 and NNAT; in contrast, INSR, IRS2 and the SLC27A2 fatty acid transporter showed decreased expression after HFO. Interestingly, SLC27A2 expression correlated negatively with diabetes- and obesity-related traits in a replication cohort of 142 individuals. DNA methylation at 652 CpG sites (including in CDK5, IGFBP5 and SLC2A4) was altered in SAT after overfeeding in this and in another cohort. Young men who had a LBW exhibit epigenetic alterations in their adipose tissue that potentially influence insulin resistance and risk of type 2 diabetes. Short-term overfeeding influences gene transcription and, to some extent, DNA methylation in adipose tissue; there was no major difference in this response between LBW and control participants.

Closeup view of the aft fuselage of the Orbiter Discovery ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the aft fuselage of the Orbiter Discovery on the starboard side looking forward. This view is of the attach surface for the Orbiter Maneuvering System/Reaction Control System (OMS/RCS) Pod. The OMS/RCS pods are removed for processing and reconditioning at another facility. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Discovery Orbiter Major Modifications

NASA Image and Video Library

2003-08-27

During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician moves a circuit reset on the cockpit console. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

Non-gravitational effects on genus penicillium

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

Loup, M.

1995-09-01

In September 1994, Shuttle Orbiter Discovery, STS-64, launched into space. Aboard that shuttle was a payload containing Fungi spores, genus Penicillium. With the over looking help of Dr. Audrey Gabel, Associate Professor of Biology at Black Hills State University, investigations on differing media types began. Basis for this experimentation was to determine if there was any differences between the space exposed spores and control spores. Studies concluded that there were differences and those differences were then recorded. It was hypothesized the spores may have been effected causing differences in growth rate, colony size, depth and margins, coloring, germination, and growthmore » on different media.« less

Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity?

PubMed

Weidel, Elisabeth; Negri, Matthias; Empting, Martin; Hinsberger, Stefan; Hartmann, Rolf W

2014-01-01

In order to identify new scaffolds for drug discovery, surface plasmon resonance is frequently used to screen structurally diverse libraries. Usually, hit rates are low and identification processes are time consuming. Hence, approaches which improve hit rates and, thus, reduce the library size are required. In this work, we studied three often used strategies for their applicability to identify inhibitors of PqsD. In two of them, target-specific aspects like inhibition of a homologous protein or predicted binding determined by virtual screening were used for compound preselection. Finally, a fragment library, covering a large chemical space, was screened and served as comparison. Indeed, higher hit rates were observed for methods employing preselected libraries indicating that target-oriented compound selection provides a time-effective alternative.

The variable sky of deep synoptic surveys

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

Ridgway, Stephen T.; Matheson, Thomas; Mighell, Kenneth J.

2014-11-20

The discovery of variable and transient sources is an essential product of synoptic surveys. The alert stream will require filtering for personalized criteria—a process managed by a functionality commonly described as a Broker. In order to understand quantitatively the magnitude of the alert generation and Broker tasks, we have undertaken an analysis of the most numerous types of variable targets in the sky—Galactic stars, quasi-stellar objects (QSOs), active galactic nuclei (AGNs), and asteroids. It is found that the Large Synoptic Survey Telescope (LSST) will be capable of discovering ∼10{sup 5} high latitude (|b| > 20°) variable stars per night atmore » the beginning of the survey. (The corresponding number for |b| < 20° is orders of magnitude larger, but subject to caveats concerning extinction and crowding.) However, the number of new discoveries may well drop below 100 per night within less than one year. The same analysis applied to GAIA clarifies the complementarity of the GAIA and LSST surveys. Discovery of AGNs and QSOs are each predicted to begin at ∼3000 per night and decrease by 50 times over four years. Supernovae are expected at ∼1100 per night, and after several survey years will dominate the new variable discovery rate. LSST asteroid discoveries will start at >10{sup 5} per night, and if orbital determination has a 50% success rate per epoch, they will drop below 1000 per night within two years.« less

Oncology drug discovery: planning a turnaround.

PubMed

Toniatti, Carlo; Jones, Philip; Graham, Hilary; Pagliara, Bruno; Draetta, Giulio

2014-04-01

We have made remarkable progress in our understanding of the pathophysiology of cancer. This improved understanding has resulted in increasingly effective targeted therapies that are better tolerated than conventional cytotoxic agents and even curative in some patients. Unfortunately, the success rate of drug approval has been limited, and therapeutic improvements have been marginal, with too few exceptions. In this article, we review the current approach to oncology drug discovery and development, identify areas in need of improvement, and propose strategies to improve patient outcomes. We also suggest future directions that may improve the quality of preclinical and early clinical drug evaluation, which could lead to higher approval rates of anticancer drugs.

MicroRNA array normalization: an evaluation using a randomized dataset as the benchmark.

PubMed

Qin, Li-Xuan; Zhou, Qin

2014-01-01

MicroRNA arrays possess a number of unique data features that challenge the assumption key to many normalization methods. We assessed the performance of existing normalization methods using two microRNA array datasets derived from the same set of tumor samples: one dataset was generated using a blocked randomization design when assigning arrays to samples and hence was free of confounding array effects; the second dataset was generated without blocking or randomization and exhibited array effects. The randomized dataset was assessed for differential expression between two tumor groups and treated as the benchmark. The non-randomized dataset was assessed for differential expression after normalization and compared against the benchmark. Normalization improved the true positive rate significantly in the non-randomized data but still possessed a false discovery rate as high as 50%. Adding a batch adjustment step before normalization further reduced the number of false positive markers while maintaining a similar number of true positive markers, which resulted in a false discovery rate of 32% to 48%, depending on the specific normalization method. We concluded the paper with some insights on possible causes of false discoveries to shed light on how to improve normalization for microRNA arrays.

MicroRNA Array Normalization: An Evaluation Using a Randomized Dataset as the Benchmark

PubMed Central

Qin, Li-Xuan; Zhou, Qin

2014-01-01

MicroRNA arrays possess a number of unique data features that challenge the assumption key to many normalization methods. We assessed the performance of existing normalization methods using two microRNA array datasets derived from the same set of tumor samples: one dataset was generated using a blocked randomization design when assigning arrays to samples and hence was free of confounding array effects; the second dataset was generated without blocking or randomization and exhibited array effects. The randomized dataset was assessed for differential expression between two tumor groups and treated as the benchmark. The non-randomized dataset was assessed for differential expression after normalization and compared against the benchmark. Normalization improved the true positive rate significantly in the non-randomized data but still possessed a false discovery rate as high as 50%. Adding a batch adjustment step before normalization further reduced the number of false positive markers while maintaining a similar number of true positive markers, which resulted in a false discovery rate of 32% to 48%, depending on the specific normalization method. We concluded the paper with some insights on possible causes of false discoveries to shed light on how to improve normalization for microRNA arrays. PMID:24905456

iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-Energy Trigger

NASA Technical Reports Server (NTRS)

Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; Horesh, Assaf; Corsi, Alessandra; Fox, Derek B.; Cao, Yi; Kasliwal, Mansi M.; Lien, Amy; Arcavi, Iair;

iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-energy Trigger

NASA Astrophysics Data System (ADS)

Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; Horesh, Assaf; Corsi, Alessandra; Fox, Derek B.; Cao, Yi; Kasliwal, Mansi M.; Lien, Amy; Arcavi, Iair; Bloom, Joshua S.; Butler, Nat R.; Cucchiara, Antonino; de Diego, José A.; Filippenko, Alexei V.; Gal-Yam, Avishay; Gehrels, Neil; Georgiev, Leonid; Jesús González, J.; Graham, John F.; Greiner, Jochen; Kann, D. Alexander; Klein, Christopher R.; Knust, Fabian; Kulkarni, S. R.; Kutyrev, Alexander; Laher, Russ; Lee, William H.; Nugent, Peter E.; Prochaska, J. Xavier; Ramirez-Ruiz, Enrico; Richer, Michael G.; Rubin, Adam; Urata, Yuji; Varela, Karla; Watson, Alan M.; Wozniak, Przemek R.

2015-04-01

We report here the discovery by the Intermediate Palomar Transient Factory (iPTF) of iPTF14yb, a luminous ({{M}r}≈ -27.8 mag), cosmological (redshift 1.9733), rapidly fading optical transient. We demonstrate, based on probabilistic arguments and a comparison with the broader population, that iPTF14yb is the optical afterglow of the long-duration gamma-ray burst GRB 140226A. This marks the first unambiguous discovery of a GRB afterglow prior to (and thus entirely independent of) an associated high-energy trigger. We estimate the rate of iPTF14yb-like sources (i.e., cosmologically distant relativistic explosions) based on iPTF observations, inferring an all-sky value of {{\\Re }rel}=610 yr-1 (68% confidence interval of 110-2000 yr-1). Our derived rate is consistent (within the large uncertainty) with the all-sky rate of on-axis GRBs derived by the Swift satellite. Finally, we briefly discuss the implications of the nondetection to date of bona fide “orphan” afterglows (i.e., those lacking detectable high-energy emission) on GRB beaming and the degree of baryon loading in these relativistic jets.

Modern approaches to accelerate discovery of new antischistosomal drugs.

PubMed

Neves, Bruno Junior; Muratov, Eugene; Machado, Renato Beilner; Andrade, Carolina Horta; Cravo, Pedro Vitor Lemos

2016-06-01

The almost exclusive use of only praziquantel for the treatment of schistosomiasis has raised concerns about the possible emergence of drug-resistant schistosomes. Consequently, there is an urgent need for new antischistosomal drugs. The identification of leads and the generation of high quality data are crucial steps in the early stages of schistosome drug discovery projects. Herein, the authors focus on the current developments in antischistosomal lead discovery, specifically referring to the use of automated in vitro target-based and whole-organism screens and virtual screening of chemical databases. They highlight the strengths and pitfalls of each of the above-mentioned approaches, and suggest possible roadmaps towards the integration of several strategies, which may contribute for optimizing research outputs and led to more successful and cost-effective drug discovery endeavors. Increasing partnerships and access to funding for drug discovery have strengthened the battle against schistosomiasis in recent years. However, the authors believe this battle also includes innovative strategies to overcome scientific challenges. In this context, significant advances of in vitro screening as well as computer-aided drug discovery have contributed to increase the success rate and reduce the costs of drug discovery campaigns. Although some of these approaches were already used in current antischistosomal lead discovery pipelines, the integration of these strategies in a solid workflow should allow the production of new treatments for schistosomiasis in the near future.

Comparative mass spectrometry-based metabolomics strategies for the investigation of microbial secondary metabolites.

PubMed

Covington, Brett C; McLean, John A; Bachmann, Brian O

2017-01-04

Covering: 2000 to 2016The labor-intensive process of microbial natural product discovery is contingent upon identifying discrete secondary metabolites of interest within complex biological extracts, which contain inventories of all extractable small molecules produced by an organism or consortium. Historically, compound isolation prioritization has been driven by observed biological activity and/or relative metabolite abundance and followed by dereplication via accurate mass analysis. Decades of discovery using variants of these methods has generated the natural pharmacopeia but also contributes to recent high rediscovery rates. However, genomic sequencing reveals substantial untapped potential in previously mined organisms, and can provide useful prescience of potentially new secondary metabolites that ultimately enables isolation. Recently, advances in comparative metabolomics analyses have been coupled to secondary metabolic predictions to accelerate bioactivity and abundance-independent discovery work flows. In this review we will discuss the various analytical and computational techniques that enable MS-based metabolomic applications to natural product discovery and discuss the future prospects for comparative metabolomics in natural product discovery.

Discovery of innovative therapeutics: today's realities and tomorrow's vision. 2. Pharma's challenges and their commitment to innovation.

PubMed

Abou-Gharbia, Magid; Childers, Wayne E

2014-07-10

The pharmaceutical industry is facing enormous challenges, including reduced efficiency, stagnant success rate, patent expirations for key drugs, fierce price competition from generics, high regulatory hurdles, and the industry's perceived tarnished image. Pharma has responded by embarking on a range of initiatives. Other sectors, including NIH, have also responded. Academic drug discovery groups have appeared to support the transition of innovative academic discoveries and ideas into attractive drug discovery opportunities. Part 1 of this two-part series discussed the criticisms that have been leveled at the pharmaceutical industry over the past 3 decades and summarized the supporting data for and against these criticisms. This second installment will focus on the current challenges facing the pharmaceutical industry and Pharma's responses, focusing on the industry's changing perspective and new business models for coping with the loss of talent and declining clinical pipelines as well as presenting some examples of recent drug discovery successes.

Space Shuttle Discovery Launch

NASA Image and Video Library

2008-05-31

NASA Administrator, Michael Griffin watches the launch of the Space Shuttle Discovery (STS-124) from the Launch Control Center Saturday, May 31, 2008, at the Kennedy Space Center in Cape Canaveral, Fla. The Shuttle lifted off from launch pad 39A at 5:02 p.m. EDT. Photo Credit: (NASA/Bill Ingalls)

19 CFR 19.12 - Inventory control and recordkeeping system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... invoice with any discrepancy reported to the port director as provided in § 19.6(a). (3) Recordation... discovery. The responsible party must pay the applicable duties, taxes and interest on thefts and shortages... discovery. The responsible party must pay the applicable duties, taxes and interest on thefts and shortages...

General view of the aft, starboard section of the Orbiter ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

General view of the aft, starboard section of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the main engines and Orbiter Maneuvering System/Reaction Control System pods are removed in this photo. The flexible hoses protruding from the starboard aft section are to control temperature, humidity and pressure in the orbiter's void spaces during its down time. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility.

PubMed

Wrensch, Margaret; Jenkins, Robert B; Chang, Jeffrey S; Yeh, Ru-Fang; Xiao, Yuanyuan; Decker, Paul A; Ballman, Karla V; Berger, Mitchel; Buckner, Jan C; Chang, Susan; Giannini, Caterina; Halder, Chandralekha; Kollmeyer, Thomas M; Kosel, Matthew L; LaChance, Daniel H; McCoy, Lucie; O'Neill, Brian P; Patoka, Joe; Pico, Alexander R; Prados, Michael; Quesenberry, Charles; Rice, Terri; Rynearson, Amanda L; Smirnov, Ivan; Tihan, Tarik; Wiemels, Joe; Yang, Ping; Wiencke, John K

2009-08-01

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component-adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10(-6) using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 x 10(-8), replication P = 0.0038 and combined P = 1.85 x 10(-10). On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 x 10(-7), replication P = 0.00035 and combined P = 3.40 x 10(-9). For both SNPs, the direction of association was the same in discovery and replication phases.

KSC-2009-1949

NASA Image and Video Library

2009-03-03

CAPE CANAVERAL, Fla. – One of the three thoroughly inspected gaseous hydrogen flow control valves is shown after its arrival at NASA's Kennedy Space Center in Florida. Technicians installed and retested them in space shuttle Discovery. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have worked to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Space Shuttle Program managers decided to replace Discovery's valves with others that have undergone a detailed eddy current inspection. Program managers will review the testing and determine whether to meet on March 6 for the Flight Readiness Review for the STS-119 mission. Launch of Discovery tentatively is targeted for March 12. Photo credit: NASA/Chris Rhodes

KSC-2009-1950

NASA Image and Video Library

2009-03-03

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, technicians prepare to install three gaseous hydrogen flow control valves on space shuttle Discovery. The valves were retested after installation. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have worked to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Space Shuttle Program managers decided to replace Discovery's valves with others that have undergone a detailed eddy current inspection. Program managers will review the testing and determine whether to meet on March 6 for the Flight Readiness Review for the STS-119 mission. Launch of Discovery tentatively is targeted for March 12. Photo credit: NASA/Chris Rhodes

KSC-2009-1951

NASA Image and Video Library

2009-03-03

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, technicians install three gaseous hydrogen flow control valves on space shuttle Discovery. The valves were retested after installation. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have worked to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Space Shuttle Program managers decided to replace Discovery's valves with others that have undergone a detailed eddy current inspection. Program managers will review the testing and determine whether to meet on March 6 for the Flight Readiness Review for the STS-119 mission. Launch of Discovery tentatively is targeted for March 12. Photo credit: NASA/Chris Rhodes

KSC-2009-1948

NASA Image and Video Library

2009-03-03

CAPE CANAVERAL, Fla. – One of the three thoroughly inspected gaseous hydrogen flow control valves is shown after its arrival at NASA's Kennedy Space Center in Florida. Technicians installed and retested them in space shuttle Discovery. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have worked to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Space Shuttle Program managers decided to replace Discovery's valves with others that have undergone a detailed eddy current inspection. Program managers will review the testing and determine whether to meet on March 6 for the Flight Readiness Review for the STS-119 mission. Launch of Discovery tentatively is targeted for March 12. Photo credit: NASA/Chris Rhodes

Comparative biology of zebra mussels in Europe and North America: an overview

USGS Publications Warehouse

Mackie, Gerald L.; Schloesser, Don W.

1996-01-01

SYNOPSIS. Since the discovery of the zebra mussel, Dreissena polymorpha, in the Great Lakes in 1988 comparisons have been made with mussel populations in Europe and the former Soviet Union. These comparisons include: Population dynamics, growth and mortality rates, ecological tolerances and requirements, dispersal rates and patterns, and ecological impacts. North American studies, mostly on the zebra mussel and a few on a second introduced species, the quagga mussel, Dreissena bugensis, have revealed some similarities and some differences. To date it appears that North American populations of zebra mussels are similar to European populations in their basic biological characteristics, population growth and mortality rates, and dispersal mechanisms and rates. Relative to European populations differences have been demonstrated for: (1) individual growth rates; (2) life spans; (3) calcium and pH tolerances and requirements; (4) potential distribution limits; and (5) population densities of veligers and adults. In addition, studies on the occurrence of the two dreissenid species in the Great Lakes are showing differences in their modes of life, depth distributions, and growth rates. As both species spread throughout North America, comparisons between species and waterbodies will enhance our ability to more effectively control these troublesome species.

Bima field, Indonesia: a sleeping giant

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

Prior, S.W.

1986-07-01

The recent Pertamina-ARCO Bima field discovery is 50 mi north of Jakarta, Indonesia, on the east flank of the Sunda basin. More than 1 billion bbl of oil are trapped in the Oligocene-Miocene Batu Raja Limestone within a productive area exceeding 25 mi/sup 2/. Additional oil is trapped in Oligocene Talang Akar sandstone reservoirs. The ZZZ-1 wildcat well drilled into the northern featheredge of the field in October 1974. A drill-stem test of the Batu Raja flowed 87 BOPD of heavy oil, and ZZZ-1 was plugged and abandoned as a noncommercial discovery. Postdrilling assessment suggested that the accumulation was stratigraphicallymore » controlled, and no delineation wells were drilled for 9 years. A second test of this trend was finally made in November 1983, to evaluate what was considered a separate Batu Raja closure updip from ZZZ-1. The ZU-1 well found a common oil-water contact with ZZZ-1 that suggested a structurally controlled giant field had been discovered. A series of step-out wells based on a seismic reinterpretation proved this hypothesis to be true. Phase one development drilling began in November 1985, and 57 wells should be completed within the next year. About 60 million bbl of reserves will be developed at an initial rate of about 50,000 BOPD. Phase two plans now in progress could develop an additional 40 million bbl of reserves.« less

Net present value approaches for drug discovery.

PubMed

Svennebring, Andreas M; Wikberg, Jarl Es

2013-12-01

Three dedicated approaches to the calculation of the risk-adjusted net present value (rNPV) in drug discovery projects under different assumptions are suggested. The probability of finding a candidate drug suitable for clinical development and the time to the initiation of the clinical development is assumed to be flexible in contrast to the previously used models. The rNPV of the post-discovery cash flows is calculated as the probability weighted average of the rNPV at each potential time of initiation of clinical development. Practical considerations how to set probability rates, in particular during the initiation and termination of a project is discussed.

An investigation of the false discovery rate and the misinterpretation of p-values

PubMed Central

Colquhoun, David

2014-01-01

If you use p=0.05 to suggest that you have made a discovery, you will be wrong at least 30% of the time. If, as is often the case, experiments are underpowered, you will be wrong most of the time. This conclusion is demonstrated from several points of view. First, tree diagrams which show the close analogy with the screening test problem. Similar conclusions are drawn by repeated simulations of t-tests. These mimic what is done in real life, which makes the results more persuasive. The simulation method is used also to evaluate the extent to which effect sizes are over-estimated, especially in underpowered experiments. A script is supplied to allow the reader to do simulations themselves, with numbers appropriate for their own work. It is concluded that if you wish to keep your false discovery rate below 5%, you need to use a three-sigma rule, or to insist on p≤0.001. And never use the word ‘significant’. PMID:26064558

Inverse comorbidity in multiple sclerosis: Findings in a complete nationwide cohort.

PubMed

Thormann, Anja; Koch-Henriksen, Nils; Laursen, Bjarne; Sørensen, Per Soelberg; Magyari, Melinda

2016-11-01

Inverse comorbidity is disease occurring at lower rates than expected among persons with a given index disease. The objective was to identify inverse comorbidity in MS. We performed a combined case-control and cohort study in a total nationwide cohort of cases with clinical onset of MS 1980-2005. We randomly matched each MS-case with five population controls. Comorbidity data were obtained from multiple, independent nationwide registries. Cases and controls were followed from January 1977 to the index date, and from the index date through December 2012. We controlled for false discovery rate and investigated each of eight pre-specified comorbidity categories: psychiatric, cerebrovascular, cardiovascular, lung, and autoimmune comorbidities, diabetes, cancer, and Parkinson's disease. A total of 8947 MS-cases and 44,735 controls were eligible for inclusion. We found no inverse associations with MS before the index date. After the index date, we found a decreased occurrence of chronic lung disease (asthma and chronic obstructive pulmonary disease) (HR 0.80 (95% CI 0.75-0.86, p<0.00025)) and overall cancer (HR 0.88 (95% CI 0.81-0.95, p=0.0005)) among MS-cases. This study showed a decreased risk of cancers and pulmonary diseases after onset of MS. Identification of inverse comorbidity and of its underlying mechanisms may provide important new entry points into the understanding of MS. Copyright © 2016 Elsevier B.V. All rights reserved.

Experimental viscous fingering in a tapered radial Hele-Shaw cell

NASA Astrophysics Data System (ADS)

Bongrand, Gregoire; Tsai, Peichun Amy; Complex Fludis Group Team

2017-11-01

The fluid-fluid displacement in porous media is a common process that finds direct applications in various fields, such as enhanced oil recovery and geological CO2 sequestration. In this work, we experimentally investigate the influence of converging cells on viscous fingering instabilities using a radially-tapered cell. For air displacing oil, in contrast to the classical Saffman-Taylor fingering, our results show that a converging gradient in a radial propagation can provide a stabilizing effect and hinder fingering. For a fixed gap gradient and thickness, with increasing injection rates we find a stable displacement under small flow rates, whereas unstable fingering occurs above a certain threshold. We further investigate this critical flow rate delineating the stable and unstable regimes for different gap gradients. These results reveal that the displacement efficiency not only depends on the fluid properties but also on the interfacial velocity and channel structure. The latter factors provide a useful and convenient control to either trigger or inhibit fingering instability. NSERC Discovery, Accelerator, and CRC programs.

KSC-2009-2102

NASA Image and Video Library

2009-03-15

CAPE CANAVERAL, Fla. – In Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida, Flow Director for space shuttle Discovery Stephanie Stilson (center) and Shuttle Launch Director Mike Leinbach applaud the mission management team for the successful launch of space shuttle Discovery on the STS-119 mission. Launch was on time at 7:43 p.m. EDT. The STS-119 mission is the 28th to the space station and Discovery's 36th flight. Discovery will deliver the final pair of power-generating solar array wings and the S6 truss segment. Installation of S6 will signal the station's readiness to house a six-member crew for conducting increased science. Photo credit: NASA/Kim Shiflett

Transfer of the MPLM Leonardo from the ISS to the Orbiter Discovery Payload Bay

NASA Image and Video Library

2006-07-14

ISS013-E-51269 (14 July 2006) --- Canadarm2 or the Space Station Remote Manipulator System (SSRMS) arm (out of frame) grasps the Italian-built Multi-Purpose Logistics Module Leonardo to place it back in Discovery's cargo bay. On the other end of the arm, inside the shirt sleeve environment of the Destiny laboratory on the International Space Station, astronauts Stephanie D. Wilson and Lisa M. Nowak, STS-121 mission specialists, were in control of the transfer. The MPLM was being moved from its temporary parking place on the station's Unity node to the payload bay of Discovery for the return trip to Earth. Discovery's vertical stabilizer is at left.

Allosteric Tuning of Caspase-7: A Fragment-Based Drug Discovery Approach.

PubMed

Vance, Nicholas R; Gakhar, Lokesh; Spies, M Ashley

2017-11-13

The caspase family of cysteine proteases are highly sought-after drug targets owing to their essential roles in apoptosis, proliferation, and inflammation pathways. High-throughput screening efforts to discover inhibitors have gained little traction. Fragment-based screening has emerged as a powerful approach for the discovery of innovative drug leads. This method has become a central facet of drug discovery campaigns in the pharmaceutical industry and academia. A fragment-based drug discovery campaign against human caspase-7 resulted in the discovery of a novel series of allosteric inhibitors. An X-ray crystal structure of caspase-7 bound to a fragment hit and a thorough kinetic characterization of a zymogenic form of the enzyme were used to investigate the allosteric mechanism of inhibition. This work further advances our understanding of the mechanisms of allosteric control of this class of pharmaceutically relevant enzymes, and provides a new path forward for drug discovery efforts. © 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Discovery and Development of ATP-Competitive mTOR Inhibitors Using Computational Approaches.

PubMed

Luo, Yao; Wang, Ling

2017-11-16

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries. Besides, computational approaches were also applied to study protein-ligand interactions mechanisms and in natural product-driven drug discovery. Herein, we survey the most recent progress on the application of computational approaches to advance the discovery and development of compounds targeting mTOR. Future directions in the discovery of new mTOR inhibitors using computational methods are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

WebMOTIFS: automated discovery, filtering and scoring of DNA sequence motifs using multiple programs and Bayesian approaches

PubMed Central

Romer, Katherine A.; Kayombya, Guy-Richard; Fraenkel, Ernest

2007-01-01

WebMOTIFS provides a web interface that facilitates the discovery and analysis of DNA-sequence motifs. Several studies have shown that the accuracy of motif discovery can be significantly improved by using multiple de novo motif discovery programs and using randomized control calculations to identify the most significant motifs or by using Bayesian approaches. WebMOTIFS makes it easy to apply these strategies. Using a single submission form, users can run several motif discovery programs and score, cluster and visualize the results. In addition, the Bayesian motif discovery program THEME can be used to determine the class of transcription factors that is most likely to regulate a set of sequences. Input can be provided as a list of gene or probe identifiers. Used with the default settings, WebMOTIFS accurately identifies biologically relevant motifs from diverse data in several species. WebMOTIFS is freely available at http://fraenkel.mit.edu/webmotifs. PMID:17584794

Response to comments on "Can we name Earth's species before they go extinct?".

PubMed

Costello, Mark J; May, Robert M; Stork, Nigel E

2013-07-19

Mora et al. disputed that most species will be discovered before they go extinct, but not our main recommendations to accelerate species' discoveries. We show that our conclusions would be unaltered by discoveries of more microscopic species and reinforce our estimates of species description and extinction rates, that taxonomic effort has never been greater, and that there are 2 to 8 million species on Earth.

Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts

PubMed Central

Kelsen, Judith; Bittinger, Kyle; Pauly-Hubbard, Helen; Posivak, Leah; Grunberg, Stephanie; Baldassano, Robert; Lewis, James D; Wu, Gary D; Bushman, Frederic D

2016-01-01

Background Oral manifestations are common in Crohn's disease (CD). Here we characterized the subgingival microbiota in pediatric CD patients initiating therapy and after 8 weeks to identify microbial community features associated with CD and therapy. Methods Pediatric CD patients were recruited from The Children's Hospital of Pennsylvania. Healthy control subjects were recruited from primary care or orthopedics clinic. Subgingival plaque samples were collected at initiation of therapy and after 8 weeks. Treatment exposures included 5-ASAs, immunomodualtors, steroids, and infliximab. The microbiota was characterized by 16S rRNA gene sequencing. The study was repeated in separate discovery (35 CD, 43 healthy) and validation cohorts (43 CD, 31 healthy). Results A majority of subjects in both cohorts demonstrated clinical response after 8 weeks of therapy (discovery cohort 88%, validation cohort 79%). At week 0, both antibiotic exposure and disease state were associated with differences in bacterial community composition. Seventeen genera were identified in the discovery cohort as candidate biomarkers, of which 11 were confirmed in the validation cohort. Capnocytophaga, Rothia, and TM7 were more abundant in CD relative to healthy controls. Other bacteria were reduced in abundance with antibiotic exposure among CD subjects. CD-associated genera were not enriched compared to healthy controls after 8 weeks of therapy. Conclusions Subgingival microbial community structure differed with CD and antibiotic use. Results in the discovery cohort were replicated in a separate validation cohort. Several potentially pathogenic bacterial lineages were associated with CD but were not diminished in abundance by antibiotic treatment, suggesting targets for additional surveillance. PMID:26288001

Alterations of the Subgingival Microbiota in Pediatric Crohn's Disease Studied Longitudinally in Discovery and Validation Cohorts.

PubMed

Kelsen, Judith; Bittinger, Kyle; Pauly-Hubbard, Helen; Posivak, Leah; Grunberg, Stephanie; Baldassano, Robert; Lewis, James D; Wu, Gary D; Bushman, Frederic D

2015-12-01

Oral manifestations are common in Crohn's disease (CD). Here we characterized the subgingival microbiota in pediatric patients with CD initiating therapy and after 8 weeks to identify microbial community features associated with CD and therapy. Pediatric patients with CD were recruited from The Children's Hospital of Pennsylvania. Healthy control subjects were recruited from primary care or orthopedics clinic. Subgingival plaque samples were collected at initiation of therapy and after 8 weeks. Treatment exposures included 5-ASAs, immunomodulators, steroids, and infliximab. The microbiota was characterized by 16S rRNA gene sequencing. The study was repeated in separate discovery (35 CD, 43 healthy) and validation cohorts (43 CD, 31 healthy). Most subjects in both cohorts demonstrated clinical response after 8 weeks of therapy (discovery cohort 88%, validation cohort 79%). At week 0, both antibiotic exposure and disease state were associated with differences in bacterial community composition. Seventeen genera were identified in the discovery cohort as candidate biomarkers, of which 11 were confirmed in the validation cohort. Capnocytophaga, Rothia, and TM7 were more abundant in CD relative to healthy controls. Other bacteria were reduced in abundance with antibiotic exposure among CD subjects. CD-associated genera were not enriched compared with healthy controls after 8 weeks of therapy. Subgingival microbial community structure differed with CD and antibiotic use. Results in the discovery cohort were replicated in a separate validation cohort. Several potentially pathogenic bacterial lineages were associated with CD but were not diminished in abundance by antibiotic treatment, suggesting targets for additional surveillance.

Paraphrasing and Prediction with Self-Explanation as Generative Strategies for Learning Science Principles in a Simulation

ERIC Educational Resources Information Center

Morrison, Jennifer R.; Bol, Linda; Ross, Steven M.; Watson, Ginger S.

2015-01-01

This study examined the incorporation of generative strategies for the guided discovery of physics principles in a simulation. Participants who either paraphrased or predicted and self-explained guided discovery assignments exhibited improved performance on an achievement test as compared to a control group. Calibration accuracy (the…

10 CFR 784.12 - Terms and conditions of waivers.

Code of Federal Regulations, 2014 CFR

2014-01-01

... covering an invention or discovery which is not a Subject Invention and which is owned or controlled by the... asserted by the Contractor or its employees with respect to any invention or discovery made or conceived in... information regarding scientific or technical developments conceived or first actually reduced to practice in...

10 CFR 784.12 - Terms and conditions of waivers.

Code of Federal Regulations, 2011 CFR

2011-01-01

... covering an invention or discovery which is not a Subject Invention and which is owned or controlled by the... asserted by the Contractor or its employees with respect to any invention or discovery made or conceived in... information regarding scientific or technical developments conceived or first actually reduced to practice in...

10 CFR 784.12 - Terms and conditions of waivers.

Code of Federal Regulations, 2013 CFR

2013-01-01

... covering an invention or discovery which is not a Subject Invention and which is owned or controlled by the... asserted by the Contractor or its employees with respect to any invention or discovery made or conceived in... information regarding scientific or technical developments conceived or first actually reduced to practice in...

10 CFR 784.12 - Terms and conditions of waivers.

Code of Federal Regulations, 2012 CFR

2012-01-01

... covering an invention or discovery which is not a Subject Invention and which is owned or controlled by the... asserted by the Contractor or its employees with respect to any invention or discovery made or conceived in... information regarding scientific or technical developments conceived or first actually reduced to practice in...

The combined approach of strain discovery and the inbred line technique for improving control of Delia radicum with Heterorhabditis bacteriophora

USDA-ARS?s Scientific Manuscript database

Entomopathogenic nematodes are potent biocontrol agents but their efficacy can be compromised under unfavorable environmental conditions such as cold temperatures. Discovery of new nematode species or strains that are adapted to local conditions is one approach that can be used to enhance efficacy. ...

GeoGebra Assist Discovery Learning Model for Problem Solving Ability and Attitude toward Mathematics

NASA Astrophysics Data System (ADS)

Murni, V.; Sariyasa, S.; Ardana, I. M.

2017-09-01

This study aims to describe the effet of GeoGebra utilization in the discovery learning model on mathematical problem solving ability and students’ attitude toward mathematics. This research was quasi experimental and post-test only control group design was used in this study. The population in this study was 181 of students. The sampling technique used was cluster random sampling, so the sample in this study was 120 students divided into 4 classes, 2 classes for the experimental class and 2 classes for the control class. Data were analyzed by using one way MANOVA. The results of data analysis showed that the utilization of GeoGebra in discovery learning can lead to solving problems and attitudes towards mathematics are better. This is because the presentation of problems using geogebra can assist students in identifying and solving problems and attracting students’ interest because geogebra provides an immediate response process to students. The results of the research are the utilization of geogebra in the discovery learning can be applied in learning and teaching wider subject matter, beside subject matter in this study.

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician (left) looks at the circuit breaker lights in the cabin. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

NASA Image and Video Library

2003-08-27

KENNEDY SPACE CENTER, FLA. - During power-up of the orbiter Discovery in the Orbiter Processing Facility, a technician (left) looks at the circuit breaker lights in the cabin. Discovery has been undergoing Orbiter Major Modifications in the past year, ranging from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work includes the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

Pedunculopontine Gamma Band Activity and Development.

PubMed

Garcia-Rill, Edgar; Luster, Brennon; Mahaffey, Susan; MacNicol, Melanie; Hyde, James R; D'Onofrio, Stasia M; Phillips, Cristy

2015-12-03

This review highlights the most important discovery in the reticular activating system in the last 10 years, the manifestation of gamma band activity in cells of the reticular activating system (RAS), especially in the pedunculopontine nucleus, which is in charge of waking and rapid eye movement (REM) sleep. The identification of different cell groups manifesting P/Q-type Ca(2+) channels that control waking vs. those that manifest N-type channels that control REM sleep provides novel avenues for the differential control of waking vs. REM sleep. Recent discoveries on the development of this system can help explain the developmental decrease in REM sleep and the basic rest-activity cycle.

Avoiding false discoveries in association studies.

PubMed

Sabatti, Chiara

2007-01-01

We consider the problem of controlling false discoveries in association studies. We assume that the design of the study is adequate so that the "false discoveries" are potentially only because of random chance, not to confounding or other flaws. Under this premise, we review the statistical framework for hypothesis testing and correction for multiple comparisons. We consider in detail the currently accepted strategies in linkage analysis. We then examine the underlying similarities and differences between linkage and association studies and document some of the most recent methodological developments for association mapping.

Chromatin and Transcription in Yeast

PubMed Central

Rando, Oliver J.; Winston, Fred

2012-01-01

Understanding the mechanisms by which chromatin structure controls eukaryotic transcription has been an intense area of investigation for the past 25 years. Many of the key discoveries that created the foundation for this field came from studies of Saccharomyces cerevisiae, including the discovery of the role of chromatin in transcriptional silencing, as well as the discovery of chromatin-remodeling factors and histone modification activities. Since that time, studies in yeast have continued to contribute in leading ways. This review article summarizes the large body of yeast studies in this field. PMID:22345607

Empirical performance of the calibrated self-controlled cohort analysis within temporal pattern discovery: lessons for developing a risk identification and analysis system.

PubMed

Norén, G Niklas; Bergvall, Tomas; Ryan, Patrick B; Juhlin, Kristina; Schuemie, Martijn J; Madigan, David

2013-10-01

Observational healthcare data offer the potential to identify adverse drug reactions that may be missed by spontaneous reporting. The self-controlled cohort analysis within the Temporal Pattern Discovery framework compares the observed-to-expected ratio of medical outcomes during post-exposure surveillance periods with those during a set of distinct pre-exposure control periods in the same patients. It utilizes an external control group to account for systematic differences between the different time periods, thus combining within- and between-patient confounder adjustment in a single measure. To evaluate the performance of the calibrated self-controlled cohort analysis within Temporal Pattern Discovery as a tool for risk identification in observational healthcare data. Different implementations of the calibrated self-controlled cohort analysis were applied to 399 drug-outcome pairs (165 positive and 234 negative test cases across 4 health outcomes of interest) in 5 real observational databases (four with administrative claims and one with electronic health records). Performance was evaluated on real data through sensitivity/specificity, the area under receiver operator characteristics curve (AUC), and bias. The calibrated self-controlled cohort analysis achieved good predictive accuracy across the outcomes and databases under study. The optimal design based on this reference set uses a 360 days surveillance period and a single control period 180 days prior to new prescriptions. It achieved an average AUC of 0.75 and AUC >0.70 in all but one scenario. A design with three separate control periods performed better for the electronic health records database and for acute renal failure across all data sets. The estimates for negative test cases were generally unbiased, but a minor negative bias of up to 0.2 on the RR-scale was observed with the configurations using multiple control periods, for acute liver injury and upper gastrointestinal bleeding. The calibrated self-controlled cohort analysis within Temporal Pattern Discovery shows promise as a tool for risk identification; it performs well at discriminating positive from negative test cases. The optimal parameter configuration may vary with the data set and medical outcome of interest.

Discovery of 4ms and 7 MS Pulsars in M15 (F & H)

NASA Astrophysics Data System (ADS)

Middleditch, J.

1992-12-01

Observations of M15 taken during Oct. 23-Nov. 1 1991 with the Arecibo 305-m telescope at 430 MHz, which were analyzed using 2-billion point Fourier transforms on supercomputers at Los Alamos National Laboratory, reveal two new ms pulsars in the globular cluster, M15. The sixth and fastest yet discovered in this cluster, M15F, has a spin rate of 248.3 Hz, while the eighth and latest to be discovered in this cluster has a spin rate of 148.3 Hz, the only one known so far in the frequency interval of 100-200 Hz. Further details and implications of these discoveries will be discussed.

Current NEO surveys

NASA Astrophysics Data System (ADS)

Larson, Stephen

2007-05-01

The state and discovery rate of current NEO surveys reflects incremental improvements in a number of areas, such as detector size and sensitivity, computing capacity and availability of larger apertures. The result has been an increased discovery rate even with the expected reduction of objects left to discover. There are currently about 10 telescopes ranging in size from 0.5 - 1.5-meters carrying out full or part-time, regular surveying in both hemispheres. The sky is covered between 1-2 times per lunation to V~19, with a band near the ecliptic to V~20.5. We review the current survey programs and their contribution towards the Spaceguard goal of discovering at least 90% of the NEOs larger than 1 km.

Close up view of the center console on the flight ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close up view of the center console on the flight deck of the Orbiter Discovery showing the console's instrumentation and controls. The commanders station is located to the left in this view and the pilot's station is to the right in the view. The handle and lever located on the right side of the center console and towards its front is one of a pair, the commander has one on the left of his seat in his station, of Speed Brake/Thrust Controllers. These are dual purpose controllers. During ascent the controller can be use to throttle the main engines and during entry the controllers can be used to control aerodynamic drag by opening or closing the orbiter's speed brake. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-2009-1873

NASA Image and Video Library

2009-02-25

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, technicians have removed space shuttle Discovery's three gaseous hydrogen flow control valves, two of which will undergo detailed inspection. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have been working to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Approximately 4,000 images of each valve removed will be reviewed for evidence of cracks. Valves that have flown fewer times will be installed in Discovery. NASA's Space Shuttle Program has established a plan that could support shuttle Discovery's launch to the International Space Station, tentatively targeted for March 12. An exact target launch date will be determined as work on the valves progresses. Photo credit: NASA/Dimitri Gerondidakis

Novel statistical tools for management of public databases facilitate community-wide replicability and control of false discovery.

PubMed

Rosset, Saharon; Aharoni, Ehud; Neuvirth, Hani

2014-07-01

Issues of publication bias, lack of replicability, and false discovery have long plagued the genetics community. Proper utilization of public and shared data resources presents an opportunity to ameliorate these problems. We present an approach to public database management that we term Quality Preserving Database (QPD). It enables perpetual use of the database for testing statistical hypotheses while controlling false discovery and avoiding publication bias on the one hand, and maintaining testing power on the other hand. We demonstrate it on a use case of a replication server for GWAS findings, underlining its practical utility. We argue that a shift to using QPD in managing current and future biological databases will significantly enhance the community's ability to make efficient and statistically sound use of the available data resources. © 2014 WILEY PERIODICALS, INC.

Effectiveness of discovery learning model on mathematical problem solving

NASA Astrophysics Data System (ADS)

Herdiana, Yunita; Wahyudin, Sispiyati, Ririn

2017-08-01

This research is aimed to describe the effectiveness of discovery learning model on mathematical problem solving. This research investigate the students' problem solving competency before and after learned by using discovery learning model. The population used in this research was student in grade VII in one of junior high school in West Bandung Regency. From nine classes, class VII B were randomly selected as the sample of experiment class, and class VII C as control class, which consist of 35 students every class. The method in this research was quasi experiment. The instrument in this research is pre-test, worksheet and post-test about problem solving of mathematics. Based on the research, it can be conclude that the qualification of problem solving competency of students who gets discovery learning model on level 80%, including in medium category and it show that discovery learning model effective to improve mathematical problem solving.

Direct Maximization of Protein Identifications from Tandem Mass Spectra*

PubMed Central

Spivak, Marina; Weston, Jason; Tomazela, Daniela; MacCoss, Michael J.; Noble, William Stafford

2012-01-01

The goal of many shotgun proteomics experiments is to determine the protein complement of a complex biological mixture. For many mixtures, most methodological approaches fall significantly short of this goal. Existing solutions to this problem typically subdivide the task into two stages: first identifying a collection of peptides with a low false discovery rate and then inferring from the peptides a corresponding set of proteins. In contrast, we formulate the protein identification problem as a single optimization problem, which we solve using machine learning methods. This approach is motivated by the observation that the peptide and protein level tasks are cooperative, and the solution to each can be improved by using information about the solution to the other. The resulting algorithm directly controls the relevant error rate, can incorporate a wide variety of evidence and, for complex samples, provides 18–34% more protein identifications than the current state of the art approaches. PMID:22052992

Factoring stream turbulence into global assessments of nitrogen pollution.

PubMed

Grant, Stanley B; Azizian, Morvarid; Cook, Perran; Boano, Fulvio; Rippy, Megan A

2018-03-16

The discharge of excess nitrogen to streams and rivers poses an existential threat to both humans and ecosystems. A seminal study of headwater streams across the United States concluded that in-stream removal of nitrate is controlled primarily by stream chemistry and biology. Reanalysis of these data reveals that stream turbulence (in particular, turbulent mass transfer across the concentration boundary layer) imposes a previously unrecognized upper limit on the rate at which nitrate is removed from streams. The upper limit closely approximates measured nitrate removal rates in streams with low concentrations of this pollutant, a discovery that should inform stream restoration designs and efforts to assess the effects of nitrogen pollution on receiving water quality and the global nitrogen cycle. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Latin America Report

DTIC Science & Technology

1985-07-25

renovation is not a recent discovery . In May 1984, I also rejected /Mrs Peron’s/ offer to appoint me to the tactical command that she created, and I...been marked by emphasis placed on greater discoveries of reserves. For example, at present, the proven crude supplies will suffice to cover only 14... Cobre and Mid-Claren- don and provide other irrigation facilities where they are necessary throughout the country. ’■ 4 Special rate of electricity

KSC-2009-2100

NASA Image and Video Library

2009-03-15

CAPE CANAVERAL, Fla. – In Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida, Flow Director for space shuttle Discovery Stephanie Stilson, Assistant Launch Director Pete Nickolenko and Shuttle Launch Director Mike Leinbach check the computers for follow-up images of the launch of space shuttle Discovery on the STS-119 mission. Launch was on time at 7:43 p.m. EDT. The STS-119 mission is the 28th to the space station and Discovery's 36th flight. Discovery will deliver the final pair of power-generating solar array wings and the S6 truss segment. Installation of S6 will signal the station's readiness to house a six-member crew for conducting increased science. Photo credit: NASA/Kim Shiflett

Perspectives on the agrochemical industry and agrochemical discovery.

PubMed

Sparks, Thomas C; Lorsbach, Beth A

2017-04-01

Agrochemicals have been critical to the production of food and fiber, as well as the control of vectors of disease. The need for the discovery and development of new agrochemicals continues unabated due to the loss of existing products through the development of resistance, the desire for products with more favorable environmental and toxicological profiles, shifting pest spectra, and changing agricultural needs and practices. As presented in the associated analysis of the agrochemical industry, the rising costs and complexities of agrochemical discovery have, in part, led to increasing consolidation, especially in the USA and Europe. However, as demonstrated by the present analysis, the discovery of new agrochemicals continues in spite of the challenges. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds.

PubMed

Feng, Yan; Mitchison, Timothy J; Bender, Andreas; Young, Daniel W; Tallarico, John A

2009-07-01

Multi-parameter phenotypic profiling of small molecules provides important insights into their mechanisms of action, as well as a systems level understanding of biological pathways and their responses to small molecule treatments. It therefore deserves more attention at an early step in the drug discovery pipeline. Here, we summarize the technologies that are currently in use for phenotypic profiling--including mRNA-, protein- and imaging-based multi-parameter profiling--in the drug discovery context. We think that an earlier integration of phenotypic profiling technologies, combined with effective experimental and in silico target identification approaches, can improve success rates of lead selection and optimization in the drug discovery process.

Mesoionic pyrido[1,2-a]pyrimidinones: Discovery of dicloromezotiaz as a lepidoptera insecticide acting on nicotinic acetylcholine receptors1,2.

PubMed

Zhang, Wenming; Holyoke, Caleb W; Barry, James; Cordova, Daniel; Leighty, Robert M; Tong, My-Hanh T; Hughes, Kenneth A; Lahm, George P; Pahutski, Thomas F; Xu, Ming; Briddell, Twyla A; McCann, Stephen F; Henry, Yewande T; Chen, Yuzhong

2017-02-15

A novel class of mesoionic pyrido[1,2-a]pyrimidinones has been discovered with exceptional insecticidal activity controlling a number of insect species. In this communication, we report the part of the optimization program that led to the identification of dicloromezotiaz as a potent insecticide to control a broad range of lepidoptera. Our efforts in discovery, synthesis, structure-activity relationship elucidation, and biological activity evaluation are also presented. Copyright © 2017 Elsevier Ltd. All rights reserved.

Experimental Null Method to Guide the Development of Technical Procedures and to Control False-Positive Discovery in Quantitative Proteomics.

PubMed

Shen, Xiaomeng; Hu, Qiang; Li, Jun; Wang, Jianmin; Qu, Jun

2015-10-02

Comprehensive and accurate evaluation of data quality and false-positive biomarker discovery is critical to direct the method development/optimization for quantitative proteomics, which nonetheless remains challenging largely due to the high complexity and unique features of proteomic data. Here we describe an experimental null (EN) method to address this need. Because the method experimentally measures the null distribution (either technical or biological replicates) using the same proteomic samples, the same procedures and the same batch as the case-vs-contol experiment, it correctly reflects the collective effects of technical variability (e.g., variation/bias in sample preparation, LC-MS analysis, and data processing) and project-specific features (e.g., characteristics of the proteome and biological variation) on the performances of quantitative analysis. To show a proof of concept, we employed the EN method to assess the quantitative accuracy and precision and the ability to quantify subtle ratio changes between groups using different experimental and data-processing approaches and in various cellular and tissue proteomes. It was found that choices of quantitative features, sample size, experimental design, data-processing strategies, and quality of chromatographic separation can profoundly affect quantitative precision and accuracy of label-free quantification. The EN method was also demonstrated as a practical tool to determine the optimal experimental parameters and rational ratio cutoff for reliable protein quantification in specific proteomic experiments, for example, to identify the necessary number of technical/biological replicates per group that affords sufficient power for discovery. Furthermore, we assessed the ability of EN method to estimate levels of false-positives in the discovery of altered proteins, using two concocted sample sets mimicking proteomic profiling using technical and biological replicates, respectively, where the true-positives/negatives are known and span a wide concentration range. It was observed that the EN method correctly reflects the null distribution in a proteomic system and accurately measures false altered proteins discovery rate (FADR). In summary, the EN method provides a straightforward, practical, and accurate alternative to statistics-based approaches for the development and evaluation of proteomic experiments and can be universally adapted to various types of quantitative techniques.

Linkage effects between deposit discovery and postdiscovery exploratory drilling

USGS Publications Warehouse

Drew, Lawrence J.

1975-01-01

For the 1950-71 period of petroleum exploration in the Powder River Basin, northeastern Wyoming and southeastern Montana, three specific topics were investigated. First, the wildcat wells drilled during the ambient phases of exploration are estimated to have discovered 2.80 times as much petroleum per well as the wildcat wells drilled during the cyclical phases of exploration, periods when exploration plays were active. Second, the hypothesis was tested and verified that during ambient phases of exploration the discovery of deposits could be anticipated by a small but statistically significant rise in the ambient drilling rate during the year prior to the year of discovery. Closer examination of the data suggests that this anticipation effect decreases through time. Third, a regression model utilizing the two independent variables of (1) the volume of petroleum contained in each deposit discovered in a cell and the directly adjacent cells and (2) the respective depths of these deposits was constructed to predict the expected yearly cyclical wildcat drilling rate in four 30 by 30 min (approximately 860 mi2) sized cells. In two of these cells relatively large volumes of petroleum were discovered, whereas in the other two cells smaller volumes were discovered. The predicted and actual rates of wildcat drilling which occurred in each cell agreed rather closely.

iPTF14yb: The First Discovery of a Gamma-Ray Burst Afterglow Independent of a High-Energy Trigger

DOE PAGES

Cenko, S. Bradley; Urban, Alex L.; Perley, Daniel A.; ...

2015-04-20

We report here the discovery by the Intermediate Palomar Transient Factory (iPTF) of iPTF14yb, a luminous (Msub>r ≈ ₋27.8 mag), cosmological (redshift 1.9733), rapidly fading optical transient. We demonstrate, based on probabilistic arguments and a comparison with the broader population, that iPTF14yb is the optical afterglow of the long-duration gamma-ray burst GRB140226A. This marks the rst unambiguous discovery of a GRB afterglow prior to (and thus entirely independent of) an associated high-energy trigger. We estimate the rate of iPTF14yb-like sources (i.e., cosmologically dis- tant relativistic explosions) based on iPTF observations, inferring an all-sky value ofmore » $$R_{rel}$$ = 610yr -1 (68% con dence interval of 110{2000 yr -1). Our derived rate is consistent (within the large uncer- tainty) with the all-sky rate of on-axis GRBs derived by the Swift satellite. Finally, we brie y discuss the implications of the nondetection to date of bona de \\orphan" afterglows (i.e., those lacking de- tectable high-energy emission) on GRB beaming and the degree of baryon loading in these relativistic jets.« less

Long-Period Planets in Open Clusters and the Evolution of Planetary Systems

NASA Astrophysics Data System (ADS)

Quinn, Samuel N.; White, Russel; Latham, David W.; Stefanik, Robert

2018-01-01

Recent discoveries of giant planets in open clusters confirm that they do form and migrate in relatively dense stellar groups, though overall occurrence rates are not yet well constrained because the small sample of giant planets discovered thus far predominantly have short periods. Moreover, planet formation rates and the architectures of planetary systems in clusters may vary significantly -- e.g., due to intercluster differences in the chemical properties that regulate the growth of planetary embryos or in the stellar space density and binary populations, which can influence the dynamical evolution of planetary systems. Constraints on the population of long-period Jovian planets -- those representing the reservoir from which many hot Jupiters likely form, and which are most vulnerable to intracluster dynamical interactions -- can help quantify how the birth environment affects formation and evolution, particularly through comparison of populations possessing a range of ages and chemical and dynamical properties. From our ongoing RV survey of open clusters, we present the discovery of several long-period planets and candidate substellar companions in the Praesepe, Coma Berenices, and Hyades open clusters. From these discoveries, we improve estimates of giant planet occurrence rates in clusters, and we note that high eccentricities in several of these systems support the prediction that the birth environment helps shape planetary system architectures.

Discovery radiomics via evolutionary deep radiomic sequencer discovery for pathologically proven lung cancer detection.

PubMed

Shafiee, Mohammad Javad; Chung, Audrey G; Khalvati, Farzad; Haider, Masoom A; Wong, Alexander

2017-10-01

While lung cancer is the second most diagnosed form of cancer in men and women, a sufficiently early diagnosis can be pivotal in patient survival rates. Imaging-based, or radiomics-driven, detection methods have been developed to aid diagnosticians, but largely rely on hand-crafted features that may not fully encapsulate the differences between cancerous and healthy tissue. Recently, the concept of discovery radiomics was introduced, where custom abstract features are discovered from readily available imaging data. We propose an evolutionary deep radiomic sequencer discovery approach based on evolutionary deep intelligence. Motivated by patient privacy concerns and the idea of operational artificial intelligence, the evolutionary deep radiomic sequencer discovery approach organically evolves increasingly more efficient deep radiomic sequencers that produce significantly more compact yet similarly descriptive radiomic sequences over multiple generations. As a result, this framework improves operational efficiency and enables diagnosis to be run locally at the radiologist's computer while maintaining detection accuracy. We evaluated the evolved deep radiomic sequencer (EDRS) discovered via the proposed evolutionary deep radiomic sequencer discovery framework against state-of-the-art radiomics-driven and discovery radiomics methods using clinical lung CT data with pathologically proven diagnostic data from the LIDC-IDRI dataset. The EDRS shows improved sensitivity (93.42%), specificity (82.39%), and diagnostic accuracy (88.78%) relative to previous radiomics approaches.

Brief Report: Single-nucleotide polymorphisms in VKORC1 are risk factors for systemic lupus erythematosus in Asians.

PubMed

Kaiser, Rachel; Taylor, Kimberly E; Deng, Yun; Zhao, Jian; Li, Yonghong; Nititham, Joanne; Chang, Monica; Catanese, Joseph; Begovich, Ann B; Brown, Elizabeth E; Edberg, Jeffrey C; McGwin, Gerald; Alarcón, Graciela S; Ramsey-Goldman, Rosalind; Reveille, John D; Vila, Luis M; Petri, Michelle; Kimberly, Robert P; Feng, Xuebing; Sun, Lingyun; Shen, Nan; Li, Wei; Lu, Jian-Xin; Wakeland, Edward K; Li, Quan-Zhen; Yang, Wanling; Lau, Yu-Lung; Liu, Fei-Lan; Chang, Deh-Ming; Yu, Chack-Yung; Song, Yeong W; Tsao, Betty P; Criswell, Lindsey A

2013-01-01

The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects. Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort. Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032. Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis. Copyright © 2013 by the American College of Rheumatology.

On the Discovery of Evolving Truth

PubMed Central

Li, Yaliang; Li, Qi; Gao, Jing; Su, Lu; Zhao, Bo; Fan, Wei; Han, Jiawei

2015-01-01

In the era of big data, information regarding the same objects can be collected from increasingly more sources. Unfortunately, there usually exist conflicts among the information coming from different sources. To tackle this challenge, truth discovery, i.e., to integrate multi-source noisy information by estimating the reliability of each source, has emerged as a hot topic. In many real world applications, however, the information may come sequentially, and as a consequence, the truth of objects as well as the reliability of sources may be dynamically evolving. Existing truth discovery methods, unfortunately, cannot handle such scenarios. To address this problem, we investigate the temporal relations among both object truths and source reliability, and propose an incremental truth discovery framework that can dynamically update object truths and source weights upon the arrival of new data. Theoretical analysis is provided to show that the proposed method is guaranteed to converge at a fast rate. The experiments on three real world applications and a set of synthetic data demonstrate the advantages of the proposed method over state-of-the-art truth discovery methods. PMID:26705502

KSC-04pd0464

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - The body flap is installed on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0463

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - The body flap is installed on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

Getting physical to fix pharma

NASA Astrophysics Data System (ADS)

Connelly, Patrick R.; Vuong, T. Minh; Murcko, Mark A.

2011-09-01

Powerful technologies allow the synthesis and testing of large numbers of new compounds, but the failure rate of pharmaceutical R&D remains very high. Greater understanding of the fundamental physical chemical behaviour of molecules could be the key to greatly enhancing the success rate of drug discovery.

Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae

PubMed Central

Conrad, Michaela; Schothorst, Joep; Kankipati, Harish Nag; Van Zeebroeck, Griet; Rubio-Texeira, Marta; Thevelein, Johan M

2014-01-01

The yeast Saccharomyces cerevisiae has been a favorite organism for pioneering studies on nutrient-sensing and signaling mechanisms. Many specific nutrient responses have been elucidated in great detail. This has led to important new concepts and insight into nutrient-controlled cellular regulation. Major highlights include the central role of the Snf1 protein kinase in the glucose repression pathway, galactose induction, the discovery of a G-protein-coupled receptor system, and role of Ras in glucose-induced cAMP signaling, the role of the protein synthesis initiation machinery in general control of nitrogen metabolism, the cyclin-controlled protein kinase Pho85 in phosphate regulation, nitrogen catabolite repression and the nitrogen-sensing target of rapamycin pathway, and the discovery of transporter-like proteins acting as nutrient sensors. In addition, a number of cellular targets, like carbohydrate stores, stress tolerance, and ribosomal gene expression, are controlled by the presence of multiple nutrients. The protein kinase A signaling pathway plays a major role in this general nutrient response. It has led to the discovery of nutrient transceptors (transporter receptors) as nutrient sensors. Major shortcomings in our knowledge are the relationship between rapid and steady-state nutrient signaling, the role of metabolic intermediates in intracellular nutrient sensing, and the identity of the nutrient sensors controlling cellular growth. PMID:24483210

Subjective Cognitive Decline Is Associated With Altered Default Mode Network Connectivity in Individuals With a Family History of Alzheimer's Disease.

PubMed

Verfaillie, Sander C J; Pichet Binette, Alexa; Vachon-Presseau, Etienne; Tabrizi, Shirin; Savard, Mélissa; Bellec, Pierre; Ossenkoppele, Rik; Scheltens, Philip; van der Flier, Wiesje M; Breitner, John C S; Villeneuve, Sylvia

2018-05-01

Both subjective cognitive decline (SCD) and a family history of Alzheimer's disease (AD) portend risk of brain abnormalities and progression to dementia. Posterior default mode network (pDMN) connectivity is altered early in the course of AD. It is unclear whether SCD predicts similar outcomes in cognitively normal individuals with a family history of AD. We studied 124 asymptomatic individuals with a family history of AD (age 64 ± 5 years). Participants were categorized as having SCD if they reported that their memory was becoming worse (SCD + ). We used extensive neuropsychological assessment to investigate five different cognitive domain performances at baseline (n = 124) and 1 year later (n = 59). We assessed interconnectivity among three a priori defined ROIs: pDMN, anterior ventral DMN, medial temporal memory system (MTMS), and the connectivity of each with the rest of brain. Sixty-eight (55%) participants reported SCD. Baseline cognitive performance was comparable between groups (all false discovery rate-adjusted p values > .05). At follow-up, immediate and delayed memory improved across groups, but the improvement in immediate memory was reduced in SCD + compared with SCD - (all false discovery rate-adjusted p values < .05). When compared with SCD - , SCD + subjects showed increased pDMN-MTMS connectivity (false discovery rate-adjusted p < .05). Higher connectivity between the MTMS and the rest of the brain was associated with better baseline immediate memory, attention, and global cognition, whereas higher MTMS and pDMN-MTMS connectivity were associated with lower immediate memory over time (all false discovery rate-adjusted p values < .05). SCD in cognitively normal individuals is associated with diminished immediate memory practice effects and a brain connectivity pattern that mirrors early AD-related connectivity failure. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Venus Aerobot Multisonde Mission

NASA Technical Reports Server (NTRS)

Cutts, James A.; Kerzhanovich, Viktor; Balaram, J. Bob; Campbell, Bruce; Gershaman, Robert; Greeley, Ronald; Hall, Jeffery L.; Cameron, Jonathan; Klaasen, Kenneth; Hansen, David M.

1999-01-01

Robotic exploration of Venus presents many challenges because of the thick atmosphere and the high surface temperatures. The Venus Aerobot Multisonde mission concept addresses these challenges by using a robotic balloon or aerobot to deploy a number of short lifetime probes or sondes to acquire images of the surface. A Venus aerobot is not only a good platform for precision deployment of sondes but is very effective at recovering high rate data. This paper describes the Venus Aerobot Multisonde concept and discusses a proposal to NASA's Discovery program using the concept for a Venus Exploration of Volcanoes and Atmosphere (VEVA). The status of the balloon deployment and inflation, balloon envelope, communications, thermal control and sonde deployment technologies are also reviewed.

Discovery of a metalloenzyme-like cooperative catalytic system of metal nanoclusters and catechol derivatives for the aerobic oxidation of amines.

PubMed

Yuan, Hao; Yoo, Woo-Jin; Miyamura, Hiroyuki; Kobayashi, Shū

2012-08-29

We have discovered a new class of cooperative catalytic system, consisting of heterogeneous polymer-immobilized bimetallic Pt/Ir alloyed nanoclusters (NCs) and 4-tert-butylcatechol, for the aerobic oxidation of amines to imines under ambient conditions. After optimization, the desired imines were obtained in good to excellent yields with broad substrate scope. The reaction rate was determined to be first-order with respect to the substrate and catechol and zero-order for the alloyed Pt/Ir NC catalyst. Control studies revealed that both the heterogeneous NC catalyst and 4-tert-butylcatechol are essential and act cooperatively to facilitate the aerobic oxidation under mild conditions.

Inkjet formation of unilamellar lipid vesicles for cell-like encapsulation†

PubMed Central

Stachowiak, Jeanne C.; Richmond, David L.; Li, Thomas H.; Brochard-Wyart, Françoise

2010-01-01

Encapsulation of macromolecules within lipid vesicles has the potential to drive biological discovery and enable development of novel, cell-like therapeutics and sensors. However, rapid and reliable production of large numbers of unilamellar vesicles loaded with unrestricted and precisely-controlled contents requires new technologies that overcome size, uniformity, and throughput limitations of existing approaches. Here we present a high-throughput microfluidic method for vesicle formation and encapsulation using an inkjet printer at rates up to 200 Hz. We show how multiple high-frequency pulses of the inkjet’s piezoelectric actuator create a microfluidic jet that deforms a bilayer lipid membrane, controlling formation of individual vesicles. Variations in pulse number, pulse voltage, and solution viscosity are used to control the vesicle size. As a first step toward cell-like reconstitution using this method, we encapsulate the cytoskeletal protein actin and use co-encapsulated microspheres to track its polymerization into a densely entangled cytoskeletal network upon vesicle formation. PMID:19568667

Relative Quantification and Higher-Order Modeling of the Plasma Glycan Cancer Burden Ratio in Ovarian Cancer Case-Control Samples

PubMed Central

Hecht, Elizabeth S.; Scholl, Elizabeth H.; Walker, S. Hunter; Taylor, Amber D.; Cliby, William A.; Motsinger-Reif, Alison A.; Muddiman, David C.

2016-01-01

An early-stage, population-wide biomarker for ovarian cancer (OVC) is essential to reverse its high mortality rate. Aberrant glycosylation by OVC has been reported, but studies have yet to identify an N-glycan with sufficiently high specificity. We curated a human biorepository of 82 case-control plasma samples, with 27%, 12%, 46%, and 15% falling across stages I–IV, respectively. For relatve quantitation, glycans were analyzed by the individuality normalization when labeling with glycan hydrazide tags (INLIGHT) strategy for enhanced electrospray ionization, MS/MS analysis. Sixty-three glycan cancer burden ratios (GBRs), defined as the log10 ratio of the case-control extracted ion chromatogram abundances, were calculated above the limit of detection. The final GBR models, built using stepwise forward regression, included three significant terms: OVC stage, normalized mean GBR, and tag chemical purity; glycan class, fucosylation, or sialylation were not significant variables. After Bonferroni correction, seven N-glycans were identified as significant (p < 0.05), and after false discovery rate correction, an additional four glycans were determined to be significant (p < 0.05), with one borderline (p = 0.05). For all N-glycans, the vectors of the effects from stages II–IV were sequentially reversed, suggesting potential biological changes in OVC morphology or in host response. PMID:26347193

Discovery of potential protein biomarkers of lung adenocarcinoma in bronchoalveolar lavage fluid by SWATH MS data-independent acquisition and targeted data extraction.

PubMed

Ortea, I; Rodríguez-Ariza, A; Chicano-Gálvez, E; Arenas Vacas, M S; Jurado Gámez, B

2016-04-14

Lung cancer currently ranks as the neoplasia with the highest global mortality rate. Although some improvements have been introduced in recent years, new advances in diagnosis are required in order to increase survival rates. New mildly invasive endoscopy-based diagnostic techniques include the collection of bronchoalveolar lavage fluid (BALF), which is discarded after using a portion of the fluid for standard pathological procedures. BALF proteomic analysis can contribute to clinical practice with more sensitive biomarkers, and can complement cytohistological studies by aiding in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. The range of quantitative proteomics methodologies used for biomarker discovery is currently being broadened with the introduction of data-independent acquisition (DIA) analysis-related approaches that address the massive quantitation of the components of a proteome. Here we report for the first time a DIA-based quantitative proteomics study using BALF as the source for the discovery of potential lung cancer biomarkers. The results have been encouraging in terms of the number of identified and quantified proteins. A panel of candidate protein biomarkers for adenocarcinoma in BALF is reported; this points to the activation of the complement network as being strongly over-represented and suggests this pathway as a potential target for lung cancer research. In addition, the results reported for haptoglobin, complement C4-A, and glutathione S-transferase pi are consistent with previous studies, which indicates that these proteins deserve further consideration as potential lung cancer biomarkers in BALF. Our study demonstrates that the analysis of BALF proteins by liquid chromatography-tandem mass spectrometry (LC-MS/MS), combining a simple sample pre-treatment and SWATH DIA MS, is a useful method for the discovery of potential lung cancer biomarkers. Bronchoalveolar lavage fluid (BALF) analysis can contribute to clinical practice with more sensitive biomarkers, thus complementing cytohistological studies in order to aid in the diagnosis, prognosis, and subtyping of lung cancer, as well as the monitoring of treatment response. Here we report a panel of candidate protein biomarkers for adenocarcinoma in BALF. Forty-four proteins showed a fold-change higher than 3.75 among adenocarcinoma patients compared with controls. This report is the first DIA-based quantitative proteomics study to use bronchoalveolar lavage fluid (BALF) as a matrix for discovering potential biomarkers. The results are encouraging in terms of the number of identified and quantified proteins, demonstrating that the analysis of BALF proteins by a SWATH approach is a useful method for the discovery of potential biomarkers of pulmonary diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Corra: Computational framework and tools for LC-MS discovery and targeted mass spectrometry-based proteomics

PubMed Central

Brusniak, Mi-Youn; Bodenmiller, Bernd; Campbell, David; Cooke, Kelly; Eddes, James; Garbutt, Andrew; Lau, Hollis; Letarte, Simon; Mueller, Lukas N; Sharma, Vagisha; Vitek, Olga; Zhang, Ning; Aebersold, Ruedi; Watts, Julian D

2008-01-01

Background Quantitative proteomics holds great promise for identifying proteins that are differentially abundant between populations representing different physiological or disease states. A range of computational tools is now available for both isotopically labeled and label-free liquid chromatography mass spectrometry (LC-MS) based quantitative proteomics. However, they are generally not comparable to each other in terms of functionality, user interfaces, information input/output, and do not readily facilitate appropriate statistical data analysis. These limitations, along with the array of choices, present a daunting prospect for biologists, and other researchers not trained in bioinformatics, who wish to use LC-MS-based quantitative proteomics. Results We have developed Corra, a computational framework and tools for discovery-based LC-MS proteomics. Corra extends and adapts existing algorithms used for LC-MS-based proteomics, and statistical algorithms, originally developed for microarray data analyses, appropriate for LC-MS data analysis. Corra also adapts software engineering technologies (e.g. Google Web Toolkit, distributed processing) so that computationally intense data processing and statistical analyses can run on a remote server, while the user controls and manages the process from their own computer via a simple web interface. Corra also allows the user to output significantly differentially abundant LC-MS-detected peptide features in a form compatible with subsequent sequence identification via tandem mass spectrometry (MS/MS). We present two case studies to illustrate the application of Corra to commonly performed LC-MS-based biological workflows: a pilot biomarker discovery study of glycoproteins isolated from human plasma samples relevant to type 2 diabetes, and a study in yeast to identify in vivo targets of the protein kinase Ark1 via phosphopeptide profiling. Conclusion The Corra computational framework leverages computational innovation to enable biologists or other researchers to process, analyze and visualize LC-MS data with what would otherwise be a complex and not user-friendly suite of tools. Corra enables appropriate statistical analyses, with controlled false-discovery rates, ultimately to inform subsequent targeted identification of differentially abundant peptides by MS/MS. For the user not trained in bioinformatics, Corra represents a complete, customizable, free and open source computational platform enabling LC-MS-based proteomic workflows, and as such, addresses an unmet need in the LC-MS proteomics field. PMID:19087345

Glioblastoma: Vascular Habitats Detected at Preoperative Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging Predict Survival.

PubMed

Juan-Albarracín, Javier; Fuster-Garcia, Elies; Pérez-Girbés, Alexandre; Aparici-Robles, Fernando; Alberich-Bayarri, Ángel; Revert-Ventura, Antonio; Martí-Bonmatí, Luis; García-Gómez, Juan M

2018-06-01

Purpose To determine if preoperative vascular heterogeneity of glioblastoma is predictive of overall survival of patients undergoing standard-of-care treatment by using an unsupervised multiparametric perfusion-based habitat-discovery algorithm. Materials and Methods Preoperative magnetic resonance (MR) imaging including dynamic susceptibility-weighted contrast material-enhanced perfusion studies in 50 consecutive patients with glioblastoma were retrieved. Perfusion parameters of glioblastoma were analyzed and used to automatically draw four reproducible habitats that describe the tumor vascular heterogeneity: high-angiogenic and low-angiogenic regions of the enhancing tumor, potentially tumor-infiltrated peripheral edema, and vasogenic edema. Kaplan-Meier and Cox proportional hazard analyses were conducted to assess the prognostic potential of the hemodynamic tissue signature to predict patient survival. Results Cox regression analysis yielded a significant correlation between patients' survival and maximum relative cerebral blood volume (rCBV max ) and maximum relative cerebral blood flow (rCBF max ) in high-angiogenic and low-angiogenic habitats (P < .01, false discovery rate-corrected P < .05). Moreover, rCBF max in the potentially tumor-infiltrated peripheral edema habitat was also significantly correlated (P < .05, false discovery rate-corrected P < .05). Kaplan-Meier analysis demonstrated significant differences between the observed survival of populations divided according to the median of the rCBV max or rCBF max at the high-angiogenic and low-angiogenic habitats (log-rank test P < .05, false discovery rate-corrected P < .05), with an average survival increase of 230 days. Conclusion Preoperative perfusion heterogeneity contains relevant information about overall survival in patients who undergo standard-of-care treatment. The hemodynamic tissue signature method automatically describes this heterogeneity, providing a set of vascular habitats with high prognostic capabilities. © RSNA, 2018.

Closeup view of the Pilot's Seat on the Flight Deck ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the Pilot's Seat on the Flight Deck of the Orbiter Discovery. It appears the Orbiter is in the roll out / launch pad configuration. A protective cover is over the Rotational Hand Controller to protect it during the pilot's ingress. Control panels R1 and R2 are prominent in this view. Panel R1 has switches for control and maintenance of on-board cryogenics for the fuel cells among other functions and panel R2 has switches and controls for the Auxiliary Power Units, ET umbilical doors as well as other operational controls. Note the portable fire extinguisher in the lower right corner of the image. This photograph was taken at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Close up view of the Commander's Seat on the Flight ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close up view of the Commander's Seat on the Flight Deck of the Orbiter Discovery. Toward the right of the view and in front of te seat is the commander's Rotational Hand Controller. The pilot station has an identical controller. These control the acceleration in the roll pitch and yaw directions via the reaction control system and/or the orbiter maneuvering system while outside of Earth's atmosphere or via the orbiter's aerosurfaces wile in Earth's atmosphere when the atmospheric density permits the surfaces to be effective. There are a number of switches on the controller, most notably a trigger switch which is a push-to-talk switch for voice communication and a large button on top of the controller which is a switch to engage the backup flight system. This view was taken at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

NASA Space Engineering Research Center for utilization of local planetary resources

NASA Technical Reports Server (NTRS)

Ramohalli, Kumar; Lewis, John S.

1991-01-01

Because of a change in the NASA funding cycle, the present reporting period covers only the six months from March to September 1991. Nevertheless, remarkable progress was made in a number of areas, some of the most noteworthy of which are: (1) Engineering operation of a breadboard CO2 yields O2 demonstration plant that produced over 10 grams of oxygen per day during several runs of over 100 hours each with a single electrolytic cell. Complete automation of controls, monitoring of various inputs/outputs and critical internal variables, diagnostics, and emergency shutdown in an orderly manner were also included. Moreover, 4-cell and 16-cell units, capable of much higher rates of production, were assembled and tested. (2) Demonstration of a 200 percent increase in the carbothermal reduction of ilmenite through vapor deposition of carbon layers on particles of that material. (3) Demonstration of the deposition of strong iron films from carbonyl chemical vapor deposition, establishing the crucial role of additive gases in governing the process. (4) Discovery of an apparent 800 percent increase in the conversion rates of a modified ilmenite simulant in a plasma-augmented reactor, including direct enhancement by solar radiation absorption. (5) Proof that test specimens of lunar soil with small amounts of metallic additives, recrystallized at moderate temperatures, exhibit an improvement of several orders of magnitude in ductility/tensile strength. (6) Experiments establishing the feasibility of producing silicon-based polymers from indigenous lunar materials. (7) Application of CCD technology to the production of maps of TiO2 abundance, defining primary ilmenite deposits, on the disk of the full moon. (8) Attainment of a discovery rate of approximately 3 new near-Earth asteroids per month by Spacewatch, more than doubling the previous global rate. (9) Coordination of industry and university magma electrolysis investigations in a workshop designed to define remaining problem areas and propose critical experiments.

Detecting differentially expressed genes in heterogeneous diseases using half Student's t-test.

PubMed

Hsu, Chun-Lun; Lee, Wen-Chung

2010-12-01

Microarray technology provides information about hundreds and thousands of gene-expression data in a single experiment. To search for disease-related genes, researchers test for those genes that are differentially expressed between the case subjects and the control subjects. The authors propose a new test, the 'half Student's t-test', specifically for detecting differentially expressed genes in heterogeneous diseases. Monte-Carlo simulation shows that the test maintains the nominal α level quite well for both normal and non-normal distributions. Power of the half Student's t is higher than that of the conventional 'pooled' Student's t when there is heterogeneity in the disease under study. The power gain by using the half Student's t can reach ∼10% when the standard deviation of the case group is 50% larger than that of the control group. Application to a colon cancer data reveals that when the false discovery rate (FDR) is controlled at 0.05, the half Student's t can detect 344 differentially expressed genes, whereas the pooled Student's t can detect only 65 genes. Or alternatively, if only 50 genes are to be selected, the FDR for the pooled Student's t has to be set at 0.0320 (false positive rate of ∼3%), but for the half Student's t, it can be at as low as 0.0001 (false positive rate of about one per ten thousands). The half Student's t-test is to be recommended for the detection of differentially expressed genes in heterogeneous diseases.

The Gulf of Guinea and its Strategic Center Point: How Nigeria Will Bridge American and African Cooperation

DTIC Science & Technology

2009-04-01

Services , Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware...Within four years, there were 43 additional discoveries , the highest rate of any location in the world.13 Deep-water oil fields provide the region and...for continued discoveries of high quality crude oil is extremely likely, spurring interest and development in the region. The geographic

KSC-2009-1875

NASA Image and Video Library

2009-02-25

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, a technician holds one of space shuttle Discovery's gaseous hydrogen flow control valves after its removal. Two of the three valves being removed will undergo detailed inspection. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have been working to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Approximately 4,000 images of each valve removed will be reviewed for evidence of cracks. Valves that have flown fewer times will be installed in Discovery. NASA's Space Shuttle Program has established a plan that could support shuttle Discovery's launch to the International Space Station, tentatively targeted for March 12. An exact target launch date will be determined as work on the valves progresses. Photo credit: NASA/Dimitri Gerondidakis

KSC-2009-1876

NASA Image and Video Library

2009-02-25

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, a technician holds one of space shuttle Discovery's gaseous hydrogen flow control valves after its removal. Two of the three valves being removed will undergo detailed inspection. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have been working to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Approximately 4,000 images of each valve removed will be reviewed for evidence of cracks. Valves that have flown fewer times will be installed in Discovery. NASA's Space Shuttle Program has established a plan that could support shuttle Discovery's launch to the International Space Station, tentatively targeted for March 12. An exact target launch date will be determined as work on the valves progresses. Photo credit: NASA/Dimitri Gerondidakis

KSC-2009-1874

NASA Image and Video Library

2009-02-25

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, a technician bags one of space shuttle Discovery's gaseous hydrogen flow control valves after its removal. Two of the three valves being removed will undergo detailed inspection. Part of the main propulsion system, the valves channel gaseous hydrogen from the main engines to the external tank. NASA and contractor teams have been working to identify what caused damage to a flow control valve on shuttle Endeavour during its November 2008 flight. Approximately 4,000 images of each valve removed will be reviewed for evidence of cracks. Valves that have flown fewer times will be installed in Discovery. NASA's Space Shuttle Program has established a plan that could support shuttle Discovery's launch to the International Space Station, tentatively targeted for March 12. An exact target launch date will be determined as work on the valves progresses. Photo credit: NASA/Dimitri Gerondidakis

A statistical method for the conservative adjustment of false discovery rate (q-value).

PubMed

Lai, Yinglei

2017-03-14

q-value is a widely used statistical method for estimating false discovery rate (FDR), which is a conventional significance measure in the analysis of genome-wide expression data. q-value is a random variable and it may underestimate FDR in practice. An underestimated FDR can lead to unexpected false discoveries in the follow-up validation experiments. This issue has not been well addressed in literature, especially in the situation when the permutation procedure is necessary for p-value calculation. We proposed a statistical method for the conservative adjustment of q-value. In practice, it is usually necessary to calculate p-value by a permutation procedure. This was also considered in our adjustment method. We used simulation data as well as experimental microarray or sequencing data to illustrate the usefulness of our method. The conservativeness of our approach has been mathematically confirmed in this study. We have demonstrated the importance of conservative adjustment of q-value, particularly in the situation that the proportion of differentially expressed genes is small or the overall differential expression signal is weak.

Discovery of abundant hydrothermal venting on the ultraslow-spreading Gakkel ridge in the Arctic Ocean.

PubMed

Edmonds, H N; Michael, P J; Baker, E T; Connelly, D P; Snow, J E; Langmuir, C H; Dick, H J B; Mühe, R; German, C R; Graham, D W

2003-01-16

Submarine hydrothermal venting along mid-ocean ridges is an important contributor to ridge thermal structure, and the global distribution of such vents has implications for heat and mass fluxes from the Earth's crust and mantle and for the biogeography of vent-endemic organisms. Previous studies have predicted that the incidence of hydrothermal venting would be extremely low on ultraslow-spreading ridges (ridges with full spreading rates <2 cm x yr(-1)-which make up 25 per cent of the global ridge length), and that such vent systems would be hosted in ultramafic in addition to volcanic rocks. Here we present evidence for active hydrothermal venting on the Gakkel ridge, which is the slowest spreading (0.6-1.3 cm x yr(-1)) and least explored mid-ocean ridge. On the basis of water column profiles of light scattering, temperature and manganese concentration along 1,100 km of the rift valley, we identify hydrothermal plumes dispersing from at least nine to twelve discrete vent sites. Our discovery of such abundant venting, and its apparent localization near volcanic centres, requires a reassessment of the geologic conditions that control hydrothermal circulation on ultraslow-spreading ridges.

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

PubMed

Isgut, Monica; Rao, Mukkavilli; Yang, Chunhua; Subrahmanyam, Vangala; Rida, Padmashree C G; Aneja, Ritu

2018-03-01

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs. © 2017 Wiley Periodicals, Inc.

Oblique view of the Orbiter Discovery from an elevated platform ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Oblique view of the Orbiter Discovery from an elevated platform in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the Forward Reaction Control System (RCS) Module from the forward section and the Orbiter Maneuvering System (OMS)/RCS pods from the aft section have been removed. Ground support equipment called Strongbacks are attached to the payload bay doors and the Flight Deck windows have been covered by ground support equipment. Also note the scale figure standing by the Orbiter. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

PubMed Central

Pandey, Udai Bhan

2011-01-01

The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

Which are the greatest recent discoveries and the greatest future challenges in nutrition?

PubMed

Katan, M B; Boekschoten, M V; Connor, W E; Mensink, R P; Seidell, J; Vessby, B; Willett, W

2009-01-01

Nutrition science aims to create new knowledge, but scientists rarely sit back to reflect on what nutrition research has achieved in recent decades. We report the outcome of a 1-day symposium at which the audience was asked to vote on the greatest discoveries in nutrition since 1976 and on the greatest challenges for the coming 30 years. Most of the 128 participants were Dutch scientists working in nutrition or related biomedical and public health fields. Candidate discoveries and challenges were nominated by five invited speakers and by members of the audience. Ballot forms were then prepared on which participants selected one discovery and one challenge. A total of 15 discoveries and 14 challenges were nominated. The audience elected Folic acid prevents birth defects as the greatest discovery in nutrition science since 1976. Controlling obesity and insulin resistance through activity and diet was elected as the greatest challenge for the coming 30 years. This selection was probably biased by the interests and knowledge of the speakers and the audience. For the present review, we therefore added 12 discoveries from the period 1976 to 2006 that we judged worthy of consideration, but that had not been nominated at the meeting. The meeting did not represent an objective selection process, but it did demonstrate that the past 30 years have yielded major new discoveries in nutrition and health.

Function-driven discovery of disease genes in zebrafish using an integrated genomics big data resource.

PubMed

Shim, Hongseok; Kim, Ji Hyun; Kim, Chan Yeong; Hwang, Sohyun; Kim, Hyojin; Yang, Sunmo; Lee, Ji Eun; Lee, Insuk

2016-11-16

Whole exome sequencing (WES) accelerates disease gene discovery using rare genetic variants, but further statistical and functional evidence is required to avoid false-discovery. To complement variant-driven disease gene discovery, here we present function-driven disease gene discovery in zebrafish (Danio rerio), a promising human disease model owing to its high anatomical and genomic similarity to humans. To facilitate zebrafish-based function-driven disease gene discovery, we developed a genome-scale co-functional network of zebrafish genes, DanioNet (www.inetbio.org/danionet), which was constructed by Bayesian integration of genomics big data. Rigorous statistical assessment confirmed the high prediction capacity of DanioNet for a wide variety of human diseases. To demonstrate the feasibility of the function-driven disease gene discovery using DanioNet, we predicted genes for ciliopathies and performed experimental validation for eight candidate genes. We also validated the existence of heterozygous rare variants in the candidate genes of individuals with ciliopathies yet not in controls derived from the UK10K consortium, suggesting that these variants are potentially involved in enhancing the risk of ciliopathies. These results showed that an integrated genomics big data for a model animal of diseases can expand our opportunity for harnessing WES data in disease gene discovery. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Discovery of Novel Rhabdoviruses in the Blood of Healthy Individuals from West Africa

PubMed Central

Folarin, Onikepe A.; Grove, Jessica N.; Odia, Ikponmwonsa; Ehiane, Philomena E.; Omoniwa, Omowunmi; Omoregie, Omigie; Jiang, Pan-Pan; Yozwiak, Nathan L.; Matranga, Christian B.; Yang, Xiao; Gire, Stephen K.; Winnicki, Sarah; Tariyal, Ridhi; Schaffner, Stephen F.; Okokhere, Peter O.; Okogbenin, Sylvanus; Akpede, George O.; Asogun, Danny A.; Agbonlahor, Dennis E.; Walker, Peter J.; Tesh, Robert B.; Levin, Joshua Z.; Garry, Robert F.; Sabeti, Pardis C.; Happi, Christian T.

2015-01-01

Next-generation sequencing (NGS) has the potential to transform the discovery of viruses causing unexplained acute febrile illness (UAFI) because it does not depend on culturing the pathogen or a priori knowledge of the pathogen’s nucleic acid sequence. More generally, it has the potential to elucidate the complete human virome, including viruses that cause no overt symptoms of disease, but may have unrecognized immunological or developmental consequences. We have used NGS to identify RNA viruses in the blood of 195 patients with UAFI and compared them with those found in 328 apparently healthy (i.e., no overt signs of illness) control individuals, all from communities in southeastern Nigeria. Among UAFI patients, we identified the presence of nucleic acids from several well-characterized pathogenic viruses, such as HIV-1, hepatitis, and Lassa virus. In our cohort of healthy individuals, however, we detected the nucleic acids of two novel rhabdoviruses. These viruses, which we call Ekpoma virus-1 (EKV-1) and Ekpoma virus-2 (EKV-2), are highly divergent, with little identity to each other or other known viruses. The most closely related rhabdoviruses are members of the genus Tibrovirus and Bas-Congo virus (BASV), which was recently identified in an individual with symptoms resembling hemorrhagic fever. Furthermore, by conducting a serosurvey of our study cohort, we find evidence for remarkably high exposure rates to the identified rhabdoviruses. The recent discoveries of novel rhabdoviruses by multiple research groups suggest that human infection with rhabdoviruses might be common. While the prevalence and clinical significance of these viruses are currently unknown, these viruses could have previously unrecognized impacts on human health; further research to understand the immunological and developmental impact of these viruses should be explored. More generally, the identification of similar novel viruses in individuals with and without overt symptoms of disease highlights the need for a broader understanding of the human virome as efforts for viral detection and discovery advance. PMID:25781465

Isomer-specific profiling of N-glycans derived from human serum for potential biomarker discovery in pancreatic cancer.

PubMed

Liu, Yufei; Wang, Chang; Wang, Ran; Wu, Yike; Zhang, Liang; Liu, Bi-Feng; Cheng, Liming; Liu, Xin

2018-06-15

Glycosylation is one of the most important post-translational modifications of protein. Recently, global profiling of human serum glycomics has become a noninvasive method for cancer-related biomarker discovery and many studies have focused on compositional glycan profiling. In contrast, structure-specific glycan profiling may provide more potential biomarkers with higher specificity than compositional profiling. In this work, N-glycans released from human serum were neutralized with methylamine and reduced by ammonia-borane complex prior to profiling using nanoLC-ESI-MS with porous graphitized carbon (PGC) and relative abundances of over 280 isomers were compared between pancreatic cancer (PC) cases (n = 32) and healthy controls (n = 32). Statistical analysis identified 25 specific-isomeric biomarkers with significant differences (p-value < 0.05). ROC and PCA analysis were performed to assess the potential biomarkers which were identified as being significantly altered in cancer. The AUCs of the significantly changed specific-isomers were ranging from 0.712 to 0.949. In addition, with the combination of all potential biomarkers, a higher AUC of 0.976 with sensitivity (93.5%) and specificity (90.6%) was obtained. Overall, the proposed strategy coupled to relative quantitative analysis of isomeric glycans make it possible to discover new biomarkers for the diagnosis of PC. Pancreatic cancer (PC) has a poor prognosis with a five-year survival rate <5%. Therefore, a strategy for accurate diagnosis of PC is indeed required. In this paper, a dual-derivatized strategy for structure-specific glycan profiling has been used and according to our best knowledge, this is the first application of this strategy for PC biomarker discovery, in which the separation, identification and relative quantification of isomeric glycans can be simultaneously obtained. In addition, by in-depth analysis of isomeric glycans, the full description of the stereo- and region- diversity of glycans can also be achieved, which might provide more potential information for PC biomarker discovery. Copyright © 2018 Elsevier B.V. All rights reserved.

The Vildagliptin Experience - 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration.

PubMed

Foley, James E; Ahrén, Bo

2017-08-01

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

View of the mission control center during STS 51-I

NASA Image and Video Library

1985-08-27

51I-S-189 (27 Aug 1985) --- View of the mission control center (MCC) during STS 51-I as flight controllers watch monitors at consoles to follow the extravehicular activity of two of the Discovery's astronauts.

Environmental Control and Life Support Systems and Power Systems ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Environmental Control and Life Support Systems and Power Systems - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

PubMed Central

Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

2009-01-01

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

How to revive breakthrough innovation in the pharmaceutical industry.

PubMed

Munos, Bernard H; Chin, William W

2011-06-29

Over the past 20 years, pharmaceutical companies have implemented conservative management practices to improve the predictability of therapeutics discovery and success rates of drug candidates. This approach has often yielded compounds that are only marginally better than existing therapies, yet require larger, longer, and more complex trials. To fund them, companies have shifted resources away from drug discovery to late clinical development; this has hurt innovation and amplified the crisis brought by the expiration of patents on many best-selling drugs. Here, we argue that more breakthrough therapeutics will reach patients only if the industry ceases to pursue "safe" incremental innovation, re-engages in high-risk discovery research, and adopts collaborative innovation models that allow sharing of knowledge and costs among collaborators.

37 CFR 351.5 - Discovery in royalty rate proceedings.

Code of Federal Regulations, 2010 CFR

2010-07-01

... proceedings. 351.5 Section 351.5 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF... matter, not privileged, that is relevant to the claim or defense of any party. Relevant information need... information and materials. (1) In any royalty rate proceeding scheduled to commence prior to January 1, 2011...

STS-39 OV-103 reaction control system (RCS) jets fire during onorbit maneuver

NASA Image and Video Library

1991-05-06

STS039-27-016 (28 April-6 May 1991) --- The Space Shuttle Discovery fires reaction control subsystem (RCS) thrusters in this 35mm frame, taken from inside the crew cabin. Seen in Discovery's payload bay are the tops of cannisters on the STP-1 payload, configured on the STS 39 Hitchhiker carrier; and the Air Force Program (AFP) 675 package. AFP-675 consists of the Cryogenic Infrared Radiance Instrumentation for Shuttle (CIRRIS)-1A; Far Ultraviolet Camera (FAR-UV) Experiment; Horizon Ultraviolet Program (HUP); Quadruple Ion Neutral Mass Spectrometer (QINMS); and the Uniformly Redundant Array (URA).

Improving the quality of biomarker discovery research: the right samples and enough of them.

PubMed

Pepe, Margaret S; Li, Christopher I; Feng, Ziding

2015-06-01

Biomarker discovery research has yielded few biomarkers that validate for clinical use. A contributing factor may be poor study designs. The goal in discovery research is to identify a subset of potentially useful markers from a large set of candidates assayed on case and control samples. We recommend the PRoBE design for selecting samples. We propose sample size calculations that require specifying: (i) a definition for biomarker performance; (ii) the proportion of useful markers the study should identify (Discovery Power); and (iii) the tolerable number of useless markers amongst those identified (False Leads Expected, FLE). We apply the methodology to a study of 9,000 candidate biomarkers for risk of colon cancer recurrence where a useful biomarker has positive predictive value ≥ 30%. We find that 40 patients with recurrence and 160 without recurrence suffice to filter out 98% of useless markers (2% FLE) while identifying 95% of useful biomarkers (95% Discovery Power). Alternative methods for sample size calculation required more assumptions. Biomarker discovery research should utilize quality biospecimen repositories and include sample sizes that enable markers meeting prespecified performance characteristics for well-defined clinical applications to be identified. The scientific rigor of discovery research should be improved. ©2015 American Association for Cancer Research.

Polymorphisms in CARS are associated with gastric cancer risk: a two-stage case-control study in the Chinese population.

PubMed

Tian, Tian; Xiao, Ling; Du, Jiangbo; Zhu, Xun; Gu, Yayun; Qin, Na; Yan, Caiwang; Liu, Li; Ma, Hongxia; Jiang, Yue; Chen, Jiaping; Yu, Hao; Dai, Juncheng

2017-11-01

The cysteinyl transfer RNA synthetase gene (CARS) is located on chromosome band 11p15.5, which is an important tumor-suppressor gene region. Mutations in CARS have been identified in many kinds of cancers; however, evidence for a relationship between genetic variants in CARS and gastric cancer at the population level is still lacking. Thus, we explored the association of variants in CARS with gastric cancer using a two-stage case-control strategy in Chinese. We undertook a two-stage case-control study to investigate the association between polymorphisms in CARS and risk of gastric cancer with use of an Illumina Infinium ® BeadChip and an ABI 7900 system. Four single nucleotide polymorphisms (SNPs) were significantly associated with gastric cancer risk in both the discovery stage and the validation stage after adjustment for age and sex. In addition, the combined results of the two stages showed these SNPs were related to gastric cancer risk (P false discovery rate  ≤ 0.001 for rs384,490, rs729662, rs2071101, and rs7394702). In silico analyses revealed that rs384490 and rs7394702 could affect transcription factor response elements or DNA methylation of CARS, and rs729662 was associated with the prognosis of gastric cancer. Additionally, expression quantitative trait loci analysis showed rs384490 and rs729662 might alter expression of CARS-related genes. The potential functional SNPs in CARS might influence the biological functions of CARS or CARS-related genes and ultimately modify the occurrence and development of gastric cancer in Chinese. Further large-scale population-based studies or biological functional assays are warranted to validate our findings.

On the history of the solar wind discovery

NASA Astrophysics Data System (ADS)

Obridko, V. N.; Vaisberg, O. L.

2017-03-01

The discovery of the solar wind has been an outstanding achievement in heliophysics and space physics. The solar wind plays a crucial role in the processes taking place in the Solar System. In recent decades, it has been recognized as the main factor that controls the terrestrial effects of space weather. The solar wind is an unusual plasma laboratory of giant scale with a fantastic diversity of parameters and operating modes, and devoid of influence from the walls of laboratory plasma systems. It is also the only kind of stellar wind accessible for direct study. The history of this discovery is quite dramatic. Like many remarkable discoveries, it had several predecessors. However, the honor of a discovery usually belongs to a scientist who was able to more fully explain the phenomenon. Such a man is deservedly considered the US theorist Eugene Parker, who discovered the solar wind, as we know it today, almost "with the point of his pen". In 2017, we will celebrate the 90th anniversary birthday of Eugene Parker.

Discovery and development of new antibacterial drugs: learning from experience?

PubMed

Jackson, Nicole; Czaplewski, Lloyd; Piddock, Laura J V

2018-06-01

Antibiotic (antibacterial) resistance is a serious global problem and the need for new treatments is urgent. The current antibiotic discovery model is not delivering new agents at a rate that is sufficient to combat present levels of antibiotic resistance. This has led to fears of the arrival of a 'post-antibiotic era'. Scientific difficulties, an unfavourable regulatory climate, multiple company mergers and the low financial returns associated with antibiotic drug development have led to the withdrawal of many pharmaceutical companies from the field. The regulatory climate has now begun to improve, but major scientific hurdles still impede the discovery and development of novel antibacterial agents. To facilitate discovery activities there must be increased understanding of the scientific problems experienced by pharmaceutical companies. This must be coupled with addressing the current antibiotic resistance crisis so that compounds and ultimately drugs are delivered to treat the most urgent clinical challenges. By understanding the causes of the failures and successes of the pharmaceutical industry's research history, duplication of discovery programmes will be reduced, increasing the productivity of the antibiotic drug discovery pipeline by academia and small companies. The most important scientific issues to address are getting molecules into the Gram-negative bacterial cell and avoiding their efflux. Hence screening programmes should focus their efforts on whole bacterial cells rather than cell-free systems. Despite falling out of favour with pharmaceutical companies, natural product research still holds promise for providing new molecules as a basis for discovery.

Discovery of Novel Mammary Developmental and Cancer Genes Using ENU Mutagenesis

DTIC Science & Technology

2002-10-01

death rates we need new therapeutic targets, currently a major challenge facing cancer researchers This requires an understanding of the undiscovered pathways that operate to drive breast cancer cell proliferation, cell survival and cell differentiation, pathways which are also likely to operate during normal mammary development, and which go awry in cancer The discovery of signalling pathways operative in breast cancer has utilised examination of mammary gland development following systemic endocrine ablation or viral insertion, positional cloning in affected families and

Single nucleotide polymorphism discovery in rainbow trout by deep sequencing of a reduced representation library.

PubMed

Sánchez, Cecilia Castaño; Smith, Timothy P L; Wiedmann, Ralph T; Vallejo, Roger L; Salem, Mohamed; Yao, Jianbo; Rexroad, Caird E

2009-11-25

To enhance capabilities for genomic analyses in rainbow trout, such as genomic selection, a large suite of polymorphic markers that are amenable to high-throughput genotyping protocols must be identified. Expressed Sequence Tags (ESTs) have been used for single nucleotide polymorphism (SNP) discovery in salmonids. In those strategies, the salmonid semi-tetraploid genomes often led to assemblies of paralogous sequences and therefore resulted in a high rate of false positive SNP identification. Sequencing genomic DNA using primers identified from ESTs proved to be an effective but time consuming methodology of SNP identification in rainbow trout, therefore not suitable for high throughput SNP discovery. In this study, we employed a high-throughput strategy that used pyrosequencing technology to generate data from a reduced representation library constructed with genomic DNA pooled from 96 unrelated rainbow trout that represent the National Center for Cool and Cold Water Aquaculture (NCCCWA) broodstock population. The reduced representation library consisted of 440 bp fragments resulting from complete digestion with the restriction enzyme HaeIII; sequencing produced 2,000,000 reads providing an average 6 fold coverage of the estimated 150,000 unique genomic restriction fragments (300,000 fragment ends). Three independent data analyses identified 22,022 to 47,128 putative SNPs on 13,140 to 24,627 independent contigs. A set of 384 putative SNPs, randomly selected from the sets produced by the three analyses were genotyped on individual fish to determine the validation rate of putative SNPs among analyses, distinguish apparent SNPs that actually represent paralogous loci in the tetraploid genome, examine Mendelian segregation, and place the validated SNPs on the rainbow trout linkage map. Approximately 48% (183) of the putative SNPs were validated; 167 markers were successfully incorporated into the rainbow trout linkage map. In addition, 2% of the sequences from the validated markers were associated with rainbow trout transcripts. The use of reduced representation libraries and pyrosequencing technology proved to be an effective strategy for the discovery of a high number of putative SNPs in rainbow trout; however, modifications to the technique to decrease the false discovery rate resulting from the evolutionary recent genome duplication would be desirable.

Reduced DNA methylation and psychopathology following endogenous hypercortisolism - a genome-wide study.

PubMed

Glad, Camilla A M; Andersson-Assarsson, Johanna C; Berglund, Peter; Bergthorsdottir, Ragnhildur; Ragnarsson, Oskar; Johannsson, Gudmundur

2017-03-16

Patients with Cushing's Syndrome (CS) in remission were used as a model to test the hypothesis that long-standing excessive cortisol exposure induces changes in DNA methylation that are associated with persisting neuropsychological consequences. Genome-wide DNA methylation was assessed in 48 women with CS in long-term remission (cases) and 16 controls matched for age, gender and education. The Fatigue impact scale and the comprehensive psychopathological rating scale were used to evaluate fatigue, depression and anxiety. Cases had lower average global DNA methylation than controls (81.2% vs 82.7%; p = 0.002). Four hundred and sixty-one differentially methylated regions, containing 3,246 probes mapping to 337 genes were identified. After adjustment for age and smoking, 731 probes in 236 genes were associated with psychopathology (fatigue, depression and/or anxiety). Twenty-four gene ontology terms were associated with psychopathology; terms related to retinoic acid receptor signalling were the most common (adjusted p = 0.0007). One gene in particular, COL11A2, was associated with fatigue following a false discovery rate correction. Our findings indicate that hypomethylation of FKBP5 and retinoic acid receptor related genes serve a potential mechanistic explanation for long-lasting GC-induced psychopathology.

Studies of a Next-Generation Silicon-Photomultiplier-Based Time-of-Flight PET/CT System.

PubMed

Hsu, David F C; Ilan, Ezgi; Peterson, William T; Uribe, Jorge; Lubberink, Mark; Levin, Craig S

2017-09-01

This article presents system performance studies for the Discovery MI PET/CT system, a new time-of-flight system based on silicon photomultipliers. System performance and clinical imaging were compared between this next-generation system and other commercially available PET/CT and PET/MR systems, as well as between different reconstruction algorithms. Methods: Spatial resolution, sensitivity, noise-equivalent counting rate, scatter fraction, counting rate accuracy, and image quality were characterized with the National Electrical Manufacturers Association NU-2 2012 standards. Energy resolution and coincidence time resolution were measured. Tests were conducted independently on two Discovery MI scanners installed at Stanford University and Uppsala University, and the results were averaged. Back-to-back patient scans were also performed between the Discovery MI, Discovery 690 PET/CT, and SIGNA PET/MR systems. Clinical images were reconstructed using both ordered-subset expectation maximization and Q.Clear (block-sequential regularized expectation maximization with point-spread function modeling) and were examined qualitatively. Results: The averaged full widths at half maximum (FWHMs) of the radial/tangential/axial spatial resolution reconstructed with filtered backprojection at 1, 10, and 20 cm from the system center were, respectively, 4.10/4.19/4.48 mm, 5.47/4.49/6.01 mm, and 7.53/4.90/6.10 mm. The averaged sensitivity was 13.7 cps/kBq at the center of the field of view. The averaged peak noise-equivalent counting rate was 193.4 kcps at 21.9 kBq/mL, with a scatter fraction of 40.6%. The averaged contrast recovery coefficients for the image-quality phantom were 53.7, 64.0, 73.1, 82.7, 86.8, and 90.7 for the 10-, 13-, 17-, 22-, 28-, and 37-mm-diameter spheres, respectively. The average photopeak energy resolution was 9.40% FWHM, and the average coincidence time resolution was 375.4 ps FWHM. Clinical image comparisons between the PET/CT systems demonstrated the high quality of the Discovery MI. Comparisons between the Discovery MI and SIGNA showed a similar spatial resolution and overall imaging performance. Lastly, the results indicated significantly enhanced image quality and contrast-to-noise performance for Q.Clear, compared with ordered-subset expectation maximization. Conclusion: Excellent performance was achieved with the Discovery MI, including 375 ps FWHM coincidence time resolution and sensitivity of 14 cps/kBq. Comparisons between reconstruction algorithms and other multimodal silicon photomultiplier and non-silicon photomultiplier PET detector system designs indicated that performance can be substantially enhanced with this next-generation system. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Unconfirmed Near-Earth Objects

NASA Astrophysics Data System (ADS)

Vereš, Peter; Payne, Matthew J.; Holman, Matthew J.; Farnocchia, Davide; Williams, Gareth V.; Keys, Sonia; Boardman, Ian

2018-07-01

We studied the Near-Earth Asteroid (NEA) candidates posted on the Minor Planet Center’s Near-Earth Object Confirmation Page (NEOCP) between years 2013 and 2016. Out of more than 17000 NEA candidates, while the majority became either new discoveries or were associated with previously known objects, about 11% were unable to be followed-up or confirmed. We further demonstrate that of the unconfirmed candidates, 926 ± 50 are likely to be NEAs, representing 18% of discovered NEAs in that period. Only 11% (∼93) of the unconfirmed NEA candidates were large (having absolute magnitude H < 22). To identify the reasons why these NEAs were not recovered, we analyzed those from the most prolific asteroid surveys: Pan-STARRS, the Catalina Sky Survey, the Dark Energy Survey, and the Space Surveillance Telescope. We examined the influence of plane-of-sky positions and rates of motion, brightnesses, submission delays, and computed absolute magnitudes, as well as correlations with the phase of the moon and seasonal effects. We find that delayed submission of newly discovered NEA candidate to the NEOCP drove a large fraction of the unconfirmed NEA candidates. A high rate of motion was another significant contributing factor. We suggest that prompt submission of suspected NEA discoveries and rapid response to fast-moving targets and targets with fast growing ephemeris uncertainty would allow better coordination among dedicated follow-up observers, decrease the number of unconfirmed NEA candidates, and increase the discovery rate of NEAs.

Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening

PubMed Central

2017-01-01

Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior. Monte Carlo screening simulation data showed that increasing mean library sampling (ε), mean droplet occupancy, or library hit rate all increase the false discovery rate (FDR). Compounds identified as hits on k > 1 beads (the replicate k class) were much more likely to be authentic hits than singletons (k = 1), in agreement with previous findings. Here, we explain this observation by deriving an equation for authenticity, which reduces to the product of a library sampling bias term (exponential in k) and a sampling saturation term (exponential in ε) setting a threshold that the k-dependent bias must overcome. The equation thus quantitatively describes why each hit structure’s FDR is based on its k class, and further predicts the feasibility of intentionally populating droplets with multiple library beads, assaying the micromixtures for function, and identifying the active members by statistical deconvolution. PMID:28682059

View of Mission Control Center during the Apollo 13 oxygen cell failure

NASA Technical Reports Server (NTRS)

1970-01-01

Mrs. Mary Haise receives an explanation of the revised flight plan of the Apollo 13 mission from Astronaut Gerald P. Carr in the Viewing Room of Mission Control Center, bldg 30, Manned Spacecraft Center (MSC). Her husband, Astronaut Fred W. Haise Jr., was joining the fellow crew members in making corrections in their spacecraft following discovery of an oxygen cell failure several hours earlier (34900); Dr. Charles A. Berry, Director of Medical Research and Operations Directorate at MSC, converses with Mrs. Marilyn Lovell in the Viewing Room of Mission Control Center. Mrs. Lovell's husband, Astronaut James A. Lovell Jr., was busily making corrections inside the spacecraft following discovery of an oxygen cell failure several hours earlier (34901).

Natural-product-derived fragments for fragment-based ligand discovery

NASA Astrophysics Data System (ADS)

Over, Björn; Wetzel, Stefan; Grütter, Christian; Nakai, Yasushi; Renner, Steffen; Rauh, Daniel; Waldmann, Herbert

2013-01-01

Fragment-based ligand and drug discovery predominantly employs sp2-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

Organic synthesis provides opportunities to transform drug discovery

NASA Astrophysics Data System (ADS)

Blakemore, David C.; Castro, Luis; Churcher, Ian; Rees, David C.; Thomas, Andrew W.; Wilson, David M.; Wood, Anthony

2018-04-01

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Yield of the RYR2 Genetic Test in Suspected Catecholaminergic Polymorphic Ventricular Tachycardia and Implications for Test Interpretation.

PubMed

Kapplinger, Jamie D; Pundi, Krishna N; Larson, Nicholas B; Callis, Thomas E; Tester, David J; Bikker, Hennie; Wilde, Arthur A M; Ackerman, Michael J

2018-02-01

Pathogenic RYR2 variants account for ≈60% of clinically definite cases of catecholaminergic polymorphic ventricular tachycardia. However, the rate of rare benign RYR2 variants identified in the general population remains a challenge for genetic test interpretation. Therefore, we examined the results of the RYR2 genetic test among patients referred for commercial genetic testing and examined factors impacting variant interpretability. Frequency and location comparisons were made for RYR2 variants identified among 1355 total patients of varying clinical certainty and 60 706 Exome Aggregation Consortium controls. The impact of the clinical phenotype on the yield of RYR2 variants was examined. Six in silico tools were assessed using patient- and control-derived variants. A total of 18.2% (218/1200) of patients referred for commercial testing hosted rare RYR2 variants, statistically less than the 59% (46/78) yield among clinically definite cases, resulting in a much higher potential genetic false discovery rate among referrals considering the 3.2% background rate of rare, benign RYR2 variants. Exclusion of clearly putative pathogenic variants further complicates the interpretation of the next novel RYR2 variant. Exonic/topologic analyses revealed overrepresentation of patient variants in exons covering only one third of the protein. In silico tools largely failed to show evidence toward enhancement of variant interpretation. Current expert recommendations have resulted in increased use of RYR2 genetic testing in patients with questionable clinical phenotypes. Using the largest to date catecholaminergic polymorphic ventricular tachycardia patient versus control comparison, this study highlights important variables in the interpretation of variants to overcome the 3.2% background rate that confounds RYR2 variant interpretation. © 2018 American Heart Association, Inc.

STS-26 MS Nelson adjusts ADSF power cable on Discovery's middeck

NASA Technical Reports Server (NTRS)

1988-01-01

STS-26 Mission Specialist (MS) George D. Nelson adjusts power cable on automated directional solidification furnace (ADSF) support electronics package. ADSF is located in forward (starboard side) lockers on Discovery's, Orbiter Vehicle (OV) 103's, middeck. ADSF consists of the furnace container (left) and the control electronics container (right). An Air National Guard, Houston, Texas, decal appears on middeck locker above ADSF.

Synthesis of (±)-amathaspiramide F and discovery of an unusual stereocontrolling element for the [2,3]-Stevens rearrangement.

PubMed

Soheili, Arash; Tambar, Uttam K

2013-10-04

A formal total synthesis of (±)-amathaspiramide F through a tandem palladium-catalyzed allylic amination/[2,3]-Stevens rearrangement is reported. The unexpected diastereoselectivity of the [2,3]-Stevens rearrangement was controlled by the substitution patterns of an aromatic ring. This discovery represents a new stereocontrolling element for [2,3]-sigmatropic rearrangements in complex molecular settings.

Oblique view at ground level looking at the aft and ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Oblique view at ground level looking at the aft and port side of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note that the Orbiter Maneuvering System/Reaction Control System pods and the Shuttle Main Engines are removed in this image. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup view of the aft flight deck of the Orbiter ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the aft flight deck of the Orbiter Discovery looking at the aft center control panels A6, A7, A8, A12, A13, A14, A16 and A17. This View was taken at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-04pd0459

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility help move the body flap into position on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0461

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - A worker on a ladder (lower left) observes installation of the body flap onto the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0462

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - Workers on ladders (left and right) check installation of the body flap onto the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0452

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the body flap for the orbiter Discovery is prepared for installation. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04PD-0462

NASA Technical Reports Server (NTRS)

2004-01-01

KENNEDY SPACE CENTER, FLA. Workers on ladders (left and right) check installation of the body flap onto the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

Observed oil and gas field size distributions: A consequence of the discovery process and prices of oil and gas

USGS Publications Warehouse

Drew, L.J.; Attanasi, E.D.; Schuenemeyer, J.H.

1988-01-01

If observed oil and gas field size distributions are obtained by random samplings, the fitted distributions should approximate that of the parent population of oil and gas fields. However, empirical evidence strongly suggests that larger fields tend to be discovered earlier in the discovery process than they would be by random sampling. Economic factors also can limit the number of small fields that are developed and reported. This paper examines observed size distributions in state and federal waters of offshore Texas. Results of the analysis demonstrate how the shape of the observable size distributions change with significant hydrocarbon price changes. Comparison of state and federal observed size distributions in the offshore area shows how production cost differences also affect the shape of the observed size distribution. Methods for modifying the discovery rate estimation procedures when economic factors significantly affect the discovery sequence are presented. A primary conclusion of the analysis is that, because hydrocarbon price changes can significantly affect the observed discovery size distribution, one should not be confident about inferring the form and specific parameters of the parent field size distribution from the observed distributions. ?? 1988 International Association for Mathematical Geology.

Apparently low reproducibility of true differential expression discoveries in microarray studies.

PubMed

Zhang, Min; Yao, Chen; Guo, Zheng; Zou, Jinfeng; Zhang, Lin; Xiao, Hui; Wang, Dong; Yang, Da; Gong, Xue; Zhu, Jing; Li, Yanhui; Li, Xia

2008-09-15

Differentially expressed gene (DEG) lists detected from different microarray studies for a same disease are often highly inconsistent. Even in technical replicate tests using identical samples, DEG detection still shows very low reproducibility. It is often believed that current small microarray studies will largely introduce false discoveries. Based on a statistical model, we show that even in technical replicate tests using identical samples, it is highly likely that the selected DEG lists will be very inconsistent in the presence of small measurement variations. Therefore, the apparently low reproducibility of DEG detection from current technical replicate tests does not indicate low quality of microarray technology. We also demonstrate that heterogeneous biological variations existing in real cancer data will further reduce the overall reproducibility of DEG detection. Nevertheless, in small subsamples from both simulated and real data, the actual false discovery rate (FDR) for each DEG list tends to be low, suggesting that each separately determined list may comprise mostly true DEGs. Rather than simply counting the overlaps of the discovery lists from different studies for a complex disease, novel metrics are needed for evaluating the reproducibility of discoveries characterized with correlated molecular changes. Supplementaty information: Supplementary data are available at Bioinformatics online.

FDR doesn't Tell the Whole Story: Joint Influence of Effect Size and Covariance Structure on the Distribution of the False Discovery Proportions

NASA Technical Reports Server (NTRS)

Feiveson, Alan H.; Ploutz-Snyder, Robert; Fiedler, James

2011-01-01

As part of a 2009 Annals of Statistics paper, Gavrilov, Benjamini, and Sarkar report results of simulations that estimated the false discovery rate (FDR) for equally correlated test statistics using a well-known multiple-test procedure. In our study we estimate the distribution of the false discovery proportion (FDP) for the same procedure under a variety of correlation structures among multiple dependent variables in a MANOVA context. Specifically, we study the mean (the FDR), skewness, kurtosis, and percentiles of the FDP distribution in the case of multiple comparisons that give rise to correlated non-central t-statistics when results at several time periods are being compared to baseline. Even if the FDR achieves its nominal value, other aspects of the distribution of the FDP depend on the interaction between signed effect sizes and correlations among variables, proportion of true nulls, and number of dependent variables. We show examples where the mean FDP (the FDR) is 10% as designed, yet there is a surprising probability of having 30% or more false discoveries. Thus, in a real experiment, the proportion of false discoveries could be quite different from the stipulated FDR.

Fire Control and Human Evolution.

ERIC Educational Resources Information Center

Russell, Claire

1978-01-01

Briefly outlines some aspects of the discovery of fire control by primitive people, such as the preadaptation for speech, the evolution of the human brain, and natural selection for human nakedness or loss of hair. (CS)

KSC-2010-4453

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This orbiter tribute of space shuttle Discovery, or OV-103, hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo

Julian Davies and the discovery of kanamycin resistance transposon Tn5.

PubMed

Berg, Douglas E

2017-04-01

This paper recounts some of my fond memories of a collaboration between Julian Davies and myself that started in 1974 in Geneva and that led to our serendipitous discovery of the bacterial kanamycin resistance transposon Tn5, and aspects of the lasting positive impact of our interaction and discovery on me and the community. Tn5 was one of the first antibiotic resistance transposons to be found. Its analysis over the ensuing decades provided valuable insights into mechanisms and control of transposition, and led to its use as a much-valued tool in diverse areas of molecular genetics, as also will be discussed here.

KSC01padig259

NASA Image and Video Library

2001-08-08

KENNEDY SPACE CENTER, Fla. -- On Launch Pad 39a, the Rotating Service Structure rolls back from around Space Shuttle Discovery in preparation for launch on mission STS-105. On the mission, Discovery will be transporting the Expedition Three crew and several payloads and scientific experiments to the ISS, including the Early Ammonia Servicer (EAS) tank. The EAS, which will support the thermal control subsystems until a permanent system is activated, will be attached to the Station during two spacewalks. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station. Launch is scheduled for 5:38 p.m. EDT Aug. 9

KSC-01pp1413

NASA Image and Video Library

2001-08-05

KENNEDY SPACE CENTER, Fla. -- STS-105 Commander Scott Horowitz arrives at KSC aboard a T-38 jet to make final preparations for launch. On mission STS-105, Discovery will be transporting the Expedition Three crew and several payloads and scientific experiments to the International Space Station. The Early Ammonia Servicer (EAS) tank, which will support the thermal control subsystems until a permanent system is activated, will be attached to the Station during two spacewalks. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station. Launch of Discovery on mission STS-105 is scheduled for Aug. 9, 2001

KSC-2009-2103

NASA Image and Video Library

2009-03-15

CAPE CANAVERAL, Fla. – In Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida, Center Director Bob Cabana (with microphone) congratulates the mission management team after the successful launch of space shuttle Discovery on the STS-119 mission. Launch was on time at 7:43 p.m. EDT. The STS-119 mission is the 28th to the space station and Discovery's 36th flight. Discovery will deliver the final pair of power-generating solar array wings and the S6 truss segment. Installation of S6 will signal the station's readiness to house a six-member crew for conducting increased science. Photo credit: NASA/Kim Shiflett

KSC-2011-1044

NASA Image and Video Library

2011-01-07

CAPE CANAVERAL, Fla. -- In the Launch Control Center at NASA's Kennedy Space Center in Florida, Bart Pannullo, the vehicle processing engineer for space shuttle Discovery, sits at his console in Firing Room 4 along with other STS-133 launch team members to rehearse procedures for the liftoff of Discovery's final mission. The team at Kennedy also participated in launch simulations with personnel at NASA's Johnson Space Center in Houston. Discovery's next launch opportunity to the International Space Station on the STS-133 mission is planned for no earlier than Feb. 24. For more information on STS-133, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Kim Shiflett

Transfer of the MPLM Leonardo from the ISS to the Orbiter Discovery Payload Bay

NASA Image and Video Library

2006-07-14

ISS013-E-51263 (14 July 2006) --- Canadarm2 or the Space Station Remote Manipulator System (SSRMS) arm grasps the Italian-built Multi-Purpose Logistics Module Leonardo to place it back in Discovery's cargo bay. On the other end of the arm, inside the shirt sleeve environment of the Destiny laboratory on the International Space Station, astronauts Stephanie D. Wilson and Lisa M. Nowak, STS-121 mission specialists, were in control of the transfer. The MPLM was being moved from its temporary parking place on the station's Unity node to the payload bay of Discovery for the return trip to Earth.

Transfer of the MPLM Leonardo from the ISS to the Orbiter Discovery Payload Bay

NASA Image and Video Library

2006-07-14

ISS013-E-51264 (14 July 2006) --- Canadarm2 or the Space Station Remote Manipulator System (SSRMS) arm grasps the Italian-built Multi-Purpose Logistics Module Leonardo to place it back in Discovery's cargo bay. On the other end of the arm, inside the shirt sleeve environment of the Destiny laboratory on the International Space Station, astronauts Stephanie D. Wilson and Lisa M. Nowak, STS-121 mission specialists, were in control of the transfer. The MPLM was being moved from its temporary parking place on the station's Unity node to the payload bay of Discovery for the return trip to Earth.

Transfer of the MPLM Leonardo from the ISS to the Orbiter Discovery Payload Bay

NASA Image and Video Library

2006-07-14

ISS013-E-51265 (14 July 2006) --- Canadarm2 or the Space Station Remote Manipulator System (SSRMS) arm (out of frame) grasps the Italian-built Multi-Purpose Logistics Module Leonardo to place it back in Discovery's cargo bay. On the other end of the arm, inside the shirt sleeve environment of the Destiny laboratory on the International Space Station, astronauts Stephanie D. Wilson and Lisa M. Nowak, STS-121 mission specialists, were in control of the transfer. The MPLM was being moved from its temporary parking place on the station's Unity node to the payload bay of Discovery for the return trip to Earth.

Flight Control Using Distributed Shape-Change Effector Arrays

NASA Technical Reports Server (NTRS)

Raney, David L.; Montgomery, Raymond C.; Green, Lawrence I.; Park, Michael A.

2000-01-01

Recent discoveries in material science and fluidics have been used to create a variety of novel effector devices that offer great potential to enable new approaches to aerospace vehicle flight control. Examples include small inflatable blisters, shape-memory alloy diaphragms, and piezoelectric patches that may be used to produce distortions or bumps on the surface of an airfoil to generate control moments. Small jets have also been used to produce a virtual shape-change through fluidic means by creating a recirculation bubble on the surface of an airfoil. An advanced aerospace vehicle might use distributed arrays of hundreds of such devices to generate moments for stabilization and maneuver control, either augmenting or replacing conventional ailerons, flaps or rudders. This research demonstrates the design and use of shape-change device arrays for a tailless aircraft in a low-rate maneuvering application. A methodology for assessing the control authority of the device arrays is described, and a suite of arrays is used in a dynamic simulation to illustrate allocation and deployment methodologies. Although the authority of the preliminary shape-change array designs studied in this paper appeared quite low, the simulation results indicate that the effector suite possessed sufficient authority to stabilize and maneuver the vehicle in mild turbulence.

Hydrogen storage materials discovery via high throughput ball milling and gas sorption.

PubMed

Li, Bin; Kaye, Steven S; Riley, Conor; Greenberg, Doron; Galang, Daniel; Bailey, Mark S

2012-06-11

The lack of a high capacity hydrogen storage material is a major barrier to the implementation of the hydrogen economy. To accelerate discovery of such materials, we have developed a high-throughput workflow for screening of hydrogen storage materials in which candidate materials are synthesized and characterized via highly parallel ball mills and volumetric gas sorption instruments, respectively. The workflow was used to identify mixed imides with significantly enhanced absorption rates relative to Li2Mg(NH)2. The most promising material, 2LiNH2:MgH2 + 5 atom % LiBH4 + 0.5 atom % La, exhibits the best balance of absorption rate, capacity, and cycle-life, absorbing >4 wt % H2 in 1 h at 120 °C after 11 absorption-desorption cycles.

Discovery and Orbital Determination of the Transient X-Ray Pulsar GRO J1750-27

NASA Technical Reports Server (NTRS)

Scott, D. M.; Finger, M. H.; Wilson, R. B.; Koh, D. T.; Prince, T. A.; Vaughan, B. A.; Chakrabarty, D.

1997-01-01

We report on the discovery and hard X-ray (20 - 70 keV) observations of the 4.45 s period transient X-ray pulsar GRO J1750-27 with the BATSE all-sky monitor on board CGRO. A relatively faint out- burst (less than 30 mcrab peak) lasting at least 60 days was observed during which the spin-up rate peaked at 38 pHz/s and was correlated with the pulsed intensity. An orbit with a period of 29.8 days was found. The large spin-up rate, spin period, and orbital period together suggest that accretion is occurring from a disk and that the outburst is a "giant" outburst typical of a Be/X-ray transient system. No optical counterpart has yet been reported.

Discovery and Orbital Determination of the Transient X-Ray Pulsar GRO J1750-27

NASA Technical Reports Server (NTRS)

Scott, D. M.; Finger, M. H.; Wilson, R. B.; Koh, D. T.; Prince, T. A.; Vaughan, B. A.; Chakrabarty, D.

1997-01-01

We report on the discovery and hard X-ray (20-70 keV) observations of the 4.45 second period transient X-ray pulsar GRO J1750-27 with the BATSE all-sky monitor on board CCRO. A relatively faint outburst (< 30 mCrab peak) lasting at least 60 days was observed during which the spin-up rate peaked at 38 pHz/sec and was correlated with the pulsed intensity. An orbit with a period of 29.8 days was found. The large spin-up rate, spin period and orbital period together suggest that accretion is occurring from a disk and that the outburst is a 'giant' outburst typical of a Be/X-ray transient system. No optical counterpart has been reported yet.

Financing drug discovery for orphan diseases.

PubMed

Fagnan, David E; Gromatzky, Austin A; Stein, Roger M; Fernandez, Jose-Maria; Lo, Andrew W

2014-05-01

Recently proposed 'megafund' financing methods for funding translational medicine and drug development require billions of dollars in capital per megafund to de-risk the drug discovery process enough to issue long-term bonds. Here, we demonstrate that the same financing methods can be applied to orphan drug development but, because of the unique nature of orphan diseases and therapeutics (lower development costs, faster FDA approval times, lower failure rates and lower correlation of failures among disease targets) the amount of capital needed to de-risk such portfolios is much lower in this field. Numerical simulations suggest that an orphan disease megafund of only US$575 million can yield double-digit expected rates of return with only 10-20 projects in the portfolio. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Two Long-Term Intermittent Pulsars Discovered in the PALFA Survey

NASA Astrophysics Data System (ADS)

Lyne, A. G.; Stappers, B. W.; Freire, P. C. C.; Hessels, J. W. T.; Kaspi, V. M.; Allen, B.; Bogdanov, S.; Brazier, A.; Camilo, F.; Cardoso, F.; Chatterjee, S.; Cordes, J. M.; Crawford, F.; Deneva, J. S.; Ferdman, R. D.; Jenet, F. A.; Knispel, B.; Lazarus, P.; van Leeuwen, J.; Lynch, R.; Madsen, E.; McLaughlin, M. A.; Parent, E.; Patel, C.; Ransom, S. M.; Scholz, P.; Seymour, A.; Siemens, X.; Spitler, L. G.; Stairs, I. H.; Stovall, K.; Swiggum, J.; Wharton, R. S.; Zhu, W. W.

2017-01-01

We report the discovery of two long-term intermittent radio pulsars in the ongoing Pulsar Arecibo L-Band Feed Array survey. Following discovery with the Arecibo Telescope, extended observations of these pulsars over several years at Jodrell Bank Observatory have revealed the details of their rotation and radiation properties. PSRs J1910+0517 and J1929+1357 show long-term extreme bimodal intermittency, switching between active (ON) and inactive (OFF) emission states and indicating the presence of a large, hitherto unrecognized underlying population of such objects. For PSR J1929+1357, the initial duty cycle was fON = 0.008, but two years later, this changed quite abruptly to fON = 0.16. This is the first time that a significant evolution in the activity of an intermittent pulsar has been seen, and we show that the spin-down rate of the pulsar is proportional to the activity. The spin-down rate of PSR J1929+1357 is increased by a factor of 1.8 when it is in active mode, similar to the increase seen in the other three known long-term intermittent pulsars. These discoveries increase the number of known pulsars displaying long-term intermittency to five. These five objects display a remarkably narrow range of spin-down power (\\dot{E} ˜ {10}32 {erg} {{{s}}}-1) and accelerating potential above their polar caps. If confirmed by further discoveries, this trend might be important for understanding the physical mechanisms that cause intermittency.

Novel proteins associated with risk for coronary heart disease or stroke among postmenopausal women identified by in-depth plasma proteome profiling

PubMed Central

2010-01-01

Background Coronary heart disease (CHD) and stroke were key outcomes in the Women's Health Initiative (WHI) randomized trials of postmenopausal estrogen and estrogen plus progestin therapy. We recently reported a large number of changes in blood protein concentrations in the first year following randomization in these trials using an in-depth quantitative proteomics approach. However, even though many affected proteins are in pathways relevant to the observed clinical effects, the relationships of these proteins to CHD and stroke risk among postmenopausal women remains substantially unknown. Methods The same in-depth proteomics platform was applied to plasma samples, obtained at enrollment in the WHI Observational Study, from 800 women who developed CHD and 800 women who developed stroke during cohort follow-up, and from 1-1 matched controls. A plasma pooling strategy, followed by extensive fractionation prior to mass spectrometry, was used to identify proteins related to disease incidence, and the overlap of these proteins with those affected by hormone therapy was examined. Replication studies, using enzyme-linked-immunosorbent assay (ELISA), were carried out in the WHI hormone therapy trial cohorts. Results Case versus control concentration differences were suggested for 37 proteins (nominal P < 0.05) for CHD, with three proteins, beta-2 microglobulin (B2M), alpha-1-acid glycoprotein 1 (ORM1), and insulin-like growth factor binding protein acid labile subunit (IGFALS) having a false discovery rate < 0.05. Corresponding numbers for stroke were 47 proteins with nominal P < 0.05, three of which, apolipoprotein A-II precursor (APOA2), peptidyl-prolyl isomerase A (PPIA), and insulin-like growth factor binding protein 4 (IGFBP4), have a false discovery rate < 0.05. Other proteins involved in insulin-like growth factor signaling were also highly ranked. The associations of B2M with CHD (P < 0.001) and IGFBP4 with stroke (P = 0.005) were confirmed using ELISA in replication studies, and changes in these proteins following the initiation of hormone therapy use were shown to have potential to help explain hormone therapy effects on those diseases. Conclusions In-depth proteomic discovery analysis of prediagnostic plasma samples identified B2M and IGFBP4 as risk markers for CHD and stroke respectively, and provided a number of candidate markers of disease risk and candidate mediators of hormone therapy effects on CHD and stroke. Clinical Trials Registration ClinicalTrials.gov identifier: NCT00000611 PMID:20667078

OGLE ATLAS OF CLASSICAL NOVAE. II. MAGELLANIC CLOUDS

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

Mróz, P.; Udalski, A.; Poleski, R.

2016-01-15

The population of classical novae in the Magellanic Clouds was poorly known because of a lack of systematic studies. There were some suggestions that nova rates per unit mass in the Magellanic Clouds were higher than in any other galaxy. Here, we present an analysis of data collected over 16 years by the OGLE survey with the aim of characterizing the nova population in the Clouds. We found 20 eruptions of novae, half of which are new discoveries. We robustly measure nova rates of 2.4 ± 0.8 yr{sup −1} (LMC) and 0.9 ± 0.4 yr{sup −1} (SMC) and confirm that the K-band luminosity-specific novamore » rates in both Clouds are 2–3 times higher than in other galaxies. This can be explained by the star formation history in the Magellanic Clouds, specifically the re-ignition of the star formation rate a few Gyr ago. We also present the discovery of the intriguing system OGLE-MBR133.25.1160, which mimics recurrent nova eruptions.« less

Reinforce: An Ensemble Approach for Inferring PPI Network from AP-MS Data.

PubMed

Tian, Bo; Duan, Qiong; Zhao, Can; Teng, Ben; He, Zengyou

2017-05-17

Affinity Purification-Mass Spectrometry (AP-MS) is one of the most important technologies for constructing protein-protein interaction (PPI) networks. In this paper, we propose an ensemble method, Reinforce, for inferring PPI network from AP-MS data set. The new algorithm named Reinforce is based on rank aggregation and false discovery rate control. Under the null hypothesis that the interaction scores from different scoring methods are randomly generated, Reinforce follows three steps to integrate multiple ranking results from different algorithms or different data sets. The experimental results show that Reinforce can get more stable and accurate inference results than existing algorithms. The source codes of Reinforce and data sets used in the experiments are available at: https://sourceforge.net/projects/reinforce/.

The Molecular Biology of Adenoid Cystic Carcinoma

PubMed Central

Liu, Jia; Shao, Chunbo; Tan, Marietta L.; Mu, David; Ferris, Robert L.; Ha, Patrick K.

2011-01-01

Background Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. Standard treatment, including surgery with postoperative radiation therapy have attained reasonable local control rates, but the propensity for distant metastases has limited any improvement in survival over time. Our understanding of the molecular mechanisms driving adenoid cystic carcinoma is quite rudimentary, due to the infrequent nature of its occurrence. Methods An extensive literature review was performed on salivary gland adenoid cystic carcinoma and basic science research findings. Results This review highlights many findings that are emerging about the carcinogenesis of ACC including cytogenetics, tumor suppressor genes, oncogenes, epigenetic alterations, mitochondrial alterations, and biomarker studies. Conclusions While there have been many discoveries, much still remains unknown about this rare malignancy. PMID:22006498

Building one molecule from a reservoir of two atoms

NASA Astrophysics Data System (ADS)

Liu, L. R.; Hood, J. D.; Yu, Y.; Zhang, J. T.; Hutzler, N. R.; Rosenband, T.; Ni, K.-K.

2018-05-01

Chemical reactions typically proceed via stochastic encounters between reactants. Going beyond this paradigm, we combined exactly two atoms in a single, controlled reaction. The experimental apparatus traps two individual laser-cooled atoms [one sodium (Na) and one cesium (Cs)] in separate optical tweezers and then merges them into one optical dipole trap. Subsequently, photoassociation forms an excited-state NaCs molecule. The discovery of previously unseen resonances near the molecular dissociation threshold and measurement of collision rates are enabled by the tightly trapped ultracold sample of atoms. As laser-cooling and trapping capabilities are extended to more elements, the technique will enable the study of more diverse, and eventually more complex, molecules in an isolated environment, as well as synthesis of designer molecules for qubits.

Big data in biomedicine.

PubMed

Costa, Fabricio F

2014-04-01

The increasing availability and growth rate of biomedical information, also known as 'big data', provides an opportunity for future personalized medicine programs that will significantly improve patient care. Recent advances in information technology (IT) applied to biomedicine are changing the landscape of privacy and personal information, with patients getting more control of their health information. Conceivably, big data analytics is already impacting health decisions and patient care; however, specific challenges need to be addressed to integrate current discoveries into medical practice. In this article, I will discuss the major breakthroughs achieved in combining omics and clinical health data in terms of their application to personalized medicine. I will also review the challenges associated with using big data in biomedicine and translational science. Copyright © 2013 Elsevier Ltd. All rights reserved.

Basics of Antibody Phage Display Technology.

PubMed

Ledsgaard, Line; Kilstrup, Mogens; Karatt-Vellatt, Aneesh; McCafferty, John; Laustsen, Andreas H

2018-06-09

Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of the M13 phage and the basics of phage display technology are presented together with important factors influencing the success rates of phage display experiments. Moreover, the pros and cons of different antigen display methods and the use of naïve versus immunized phage display antibody libraries is discussed, and selected examples from the field of antivenom research are highlighted. This review thus provides in-depth knowledge on the principles and use of phage display technology with a special focus on discovery of antibodies that target animal toxins.

Research of Ad Hoc Networks Access Algorithm

NASA Astrophysics Data System (ADS)

Xiang, Ma

With the continuous development of mobile communication technology, Ad Hoc access network has become a hot research, Ad Hoc access network nodes can be used to expand capacity of multi-hop communication range of mobile communication system, even business adjacent to the community, improve edge data rates. When the ad hoc network is the access network of the internet, the gateway discovery protocol is very important to choose the most appropriate gateway to guarantee the connectivity between ad hoc network and IP based fixed networks. The paper proposes a QoS gateway discovery protocol which uses the time delay and stable route to the gateway selection conditions. And according to the gateway discovery protocol, it also proposes a fast handover scheme which can decrease the handover time and improve the handover efficiency.

Systems biology-embedded target validation: improving efficacy in drug discovery.

PubMed

Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

2014-01-01

The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

PubMed

Schmit, Stephanie L; Edlund, Christopher K; Schumacher, Fredrick R; Gong, Jian; Harrison, Tabitha A; Huyghe, Jeroen R; Qu, Chenxu; Melas, Marilena; Van Den Berg, David J; Wang, Hansong; Tring, Stephanie; Plummer, Sarah J; Albanes, Demetrius; Alonso, M Henar; Amos, Christopher I; Anton, Kristen; Aragaki, Aaron K; Arndt, Volker; Barry, Elizabeth L; Berndt, Sonja I; Bezieau, Stéphane; Bien, Stephanie; Bloomer, Amanda; Boehm, Juergen; Boutron-Ruault, Marie-Christine; Brenner, Hermann; Brezina, Stefanie; Buchanan, Daniel D; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Carlson, Christopher S; Castelao, Jose E; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Cheng, Iona; Cheng, Ya-Wen; Chin, Lee Soo; Church, James M; Church, Timothy; Coetzee, Gerhard A; Cotterchio, Michelle; Cruz Correa, Marcia; Curtis, Keith R; Duggan, David; Easton, Douglas F; English, Dallas; Feskens, Edith J M; Fischer, Rocky; FitzGerald, Liesel M; Fortini, Barbara K; Fritsche, Lars G; Fuchs, Charles S; Gago-Dominguez, Manuela; Gala, Manish; Gallinger, Steven J; Gauderman, W James; Giles, Graham G; Giovannucci, Edward L; Gogarten, Stephanie M; Gonzalez-Villalpando, Clicerio; Gonzalez-Villalpando, Elena M; Grady, William M; Greenson, Joel K; Gsur, Andrea; Gunter, Marc; Haiman, Christopher A; Hampe, Jochen; Harlid, Sophia; Harju, John F; Hayes, Richard B; Hofer, Philipp; Hoffmeister, Michael; Hopper, John L; Huang, Shu-Chen; Huerta, Jose Maria; Hudson, Thomas J; Hunter, David J; Idos, Gregory E; Iwasaki, Motoki; Jackson, Rebecca D; Jacobs, Eric J; Jee, Sun Ha; Jenkins, Mark A; Jia, Wei-Hua; Jiao, Shuo; Joshi, Amit D; Kolonel, Laurence N; Kono, Suminori; Kooperberg, Charles; Krogh, Vittorio; Kuehn, Tilman; Küry, Sébastien; LaCroix, Andrea; Laurie, Cecelia A; Lejbkowicz, Flavio; Lemire, Mathieu; Lenz, Heinz-Josef; Levine, David; Li, Christopher I; Li, Li; Lieb, Wolfgang; Lin, Yi; Lindor, Noralane M; Liu, Yun-Ru; Loupakis, Fotios; Lu, Yingchang; Luh, Frank; Ma, Jing; Mancao, Christoph; Manion, Frank J; Markowitz, Sanford D; Martin, Vicente; Matsuda, Koichi; Matsuo, Keitaro; McDonnell, Kevin J; McNeil, Caroline E; Milne, Roger; Molina, Antonio J; Mukherjee, Bhramar; Murphy, Neil; Newcomb, Polly A; Offit, Kenneth; Omichessan, Hanane; Palli, Domenico; Cotoré, Jesus P Paredes; Pérez-Mayoral, Julyann; Pharoah, Paul D; Potter, John D; Qu, Conghui; Raskin, Leon; Rennert, Gad; Rennert, Hedy S; Riggs, Bridget M; Schafmayer, Clemens; Schoen, Robert E; Sellers, Thomas A; Seminara, Daniela; Severi, Gianluca; Shi, Wei; Shibata, David; Shu, Xiao-Ou; Siegel, Erin M; Slattery, Martha L; Southey, Melissa; Stadler, Zsofia K; Stern, Mariana C; Stintzing, Sebastian; Taverna, Darin; Thibodeau, Stephen N; Thomas, Duncan C; Trichopoulou, Antonia; Tsugane, Shoichiro; Ulrich, Cornelia M; van Duijnhoven, Franzel J B; van Guelpan, Bethany; Vijai, Joseph; Virtamo, Jarmo; Weinstein, Stephanie J; White, Emily; Win, Aung Ko; Wolk, Alicja; Woods, Michael; Wu, Anna H; Wu, Kana; Xiang, Yong-Bing; Yen, Yun; Zanke, Brent W; Zeng, Yi-Xin; Zhang, Ben; Zubair, Niha; Kweon, Sun-Seog; Figueiredo, Jane C; Zheng, Wei; Marchand, Loic Le; Lindblom, Annika; Moreno, Victor; Peters, Ulrike; Casey, Graham; Hsu, Li; Conti, David V; Gruber, Stephen B

2018-06-16

Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

A Control Strategy for High-Performance Macromolecular Materials

DTIC Science & Technology

2007-01-04

None as of this date. Potential transitions with Moldflow Corporation, Boston, MA. New Discoveries None as of this date. Contract FA9550-06-C-0017, Final Technical Report, Submitted by Nonlinear Control Strategies, Inc.

77 FR 20491 - National Cancer Control Month, 2012

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-05

... discoveries. During National Cancer Control Month, we remember those we have lost, support Americans fighting... combatting cancer. We owe the knowledge we have gained and the lives we have saved to the countless doctors...

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 1. The Russell-Muller debate

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

Calabrese, Edward J., E-mail: edwardc@schoolph.uma

This paper assesses the discovery of the dose-rate effect in radiation genetics and how it challenged fundamental tenets of the linear non-threshold (LNT) dose response model, including the assumptions that all mutational damage is cumulative and irreversible and that the dose-response is linear at low doses. Newly uncovered historical information also describes how a key 1964 report by the International Commission for Radiological Protection (ICRP) addressed the effects of dose rate in the assessment of genetic risk. This unique story involves assessments by two leading radiation geneticists, Hermann J. Muller and William L. Russell, who independently argued that the report'smore » Genetic Summary Section on dose rate was incorrect while simultaneously offering vastly different views as to what the report's summary should have contained. This paper reveals occurrences of scientific disagreements, how conflicts were resolved, which view(s) prevailed and why. During this process the Nobel Laureate, Muller, provided incorrect information to the ICRP in what appears to have been an attempt to manipulate the decision-making process and to prevent the dose-rate concept from being adopted into risk assessment practices. - Highlights: • The discovery of radiation dose rate challenged the scientific basis of LNT. • Radiation dose rate occurred in males and females. • The dose rate concept supported a threshold dose-response for radiation.« less

Detail view of the starboard side of the aft fuselage ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail view of the starboard side of the aft fuselage of the Orbiter Discovery in the Orbiter Processing Facility at Kennedy Space Center with the Orbiter Maneuvering/Reaction Control Systems Pod removed and exposing the insulating foil used to protect the orbiter structure from the heat generated by the maneuvering and reaction control engines. Also note in the view that the aft fuselage access door has bee removed and also note the ground support equipment attached to the T-0 umbilical plate in the lower left of the view. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Improving Middle School Students’ Critical Thinking Skills Through Reading Infusion-Loaded Discovery Learning Model in the Science Instruction

NASA Astrophysics Data System (ADS)

Nuryakin; Riandi

2017-02-01

A study has been conducted to obtain a depiction of middle school students’ critical thinking skills improvement through the implementation of reading infusion-loaded discovery learning model in science instruction. A quasi-experimental study with the pretest-posttest control group design was used to engage 55 eighth-year middle school students in Tasikmalaya, which was divided into the experimental and control group respectively were 28 and 27 students. Critical thinking skills were measured using a critical thinking skills test in multiple-choice with reason format questions that administered before and after a given instruction. The test was 28 items encompassing three essential concepts, vibration, waves and auditory senses. The critical thinking skills improvement was determined by using the normalized gain score and statistically analyzed by using Mann-Whitney U test.. The findings showed that the average of students’ critical thinking skills normalized gain score of both groups were 59 and 43, respectively for experimental and control group in the medium category. There were significant differences between both group’s improvement. Thus, the implementation of reading infusion-loaded discovery learning model could further improve middle school students’ critical thinking skills than conventional learning.

Developments in SPR Fragment Screening.

PubMed

Chavanieu, Alain; Pugnière, Martine

2016-01-01

Fragment-based approaches have played an increasing role alongside high-throughput screening in drug discovery for 15 years. The label-free biosensor technology based on surface plasmon resonance (SPR) is now sensitive and informative enough to serve during primary screens and validation steps. In this review, the authors discuss the role of SPR in fragment screening. After a brief description of the underlying principles of the technique and main device developments, they evaluate the advantages and adaptations of SPR for fragment-based drug discovery. SPR can also be applied to challenging targets such as membrane receptors and enzymes. The high-level of immobilization of the protein target and its stability are key points for a relevant screening that can be optimized using oriented immobilized proteins and regenerable sensors. Furthermore, to decrease the rate of false negatives, a selectivity test may be performed in parallel on the main target bearing the binding site mutated or blocked with a low-off-rate ligand. Fragment-based drug design, integrated in a rational workflow led by SPR, will thus have a predominant role for the next wave of drug discovery which could be greatly enhanced by new improvements in SPR devices.

Common characteristics of open source software development and applicability for drug discovery: a systematic review.

PubMed

Ardal, Christine; Alstadsæter, Annette; Røttingen, John-Arne

2011-09-28

Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents.

The prince and the pauper. A tale of anticancer targeted agents.

PubMed

Dueñas-González, Alfonso; García-López, Patricia; Herrera, Luis Alonso; Medina-Franco, Jose Luis; González-Fierro, Aurora; Candelaria, Myrna

2008-10-23

Cancer rates are set to increase at an alarming rate, from 10 million new cases globally in 2000 to 15 million in 2020. Regarding the pharmacological treatment of cancer, we currently are in the interphase of two treatment eras. The so-called pregenomic therapy which names the traditional cancer drugs, mainly cytotoxic drug types, and post-genomic era-type drugs referring to rationally-based designed. Although there are successful examples of this newer drug discovery approach, most target-specific agents only provide small gains in symptom control and/or survival, whereas others have consistently failed in the clinical testing. There is however, a characteristic shared by these agents: -their high cost-. This is expected as drug discovery and development is generally carried out within the commercial rather than the academic realm. Given the extraordinarily high therapeutic drug discovery-associated costs and risks, it is highly unlikely that any single public-sector research group will see a novel chemical "probe" become a "drug". An alternative drug development strategy is the exploitation of established drugs that have already been approved for treatment of non-cancerous diseases and whose cancer target has already been discovered. This strategy is also denominated drug repositioning, drug repurposing, or indication switch. Although traditionally development of these drugs was unlikely to be pursued by Big Pharma due to their limited commercial value, biopharmaceutical companies attempting to increase productivity at present are pursuing drug repositioning. More and more companies are scanning the existing pharmacopoeia for repositioning candidates, and the number of repositioning success stories is increasing. Here we provide noteworthy examples of known drugs whose potential anticancer activities have been highlighted, to encourage further research on these known drugs as a means to foster their translation into clinical trials utilizing the more limited public-sector resources. If these drug types eventually result in being effective, it follows that they could be much more affordable for patients with cancer; therefore, their contribution in terms of reducing cancer mortality at the global level would be greater.

The discovery of human auditory-motor entrainment and its role in the development of neurologic music therapy.

PubMed

Thaut, Michael H

2015-01-01

The discovery of rhythmic auditory-motor entrainment in clinical populations was a historical breakthrough in demonstrating for the first time a neurological mechanism linking music to retraining brain and behavioral functions. Early pilot studies from this research center were followed up by a systematic line of research studying rhythmic auditory stimulation on motor therapies for stroke, Parkinson's disease, traumatic brain injury, cerebral palsy, and other movement disorders. The comprehensive effects on improving multiple aspects of motor control established the first neuroscience-based clinical method in music, which became the bedrock for the later development of neurologic music therapy. The discovery of entrainment fundamentally shifted and extended the view of the therapeutic properties of music from a psychosocially dominated view to a view using the structural elements of music to retrain motor control, speech and language function, and cognitive functions such as attention and memory. © 2015 Elsevier B.V. All rights reserved.

BCL-2: Long and winding path from discovery to therapeutic target

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

Schenk, Robyn L.; Strasser, Andreas; Department of Medical Biology, University of Melbourne, Parkville, Melbourne, Victoria 3010

In 1988, the BCL-2 protein was found to promote cancer by limiting cell death rather than enhancing proliferation. This discovery set the wheels in motion for an almost 30 year journey involving many international research teams that has recently culminated in the approval for a drug, ABT-199/venetoclax/Venclexta that targets this protein in the treatment of cancer. This review will describe the long and winding path from the discovery of this protein and understanding the fundamental process of apoptosis that BCL-2 and its numerous homologues control, through to its exploitation as a drug target that is set to have significant benefitmore » for cancer patients. - Highlights: • BCL-2 proteins control the intrinsic or mitochondrial pathway of apoptosis. • Defective apoptosis is a hallmark of cancer. • BH3-mimetics inhibit pro-survival BCL-2 proteins to induce cancer cell death. • ABT-199/venetoclax is approved for treatment of chronic lymphocytic leukaemia.« less

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

PubMed

Zhang, Yan; Yang, Jing; Zhang, Jing; Sun, Liangdan; Hirankarn, Nattiya; Pan, Hai-Feng; Lau, Chak Sing; Chan, Tak Mao; Lee, Tsz Leung; Leung, Alexander Moon Ho; Mok, Chi Chiu; Zhang, Lu; Wang, Yongfei; Shen, Jiangshan Jane; Wong, Sik Nin; Lee, Ka Wing; Ho, Marco Hok Kung; Lee, Pamela Pui Wah; Chung, Brian Hon-Yin; Chong, Chun Yin; Wong, Raymond Woon Sing; Mok, Mo Yin; Wong, Wilfred Hing Sang; Tong, Kwok Lung; Tse, Niko Kei Chiu; Li, Xiang-Pei; Avihingsanon, Yingyos; Rianthavorn, Pornpimol; Deekajorndej, Thavatchai; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk; Ying, Shirley King Yee; Fung, Samuel Ka Shun; Lai, Wai Ming; Wong, Chun-Ming; Ng, Irene Oi Lin; Garcia-Barcelo, Maria-Merce; Cherny, Stacey S; Cui, Yong; Sham, Pak Chung; Yang, Sen; Ye, Dong-Qing; Zhang, Xue-Jun; Lau, Yu Lung; Yang, Wanling

2016-05-01

Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Interacting with Petabytes of Earth Science Data using Jupyter Notebooks, IPython Widgets and Google Earth Engine

NASA Astrophysics Data System (ADS)

Erickson, T. A.; Granger, B.; Grout, J.; Corlay, S.

2017-12-01

The volume of Earth science data gathered from satellites, aircraft, drones, and field instruments continues to increase. For many scientific questions in the Earth sciences, managing this large volume of data is a barrier to progress, as it is difficult to explore and analyze large volumes of data using the traditional paradigm of downloading datasets to a local computer for analysis. Furthermore, methods for communicating Earth science algorithms that operate on large datasets in an easily understandable and reproducible way are needed. Here we describe a system for developing, interacting, and sharing well-documented Earth Science algorithms that combines existing software components: Jupyter Notebook: An open-source, web-based environment that supports documents that combine code and computational results with text narrative, mathematics, images, and other media. These notebooks provide an environment for interactive exploration of data and development of well documented algorithms. Jupyter Widgets / ipyleaflet: An architecture for creating interactive user interface controls (such as sliders, text boxes, etc.) in Jupyter Notebooks that communicate with Python code. This architecture includes a default set of UI controls (sliders, dropboxes, etc.) as well as APIs for building custom UI controls. The ipyleaflet project is one example that offers a custom interactive map control that allows a user to display and manipulate geographic data within the Jupyter Notebook. Google Earth Engine: A cloud-based geospatial analysis platform that provides access to petabytes of Earth science data via a Python API. The combination of Jupyter Notebooks, Jupyter Widgets, ipyleaflet, and Google Earth Engine makes it possible to explore and analyze massive Earth science datasets via a web browser, in an environment suitable for interactive exploration, teaching, and sharing. Using these environments can make Earth science analyses easier to understand and reproducible, which may increase the rate of scientific discoveries and the transition of discoveries into real-world impacts.

Detail View looking at the protected structure and landing gear ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail View looking at the protected structure and landing gear housing in the void created by the removal of the Forward Reaction Control System Module from the forward section of the Orbiter Discovery. This view was taken from the service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup view of the payload bay side of the aft ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the payload bay side of the aft fuselage bulkhead of the Orbiter Discovery. This image has a detailed portions of the Remote Manipulator System and the Orbiter Maneuvering System/Reaction Control System Pods. This photograph wa taken in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-04pd0458

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility lean toward the body flap to be installed on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0456

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the body flap is moved into position for installation on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0454

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - A Hyster forklift in the Orbiter Processing Facility lifts the body flap to be installed on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0453

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - Workers in the Orbiter Processing Facility help prepare the body flap for lifting prior to installation on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0457

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, the body flap is moved into position for installation on the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0455

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - A Hyster forklift in the Orbiter Processing Facility moves the body flap toward the aft of the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

KSC-04pd0460

NASA Image and Video Library

2004-03-12

KENNEDY SPACE CENTER, FLA. - In the Orbiter Processing Facility, A Hyster forklift supports the body flap as workers secure it to the orbiter Discovery. The body flap is an aluminum structure consisting of ribs, spars, skin panels and a trailing edge assembly. It thermally shields the three main engines during entry and provides pitch control trim during landing approach. Discovery is being processed for launch on the first Return to Flight mission, STS-114.

Knowledge Discovery from Posts in Online Health Communities Using Unified Medical Language System.

PubMed

Chen, Donghua; Zhang, Runtong; Liu, Kecheng; Hou, Lei

2018-06-19

Patient-reported posts in Online Health Communities (OHCs) contain various valuable information that can help establish knowledge-based online support for online patients. However, utilizing these reports to improve online patient services in the absence of appropriate medical and healthcare expert knowledge is difficult. Thus, we propose a comprehensive knowledge discovery method that is based on the Unified Medical Language System for the analysis of narrative posts in OHCs. First, we propose a domain-knowledge support framework for OHCs to provide a basis for post analysis. Second, we develop a Knowledge-Involved Topic Modeling (KI-TM) method to extract and expand explicit knowledge within the text. We propose four metrics, namely, explicit knowledge rate, latent knowledge rate, knowledge correlation rate, and perplexity, for the evaluation of the KI-TM method. Our experimental results indicate that our proposed method outperforms existing methods in terms of providing knowledge support. Our method enhances knowledge support for online patients and can help develop intelligent OHCs in the future.

Comparison between project-based learning and discovery learning toward students' metacognitive strategies on global warming concept

NASA Astrophysics Data System (ADS)

Tumewu, Widya Anjelia; Wulan, Ana Ratna; Sanjaya, Yayan

2017-05-01

The purpose of this study was to know comparing the effectiveness of learning using Project-based learning (PjBL) and Discovery Learning (DL) toward students metacognitive strategies on global warming concept. A quasi-experimental research design with a The Matching-Only Pretest-Posttest Control Group Design was used in this study. The subjects were students of two classes 7th grade of one of junior high school in Bandung City, West Java of 2015/2016 academic year. The study was conducted on two experimental class, that were project-based learning treatment on the experimental class I and discovery learning treatment was done on the experimental class II. The data was collected through questionnaire to know students metacognitive strategies. The statistical analysis showed that there were statistically significant differences in students metacognitive strategies between project-based learning and discovery learning.

KSC-2011-6400

NASA Image and Video Library

2011-08-11

CAPE CANAVERAL, Fla. -- At NASA's Kennedy Space Center in Florida, space shuttles Discovery and Endeavour, their noses encased in protective plastic where their forward reaction control systems (FRCS) once resided, pause outside Orbiter Processing Facility-3 (OPF-3) for a unique photo opportunity. Discovery, which temporarily was being stored in the Vehicle Assembly Building (VAB), is switching places with Endeavour, which has been undergoing decommissioning in OPF-1. Discovery then will be rolled into OPF-1 and Endeavour into the VAB. In OPF-1, Discovery will undergo further preparations for public display at the Smithsonian's National Air and Space Museum Steven F. Udvar-Hazy Center in Virginia. Endeavour will be stored in the VAB until October when it will be moved into OPF-2 for further work to get it ready for public display at the California Science Center in Los Angeles. For more information, visit http://www.nasa.gov/shuttle. Photo credit: NASA/Jim Grossmann

Detail view of the vertical stabilizer of the Orbiter Discovery ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail view of the vertical stabilizer of the Orbiter Discovery Discovery showing the thermal protection system components with the white Advanced Flexible Reusable Surface Insulation (AFSI) Blanket and the black High-temperature Reusable Surface Insulation (HRSI) tiles along the outer edges . The marks seen on the HRSI tiles are injection point marks and holes for the application of waterproofing material. This view also a good detailed view of the two-piece rudder which is used to control the yaw position of orbiter on approach and landing in earth's atmosphere and upon landing the two-piece rudder splays open to both sides of the stabilizer to act as an air brake to help slow the craft to a stop. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

STS-105 MPLM is moved into the PCR

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- The payload canister is lifted up the Rotating Service Structure on Launch Pad 39A. At right is Space Shuttle Discovery. Inside the canister are the primary payloads on mission STS-105, the Multi-Purpose Logistics Module Leonardo and the Integrated Cargo Carrier. The ICC holds several smaller payloads, the Early Ammonia Servicer and two experiment containers. The Early Ammonia Servicer consists of two nitrogen tanks that provide compressed gaseous nitrogen to pressurize the ammonia tank and replenish it in the thermal control subsystems of the Space Station. The ICC and MPLM will be lifted into the payload changeout room and then moved into the Discoverys payload bay. The STS-105 mission includes a crew changeover on the International Space Station. Expedition Three will be traveling on Discovery to replace Expedition Two, who will return to Earth on board Discovery. Launch of STS-105 is scheduled for Aug. 9.

The Endoplasmic Reticulum-Associated Degradation Pathways of Budding Yeast

PubMed Central

Thibault, Guillaume; Ng, Davis T.W.

2012-01-01

Protein misfolding is a common cellular event that can produce intrinsically harmful products. To reduce the risk, quality control mechanisms are deployed to detect and eliminate misfolded, aggregated, and unassembled proteins. In the secretory pathway, it is mainly the endoplasmic reticulum-associated degradation (ERAD) pathways that perform this role. Here, specialized factors are organized to monitor and process the folded states of nascent polypeptides. Despite the complex structures, topologies, and posttranslational modifications of client molecules, the ER mechanisms are the best understood among all protein quality-control systems. This is the result of convergent and sometimes serendipitous discoveries by researchers from diverse fields. Although major advances in ER quality control and ERAD came from all model organisms, this review will focus on the discoveries culminating from the simple budding yeast. PMID:23209158

Discovery of specific ligands for oral squamous carcinoma to develop anti-cancer drug loaded precise targeting nanotherapeutics.

PubMed

Yang, Fan; Liu, Ruiwu; Kramer, Randall; Xiao, Wenwu; Jordan, Richard; Lam, Kit S

2012-12-01

Oral squamous cell carcinoma has a low five-year survival rate, which may be due to late detection and a lack of effective tumor-specific therapies. Using a high throughput drug discovery strategy termed one-bead one-compound combinatorial library, the authors identified six compounds with high binding affinity to different human oral squamous cell carcinoma cell lines but not to normal cells. Current work is under way to develop these ligands to oral squamous cell carcinoma specific imaging probes or therapeutic agents.

Translational aspects of blood-brain barrier transport and central nervous system effects of drugs: from discovery to patients.

PubMed

de Lange, E C M; Hammarlund-Udenaes, M

2015-04-01

The development of CNS drugs is associated with high failure rates. It is postulated that too much focus has been put on BBB permeability and too little on understanding BBB transport, which is the main limiting factor in drug delivery to the brain. An integrated approach to collecting, understanding, and handling pharmacokinetic-pharmacodynamic information from early discovery stages to the clinic is therefore recommended in order to improve translation to human drug treatment. © 2015 American Society for Clinical Pharmacology and Therapeutics.

The Future Workforce in Cancer Prevention: Advancing Discovery, Research, and Technology

PubMed Central

Newhauser, Wayne. D.; Scheurer, Michael. E.; Faupel-Badger, Jessica. M.; Clague, Jessica.; Weitzel, Jeffrey.; Woods, Kendra. V.

2012-01-01

As part of a 2 day conference on October 15 and 16, 2009, a nine-member task force composed of scientists, clinicians, educators, administrators, and students from across the United States was formed to discuss research, discovery, and technology obstacles to progress in cancer prevention and control, specifically those related to the cancer prevention workforce. This article summarizes the task force’s findings on the current state of the cancer prevention workforce in this area and its needs for the future. The task force identified two types of barriers impeding the current cancer prevention workforce in research, discovery, and technology from reaching its fullest potential: 1) limited cross-disciplinary research opportunities with underutilization of some disciplines is hampering discovery and research in cancer prevention, and 2) new research avenues are not being investigated because technology development and implementation are lagging. Examples of impediments and desired outcomes are provided in each of these areas. Recommended solutions to these problems are based on the goals of enhancing the current cancer prevention workforce and accelerating the pace of discovery and clinical translation. PMID:22314794

Potential insight for drug discovery from high fidelity receptor-mediated transduction mechanisms in insects

PubMed Central

Raffa, Robert B.; Raffa, Kenneth F.

2011-01-01

Introduction There is a pervasive and growing concern about the small number of new pharmaceutical agents. There are many proposed explanations for this trend that do not involve the drug-discovery process per se, but the discovery process itself has also come under scrutiny. If the current paradigms are indeed not working, where are novel ideas to come from? Perhaps it is time to look to novel sources. Areas covered The receptor-signaling and 2nd-messenger transduction processes present in insects are quite similar to those in mammals (involving G proteins, ion channels, etc.). However, a review of these systems reveals an unprecedented degree of high potency and receptor selectivity to an extent greater than that modeled in most current drug-discovery approaches. Expert opinion A better understanding of insect receptor pharmacology could stimulate novel theoretical and practical ideas in mammalian pharmacology (drug discovery) and, conversely, the application of pharmacology and medicinal chemistry principles could stimulate novel advances in entomology (safer and more targeted control of pest species). PMID:21984882

The future workforce in cancer prevention: advancing discovery, research, and technology.

PubMed

Newhauser, Wayne D; Scheurer, Michael E; Faupel-Badger, Jessica M; Clague, Jessica; Weitzel, Jeffrey; Woods, Kendra V

2012-05-01

As part of a 2-day conference on October 15 and 16, 2009, a nine-member task force composed of scientists, clinicians, educators, administrators, and students from across the USA was formed to discuss research, discovery, and technology obstacles to progress in cancer prevention and control, specifically those related to the cancer prevention workforce. This article summarizes the task force's findings on the current state of the cancer prevention workforce in this area and its needs for the future. The task force identified two types of barriers impeding the current cancer prevention workforce in research, discovery, and technology from reaching its fullest potential: (1) limited cross-disciplinary research opportunities with underutilization of some disciplines is hampering discovery and research in cancer prevention, and (2) new research avenues are not being investigated because technology development and implementation are lagging. Examples of impediments and desired outcomes are provided in each of these areas. Recommended solutions to these problems are based on the goals of enhancing the current cancer prevention workforce and accelerating the pace of discovery and clinical translation.

Bill Parsons with Discovery Processing Team

NASA Image and Video Library

2003-08-29

Mark McGee (right) shows the bead blasting completed on the rudder speed brake on orbiter Discovery to Shuttle Program Manager Bill Parsons (center). McGee is manager, Orbiter Processing Facility, with United Space Alliance. At left is Mark Nappi, deputy associate program manager, ground operations, USA. The work was part of Orbiter Major Modifications (OMM) that were recently completed on Discovery. The OMM work ranged from wiring, control panels and black boxes to gaseous and fluid systems tubing and components. These systems were deserviced, disassembled, inspected, modified, reassembled, checked out and reserviced, as were most other systems onboard. The work included the installation of the Multifunction Electronic Display Subsystem (MEDS) - a state-of-the-art “glass cockpit.”

Discovery of an Orally Available, Brain Penetrant BACE1 Inhibitor That Affords Robust CNS Aβ Reduction

PubMed Central

2012-01-01

Inhibition of BACE1 to prevent brain Aβ peptide formation is a potential disease-modifying approach to the treatment of Alzheimer’s disease. Despite over a decade of drug discovery efforts, the identification of brain-penetrant BACE1 inhibitors that substantially lower CNS Aβ levels following systemic administration remains challenging. In this report we describe structure-based optimization of a series of brain-penetrant BACE1 inhibitors derived from an iminopyrimidinone scaffold. Application of structure-based design in tandem with control of physicochemical properties culminated in the discovery of compound 16, which potently reduced cortex and CSF Aβ40 levels when administered orally to rats. PMID:23412139

Background controlled QTL mapping in pure-line genetic populations derived from four-way crosses

PubMed Central

Zhang, S; Meng, L; Wang, J; Zhang, L

2017-01-01

Pure lines derived from multiple parents are becoming more important because of the increased genetic diversity, the possibility to conduct replicated phenotyping trials in multiple environments and potentially high mapping resolution of quantitative trait loci (QTL). In this study, we proposed a new mapping method for QTL detection in pure-line populations derived from four-way crosses, which is able to control the background genetic variation through a two-stage mapping strategy. First, orthogonal variables were created for each marker and used in an inclusive linear model, so as to completely absorb the genetic variation in the mapping population. Second, inclusive composite interval mapping approach was implemented for one-dimensional scanning, during which the inclusive linear model was employed to control the background variation. Simulation studies using different genetic models demonstrated that the new method is efficient when considering high detection power, low false discovery rate and high accuracy in estimating quantitative trait loci locations and effects. For illustration, the proposed method was applied in a reported wheat four-way recombinant inbred line population. PMID:28722705

Background controlled QTL mapping in pure-line genetic populations derived from four-way crosses.

PubMed

Zhang, S; Meng, L; Wang, J; Zhang, L

2017-10-01

Pure lines derived from multiple parents are becoming more important because of the increased genetic diversity, the possibility to conduct replicated phenotyping trials in multiple environments and potentially high mapping resolution of quantitative trait loci (QTL). In this study, we proposed a new mapping method for QTL detection in pure-line populations derived from four-way crosses, which is able to control the background genetic variation through a two-stage mapping strategy. First, orthogonal variables were created for each marker and used in an inclusive linear model, so as to completely absorb the genetic variation in the mapping population. Second, inclusive composite interval mapping approach was implemented for one-dimensional scanning, during which the inclusive linear model was employed to control the background variation. Simulation studies using different genetic models demonstrated that the new method is efficient when considering high detection power, low false discovery rate and high accuracy in estimating quantitative trait loci locations and effects. For illustration, the proposed method was applied in a reported wheat four-way recombinant inbred line population.

Acoustic Sample Deposition MALDI-MS (ASD-MALDI-MS): A Novel Process Flow for Quality Control Screening of Compound Libraries.

PubMed

Chin, Jefferson; Wood, Elizabeth; Peters, Grace S; Drexler, Dieter M

2016-02-01

In the early stages of drug discovery, high-throughput screening (HTS) of compound libraries against pharmaceutical targets is a common method to identify potential lead molecules. For these HTS campaigns to be efficient and successful, continuous quality control of the compound collection is necessary and crucial. However, the large number of compound samples and the limited sample amount pose unique challenges. Presented here is a proof-of-concept study for a novel process flow for the quality control screening of small-molecule compound libraries that consumes only minimal amounts of samples and affords compound-specific molecular data. This process employs an acoustic sample deposition (ASD) technique for the offline sample preparation by depositing nanoliter volumes in an array format onto microscope glass slides followed by matrix-assisted laser desorption/ionization mass spectrometric (MALDI-MS) analysis. An initial study of a 384-compound array employing the ASD-MALDI-MS workflow resulted in a 75% first-pass positive identification rate with an analysis time of <1 s per sample. © 2015 Society for Laboratory Automation and Screening.

Drug-Target Kinetics in Drug Discovery.

PubMed

Tonge, Peter J

2018-01-17

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

Associating quantitative behavioral traits with gene expression in the brain: searching for diamonds in the hay.

PubMed

Reiner-Benaim, Anat; Yekutieli, Daniel; Letwin, Noah E; Elmer, Gregory I; Lee, Norman H; Kafkafi, Neri; Benjamini, Yoav

2007-09-01

Gene expression and phenotypic functionality can best be associated when they are measured quantitatively within the same experiment. The analysis of such a complex experiment is presented, searching for associations between measures of exploratory behavior in mice and gene expression in brain regions. The analysis of such experiments raises several methodological problems. First and foremost, the size of the pool of potential discoveries being screened is enormous yet only few biologically relevant findings are expected, making the problem of multiple testing especially severe. We present solutions based on screening by testing related hypotheses, then testing the hypotheses of interest. In one variant the subset is selected directly, in the other one a tree of hypotheses is tested hierarchical; both variants control the False Discovery Rate (FDR). Other problems in such experiments are in the fact that the level of data aggregation may be different for the quantitative traits (one per animal) and gene expression measurements (pooled across animals); in that the association may not be linear; and in the resolution of interest only few replications exist. We offer solutions to these problems as well. The hierarchical FDR testing strategies presented here can serve beyond the structure of our motivating example study to any complex microarray study. Supplementary data are available at Bioinformatics online.

Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo.

PubMed

Yuan, Shuofeng; Chan, Jasper Fuk-Woo; den-Haan, Helena; Chik, Kenn Ka-Heng; Zhang, Anna Jinxia; Chan, Chris Chung-Sing; Poon, Vincent Kwok-Man; Yip, Cyril Chik-Yan; Mak, Winger Wing-Nga; Zhu, Zheng; Zou, Zijiao; Tee, Kah-Meng; Cai, Jian-Piao; Chan, Kwok-Hung; de la Peña, Jorge; Pérez-Sánchez, Horacio; Cerón-Carrasco, José Pedro; Yuen, Kwok-Yung

2017-09-01

Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. Copyright © 2017 Elsevier B.V. All rights reserved.

ChIP-PaM: an algorithm to identify protein-DNA interaction using ChIP-Seq data.

PubMed

Wu, Song; Wang, Jianmin; Zhao, Wei; Pounds, Stanley; Cheng, Cheng

2010-06-03

ChIP-Seq is a powerful tool for identifying the interaction between genomic regulators and their bound DNAs, especially for locating transcription factor binding sites. However, high cost and high rate of false discovery of transcription factor binding sites identified from ChIP-Seq data significantly limit its application. Here we report a new algorithm, ChIP-PaM, for identifying transcription factor target regions in ChIP-Seq datasets. This algorithm makes full use of a protein-DNA binding pattern by capitalizing on three lines of evidence: 1) the tag count modelling at the peak position, 2) pattern matching of a specific tag count distribution, and 3) motif searching along the genome. A novel data-based two-step eFDR procedure is proposed to integrate the three lines of evidence to determine significantly enriched regions. Our algorithm requires no technical controls and efficiently discriminates falsely enriched regions from regions enriched by true transcription factor (TF) binding on the basis of ChIP-Seq data only. An analysis of real genomic data is presented to demonstrate our method. In a comparison with other existing methods, we found that our algorithm provides more accurate binding site discovery while maintaining comparable statistical power.

Drug–Target Kinetics in Drug Discovery

PubMed Central

2017-01-01

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure–kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug–target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug–target kinetics into predictions of drug activity. PMID:28640596

Association of PCK1 with Body Mass Index and Other Metabolic Features in Patients With Psychotropic Treatments.

PubMed

Saigi-Morgui, Núria; Vandenberghe, Frederik; Delacrétaz, Aurélie; Quteineh, Lina; Choong, Eva; Gholamrezaee, Mehdi; Magistretti, Pierre; Aubry, Jean-Michel; von Gunten, Armin; Preisig, Martin; Castelao, Enrique; Vollenweider, Peter; Waeber, Gerard; Kutalik, Zoltán; Conus, Philippe; Eap, Chin B

2015-10-01

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n1 = 168, n2 = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m, n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m, n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years.

Cracking the regulatory code of biosynthetic gene clusters as a strategy for natural product discovery.

PubMed

Rigali, Sébastien; Anderssen, Sinaeda; Naômé, Aymeric; van Wezel, Gilles P

2018-01-05

The World Health Organization (WHO) describes antibiotic resistance as "one of the biggest threats to global health, food security, and development today", as the number of multi- and pan-resistant bacteria is rising dangerously. Acquired resistance phenomena also impair antifungals, antivirals, anti-cancer drug therapy, while herbicide resistance in weeds threatens the crop industry. On the positive side, it is likely that the chemical space of natural products goes far beyond what has currently been discovered. This idea is fueled by genome sequencing of microorganisms which unveiled numerous so-called cryptic biosynthetic gene clusters (BGCs), many of which are transcriptionally silent under laboratory culture conditions, and by the fact that most bacteria cannot yet be cultivated in the laboratory. However, brute force antibiotic discovery does not yield the same results as it did in the past, and researchers have had to develop creative strategies in order to unravel the hidden potential of microorganisms such as Streptomyces and other antibiotic-producing microorganisms. Identifying the cis elements and their corresponding transcription factors(s) involved in the control of BGCs through bioinformatic approaches is a promising strategy. Theoretically, we are a few 'clicks' away from unveiling the culturing conditions or genetic changes needed to activate the production of cryptic metabolites or increase the production yield of known compounds to make them economically viable. In this opinion article, we describe and illustrate the idea beyond 'cracking' the regulatory code for natural product discovery, by presenting a series of proofs of concept, and discuss what still should be achieved to increase the rate of success of this strategy. Copyright © 2018 Elsevier Inc. All rights reserved.

Simulation of effect of anti-radar stealth principle

NASA Astrophysics Data System (ADS)

Zhao, Borao; Xing, Shuchen; Li, Chunyi

1988-02-01

The paper presents simulation methods and results of the anti-radar stealth principle, proving that anti-radar stealth aircraft can drastically reduce the combat efficiency of an air defense radar system. In particular, when anti-radar stealth aircraft are coordinated with jamming as a self-defense soft weapon, the discovery probability, response time and hit rate of the air defense radar system are much lower, with extensive reduction in jamming power and maximum exposure distance of self-defense and long-range support. The paper describes an assumed combat situation and construction of a calculation model for the aircraft survival rate, as well as simulation results and analysis. Four figures show an enemy bomber attacking an airfield, as well as the effects of the radar effective reflecting surface on discovery probability, guidance radius, aircraft survival and exposure distance (for long-range support and jamming).

KSC-2010-4453B

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This is a printable version of space shuttle Discovery's orbiter tribute, or OV-103, which hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo. NASA publication number: SP-2010-08-164-KSC

KSC-2010-4453A

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This is a version of space shuttle Discovery's orbiter tribute, or OV-103, which hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo. NASA publication number: SP-2010-08-164-KSC

Detail view of the forward section, port side, of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail view of the forward section, port side, of the Orbiter Discovery from an elevated platform in the Vehicle Assembly Building at NASA's Kennedy Space Center. Note the removal of the Forward Reaction Control System Module from the nose section, the ground-support window covers and the strongback attached to the payload bay door. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning

PubMed Central

Langhans, Sigrid A.

2018-01-01

Drug development is a lengthy and costly process that proceeds through several stages from target identification to lead discovery and optimization, preclinical validation and clinical trials culminating in approval for clinical use. An important step in this process is high-throughput screening (HTS) of small compound libraries for lead identification. Currently, the majority of cell-based HTS is being carried out on cultured cells propagated in two-dimensions (2D) on plastic surfaces optimized for tissue culture. At the same time, compelling evidence suggests that cells cultured in these non-physiological conditions are not representative of cells residing in the complex microenvironment of a tissue. This discrepancy is thought to be a significant contributor to the high failure rate in drug discovery, where only a low percentage of drugs investigated ever make it through the gamut of testing and approval to the market. Thus, three-dimensional (3D) cell culture technologies that more closely resemble in vivo cell environments are now being pursued with intensity as they are expected to accommodate better precision in drug discovery. Here we will review common approaches to 3D culture, discuss the significance of 3D cultures in drug resistance and drug repositioning and address some of the challenges of applying 3D cell cultures to high-throughput drug discovery. PMID:29410625

Bayesian Models Leveraging Bioactivity and Cytotoxicity Information for Drug Discovery

PubMed Central

Ekins, Sean; Reynolds, Robert C.; Kim, Hiyun; Koo, Mi-Sun; Ekonomidis, Marilyn; Talaue, Meliza; Paget, Steve D.; Woolhiser, Lisa K.; Lenaerts, Anne J.; Bunin, Barry A.; Connell, Nancy; Freundlich, Joel S.

2013-01-01

SUMMARY Identification of unique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglected diseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data, to experimentally validate virtual screening approach employing Bayesian models built with bioactivity information (single-event model) as well as bioactivity and cytotoxicity information (dual-event model). We virtually screen a commercial library and experimentally confirm actives with hit rates exceeding typical HTS results by 1-2 orders of magnitude. The first dual-event Bayesian model identified compounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a published set of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of a drug lead. These Bayesian models offer significant economies in time and cost to drug discovery. PMID:23521795

Field test of a paradigm: hysteresis of heart rate in thermoregulation by a free-ranging lizard (Pogona barbata).

PubMed Central

Grigg, G C; Seebacher, F

1999-01-01

The discovery that changes in heart rate and blood flow allow some reptiles to heat faster than they cool has become a central paradigm in our understanding of reptilian thermoregulation. However, this hysteresis in heart rate has been demonstrated only in simplistic laboratory heating and cooling trials, leaving its functional significance in free-ranging animals unproven. To test the validity of this paradigm, we measured heart rate and body temperature (Tb) in undisturbed, free-ranging bearded dragons (Pogona barbata), the species in which this phenomenon was first described. Our field data confirmed the paradigm and we found that heart rate during heating usually exceeded heart rate during cooling at any Tb. Importantly, however, we discovered that heart rate was proportionally faster in cool lizards whose Tb was still well below the 'preferred Tb range' compared to lizards whose Tb was already close to it. Similarly, heart rate during cooling was proportionally slower the warmer the lizard and the greater its cooling potential compared to lizards whose Tb was already near minimum operative temperature. Further, we predicted that, if heart rate hysteresis has functional significance, a 'reverse hysteresis' pattern should be observable when lizards risked overheating. This was indeed the case and, during heating on those occasions when Tb reached very high levels (> 40 degrees C), heart rate was significantly lower than heart rate during the immediately following cooling phase. These results demonstrate that physiological control of thermoregulation in reptiles is more complex than has been previously recognized. PMID:10418165

Natural products for pest control: an analysis of their role, value and future.

PubMed

Gerwick, B Clifford; Sparks, Thomas C

2014-08-01

Natural products (NPs) have long been used as pesticides and have broadly served as a source of inspiration for a great many commercial synthetic organic fungicides, herbicides and insecticides that are in the market today. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, NPs continue to be a source of models and templates for the development of new pest control agents. Interestingly, an examination of the literature suggests that NP models exist for many of the pest control agents that were discovered by other means, suggesting that, had circumstances been different, these NPs could have served as inspiration for the discovery of a great many more of today's pest control agents. Here, an attempt is made to answer questions regarding the existence of an NP model for existing classes of pesticides and what is needed for the discovery of new NPs and NP models for pest control agents. © 2014 Society of Chemical Industry.

Culture-independent discovery of natural products from soil metagenomes.

PubMed

Katz, Micah; Hover, Bradley M; Brady, Sean F

2016-03-01

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or "metagenomic," methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules.

The early bird gets the worm: foraging strategies of wild songbirds lead to the early discovery of food sources

PubMed Central

Farine, Damien R.; Lang, Stephen D. J.

2013-01-01

Animals need to manage the combined risks of predation and starvation in order to survive. Theoretical and empirical studies have shown that individuals can reduce predation risk by delaying feeding (and hence fat storage) until late afternoon. However, little is known about how individuals manage the opposing pressures of resource uncertainty and predation risks. We suggest that individuals should follow a two-part strategy: prioritizing the discovery of food early in the day and exploiting the best patch late in the day. Using automated data loggers, we tested whether a temporal component exists in the discovery of novel foraging locations by individuals in a mixed-species foraging guild. We found that food deployed in the morning was discovered significantly more often than food deployed in the afternoon. Based on the diurnal activity patterns in this population, overall rates of new arrivals were also significantly higher than expected in the morning and significantly lower than expected in the afternoon. These results align with our predictions of a shift from patch discovery to exploitation over the course of the day. PMID:24108676

Handling Neighbor Discovery and Rendezvous Consistency with Weighted Quorum-Based Approach

PubMed Central

Own, Chung-Ming; Meng, Zhaopeng; Liu, Kehan

2015-01-01

Neighbor discovery and the power of sensors play an important role in the formation of Wireless Sensor Networks (WSNs) and mobile networks. Many asynchronous protocols based on wake-up time scheduling have been proposed to enable neighbor discovery among neighboring nodes for the energy saving, especially in the difficulty of clock synchronization. However, existing researches are divided two parts with the neighbor-discovery methods, one is the quorum-based protocols and the other is co-primality based protocols. Their distinction is on the arrangements of time slots, the former uses the quorums in the matrix, the latter adopts the numerical analysis. In our study, we propose the weighted heuristic quorum system (WQS), which is based on the quorum algorithm to eliminate redundant paths of active slots. We demonstrate the specification of our system: fewer active slots are required, the referring rate is balanced, and remaining power is considered particularly when a device maintains rendezvous with discovered neighbors. The evaluation results showed that our proposed method can effectively reschedule the active slots and save the computing time of the network system. PMID:26404297

Occurrence of oil in the Austin Chalk at Van field, Van Zandt County, Texas: A unique geologic setting

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

Lowe, J.T.; Carrington, D.B.

1990-09-01

The Austin Chalk is buried to a depth of only 2,100-2,500 ft and has retained primary microporosity unlike the typical deep fractured chalk reservoirs. The Van structure is a complexly faulted domal anticline created by salt intrusion and is approximately 2,000 ft higher than surrounding structures in the area. A major northwest-dipping fault acts as the primary trapping mechanism. The field has produced 0.5 billion BO from thick Woodbine sands since its discovery in 1929. Occurrence of oil in the Austin Chalk has been known since the field discovery, but prior completions were low rate oil producers. Recent development ofmore » a large fracture stimulation technique has resulted in increased production rates of up to 300 BOPD. The Austin Chalk reservoir limits were determined by isopaching feet of minimum productive resistivity having porosity above a cutoff value. The resistivity/porosity isopach showed a direct correlation between Austin Chalk productivity and the Austin Chalk structure and faulting pattern. Structural evidence along with oil typing indicate that the oil in the Austin Chalk has migrated upward along fault planes and through fault juxtaposition from the Woodbine sands 200 ft below the Austin Chalk. Thin-section and scanning electron microscopy work performed on conventional cores showed that the Van Austin Chalk formation is a very fine grained limestone composed primarily of coccoliths. Various amounts of detrital illite clay are present in the coccolith matrix. All effective porosity is micro-intergranular and ranges from 15 to 35%. Based on the core analyses, the main porosity reducing agent and therefore control on reservoir quality is the amount of detrital clay present filling the micropores. Permeability is very low with values ranging from 0.01 to 1.5 md. There is no evidence of significant natural fractures in the core. Artificial fractures are therefore required to create the permeability needed to sustain commercial production rates.« less

Simulated JWST/NIRISS Transit Spectroscopy of Anticipated TESS Planets Compared to Select Discoveries from Space-Based and Ground-Based Surveys

NASA Astrophysics Data System (ADS)

Louie, Dana; Deming, Drake; Albert, Loic; Bouma, Luke; Bean, Jacob; Lopez-Morales, Mercedes

2018-01-01

The Transiting Exoplanet Survey Satellite (TESS) will embark in 2018 on a 2-year wide-field survey mission of most of the celestial sky, discovering over a thousand super-Earth and sub-Neptune-sized exoplanets potentially suitable for follow-up observations using the James Webb Space Telescope (JWST). Bouma et al. (2017) and Sullivan et al. (2015) used Monte Carlo simulations to predict the properties of the planetary systems that TESS is likely to detect, basing their simulations upon Kepler-derived planet occurrence rates and photometric performance models for the TESS cameras. We employed a JWST Near InfraRed Imager and Slitless Spectrograph (NIRISS) simulation tool to estimate the signal-to-noise (S/N) that JWST/NIRISS will attain in transmission spectroscopy of these anticipated TESS discoveries, and we then compared the S/N for anticipated TESS discoveries to our estimates of S/N for 18 known exoplanets. We analyzed the sensitivity of our results to planetary composition, cloud cover, and presence of an observational noise floor. We find that only a few anticipated TESS discoveries in the terrestrial planet regime will result in better JWST/NIRISS S/N than currently known exoplanets, such as the TRAPPIST-1 planets, GJ1132b, or LHS1140b. However, we emphasize that this outcome is based upon Kepler-derived occurrence rates, and that co-planar compact systems (e.g. TRAPPIST-1) were not included in predicting the anticipated TESS planet yield. Furthermore, our results show that several hundred anticipated TESS discoveries in the super-Earth and sub-Neptune regime will produce S/N higher than currently known exoplanets such as K2-3b or K2-3c. We apply our results to estimate the scope of a JWST follow-up observation program devoted to mapping the transition region between high molecular weight and primordial planetary atmospheres.

Chronic kidney disease management program in Shahreza, Iran.

PubMed

Barahimi, Hamid; Aghighi, Mohammad; Aghayani, Katayon; Rahimi Foroushani, Abbas

2014-11-01

Chronic kidney disease (CKD) is a public health problem that needs an integrated program to be detected, monitored, and controlled. This study reports the results of a CKD program designed and implemented in Shahreza, Iran. After initial evaluation of CKD in Shahreza, a CKD management program was developed in the Ministry of Health and the pilot project was started in February 2011 in Shahreza rural areas. The patients at risk, including those with diabetes mellitus and hypertension, were tested with serum creatinine and urine albumin-creatinine ratio. The CKD management program included training, screening, monitoring, and controlling of weight, hypertension, diabetes mellitus, lipids, and vitamin D. This pilot program was organized in the rural population aged over 30 years who were suffering from hypertension, diabetes mellitus, or both, and resulted in the discovery of cases in various stages of CKD. The prevalence of CKD in this high-risk group was 21.5%. Persistent albuminuria and a glomerular filtration rate less than 60 mL/min/1.73 m(2) were 13% and 11%, respectively. The rate of CKD stages 1, 2, 3a, 3b, 4, and 5 were 2.75%, 6.82%, 10.08%, 0.92%, 0.31%, and 0.17% respectively. After 1 year of the program implemented, incidence rate of CKD was 24% and improvement rate was 21%. In diabetic patients, the mean of hemoglobin A1c decreased from 8.5 ± 1.9% to 7.5% ± 1.8%. Integration of CKD programs in primary health care is possible and results in improvement in management of CKD patients.

IODP Expedition 351 Izu-Bonin-Mariana Arc Origins: Age Model for Site U1438

NASA Astrophysics Data System (ADS)

Morris, A.; Aljahdali, M. H.; Bandini, A. N.; do Monte Guerra, R.; Kender, S.; Maffione, M.

2014-12-01

We report preliminary paleomagnetic and paleontological results from International Ocean Discovery Program (IODP) Expedition 351, which recovered an unprecedented ~1.4 km thick volcaniclastic sedimentary record documenting the initiation and subsequent evolution of the Izu-Bonin-Mariana (IBM) intra-oceanic arc-basin system. Magnetostratigraphic and biostratigraphic constraints provide a high-resolution temporal framework for interpretation of this record.Paleomagnetic analyses of archive half core samples provide a continuous record of the geomagnetic field inclination down to 847 mbsf that allows construction of a detailed site magnetostratigraphy that closely matches the Geomagnetic Polarity Timescale (Gradstein et al., 2012). A total of 87 geomagnetic reversals have been recognized in the studied succession, extending back to ~36 Ma. Despite sporadic microfossil occurrences in parts, calcareous nannofossils, planktonic foraminifera and radiolarians each contribute to the age model for the entire Site. All nannofossil marker species for Oligocene to Eocene Zones NP25 to NP19/20 are recognised. Beneath paleomagnetic control (847-1449 mbsf), foraminifera and radiolarians provide the only age control.The most salient features of the age model are that: (i) average linear sedimentation rates during the Plio-Pleistocene range from 1.4 to 2.2 cm/ka; (ii) there was a reduction in sedimentation rates to 0.25 - 0.5 cm/ka throughout the Miocene; and (iii) sedimentation rates sharply increase again in the Oligocene to Late Eocene to a maximum of ~20 cm/ka. These quantitative constraints closely match (non-quantitative) inferences based on the lithostratigraphy of the site, with fine-grained/coarse-grained sediments dominating in periods with low/high sedimentation rates respectively.

IODP Expedition 351 Izu-Bonin-Mariana Arc Origins: Age model for Site U1438

NASA Astrophysics Data System (ADS)

Morris, Antony; Maffione, Marco; Kender, Sev; Aljahdali, Mohammed; Bandini, Alexandre; Guerra, Rodrigo do Monte

2015-04-01

We report preliminary paleomagnetic and paleontological results from International Ocean Discovery Program (IODP) Expedition 351, which recovered an unprecedented ~1.4 km thick volcaniclastic sedimentary record documenting the initiation and subsequent evolution of the Izu-Bonin-Mariana (IBM) intra-oceanic arc-basin system. Magnetostratigraphic and biostratigraphic constraints provide a high-resolution temporal framework for interpretation of this record. Paleomagnetic analyses of archive half core samples provide a continuous record of the geomagnetic field inclination down to 847 mbsf that allows construction of a detailed site magnetostratigraphy that closely matches the Geomagnetic Polarity Timescale (Gradstein et al., 2012). A total of 87 geomagnetic reversals have been recognized in the studied succession, extending back to ~36 Ma. Despite sporadic microfossil occurrences in parts, calcareous nannofossils, planktonic foraminifera and radiolarians each contribute to the age model for the entire Site. All nannofossil marker species for Oligocene to Eocene Zones NP25 to NP19/20 are recognised. Beneath paleomagnetic control (847-1449 mbsf), foraminifera and radiolarians provide the only age control. The most salient features of the age model are that: (i) average linear sedimentation rates during the Plio-Pleistocene range from 1.4 to 2.2 cm/ka; (ii) there was a reduction in sedimentation rates to 0.25 - 0.5 cm/ka throughout the Miocene; and (iii) sedimentation rates sharply increase again in the Oligocene to Late Eocene to a maximum of ~20 cm/ka. These quantitative constraints closely match (non-quantitative) inferences based on the lithostratigraphy of the site, with fine-grained/coarse-grained sediments dominating in periods with low/high sedimentation rates respectively.

Dual function of MG53 in membrane repair and insulin signaling

PubMed Central

Tan, Tao; Ko, Young-Gyu; Ma, Jianjie

2016-01-01

MG53 is a member of the TRIM-family protein that acts as a key component of the cell membrane repair machinery. MG53 is also an E3-ligase that ubiquinates insulin receptor substrate-1 and controls insulin signaling in skeletal muscle cells. Since its discovery in 2009, research efforts have been devoted to translate this basic discovery into clinical applications in human degenerative and metabolic diseases. This review article highlights the dual function of MG53 in cell membrane repair and insulin signaling, the mechanism that underlies the control of MG53 function, and the therapeutic value of targeting MG53 function in regenerative medicine. [BMB Reports 2016; 49(8): 414-423] PMID:27174502

Common characteristics of open source software development and applicability for drug discovery: a systematic review

PubMed Central

2011-01-01

Background Innovation through an open source model has proven to be successful for software development. This success has led many to speculate if open source can be applied to other industries with similar success. We attempt to provide an understanding of open source software development characteristics for researchers, business leaders and government officials who may be interested in utilizing open source innovation in other contexts and with an emphasis on drug discovery. Methods A systematic review was performed by searching relevant, multidisciplinary databases to extract empirical research regarding the common characteristics and barriers of initiating and maintaining an open source software development project. Results Common characteristics to open source software development pertinent to open source drug discovery were extracted. The characteristics were then grouped into the areas of participant attraction, management of volunteers, control mechanisms, legal framework and physical constraints. Lastly, their applicability to drug discovery was examined. Conclusions We believe that the open source model is viable for drug discovery, although it is unlikely that it will exactly follow the form used in software development. Hybrids will likely develop that suit the unique characteristics of drug discovery. We suggest potential motivations for organizations to join an open source drug discovery project. We also examine specific differences between software and medicines, specifically how the need for laboratories and physical goods will impact the model as well as the effect of patents. PMID:21955914

Natural products and drug discovery: a survey of stakeholders in industry and academia.

PubMed

Amirkia, Vafa; Heinrich, Michael

2015-01-01

In recent decades, natural products have undisputedly played a leading role in the development of novel medicines. Yet, trends in the pharmaceutical industry at the level of research investments indicate that natural product research is neither prioritized nor perceived as fruitful in drug discovery programmes as compared with incremental structural modifications and large volume HTS screening of synthetics. We seek to understand this phenomenon through insights from highly experienced natural product experts in industry and academia. We conducted a survey including a series of qualitative and quantitative questions related to current insights and prospective developments in natural product drug development. The survey was completed by a cross-section of 52 respondents in industry and academia. One recurrent theme is the dissonance between the perceived high potential of NP as drug leads among individuals and the survey participants' assessment of the overall industry and/or company level strategies and their success. The study's industry and academic respondents did not perceive current discovery efforts as more effective as compared with previous decades, yet industry contacts perceived higher hit rates in HTS efforts as compared with academic respondents. Surprisingly, many industry contacts were highly critical to prevalent company and industry-wide drug discovery strategies indicating a high level of dissatisfaction within the industry. These findings support the notion that there is an increasing gap in perception between the effectiveness of well established, commercially widespread drug discovery strategies between those working in industry and academic experts. This research seeks to shed light on this gap and aid in furthering natural product discovery endeavors through an analysis of current bottlenecks in industry drug discovery programmes.

S&TR Preview: Groundbreaking Laser Set to Energize Science

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

Haefner, Constantin

The High-Repetition-Rate Advanced Petawatt Laser System (HAPLS) is designed to fire 10 times per second, which represents a major advancement over existing petawatt lasers and opens the door to new scientific discoveries.

Migrating and Static Sand Ripples on Mars

NASA Image and Video Library

2013-08-28

This observation from NASA Mars Reconnaissance Orbiter is of one many that highlights new discoveries; one of these is that many sand dunes and ripples are moving, some at rates of several meters per year.

Linnorm: improved statistical analysis for single cell RNA-seq expression data

PubMed Central

Yip, Shun H.; Wang, Panwen; Kocher, Jean-Pierre A.; Sham, Pak Chung

2017-01-01

Abstract Linnorm is a novel normalization and transformation method for the analysis of single cell RNA sequencing (scRNA-seq) data. Linnorm is developed to remove technical noises and simultaneously preserve biological variations in scRNA-seq data, such that existing statistical methods can be improved. Using real scRNA-seq data, we compared Linnorm with existing normalization methods, including NODES, SAMstrt, SCnorm, scran, DESeq and TMM. Linnorm shows advantages in speed, technical noise removal and preservation of cell heterogeneity, which can improve existing methods in the discovery of novel subtypes, pseudo-temporal ordering of cells, clustering analysis, etc. Linnorm also performs better than existing DEG analysis methods, including BASiCS, NODES, SAMstrt, Seurat and DESeq2, in false positive rate control and accuracy. PMID:28981748

Maximizing the sensitivity and reliability of peptide identification in large-scale proteomic experiments by harnessing multiple search engines.

PubMed

Yu, Wen; Taylor, J Alex; Davis, Michael T; Bonilla, Leo E; Lee, Kimberly A; Auger, Paul L; Farnsworth, Chris C; Welcher, Andrew A; Patterson, Scott D

2010-03-01

Despite recent advances in qualitative proteomics, the automatic identification of peptides with optimal sensitivity and accuracy remains a difficult goal. To address this deficiency, a novel algorithm, Multiple Search Engines, Normalization and Consensus is described. The method employs six search engines and a re-scoring engine to search MS/MS spectra against protein and decoy sequences. After the peptide hits from each engine are normalized to error rates estimated from the decoy hits, peptide assignments are then deduced using a minimum consensus model. These assignments are produced in a series of progressively relaxed false-discovery rates, thus enabling a comprehensive interpretation of the data set. Additionally, the estimated false-discovery rate was found to have good concordance with the observed false-positive rate calculated from known identities. Benchmarking against standard proteins data sets (ISBv1, sPRG2006) and their published analysis, demonstrated that the Multiple Search Engines, Normalization and Consensus algorithm consistently achieved significantly higher sensitivity in peptide identifications, which led to increased or more robust protein identifications in all data sets compared with prior methods. The sensitivity and the false-positive rate of peptide identification exhibit an inverse-proportional and linear relationship with the number of participating search engines.

President and Mrs. Clinton watch launch of Space Shuttle Discovery

NASA Technical Reports Server (NTRS)

1998-01-01

From the roof of the Launch Control Center, U.S. President Bill Clinton and First Lady Hillary Rodham Clinton track the plume and successful launch of Space Shuttle Discovery on mission STS-95. This was the first launch of a Space Shuttle to be viewed by President Clinton, or any President to date. They attended the launch to witness the return to space of American legend John H. Glenn Jr., payload specialist on the mission.

Closeup view of the reflective insulation protecting the Crew Compartment ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the reflective insulation protecting the Crew Compartment bulkhead, orbiter structure and landing gear housing in the void created by the removal of the Forward Reaction Control System Module from the forward section of the Orbiter Discovery. This image was taken from the service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Statistical physics and physiology: monofractal and multifractal approaches

NASA Technical Reports Server (NTRS)

Stanley, H. E.; Amaral, L. A.; Goldberger, A. L.; Havlin, S.; Peng, C. K.

1999-01-01

Even under healthy, basal conditions, physiologic systems show erratic fluctuations resembling those found in dynamical systems driven away from a single equilibrium state. Do such "nonequilibrium" fluctuations simply reflect the fact that physiologic systems are being constantly perturbed by external and intrinsic noise? Or, do these fluctuations actually, contain useful, "hidden" information about the underlying nonequilibrium control mechanisms? We report some recent attempts to understand the dynamics of complex physiologic fluctuations by adapting and extending concepts and methods developed very recently in statistical physics. Specifically, we focus on interbeat interval variability as an important quantity to help elucidate possibly non-homeostatic physiologic variability because (i) the heart rate is under direct neuroautonomic control, (ii) interbeat interval variability is readily measured by noninvasive means, and (iii) analysis of these heart rate dynamics may provide important practical diagnostic and prognostic information not obtainable with current approaches. The analytic tools we discuss may be used on a wider range of physiologic signals. We first review recent progress using two analysis methods--detrended fluctuation analysis and wavelets--sufficient for quantifying monofractual structures. We then describe recent work that quantifies multifractal features of interbeat interval series, and the discovery that the multifractal structure of healthy subjects is different than that of diseased subjects.

The role of the circadian system in fractal neurophysiological control

PubMed Central

Pittman-Polletta, Benjamin R.; Scheer, Frank A.J.L.; Butler, Matthew P.; Shea, Steven A.; Hu, Kun

2013-01-01

Many neurophysiological variables such as heart rate, motor activity, and neural activity are known to exhibit intrinsic fractal fluctuations - similar temporal fluctuation patterns at different time scales. These fractal patterns contain information about health, as many pathological conditions are accompanied by their alteration or absence. In physical systems, such fluctuations are characteristic of critical states on the border between randomness and order, frequently arising from nonlinear feedback interactions between mechanisms operating on multiple scales. Thus, the existence of fractal fluctuations in physiology challenges traditional conceptions of health and disease, suggesting that high levels of integrity and adaptability are marked by complex variability, not constancy, and are properties of a neurophysiological network, not individual components. Despite the subject's theoretical and clinical interest, the neurophysiological mechanisms underlying fractal regulation remain largely unknown. The recent discovery that the circadian pacemaker (suprachiasmatic nucleus) plays a crucial role in generating fractal patterns in motor activity and heart rate sheds an entirely new light on both fractal control networks and the function of this master circadian clock, and builds a bridge between the fields of circadian biology and fractal physiology. In this review, we sketch the emerging picture of the developing interdisciplinary field of fractal neurophysiology by examining the circadian system’s role in fractal regulation. PMID:23573942

An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress

PubMed Central

Logue, Mark W.; Smith, Alicia K.; Baldwin, Clinton; Wolf, Erika J.; Guffanti, Guia; Ratanatharathorn, Andrew; Stone, Annjanette; Schichman, Steven A.; Humphries, Donald; Binder, Elisabeth B.; Arloth, Janine; Menke, Andreas; Uddin, Monica; Wildman, Derek; Galea, Sandro; Aiello, Allison E.; Koenen, Karestan C.; Miller, Mark W.

2015-01-01

We examined the association between posttraumatic stress disorder (PTSD) and gene expression using whole blood samples from a cohort of trauma-exposed white non-Hispanic male veterans (115 cases and 28 controls). 10,264 probes of genes and gene transcripts were analyzed. We found 41 that were differentially expressed in PTSD cases versus controls (multiple-testing corrected p<0.05). The most significant was DSCAM, a neurological gene expressed widely in the developing brain and in the amygdala and hippocampus of the adult brain. We then examined the 41 differentially expressed genes in a meta-analysis using two replication cohorts and found significant associations with PTSD for 7 of the 41 (p<0.05), one of which (ATP6AP1L) survived multiple-testing correction. There was also broad evidence of overlap across the discovery and replication samples for the entire set of genes implicated in the discovery data based on the direction of effect and an enrichment of p<0.05 significant probes beyond what would be expected under the null. Finally, we found that the set of differentially expressed genes from the discovery sample was enriched for genes responsive to glucocorticoid signaling with most showing reduced expression in PTSD cases compared to controls. PMID:25867994

76 FR 24055 - Agency Information Collection Activities: Proposed Collection; Comments Requested: Report of...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-29

... Collection; Comments Requested: Report of Theft or Loss of Controlled Substances; DEA Form 106 AGENCY...) Title of the Form/Collection: Report of Theft or Loss of Controlled Substances (DEA Form 106). (3... DEA-106 upon discovery of a theft or significant loss of controlled substances. This provides accurate...

KSC-2011-4778

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

KSC-2011-4779

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

KSC-2011-4781

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

KSC-2011-4782

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

KSC-2011-4780

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

KSC-2011-4777

NASA Image and Video Library

2011-06-22

CAPE CANAVERAL, Fla. - Space shuttle Discovery's orbital maneuvering system pods and forward reaction control system have been loaded into a container and are being transported from NASA's Kennedy Space Center in Florida to White Sands Space Harbor in New Mexico. There, they will undergo a complete deservicing and cleaning. The removal is part of Discovery's transition and retirement processing. Shuttle Discovery will go to the Smithsonian's National Air and Space Museum, Steven F. Udvar-Hazy Center in Chantilly, Va., Endeavour will go to the California Science Center in Los Angeles and Enterprise will be moved from the Smithsonian to the Intrepid Sea, Air and Space Museum in New York. Shuttle Atlantis will go to the Kennedy Space Center Visitor Complex. Photo credit: NASA/Jim Grossmann

Detail view of the lower portion of the vertical stabilizer ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Detail view of the lower portion of the vertical stabilizer of the Orbiter Discovery. The section below the rudder, often referred to as the "stinger", is used to house the orbiter drag chute assembly. The system consisted of a mortar deployed pilot chute, the main drag chute, a controller assembly and an attach/jettison mechanism. This system was a modification to the original design of the Orbiter Discovery to safely reduce the roll to stop distance without adversely affecting the vehicle handling qualities. This view was taken from a service platform in the Orbiter Processing Facility at Kennedy Space Center. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

KSC-01pp1417

NASA Image and Video Library

2001-08-05

KENNEDY SPACE CENTER, Fla. -- After their arrival at Kennedy Space Center’s Shuttle Landing Facility, the STS-105 crew greet the media. At the microphone is Commander Scott Horowitz. Behind him are the Expedition Three crew, Commander Frank Culbertson and cosmonauts Mikhail Tyurin and Vladimir Dezhurov. On mission STS-105, Discovery will be transporting the Expedition Three crew and several payloads and scientific experiments to the International Space Station. The Early Ammonia Servicer (EAS) tank, which will support the thermal control subsystems until a permanent system is activated, will be attached to the Station during two spacewalks. The three-member Expedition Two crew will be returning to Earth aboard Discovery after a five-month stay on the Station. Launch of Discovery on mission STS-105 is scheduled for Aug. 9

KSC-2009-4354

NASA Image and Video Library

2009-07-31

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, the payload canister is lifted up to the Payload Changeout Room in the rotating service structure. Umbilical lines that keep the payload in an environmentally controlled environment are still attached. Inside is the payload for space shuttle Discovery and the STS-128 mission, the Multi-Purpose Logistics Module Leonardo and the Lightweight Multi-Purpose Experiment Support Structure Carrier. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for August 25. Photo credit: NASA/Kim Shiflett

KSC-2009-4352

NASA Image and Video Library

2009-07-31

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, the payload canister is lifted up to the Payload Changeout Room in the rotating service structure. Umbilical lines that keep the payload in an environmentally controlled environment are still attached. Inside is the payload for space shuttle Discovery and the STS-128 mission, the Multi-Purpose Logistics Module Leonardo and the Lightweight Multi-Purpose Experiment Support Structure Carrier. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for August 25. Photo credit: NASA/Kim Shiflett

KSC-2009-4355

NASA Image and Video Library

2009-07-31

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, the payload canister is lifted up to the Payload Changeout Room in the rotating service structure. Umbilical lines that keep the payload in an environmentally controlled environment are still attached. Inside is the payload for space shuttle Discovery and the STS-128 mission, the Multi-Purpose Logistics Module Leonardo and the Lightweight Multi-Purpose Experiment Support Structure Carrier. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for August 25. Photo credit: NASA/Kim Shiflett

KSC-2009-4353

NASA Image and Video Library

2009-07-31

CAPE CANAVERAL, Fla. – On Launch Pad 39A at NASA's Kennedy Space Center in Florida, the payload canister is lifted up to the Payload Changeout Room in the rotating service structure. Umbilical lines that keep the payload in an environmentally controlled environment are still attached. Inside is the payload for space shuttle Discovery and the STS-128 mission, the Multi-Purpose Logistics Module Leonardo and the Lightweight Multi-Purpose Experiment Support Structure Carrier. Discovery's 13-day flight will deliver a new crew member and 33,000 pounds of equipment to the station. The equipment includes science and storage racks, a freezer to store research samples, a new sleeping compartment and the COLBERT treadmill. Launch of Discovery on its STS-128 mission is targeted for August 25. Photo credit: NASA/Kim Shiflett

NASA's Space Shuttle Discovery is raised to allow ample clearance for the modified 747 Shuttle Carrier Aircraft to position underneath for attachment

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

NASA's modified 747 Shuttle Carrier Aircraft is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center

NASA Image and Video Library

2005-08-18

NASA's specially modified 747 Shuttle Carrier Aircraft, or SCA, is positioned under the Space Shuttle Discovery to be attached for their ferry flight to the Kennedy Space Center in Florida. After its post-flight servicing and preparation at NASA Dryden in California, Discovery's return flight to Kennedy aboard the 747 will take approximately 2 days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

The Space Shuttle Discovery hitched a ride on a special 747 carrier aircraft for the flight from California to the Kennedy Space Center, FL, on August 19, 2005

NASA Image and Video Library

2005-08-19

The Space Shuttle Discovery hitched a ride on NASA's modified Boeing 747 Shuttle Carrier Aircraft for the flight from the Dryden Flight Research Center in California, to Kennedy Space Center, Florida, on August 19, 2005. The cross-country ferry flight to return Discovery to Florida after it's landing in California will take two days, with stops at several intermediate points for refueling. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT, August 9, 2005, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs

PubMed Central

Freedman, Adam H.; Schweizer, Rena M.; Ortega-Del Vecchyo, Diego; Han, Eunjung; Davis, Brian W.; Gronau, Ilan; Silva, Pedro M.; Galaverni, Marco; Fan, Zhenxin; Marx, Peter; Lorente-Galdos, Belen; Ramirez, Oscar; Hormozdiari, Farhad; Alkan, Can; Vilà, Carles; Squire, Kevin; Geffen, Eli; Kusak, Josip; Boyko, Adam R.; Parker, Heidi G.; Lee, Clarence; Tadigotla, Vasisht; Siepel, Adam; Bustamante, Carlos D.; Harkins, Timothy T.; Nelson, Stanley F.; Marques-Bonet, Tomas; Ostrander, Elaine A.; Wayne, Robert K.; Novembre, John

2016-01-01

Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rd top hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers. PMID:26943675

Stage-independent, single lead EEG sleep spindle detection using the continuous wavelet transform and local weighted smoothing.

PubMed

Tsanas, Athanasios; Clifford, Gari D

2015-01-01

Sleep spindles are critical in characterizing sleep and have been associated with cognitive function and pathophysiological assessment. Typically, their detection relies on the subjective and time-consuming visual examination of electroencephalogram (EEG) signal(s) by experts, and has led to large inter-rater variability as a result of poor definition of sleep spindle characteristics. Hitherto, many algorithmic spindle detectors inherently make signal stationarity assumptions (e.g., Fourier transform-based approaches) which are inappropriate for EEG signals, and frequently rely on additional information which may not be readily available in many practical settings (e.g., more than one EEG channels, or prior hypnogram assessment). This study proposes a novel signal processing methodology relying solely on a single EEG channel, and provides objective, accurate means toward probabilistically assessing the presence of sleep spindles in EEG signals. We use the intuitively appealing continuous wavelet transform (CWT) with a Morlet basis function, identifying regions of interest where the power of the CWT coefficients corresponding to the frequencies of spindles (11-16 Hz) is large. The potential for assessing the signal segment as a spindle is refined using local weighted smoothing techniques. We evaluate our findings on two databases: the MASS database comprising 19 healthy controls and the DREAMS sleep spindle database comprising eight participants diagnosed with various sleep pathologies. We demonstrate that we can replicate the experts' sleep spindles assessment accurately in both databases (MASS database: sensitivity: 84%, specificity: 90%, false discovery rate 83%, DREAMS database: sensitivity: 76%, specificity: 92%, false discovery rate: 67%), outperforming six competing automatic sleep spindle detection algorithms in terms of correctly replicating the experts' assessment of detected spindles.

Reduced Brain Gray Matter Concentration in Patients With Obstructive Sleep Apnea Syndrome

PubMed Central

Joo, Eun Yeon; Tae, Woo Suk; Lee, Min Joo; Kang, Jung Woo; Park, Hwan Seok; Lee, Jun Young; Suh, Minah; Hong, Seung Bong

2010-01-01

Study Objectives: To investigate differences in brain gray matter concentrations or volumes in patients with obstructive sleep apnea syndrome (OSA) and healthy volunteers. Designs: Optimized voxel-based morphometry, an automated processing technique for MRI, was used to characterize structural differences in gray matter in newly diagnosed male patients. Setting: University hospital Patients and Participants: The study consisted of 36 male OSA and 31 non-apneic male healthy volunteers matched for age (mean age, 44.8 years). Interventions: Using the t-test, gray matter differences were identified. The statistical significance level was set to a false discovery rate P < 0.05 with an extent threshold of kE > 200 voxels. Measurements and Results: The mean apnea-hypopnea index (AHI) of patients was 52.5/ h. On visual inspection of MRI, no structural abnormalities were observed. Compared to healthy volunteers, the gray matter concentrations of OSA patients were significantly decreased in the left gyrus rectus, bilateral superior frontal gyri, left precentral gyrus, bilateral frontomarginal gyri, bilateral anterior cingulate gyri, right insular gyrus, bilateral caudate nuclei, bilateral thalami, bilateral amygdalo-hippocampi, bilateral inferior temporal gyri, and bilateral quadrangular and biventer lobules in the cerebellum (false discovery rate P < 0.05). Gray matter volume was not different between OSA patients and healthy volunteers. Conclusions: The brain gray matter deficits may suggest that memory impairment, affective and cardiovascular disturbances, executive dysfunctions, and dysregulation of autonomic and respiratory control frequently found in OSA patients might be related to morphological differences in the brain gray matter areas. Citation: Joo EY; Tae WS; Lee MJ; Kang JW; Park HS; Lee JY; Suh M; Hong SB. Reduced brain gray matter concentration in patients with obstructive sleep apnea syndrome. SLEEP 2010;33(2):235-241. PMID:20175407

Inflammatory gene polymorphisms and risk of postoperative myocardial infarction after cardiac surgery.

PubMed

Podgoreanu, M V; White, W D; Morris, R W; Mathew, J P; Stafford-Smith, M; Welsby, I J; Grocott, H P; Milano, C A; Newman, M F; Schwinn, D A

2006-07-04

The inflammatory response triggered by cardiac surgery with cardiopulmonary bypass (CPB) is a primary mechanism in the pathogenesis of postoperative myocardial infarction (PMI), a multifactorial disorder with significant inter-patient variability poorly predicted by clinical and procedural factors. We tested the hypothesis that candidate gene polymorphisms in inflammatory pathways contribute to risk of PMI after cardiac surgery. We genotyped 48 polymorphisms from 23 candidate genes in a prospective cohort of 434 patients undergoing elective cardiac surgery with CPB. PMI was defined as creatine kinase-MB isoenzyme level > or = 10x upper limit of normal at 24 hours postoperatively. A 2-step analysis strategy was used: marker selection, followed by model building. To minimize false-positive associations, we adjusted for multiple testing by permutation analysis, Bonferroni correction, and controlling the false discovery rate; 52 patients (12%) experienced PMI. After adjusting for multiple comparisons and clinical risk factors, 3 polymorphisms were found to be independent predictors of PMI (adjusted P<0.05; false discovery rate <10%). These gene variants encode the proinflammatory cytokine interleukin 6 (IL6 -572G>C; odds ratio [OR], 2.47), and 2 adhesion molecules: intercellular adhesion molecule-1 (ICAM1 Lys469Glu; OR, 1.88), and E-selectin (SELE 98G>T; OR, 0.16). The inclusion of genotypic information from these polymorphisms improved prediction models for PMI based on traditional risk factors alone (C-statistic 0.764 versus 0.703). Functional genetic variants in cytokine and leukocyte-endothelial interaction pathways are independently associated with severity of myonecrosis after cardiac surgery. This may aid in preoperative identification of high-risk cardiac surgical patients and development of novel cardioprotective strategies.

Perforated peptic ulcer: how to improve outcome?

PubMed

Møller, Morten Hylander; Adamsen, Sven; Wøjdemann, Morten; Møller, Ann Merete

2009-01-01

Despite the introduction of histamine H2-receptor antagonists, proton-pump inhibitors and the discovery of Helicobacter pylori, both the incidence of emergency surgery for perforated peptic ulcer and the mortality rate for patients undergoing surgery for peptic ulcer perforation have increased. This increase has occurred despite improvements in perioperative treatment and monitoring. To improve the outcome of these patients, it is necessary to investigate the reasons behind this high mortality rate. In this review we evaluate the existing evidence in order to identify significant risk factors with an emphasis on risks that are preventable. A systematic review including randomized studies was carried out. There are a limited number of studies of patients with peptic ulcer perforation. Most of these studies are of low evident status. Only a few randomized, controlled trials have been published. The mortality rate and the extent of postoperative complications are fairly high but the reasons for this have not been thoroughly explained, even though a number of risk factors have been identified. Some of these risk factors can be explained by the septic state of the patient on admission. In order to improve the outcome of patients with peptic ulcer perforation, sepsis needs to be factored into the existing knowledge and treatment.

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

Creating a gold standard surgical device: scientific discoveries leading to TVT and beyond: Ulf Ulmsten Memorial Lecture 2014.

PubMed

Petros, Peter

2015-04-01

The discovery of tension-free vaginal tape (TVT) began in 1986 with two unrelated observations: pressure applied unilaterally at the midurethra controlled urine loss on coughing; implanted Teflon tape caused a collagenous tissue reaction. In 1987, Mersilene tape was implanted retropubically in 13 large dogs, with the aim of creating an artificial collagenous pubourethral neoligament. Extensive testing showed that the operation was safe and effective. In 1988-1989, human testing was carried out (n = 30). Mersilene tape cured 100 % of stress and mixed incontinence with a sling in situ; however, there was simultaneous recurrence of the two symptoms in 50 % on sling removal. X-rays showed no elevation of the bladder neck. In 1990-1993, collaboration with Ulf Ulmsten took place: a permanently implanted tape was required. Polypropylene was the ideal material. In 2003, the neoligament principle was applied as an adjustable "micro" sling to the arcus tendineus fasciae pelvis (ATFP), cardinal, uterosacral ligaments, and perineal body for cure of cystocele, rectocele, and apical prolapse. It was found that symptoms such as urgency, nocturia, chronic pelvic pain, obstructive defecation syndrome (ODS), and fecal incontinence were frequently cured or improved. The lecture concluded with advice to younger members. Without new paradigms, there are no randomized controlled trials, no meta-analyses, Cochrane. Indeed, no progress. Be open to new concepts. Read Kuhn's "The Structure of Scientific Revolutions" to understand the discovery process. Examine the relationship among symptoms, ATFP, cardinal, uterosacral ligaments, and the perineal body. This is the next paradigm. Don't disregard anomalies. Pursue them. They are the pathway to discovery. Innovation is born from challenge, not conformity. Persist, even when meeting resistance. Resistance is a sign that your discovery is important.

jsc2010e046737

NASA Image and Video Library

2010-04-05

JSC2010-E-046737 (5 April 2010) --- Flight director Tony Ceccacci is pictured in the space shuttle flight control room in the Johnson Space Center's Mission Control Center during launch countdown activities a few hundred miles away in Florida, site of space shuttle Discovery's STS-131 launch.

Overcoming the challenges of drug discovery for neglected tropical diseases: the A·WOL experience.

PubMed

Johnston, Kelly L; Ford, Louise; Taylor, Mark J

2014-03-01

Neglected tropical diseases (NTDs) are a group of 17 diseases that typically affect poor people in tropical countries. Each has been neglected for decades in terms of funding, research, and policy, but the recent grouping of them into one unit, which can be targeted using integrated control measures, together with increased advocacy has helped to place them on the global health agenda. The World Health Organization has set ambitious goals to control or eliminate 10 NTDs by 2020 and launched a roadmap in January 2012 to guide this global plan. The result of the launch meeting, which brought together representatives from the pharmaceutical industry, donors, and politicians, was the London Declaration: a series of commitments to provide more drugs, research, and funds to achieve the 2020 goals. Drug discovery and development for these diseases are extremely challenging, and this article highlights these challenges in the context of the London Declaration, before focusing on an example of a drug discovery and development program for the NTDs onchocerciasis and lymphatic filariasis (the anti-Wolbachia consortium, A·WOL).

The discoveries of molecular mechanisms for the circadian rhythm: The 2017 Nobel Prize in Physiology or Medicine.

PubMed

Huang, Rong-Chi

2018-02-01

Circadian clocks evolved to allow plants and animals to adapt their behaviors to the 24-hr change in the external environment due to the Earth's rotation. While the first scientific observation of circadian rhythm in the plant leaf movement may be dated back to the early 18th century, it took 200 years to realize that the leaf movement is controlled by an endogenous circadian clock. The cloning and characterization of the first Drosophila clock gene period in the early 1980s, independently by Jeffery C. Hall and Michael Rosbash at Brandeis University and Michael Young at Rockefeller University, paved the way for their further discoveries of additional genes and proteins, culminating in establishing the so-called transcriptional translational feedback loop (TTFL) model for the generation of autonomous oscillator with a period of ∼24 h. The 2017 Nobel Prize in Physiology or Medicine was awarded to honor their discoveries of molecular mechanisms controlling the circadian rhythm. Copyright © 2018 Chang Gung University. Published by Elsevier B.V. All rights reserved.

Estimating False Discovery Proportion Under Arbitrary Covariance Dependence*

PubMed Central

Fan, Jianqing; Han, Xu; Gu, Weijie

2012-01-01

Multiple hypothesis testing is a fundamental problem in high dimensional inference, with wide applications in many scientific fields. In genome-wide association studies, tens of thousands of tests are performed simultaneously to find if any SNPs are associated with some traits and those tests are correlated. When test statistics are correlated, false discovery control becomes very challenging under arbitrary dependence. In the current paper, we propose a novel method based on principal factor approximation, which successfully subtracts the common dependence and weakens significantly the correlation structure, to deal with an arbitrary dependence structure. We derive an approximate expression for false discovery proportion (FDP) in large scale multiple testing when a common threshold is used and provide a consistent estimate of realized FDP. This result has important applications in controlling FDR and FDP. Our estimate of realized FDP compares favorably with Efron (2007)’s approach, as demonstrated in the simulated examples. Our approach is further illustrated by some real data applications. We also propose a dependence-adjusted procedure, which is more powerful than the fixed threshold procedure. PMID:24729644

Affective science perspectives on cancer control: Strategically crafting a mutually beneficial research agenda

PubMed Central

Ferrer, Rebecca A.; McDonald, Paige Green; Barrett, Lisa Feldman

2015-01-01

Cancer control research involves the conduct of basic and applied behavioral and social sciences to reduce cancer incidence, morbidity, and mortality, and improve quality of life. Given the importance of behavior in cancer control, fundamental research is necessary to identify psychological mechanisms underlying cancer risk, prevention, and management behaviors. Cancer prevention, diagnosis, and treatment are often emotionally-laden. As such, affective science research to elucidate questions related to basic phenomenological nature of emotion, stress, and mood is necessary to understand how cancer control can be hindered or facilitated by emotional experiences. To date, the intersection of basic affective science research and cancer control remains largely unexplored. The goal of this paper is to outline key questions in the cancer control research domain that provide an ecologically valid context for new affective science discoveries. We also provide examples of ways in which basic affective discoveries could inform future cancer prevention and control research. These examples are not meant to be exhaustive or prescriptive, but instead are offered to generate creative thought about the promise of a cancer research context for answering basic affective science questions. Together, these examples provide a compelling argument for fostering collaborations between affective and cancer control scientists. PMID:25987511

Lawson's Shoehorn, or Should the Philosophy of Science Be Rated 'X'?

ERIC Educational Resources Information Center

Allchin, Douglas

2003-01-01

Addresses Lawson's (2002) interpretations of Galileo's discovery of the moons of Jupiter and other cases that exhibit historical errors. Suggests that such cases can distort history and lessons about the nature of science. (SOE)

Compound prioritization methods increase rates of chemical probe discovery in model organisms

PubMed Central

Wallace, Iain M; Urbanus, Malene L; Luciani, Genna M; Burns, Andrew R; Han, Mitchell KL; Wang, Hao; Arora, Kriti; Heisler, Lawrence E; Proctor, Michael; St. Onge, Robert P; Roemer, Terry; Roy, Peter J; Cummins, Carolyn L; Bader, Gary D; Nislow, Corey; Giaever, Guri

2011-01-01

SUMMARY Pre-selection of compounds that are more likely to induce a phenotype can increase the efficiency and reduce the costs for model organism screening. To identify such molecules, we screened ~81,000 compounds in S. cerevisiae and identified ~7,500 that inhibit cell growth. Screening these growth-inhibitory molecules across a diverse panel of model organisms resulted in an increased phenotypic hit-rate. This data was used to build a model to predict compounds that inhibit yeast growth. Empirical and in silico application of the model enriched the discovery of bioactive compounds in diverse model organisms. To demonstrate the potential of these molecules as lead chemical probes we used chemogenomic profiling in yeast and identified specific inhibitors of lanosterol synthase and of stearoyl-CoA 9-desaturase. As community resources, the ~7,500 growth-inhibitory molecules has been made commercially available and the computational model and filter used are provided. PMID:22035796

From Discovery to Justification: Outline of an Ideal Research Program in Empirical Psychology

PubMed Central

Witte, Erich H.; Zenker, Frank

2017-01-01

The gold standard for an empirical science is the replicability of its research results. But the estimated average replicability rate of key-effects that top-tier psychology journals report falls between 36 and 39% (objective vs. subjective rate; Open Science Collaboration, 2015). So the standard mode of applying null-hypothesis significance testing (NHST) fails to adequately separate stable from random effects. Therefore, NHST does not fully convince as a statistical inference strategy. We argue that the replicability crisis is “home-made” because more sophisticated strategies can deliver results the successful replication of which is sufficiently probable. Thus, we can overcome the replicability crisis by integrating empirical results into genuine research programs. Instead of continuing to narrowly evaluate only the stability of data against random fluctuations (discovery context), such programs evaluate rival hypotheses against stable data (justification context). PMID:29163256

Assessing differential gene expression with small sample sizes in oligonucleotide arrays using a mean-variance model.

PubMed

Hu, Jianhua; Wright, Fred A

2007-03-01

The identification of the genes that are differentially expressed in two-sample microarray experiments remains a difficult problem when the number of arrays is very small. We discuss the implications of using ordinary t-statistics and examine other commonly used variants. For oligonucleotide arrays with multiple probes per gene, we introduce a simple model relating the mean and variance of expression, possibly with gene-specific random effects. Parameter estimates from the model have natural shrinkage properties that guard against inappropriately small variance estimates, and the model is used to obtain a differential expression statistic. A limiting value to the positive false discovery rate (pFDR) for ordinary t-tests provides motivation for our use of the data structure to improve variance estimates. Our approach performs well compared to other proposed approaches in terms of the false discovery rate.

What we know and don't know about Earth's missing biodiversity.

PubMed

Scheffers, Brett R; Joppa, Lucas N; Pimm, Stuart L; Laurance, William F

2012-09-01

Estimates of non-microbial diversity on Earth range from 2 million to over 50 million species, with great uncertainties in numbers of insects, fungi, nematodes, and deep-sea organisms. We summarize estimates for major taxa, the methods used to obtain them, and prospects for further discoveries. Major challenges include frequent synonymy, the difficulty of discriminating certain species by morphology alone, and the fact that many undiscovered species are small, difficult to find, or have small geographic ranges. Cryptic species could be numerous in some taxa. Novel techniques, such as DNA barcoding, new databases, and crowd-sourcing, could greatly accelerate the rate of species discovery. Such advances are timely. Most missing species probably live in biodiversity hotspots, where habitat destruction is rife, and so current estimates of extinction rates from known species are too low. Copyright © 2012 Elsevier Ltd. All rights reserved.

Microbial Efflux Systems and Inhibitors: Approaches to Drug Discovery and the Challenge of Clinical Implementation

PubMed Central

Kourtesi, Christina; Ball, Anthony R; Huang, Ying-Ying; Jachak, Sanjay M; Vera, D Mariano A; Khondkar, Proma; Gibbons, Simon; Hamblin, Michael R; Tegos, George P

2013-01-01

Conventional antimicrobials are increasingly ineffective due to the emergence of multidrug-resistance among pathogenic microorganisms. The need to overcome these deficiencies has triggered exploration for novel and unconventional approaches to controlling microbial infections. Multidrug efflux systems (MES) have been a profound obstacle in the successful deployment of antimicrobials. The discovery of small molecule efflux system blockers has been an active and rapidly expanding research discipline. A major theme in this platform involves efflux pump inhibitors (EPIs) from natural sources. The discovery methodologies and the available number of natural EPI-chemotypes are increasing. Advances in our understanding of microbial physiology have shed light on a series of pathways and phenotypes where the role of efflux systems is pivotal. Complementing existing antimicrobial discovery platforms such as photodynamic therapy (PDT) with efflux inhibition is a subject under investigation. This core information is a stepping stone in the challenge of highlighting an effective drug development path for EPIs since the puzzle of clinical implementation remains unsolved. This review summarizes advances in the path of EPI discovery, discusses potential avenues of EPI implementation and development, and underlines the need for highly informative and comprehensive translational approaches. PMID:23569468

Matrix- and tensor-based recommender systems for the discovery of currently unknown inorganic compounds

NASA Astrophysics Data System (ADS)

Seko, Atsuto; Hayashi, Hiroyuki; Kashima, Hisashi; Tanaka, Isao

2018-01-01

Chemically relevant compositions (CRCs) and atomic arrangements of inorganic compounds have been collected as inorganic crystal structure databases. Machine learning is a unique approach to search for currently unknown CRCs from vast candidates. Herein we propose matrix- and tensor-based recommender system approaches to predict currently unknown CRCs from database entries of CRCs. Firstly, the performance of the recommender system approaches to discover currently unknown CRCs is examined. A Tucker decomposition recommender system shows the best discovery rate of CRCs as the majority of the top 100 recommended ternary and quaternary compositions correspond to CRCs. Secondly, systematic density functional theory (DFT) calculations are performed to investigate the phase stability of the recommended compositions. The phase stability of the 27 compositions reveals that 23 currently unknown compounds are newly found to be stable. These results indicate that the recommender system has great potential to accelerate the discovery of new compounds.

The Drug Discovery and Development Industry in India—Two Decades of Proprietary Small‐Molecule R&D

PubMed Central

2017-01-01

Abstract This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid‐2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India. PMID:28464443

A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards.

PubMed

Mordwinkin, Nicholas M; Burridge, Paul W; Wu, Joseph C

2013-02-01

Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human-induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach.

Cloud-based solution to identify statistically significant MS peaks differentiating sample categories.

PubMed

Ji, Jun; Ling, Jeffrey; Jiang, Helen; Wen, Qiaojun; Whitin, John C; Tian, Lu; Cohen, Harvey J; Ling, Xuefeng B

2013-03-23

Mass spectrometry (MS) has evolved to become the primary high throughput tool for proteomics based biomarker discovery. Until now, multiple challenges in protein MS data analysis remain: large-scale and complex data set management; MS peak identification, indexing; and high dimensional peak differential analysis with the concurrent statistical tests based false discovery rate (FDR). "Turnkey" solutions are needed for biomarker investigations to rapidly process MS data sets to identify statistically significant peaks for subsequent validation. Here we present an efficient and effective solution, which provides experimental biologists easy access to "cloud" computing capabilities to analyze MS data. The web portal can be accessed at http://transmed.stanford.edu/ssa/. Presented web application supplies large scale MS data online uploading and analysis with a simple user interface. This bioinformatic tool will facilitate the discovery of the potential protein biomarkers using MS.

The Drug Discovery and Development Industry in India-Two Decades of Proprietary Small-Molecule R&D.

PubMed

Differding, Edmond

2017-06-07

This review provides a comprehensive survey of proprietary drug discovery and development efforts performed by Indian companies between 1994 and mid-2016. It is based on the identification and detailed analysis of pharmaceutical, biotechnology, and contract research companies active in proprietary new chemical entity (NCE) research and development (R&D) in India. Information on preclinical and clinical development compounds was collected by company, therapeutic indication, mode of action, target class, and development status. The analysis focuses on the overall pipeline and its evolution over two decades, contributions by type of company, therapeutic focus, attrition rates, and contribution to Western pharmaceutical pipelines through licensing agreements. This comprehensive analysis is the first of its kind, and, in our view, represents a significant contribution to the understanding of the current state of the drug discovery and development industry in India. © 2017 The Author. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Bioinformatics in protein kinases regulatory network and drug discovery.

PubMed

Chen, Qingfeng; Luo, Haiqiong; Zhang, Chengqi; Chen, Yi-Ping Phoebe

2015-04-01

Protein kinases have been implicated in a number of diseases, where kinases participate many aspects that control cell growth, movement and death. The deregulated kinase activities and the knowledge of these disorders are of great clinical interest of drug discovery. The most critical issue is the development of safe and efficient disease diagnosis and treatment for less cost and in less time. It is critical to develop innovative approaches that aim at the root cause of a disease, not just its symptoms. Bioinformatics including genetic, genomic, mathematics and computational technologies, has become the most promising option for effective drug discovery, and has showed its potential in early stage of drug-target identification and target validation. It is essential that these aspects are understood and integrated into new methods used in drug discovery for diseases arisen from deregulated kinase activity. This article reviews bioinformatics techniques for protein kinase data management and analysis, kinase pathways and drug targets and describes their potential application in pharma ceutical industry. Copyright © 2015 Elsevier Inc. All rights reserved.

STS-105 MPLM is moved into the PCR

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Just before sunrise the payload canister arrives at Launch Pad 39A. In the background is Space Shuttle Discovery, waiting to launch on mission STS-105. Inside the canister are the primary payloads on the mission, the Multi-Purpose Logistics Module Leonardo and the Integrated Cargo Carrier. The ICC holds several smaller payloads, the Early Ammonia Servicer and two experiment containers. The Early Ammonia Servicer consists of two nitrogen tanks that provide compressed gaseous nitrogen to pressurize the ammonia tank and replenish it in the thermal control subsystems of the Space Station. The ICC and MPLM will be lifted into the payload changeout room on the Rotation Service Structure where they will be moved into the Discoverys payload bay. The STS-105 mission includes a crew changeover on the International Space Station. Expedition Three will be traveling on Discovery to replace Expedition Two, who will return to Earth on board Discovery. Launch of STS-105 is scheduled for Aug. 9.

A genome-wide association study of anorexia nervosa.

PubMed

Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

2014-10-01

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

A genome-wide association study of anorexia nervosa

PubMed Central

Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Landt, Margarita CT Slof-Op t; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

2015-01-01

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

Catalysis Science Initiative: Catalyst Design by Discovery Informatics

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

Delgass, William Nicholas; Abu-Omar, Mahdi; Caruthers, James

Catalysts selectively enhance the rates of chemical reactions toward desired products. Such reactions provide great benefit to society in major commercial sectors such as energy production, protecting the environment, and polymer products and thereby contribute heavily to the country’s gross national product. Our premise is that the level of fundamental understanding of catalytic events at the atomic and molecular scale has reached the point that more predictive methods can be developed to shorten the cycle time to new processes. The field of catalysis can be divided into two regimes: heterogeneous and homogeneous. For the heterogeneous catalysis regime, we have usedmore » the water-gas shift (WGS) reaction (CO + H2O + CO2 + H2O) over supported metals as a test bed. Detailed analysis and strong coupling of theory with experiment have led to the following conclusions: • The sequence of elementary steps goes through a COOH intermediate • The CO binding energy is a strong function of coverage of CO adsorbed on the surface in many systems • In the case of Au catalysts, the CO adsorption is generally too weak on surface with close atomic packing, but the enhanced binding at corner atoms (which are missing bonding partners) of cubo-octahedral nanoparticles increases the energy to a near optimal value and produces very active catalysts. • Reaction on the metal alone cannot account for the experimental results. The reaction is dual functional with water activation occurring at the metal-support interface. It is clear from our work that the theory component is essential, not only for prediction of new systems, but also for reconciling data and testing hypotheses regarding potential descriptors. Particularly important is the finding that the interface between nano-sized metal particles and the oxides that are used to support them represent a new state of matter in the sense that the interfacial bonding perturbs the chemical state of both metals atoms and the support atoms in the interfacial region. Some of the first theoretical descriptions of this important chemistry and potential new source of control of catalyst properties are be in preparation for submission. On the homogeneous catalysis side, we have used single site olefin polymerization as the testbed. This system is important because changes in a single ligand bonded to the catalytically active metal site can alter the rates of individual steps in the polymerization sequence and thereby change the properties of the resulting polymer, potentially improving its value in a hundred million pound per year industry. We have made a major advance in understanding such systems by developing a population balance kinetic model that allows us to predict the molecular weight distribution (MWD) of the product. That, in turn, allows use of MWD data to fit kinetic parameters. By combining monomer loss data, MWD, measurement of the number of working active sites, and polymer end group analysis, we have a rich data set that is highly discriminating of kinetic mechanism. Thus, we have a robust tool for producing high quality, detailed kinetic parameters, which we have used to refine mechanisms presented in the literature and discover relationships between steric and electronic properties of group IV catalysts and individual rate constants in a number of systems. Our recent work on six-coordinate Zr, Ti, and Hf amine bis(phenolate) systems, we have shown that: • The sterics (bulkiness) of the ligands specifically affect the chain termination reaction • The electron density on the metal controls misinsertion (flipped orientation) of the olefin into the growing polymer • Steric effects related to the size of the ortho ligand on the catalyst have been shown to strongly affect its the degree of dormancy, i.e. tendency to stop reacting • Changes in the size of the amine pendent group on the catalyst can have such a strong effect on chain termination as to change the catalyst from one that produces only oligomers to one that incorporates oligomers in polymer chains to introduce chain branching. These effects control the length of molecular chains, the number of errors in the regularity of the chains, and the variation of chain lengths in the final product distribution. These characteristics, in turn, determine the properties of the resulting polymer material. Predictive modeling of polymerization process cannot be done without the quantitative rate constant determination that our unique and comprehensive approach has produced. This tool, combined with insights on how catalyst chemistry affects the rate constants, is an important step toward establishing the quantitative relationships between catalyst chemistry and polymer properties that will allow more efficient searches for new catalysts and speed the discovery process. Thus, in both the heterogeneous and homogeneous catalysis areas, this work has brought important new understanding to the field. The technical effectiveness of our approach is demonstrated by its success. For heterogeneous catalysis, experimental work alone showed the important of the metal-support interface, but the integration with theory has allowed deeper understanding of the fundamental source of the effects and shown the path for how to use this understanding for discovery. In the case of homogeneous catalysis, methodology for determination of which reactions are needed to account for the data and the extraction of quantitative values for rate constants for those reactions allows accurate modeling of reaction behavior. This allowed correlation of trends in catalyst properties with alterations of specific rates, thus contributing to a data base that will guide catalyst discovery. While not yet realized, the economic benefits of this approach will come in significantly shortened cycle times for discovery and ability to fill product demand at lower price.« less

Transmission of chronic wasting disease in Wisconsin white-tailed deer: Implications for disease spread and management

USGS Publications Warehouse

Jennelle, Christopher S.; Henaux, Viviane; Wasserberg, Gideon; Thiagarajan, Bala; Rolley, Robert E.; Samuel, Michael D.

2014-01-01

Few studies have evaluated the rate of infection or mode of transmission for wildlife diseases, and the implications of alternative management strategies. We used hunter harvest data from 2002 to 2013 to investigate chronic wasting disease (CWD) infection rate and transmission modes, and address how alternative management approaches affect disease dynamics in a Wisconsin white-tailed deer population. Uncertainty regarding demographic impacts of CWD on cervid populations, human and domestic animal health concerns, and potential economic consequences underscore the need for strategies to control CWD distribution and prevalence. Using maximum-likelihood methods to evaluate alternative multi-state deterministic models of CWD transmission, harvest data strongly supports a frequency-dependent transmission structure with sex-specific infection rates that are two times higher in males than females. As transmissible spongiform encephalopathies are an important and difficult-to-study class of diseases with major economic and ecological implications, our work supports the hypothesis of frequency-dependent transmission in wild deer at a broad spatial scale and indicates that effective harvest management can be implemented to control CWD prevalence. Specifically, we show that harvest focused on the greater-affected sex (males) can result in stable population dynamics and control of CWD within the next 50 years, given the constraints of the model. We also provide a quantitative estimate of geographic disease spread in southern Wisconsin, validating qualitative assessments that CWD spreads relatively slowly. Given increased discovery and distribution of CWD throughout North America, insights from our study are valuable to management agencies and to the general public concerned about the impacts of CWD on white-tailed deer populations.

Transmission of Chronic Wasting Disease in Wisconsin White-Tailed Deer: Implications for Disease Spread and Management

PubMed Central

Jennelle, Christopher S.; Henaux, Viviane; Wasserberg, Gideon; Thiagarajan, Bala; Rolley, Robert E.; Samuel, Michael D.

2014-01-01

Few studies have evaluated the rate of infection or mode of transmission for wildlife diseases, and the implications of alternative management strategies. We used hunter harvest data from 2002 to 2013 to investigate chronic wasting disease (CWD) infection rate and transmission modes, and address how alternative management approaches affect disease dynamics in a Wisconsin white-tailed deer population. Uncertainty regarding demographic impacts of CWD on cervid populations, human and domestic animal health concerns, and potential economic consequences underscore the need for strategies to control CWD distribution and prevalence. Using maximum-likelihood methods to evaluate alternative multi-state deterministic models of CWD transmission, harvest data strongly supports a frequency-dependent transmission structure with sex-specific infection rates that are two times higher in males than females. As transmissible spongiform encephalopathies are an important and difficult-to-study class of diseases with major economic and ecological implications, our work supports the hypothesis of frequency-dependent transmission in wild deer at a broad spatial scale and indicates that effective harvest management can be implemented to control CWD prevalence. Specifically, we show that harvest focused on the greater-affected sex (males) can result in stable population dynamics and control of CWD within the next 50 years, given the constraints of the model. We also provide a quantitative estimate of geographic disease spread in southern Wisconsin, validating qualitative assessments that CWD spreads relatively slowly. Given increased discovery and distribution of CWD throughout North America, insights from our study are valuable to management agencies and to the general public concerned about the impacts of CWD on white-tailed deer populations. PMID:24658535

The Secant Rate of Corrosion: Correlating Observations of the USS Arizona Submerged in Pearl Harbor

NASA Astrophysics Data System (ADS)

Johnson, Donald L.; DeAngelis, Robert J.; Medlin, Dana J.; Johnson, Jon E.; Carr, James D.; Conlin, David L.

2018-03-01

Contrary to previous linear projections of steel corrosion in seawater, analysis of an inert marker embedded in USS Arizona concretion since the 7 December 1941 attack on Pearl Harbor reveals evidence that the effective corrosion rate decreases with time. The secant rate of corrosion, or SRC correlation, derived from this discovery could have a significant impact on failure analysis investigations for concreted shipwrecks or underwater structures. The correlation yields a lower rate of metal thinning than predicted. Development of the correlation is described.

Direct Comparison of the Precision of the New Hologic Horizon Model With the Old Discovery Model.

PubMed

Whittaker, LaTarsha G; McNamara, Elizabeth A; Vath, Savoun; Shaw, Emily; Malabanan, Alan O; Parker, Robert A; Rosen, Harold N

2017-11-22

Previous publications suggested that the precision of the new Hologic Horizon densitometer might be better than that of the previous Discovery model, but these observations were confounded by not using the same participants and technologists on both densitometers. We sought to study this issue methodically by measuring in vivo precision in both densitometers using the same patients and technologists. Precision studies for the Horizon and Discovery models were done by acquiring spine, hip, and forearm bone mineral density twice on 30 participants. The set of 4 scans on each participant (2 on the Discovery, 2 on the Horizon) was acquired by the same technologist using the same scanning mode. The pairs of data were used to calculate the least significant change according to the International Society for Clinical Densitometry guidelines. The significance of the difference between least significant changes was assessed using a Wilcoxon signed-rank test of the difference between the mean square error of the absolute value of the differences between paired measurements on the Discovery (Δ-Discovery) and the mean square error of the absolute value of the differences between paired measurements on the Horizon (Δ-Horizon). At virtually all anatomic sites, there was a nonsignificant trend for the precision to be better for the Horizon than for the Discovery. As more vertebrae were excluded from analysis, the precision deteriorated on both densitometers. The precision between densitometers was almost identical when reporting only 1 vertebral body. (1) There was a nonsignificant trend for greater precision on the new Hologic Horizon compared with the older Discovery model. (2) The difference in precision of the spine bone mineral density between the Horizon and the Discovery models decreases as fewer vertebrae are included. (3) These findings are substantially similar to previously published results which had not controlled as well for confounding from using different subjects and technologists. Copyright © 2017 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene

PubMed Central

Rafnar, Thorunn; Vermeulen, Sita H.; Sulem, Patrick; Thorleifsson, Gudmar; Aben, Katja K.; Witjes, J. Alfred; Grotenhuis, Anne J.; Verhaegh, Gerald W.; Hulsbergen-van de Kaa, Christina A.; Besenbacher, Soren; Gudbjartsson, Daniel; Stacey, Simon N.; Gudmundsson, Julius; Johannsdottir, Hrefna; Bjarnason, Hjordis; Zanon, Carlo; Helgadottir, Hafdis; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Jonsson, Eirikur; Geirsson, Gudmundur; Nikulasson, Sigfus; Petursdottir, Vigdis; Bishop, D. Timothy; Chung-Sak, Sei; Choudhury, Ananya; Elliott, Faye; Barrett, Jennifer H.; Knowles, Margaret A.; de Verdier, Petra J.; Ryk, Charlotta; Lindblom, Annika; Rudnai, Peter; Gurzau, Eugene; Koppova, Kvetoslava; Vineis, Paolo; Polidoro, Silvia; Guarrera, Simonetta; Sacerdote, Carlotta; Panadero, Angeles; Sanz-Velez, José I.; Sanchez, Manuel; Valdivia, Gabriel; Garcia-Prats, Maria D.; Hengstler, Jan G.; Selinski, Silvia; Gerullis, Holger; Ovsiannikov, Daniel; Khezri, Abdolaziz; Aminsharifi, Alireza; Malekzadeh, Mahyar; van den Berg, Leonard H.; Ophoff, Roel A.; Veldink, Jan H.; Zeegers, Maurice P.; Kellen, Eliane; Fostinelli, Jacopo; Andreoli, Daniele; Arici, Cecilia; Porru, Stefano; Buntinx, Frank; Ghaderi, Abbas; Golka, Klaus; Mayordomo, José I.; Matullo, Giuseppe; Kumar, Rajiv; Steineck, Gunnar; Kiltie, Anne E.; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; Kiemeney, Lambertus A.

2011-01-01

Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10−11. SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the ‘urogenous contact hypothesis’ that urine production and voiding frequency modify the risk of UBC. PMID:21750109

Closeup view of the reinforced carboncarbon nose of the Orbiter ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the reinforced carbon-carbon nose of the Orbiter Discovery from the service platform in the Orbiter Processing Facility at Kennedy Space Center. Note the clear protective shield around the nose cap, and the reflective insulation protecting the Crew Compartment bulkhead and orbiter structure in the void created by the removal of the Forward Reaction Control Module. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup oblique view of the forward and starboard sides of ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up oblique view of the forward and starboard sides of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. The view shows the void created by the removal of the Forward Reaction Control System Module. The void has a clear flexible covering to maintain positive pressure in the void to minimize foreign object contamination possibilities in the orbiter. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

Closeup view of the forward and starboard sides of the ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Close-up view of the forward and starboard sides of the Orbiter Discovery in the Vehicle Assembly Building at NASA's Kennedy Space Center. The view shows the void created by the removal of the Forward Reaction Control System Module. The void has a clear flexible covering to maintain positive pressure in the void to minimize foreign object contamination possibilities in the orbiter. - Space Transportation System, Orbiter Discovery (OV-103), Lyndon B. Johnson Space Center, 2101 NASA Parkway, Houston, Harris County, TX

The STS-92 crew is ready to leave KSC after CEIT

NASA Technical Reports Server (NTRS)

2000-01-01

STS-92 Pilot Pam Melroy poses at the Shuttle Landing Facility before flying back to Houston. She and other crew members completed their Crew Equipment Interface Test activities, looking over their mission payload and related equipment. STS-92 is scheduled to launch Oct. 5 on Shuttle Discovery from Launch Pad 39A on the fifth flight to the International Space Station. Discovery will carry the Integrated Truss Structure (ITS) Z1, the PMA-3, Ku-band Communications System, and Control Moment Gyros (CMGs).

jsc2010e046798

NASA Image and Video Library

2010-04-05

JSC2010-E-046798 (5 April 2010) --- Flight director Bryan Lunney watches the big screens in the space shuttle flight control room in the Johnson Space Center's Mission Control Center during launch countdown activities a few hundred miles away in Florida, site of space shuttle Discovery's STS-131 launch.

Novel Methods for Mosquito Control using RNAi.

USDA-ARS?s Scientific Manuscript database

The discovery and development of novel insecticides for vector control is a primary focus of toxicology research conducted at the Mosquito and Fly Research Unit, Gainesville, FL. Targeting critical genes/proteins in mosquitoes using RNA interference (RNAi) is being investigated as a method to devel...

The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005

NASA Image and Video Library

2005-08-09

The sun rises on the Space Shuttle Discovery as it rests on the runway at Edwards Air Force Base, California, after a safe landing August 9, 2005 to complete the STS-114 mission. Space Shuttle Discovery landed safely at NASA's Dryden Flight Research Center at Edwards Air Force Base in California at 5:11:22 a.m. PDT this morning, following the very successful 14-day STS-114 return to flight mission. During their two weeks in space, Commander Eileen Collins and her six crewmates tested out new safety procedures and delivered supplies and equipment the International Space Station. Discovery spent two weeks in space, where the crew demonstrated new methods to inspect and repair the Shuttle in orbit. The crew also delivered supplies, outfitted and performed maintenance on the International Space Station. A number of these tasks were conducted during three spacewalks. In an unprecedented event, spacewalkers were called upon to remove protruding gap fillers from the heat shield on Discovery's underbelly. In other spacewalk activities, astronauts installed an external platform onto the Station's Quest Airlock and replaced one of the orbital outpost's Control Moment Gyroscopes. Inside the Station, the STS-114 crew conducted joint operations with the Expedition 11 crew. They unloaded fresh supplies from the Shuttle and the Raffaello Multi-Purpose Logistics Module. Before Discovery undocked, the crews filled Raffeallo with unneeded items and returned to Shuttle payload bay. Discovery launched on July 26 and spent almost 14 days on orbit.

KSC-2010-4453C

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This orbiter tribute of space shuttle Discovery, or OV-103, hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. In 2011, the tribute was updated to reflect the crew member change on Discovery's final mission -- STS-133. Steve Bowen replaced Tim Kopra as a mission specialist on STS-133, after Kopra was injured in a bicycle accident that prevented him from flying into space. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo. NASA publication number: SP-2010-08-164-KSC

KSC-2010-4453D

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This is a version of space shuttle Discovery's orbiter tribute, or OV-103, which hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. In 2011, the tribute was updated to reflect the crew member change on Discovery's final mission -- STS-133. Steve Bowen replaced Tim Kopra as a mission specialist on STS-133, after Kopra was injured in a bicycle accident that prevented him from flying into space. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo. NASA publication number: SP-2010-08-164-KSC

KSC-2010-4453E

NASA Image and Video Library

2010-07-29

CAPE CANAVERAL, Fla. -- This is a printable version of space shuttle Discovery's orbiter tribute, or OV-103, which hangs in Firing Room 4 of the Launch Control Center at NASA's Kennedy Space Center in Florida. In 2011, the tribute was updated to reflect the crew member change on Discovery's final mission -- STS-133. Steve Bowen replaced Tim Kopra as a mission specialist on STS-133, after Kopra was injured in a bicycle accident that prevented him from flying into space. Discovery’s accomplishments include the first female shuttle pilot, Eileen Collins, on STS-63, John Glenn’s legendary return to space on STS-95, and the celebration of the 100th shuttle mission with STS-92. In addition, Discovery supported a number of Department of Defense programs, satellite deploy and repair missions and 13 International Space Station construction and operation flights. The tribute features Discovery demonstrating the rendezvous pitch maneuver on approach to the International Space Station during STS-114. Having accumulated the most space shuttle flights, Discovery’s 39 mission patches are shown circling the spacecraft. The background image was taken from the Hubble Space Telescope, which launched aboard Discovery on STS-31 and serviced by Discovery on STS-82 and STS-103. The American Flag and Bald Eagle represent Discovery’s two Return-to-Flight missions -- STS-26 and STS-114 -- and symbolize Discovery’s role in returning American astronauts to space. Five orbiter tributes are on display in the firing room, representing Atlantis, Challenger, Columbia, Endeavour and Discovery. Graphic design credit: NASA/Amy Lombardo. NASA publication number: SP-2010-08-164-KSC

The lysosome as a command-and-control center for cellular metabolism

PubMed Central

2016-01-01

Lysosomes are membrane-bound organelles found in every eukaryotic cell. They are widely known as terminal catabolic stations that rid cells of waste products and scavenge metabolic building blocks that sustain essential biosynthetic reactions during starvation. In recent years, this classical view has been dramatically expanded by the discovery of new roles of the lysosome in nutrient sensing, transcriptional regulation, and metabolic homeostasis. These discoveries have elevated the lysosome to a decision-making center involved in the control of cellular growth and survival. Here we review these recently discovered properties of the lysosome, with a focus on how lysosomal signaling pathways respond to external and internal cues and how they ultimately enable metabolic homeostasis and cellular adaptation. PMID:27621362

KSC-2011-1546

NASA Image and Video Library

2011-02-21

CAPE CANAVERAL, Fla. -- In Firing Room-4 in the Launch Control Center at NASA's Kennedy Space Center in Florida, launch controllers took their posts at about 2:30 p.m. EST for space shuttle Discovery's STS-133 mission to the International Space Station. The countdown clock began ticking backward from the T-43 hour mark at 3 p.m. Scheduled to lift off Feb. 24 at 4:50 p.m. EST, Discovery and its six-member crew will deliver the Permanent Multipurpose Module, packed with supplies and critical spare parts, as well as Robonaut 2, the dexterous humanoid astronaut helper, to the orbiting outpost. For more information on the STS-133 mission, visit www.nasa.gov/mission_pages/shuttle/shuttlemissions/sts133/. Photo credit: NASA/Frank Michaux